Clinical symptoms and genetics of the particular forms of monogenic diseases.
Inborn disorders of metabolism Principles of treatment of hereditary diseases, rehabilitation and resettlement.
General characterization of chromosome diseases. Clinical peculiarities of the main forms of chromosome diseases.
Neurofibromatosis
Neurofibromatosis was first described in 1882 by the German pathologist Friedrich Daniel von Recklinghausen.
Joseph Merrick, the Elephant Man, was once considered to have been affected with either elephantiasis or neurofibromatosis type I. However, it is now generally believed that
Neurofibromatosis-1 is found in approximately
NF-2 is less common, having one case in 50,000-120,000 live births.
Neurofibromatosis (commonly abbreviated NF) is a genetically-inherited disease in which nerve tissue grows tumors (e.g. neurofibromas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation.The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.
Neurofibromas are the subcutaneous lumps that are characteristic of the disease and increase iumber with age.
Back of an elderly woman with Neurofibromatosis.
ETHIOLOGY Neurofibromatosis is autosomal dominant, which means that it affects males and females equally and is dominant (only one copy of the affected gene is needed to get the disorder). Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. Disease severity in affected individuals, however, can vary (this is called variable expressivity). Moreover, in around half of cases there is no other affected family member because a new mutation has occurred.
Diagnostic Criteria
Neurofibromatosis type 1 – mutation of neurofibromin chromosome 17q11.2.
The diagnosis of NF1 is made if any two of the following seven criteria are met:
o Two or more neurofibromas on the skin or under the skin or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves);
o Freckling of the groin or the axilla (arm pit).
o Café au lait spots (pigmented birthmarks). Six or more measuring
o Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
o Lisch nodules (hamartomas of iris), freckling in the iris.
o Tumors on the optic nerve, also known as an optic glioma
o A first-degree relative with a diagnosis of NF1
plexiform neurofibroma
Neurofibromatosis type 2 – mutation of merlin chromosome 22q12
o Bilateral tumors, acoustic neuromas on the vestibulocochlear nerve (the eighth cranial nerve) leading to hearing loss
o the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty
o the tumors may cause: headache, balance problems, and Vertigo, facial weakness/paralysis
o patients with NF2 may also develop other brain tumors, as well as spinal tumors
o Deafness and Tinnitus
o Any relative with NF-2, diagnosed or not
Patient with multiple small cutaneous neurofibromas and a ‘café au lait spot’ (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions
Genetics and Hereditability
NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.
Both NF1 and NF2 can also appear to be spontaneous mutation, with no family history. These cases account for about one half of neurofibromatosis cases (ibid).
Effects
People with Neurofibromatosis can be affected in many different ways.There is a high incidence of learning disabilities in people with NF. It is believed that at least 50% of people with NF have learning disabilities of some type. Increased chances of development of petit mal epilepsy (a Partial absence seizure disorder) The tumors that occur can grow anywhere a nerve is present.
This means that:
They can grow in places that are very visible.
The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient’s safety.
Affected individuals may need multiple surgeries, depending on where the tumors are located.
Treatment
Because there is no cure for the disease itself, the only therapy for those people with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful. Some people may find something in the herbal remidies that can slow down the growth of these tumors.
Related disorders
Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses). In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.
Neurofibromatosis is also associated with pheochromocytoma.
Cystic fibrosis
Cystic fibrosis (also known as CF, mucovoidosis, or mucoviscidosis) is a genetic disorder known to be an inherited disease of the secretory glands, including the glands that make mucus and sweat.
Cystic fibrosis (CF) was recognized as specific entity during the 1930s. There is nothing resembling CF described in the 1032 pages of Sir Frederick Still’s 1927 Edition of Common Disorders and Diseases of Childhood. Formerly known as “cystic fibrosis of the pancreas,” this entity has increasingly been labeled simply “cystic fibrosis.”
Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world; one in twenty-two people of Mediterranean descent is a carrier of one gene for CF, making it the most common genetic disease in these populations.
An exception is
Genetics and Hereditability
Cystic Fibrosis has an autosomal recessive pattern of inheritance.
CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices and mucus. Although most people without CF have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops wheeither allele can produce a functional CFTR protein.
Molecular biology
CFTR protein – Molecular structure of the CFTR protein
The location of the CFTR gene on chromosome 7
PATHOGENESIS.
Four long-standing observations are of fundamental pathophysiologic importance: failure to clear mucous secretions, a paucity of water in mucous secretions, an elevated salt content of sweat and other serous secretions, and chronic infection limited to the respiratory tract. The relationships among these findings were unclear until the early 1980s when it was demonstrated that there is a greater negative potential difference across the respiratory epithelia of CF than of control subjects. Aberrant electrical properties were also demonstrated for CF sweat gland duct epithelium. Subsequent studies demonstrated that the apical membranes of CF epithelial cells are unable to secrete chloride ions in response to cAMP-mediated signals, and that, at least in the respiratory tract, excessive amounts of sodium are absorbed through these membranes.
Signs and symptoms
The hallmarks of cystic fibrosis are salty tasting skin, normal appetite but poor growth and poor weight gain, excess mucus production, and coughing/shortness of breath. Males can be infertile due to the condition congenital bilateral absence of the vas deferens. Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding iewborn babies with CF.
Lung and sinus disease
Aspergillus fumigatus – A common fungus which can lead to worsening lung disease in people with CF
Lung disease results from clogging the airways due to mucosa buildup and resulting inflammation. Inflammation and infection cause injury to the lungs and structural changes that lead to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages of CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing. Other symptoms include coughing up blood (hemoptysis), changes in the major airways in the lungs (bronchiectasis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body’s response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause further lung damage and does not respond to common antibiotics. Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. These polyps can block the nasal passages and increase breathing difficulties.
Gastrointestinal, liver and pancreatic disease
Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common in CF because of increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices which help break down food. These secretions block the movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the faeces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K. In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation. Older individuals with CF may also develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.
Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to cirrhosis, in which the liver fails to rid the blood of toxins and does not make important proteins such as those responsible for blood clotting.
Endocrine disease and growth
The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to diabetes that is unique to those with the disease. Cystic Fibrosis Related Diabetes (CFRD), as it is known as, shares characteristics that can be found in Type 1 and Type 2 diabetics and is one of the principal non-pulmonary complications of CF. Vitamin D is involved in calcium and phosphorus regulation. Poor uptake of vitamin D from the diet because of malabsorption leads to the bone disease osteoporosis in which weakened bones are more susceptible to fractures. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.
Example of clubbing as seen with some CF patients
Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi–factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.
Diagnosis
Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing.
Infants with an abnormal newborn screeeed a sweat test in order to confirm the CF diagnosis. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running electric current to a separate electrode on the skin. This process, called iontophoresis, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. CF can also be diagnosed by identification of mutations in the CFTR gene.
A multitude of tests are used to identify complications of CF and to monitor disease progression.
X-rays and CAT scans are used to examine the lungs for signs of damage or infection.
Examination of the sputum under a microscope is used to identify which bacteria are causing infection so that effective antibiotics can be given.
Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy.
Blood tests can identify liver abnormalities, vitamin deficiencies, and the onset of diabetes.
DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.
Prenatal diagnosis
Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the likelihood that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is found to be high, testing on the fetus can then be performed.
Couples who are at high risk for having a child with CF will often opt to perform further testing before or during pregnancy. In vitro fertilization with preimplantation genetic diagnosis offers the possibility to examine the embryo prior to its placement into the uterus. The test, performed 3 days after fertilization, looks for the presence of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is not used for embryo transfer and an embryo with at least one normal gene is implanted.
monitoring
The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. The treatment for cystic fibrosis continues throughout a patient’s life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Treatment typically occurs at specialist multidisciplinary centres, and is tailored to the individual, because of the wide variation in disease symptoms.
Targets for therapy are the lungs, gastrointestinal tract (including insulin treatment and pancreatic enzyme supplements), the reproductive organs and psychological support.
The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time consuming to the patient. One of the most important battles that CF patients face is finding the time to comply with all the prescribed treatments while balancing a normal life.
Many CF patients are on one or more antibiotics at all times, even when they are considered healthy, to suppress the infection as much as possible. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function.
Reversible airway obstruction occurs in many patients with CF, sometimes in conjunction with frank asthma or acute bronchopulmonary aspergillosis. Reversible obstruction is suggested by improvement of 15% or more in flow rates after inhalation of a bronchodilator. Treatment may include use of b{beta}-adrenergic agonists by aerosol. Cromolyn sodium or ipratropium hydrochloride are alternative agents, but their efficacy has not been studied systematically.
Corticosteroids are useful for the treatment of allergic bronchopulmonary aspergillosis and other severe reactive airways disease occasionally encountered in patients with CF. Prolonged treatment of standard CF lung disease using an alternate-day regimen initially appeared to improve pulmonary function and diminish hospitalization rates.
Systemic drugs, such as iodides and guaiphenesin, do not effectively assist with the removal of secretions from the respiratory tract.
Other methods to treat lung disease
Treatment of obstructed airways sometimes includes tracheobronchial suctioning or lavage, especially if atelectasis or mucoid impaction is present. Bronchopulmonary lavage may be performed by the instillation of saline or by a mucolytic agent through a fiberoptic bronchoscope. Antibiotics (usually gentamicin or tobramycin) may also be directly instilled at lavage, transiently achieving a much higher endobronchial concentration than can be obtained by using intravenous therapy. There is no evidence for sustained benefit from repeated endoscopic or lavage procedures.
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual’s chest with his or her hands several times a day, to loosen up secretions. Physiotherapy is essential to help manage an individuals chest on a long term basis, and can also teach techniques for the older child and teenager to manage themselves at home. Aerobic exercise is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.
As lung disease worsens, breathing support from machines may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. During severe illness, people with CF may need to have a tube placed in their throats (a procedure known as a tracheostomy) and their breathing supported by a ventilator.
A typical breathing treatment for cystic fibrosis, using a mask nebuliser and the ThAIRapy Vest
Treatment of other aspects of CF
Newborns with meconium ileus typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the faeces. Even so, most individuals with CF take additional amounts of vitamins A, D, E, and K and eat high-calorie meals.
It should be noted, however, that nutritional advice given to patients is, at best, mixed: Often, literature encourages the eating of high-fat foods without differentiating between saturated, unsaturated fat, and trans-fats; this lack of clear information runs counter to health advice given to the general population, and creates the risk of further serious health problems for people with cystic fibrosis as they grow older. So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.
The diabetes common to many CF patients is typically treated with insulin injections or an insulin pump.Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates. Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.
Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation. Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility may be overcome with intracytoplasmic sperm injection. Third party reproduction is also a possibility for women with CF.
Transplantation and gene therapy
Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung would contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function approaches a point where it threatens survival or requires assistance from mechanical devices. This point is typically when lung function declines to approximately 20 to 30 percent, however there is a small time frame when transplantation is feasible as the patient must be healthy enough to endure the procedure.
Gene therapy holds promise as a potential avenue to cure cystic fibrosis. Gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, at this time gene therapy is still a relatively inefficient treatment option. Ideally, transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. But if too few cells take up the vector and express the gene, the treatment has little effect. Additionally, problems have beeoted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.
Prognosis
In most cases, CF causes an early death. Average life expectancy is around 36.8 years according to the Cystic Fibrosis Foundation, although improvements in treatments mean a baby born today could expect to live longer
Marfan syndrome
Marfan syndrome (or Marfan’s syndrome) is a genetic disorder of the connective tissue.
It is named after Antoine Marfan, the French pediatrician who first described the condition in 1896 after noticing striking features in a 5-year-old girl. The gene linked to the disease was first identified by Francesco Ramirez at the
Epidemiology
Marfan syndrome affects males and females equally, and the mutation shows no geographical bias. Estimates indicate that approximately 60,000 (
Genetics and Hereditability
It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected FBN1 gene from either parent will have Marfan’s. This syndrome can run from mild to severe.
In addition to being a connective protein that forms the structural support for tissues outside the cell, fibrillin-1 binds to another protein, transforming growth factor beta (TGF-β). TGF-β is important in termination of acute inflammation.
Researchers now believe that the inflammatory effects of fibrillin disabling TGF-β, at the lungs, heart valves, and aorta, weaken the tissues and cause the features of Marfan syndrome. Since angiotensin II receptor blockers (ARBs) also reduce TGF-β, they have tested this by giving ARBs (losartan, etc.) to a small sample of young, severely affected Marfan syndrome patients. In some patients, the growth of the aorta was indeed reduced.
Pathogenesis
Diagnosis
A diagnosis of Marfan syndrome is based on family history and a combination of major and minor indicators of the disorder, rare in the general population, that occur in one individual. For example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.
People with Marfan’s are typically tall, with long limbs and long thin fingers.
The most serious complications are the defects of the heart valves and aorta. It may also affect the lungs, eyes, the dural sac surrounding the spinal cord, skeleton and the hard palate.
Although there are no unique signs or symptoms of Marfan syndrome, the constellation of long limbs, dislocated lenses, and aortic root dilation is sufficient to make the diagnosis with confidence. There are more than 30 other clinical features that are variably associated with the syndrome, most involving the skeleton, skin, and joints. There is a great deal of clinical variability even within families that carry the identical mutation.
The following conditions may result from Marfan syndrome but may also occur in people without any known underlying disorder.
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Aortic aneurysm or dilation Bicuspid aortic valve Cystic medial necrosis Ectopia lentis Gigantism Hernias Malocclusion Myopia Osteoarthritis Pneumothorax Scoliosis Stretch marks |
Arachnodactyly Cysts Dural ectasia Flat feet Glaucoma Hypermobility of the joints Mitral valve prolapse Obstructive lung disease Pectus carinatum or excavatum Retinal detachment Sleep apnea |
Skeletal system
The most readily visible signs are associated with the skeletal system. Many individuals with Marfan syndrome grow to above average height. Some have long slender limbs with fingers and toes that are also abnormally long and slender (arachnodactyly).
This long, slender body habitus and long, slender limbs are known as dolichostenomelia. An individual’s arms may be disproportionately long, with thin, weak wrists. In addition to affecting height and limb proportions.
Abnormal curvature of the spine (scoliosis) is common, as is abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, hammer toes, stooped shoulders, unexplained stretch marks on the skin and thin wrists. It can also cause pain in the joints, bones and muscles in some patients. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws.
Eyes
Lens dislocation in Marfan’s syndrome, the lens was kidney-shaped and was resting against the ciliary body.
Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness and astigmatism are common, but farsightedness can also result. Subluxation (dislocation) of the crystalline lens in one or both eyes (ectopia lentis) (in 80% of patients) also occurs and may be detected by an ophthalmologist or optometrist using a slit-lamp biomicroscope. In Marfan’s the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal. Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina. Early onset glaucoma can be another related problem.
Cardiovascular system
The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or Angina pectoris with pain radiating to the back, shoulder, or arm. Cold arms, hands and feet can also be linked to Marfan’s syndrome because of inadequate circulation. A heart murmur, abnormal reading on an EKG, or symptoms of angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the heart) result from cystic medial degeneration of the valves which is commonly associated with Marfan’s syndrome (see mitral valve prolapse). However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a medical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.
Lungs
Marfan syndrome is a risk factor for spontaneous pneumothorax. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, death. Marfan syndrome has also been associated with sleep apnea and idiopathic obstructive lung disease.
Central nervous system
Another condition that can reduce the quality of life for an individual, though not life-threatening, is dural ectasia, the weakening of the connective tissue of the dural sac, the membrane that encases the spinal cord. Dural ectasia can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches. Such symptoms usually diminish when the individual lies flat on his or her back. These types of symptoms might lead a doctor to order an X-ray of the lower spine. Dural ectasia is usually not visible on an X-ray in the early phases. A worsening of symptoms and the lack of finding any other cause should eventually lead a doctor to order an upright MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in an upright MRI image as a dilated pouch that is wearing away at the lumbar vertebrae.[9] Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts. Marfan syndrome is also associated with dysautonomia.
Differential diagnosis
The following disorders have similar signs and symptoms of Marfan syndrome:
Congenital Contractural Arachnodactyly (CCA) or Beals Syndrome
Ehlers-Danlos syndrome
Homocystinuria
Loeys-Dietz syndrome
MASS phenotype
Stickler syndrome
Multiple endocrine neoplasia, type 2B
Management
There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades, and clinical trials are underway for a promising new treatment. The syndrome is treated by addressing each issue as it arises, and, in particular, considering preventive medication, even for young children, to slow progression of aortic dilation.
Regular checkups by a cardiologist are needed to monitor the health of the heart valves and the aorta. The goal of treatment is to slow the progression of aortic dilation and damage to heart valves by eliminating arrythmias, minimizing the heart rate, and minimizing blood pressure. Beta blockers have been used to control arrythmias and slow the heart rate. Other medications might be needed to further minimize blood pressure without slowing the heart rate, such as ACE inhibitors and angiotensin II receptor antagonists, also known as angiontensin receptor blockers (ARBs). If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft [CAVG] or valve-sparing procedure) becomes necessary. Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis.
Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches
The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in the typical manner for the appropriate condition, such as with various kinds of pain medication or muscle relaxants. It is also common for patients to receive treatment from a physiotherapist, using TENS therapy, ultrasound and skeletal adjustment.[citatioeeded] This can also affect height, arm length, and life span. A physiotherapist can also help improve function and prevent injuries in individuals with Marfan’s. The Nuss procedure is now being offered to people with Marfan syndrome to correct ‘sunken chest’ or (pectus excavatum).Because Marfan may cause spinal abnormalities that are asymptomatic, any spinal surgery contemplated on a Marfan patient should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery.
Clinical trials have been conducted of the drug acetazolamide in the treatment of symptoms of dural ectasia. The treatment has demonstrated significant functional improvements in some sufferers. Other medical treatments, as well as physical therapy, are also available.
Treatment of a spontaneous pneumothorax is dependent on the volume of air in the pleural space and the natural progression of the individual’s condition. A small pneumothorax might resolve without active treatment in one to two weeks. Recurrent pneumothoraces might require chest surgery. Moderately sized pneumothoraces might need chest drain management for several days in a hospital. Large pneumothoraces are likely to be medical emergencies requiring emergency decompression.
Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (EDS) (also known as “Cutis hyperelastica”)
is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein in connective tissue). Connective tissue helps support the skin, muscles, ligaments and organs of the body. Depending on the individual mutation, the severity of the syndrome can vary from mild to life-threatening. There is no known cure. Treatment is supportive.
The syndrome is named after two doctors, Edvard Ehlers of
Epidemiology
Ehlers-Danlos Syndrome is an inherited disorder estimated to occur in about
Symptoms
Individual with EDS displaying hypermobile joints.
Symptoms vary widely based on which type of EDS the patient has. In each case, however, the symptoms are ultimately due to faulty or reduced amounts of Type III collagen. EDS most typically affects the joints, skin, and blood vessels, with symptoms such as loose, overly-flexible joints; smooth or stretchy, easily-bruised skin; abnormal wound healing and scar formation; and small, fragile blood vessels. All forms of EDS affect the joints, causing hypermobility, or joints that extend beyond the normal range of motion. As a result of their hypermobility, individuals with EDS are more susceptible to injuries such as: dislocations, subluxations, sprains, strains, and sometimes fractures. Because it is often undiagnosed in childhood, some instances of Ehlers-Danlos syndrome have been mischaracterized as child abuse.
Genetics
Mutations in the following can cause Ehlers-Danlos syndrome:
Fibrous proteins: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and TNXB
Enzymes: ADAMTS2, PLOD1
Mutations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue throughout the body. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder.
Inheritance patterns depend on the type of Ehlers-Danlos syndrome. Most forms of the condition are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause the disorder. The minority are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by the condition. It can also be an individual (de novo or “sporadic”) mutation. Please refer to the summary for each type of Ehlers-Danlos syndrome for a discussion of its inheritance pattern.
Treatment/management
There is no known cure for Ehlers Danlos Syndrome. The treatment is supportive. Physical therapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing) may be helpful. One should avoid activities that cause the joint to lock or overextend.
A physician may prescribe bracing to stabilize joints. Surgical repair of joints may be necessary at some time. Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints. To decrease bruising and improve wound healing, some patients have responded to ascorbic acid (vitamin C) by taking 1 to
In general, medical intervention is limited to symptomatic therapy. Prior to pregnancy, patients with EDS should have genetic counseling. Children with EDS should be provided with information about the disorder, so they can understand why contact sports and other physically stressful activities should be avoided. Children should be taught early on that demonstrating the unusual positions they can maintain due to loose joints should not be done as this may cause early degeneration of the joints. Family members, teachers and friends should be provided with information about EDS so they can accept and assist the child as necessary.
Prognosis
The outlook for individuals with EDS depends on the type of EDS with which they have been diagnosed. Symptoms vary in severity, even within one sub-type, and the frequency of complications changes on an individual basis. Some individuals have negligible symptoms while others are severely restricted in their daily life. Extreme joint instability, pain, and spinal deformities may limit a person’s mobility. Most individuals will have a normal lifespan. However, those with blood vessel involvement have an increased risk of fatal complications.
EDS is a lifelong condition. Affected individuals may face social obstacles related to their disease on a daily basis. Some people with EDS have reported living with fears of significant and painful ruptures, becoming pregnant, their condition worsening, becoming unemployed due to physical and emotional burdens, and social stigmatization in general.
Prader-Willi syndrome
Prader-Willi Syndrome (PWS) is an uncommon genetic disorder. It causes poor muscle tone, low levels of sex hormones and a constant feeling of hunger. The part of the brain that controls feelings of fullness or hunger does not work properly in people with PWS. They overeat, leading to obesity.
There are generally two stages of symptoms for people with Prader-Willi syndrome:
Stage 1–As newborns, babies with Prader-Willi can have low muscle tone, which can affect their ability to suck properly. As a result, babies may need special feeding techniques to help them eat, and infants may have problems gaining weight. As these babies grow older, their strength and muscle tone usually get better. They meet motor milestones, but are usually slower in doing so.
Stage 2–Between the ages of 1 and 6 years old, the disorder changes to one of constant hunger and food seeking. Most people with Prader-Willi syndrome have an insatiable appetite, meaning they never feel full. In fact, their brains are telling them they are starving. They may have trouble regulating their own eating and may need external restrictions on food, including locked kitchen and food storage areas.
This problem is made worse because people with Prader-Willi syndrome use fewer calories than those without the syndrome because they have less muscle mass. The combination of eating massive amounts of food and not burning enough calories can lead to life-threatening obesity if the diet is not kept under strict control.
There are other symptoms that may affect people with Prader-Willi, including:
1. Behavioral problems, usually during transitions and unanticipated changes, such as stubbornness or temper tantrums
2. Delayed motor skills and speech due to low muscle tone
3. Cognitive problems, ranging from near normal intelligence to mild mental retardation; learning disabilities are common
4. Repetitive thoughts and verbalizations
5. Collecting and hoarding of possessions
6. Picking at skin
7. Low sex hormone levels
Prader-Willi syndrome is considered a spectrum disorder, meaning not all symptoms will occur in everyone affected and the symptoms may range from mild to severe.
People with Prader-Willi often have some mental strengths as well, such as skills in jigsaw puzzles. If obesity is prevented, people with the syndrome can live a normal lifespan.
Babies with PWS are usually floppy, with poor muscle tone, and have trouble sucking. Boys may have undescended testicles. Later, other signs appear. These include
Short stature
Poor motor skills
Weight gain
Underdeveloped sex organs
Mild mental retardation and learning disabilities
There is no cure for PWS. Growth hormone and exercise can help build muscle mass and control weight.
TABLE 3. Suggested New Criteria to Prompt DNA Testing for PWS
Age at Assessment Features Sufficient to Prompt DNA Testing
|
Birth to 2 y |
1. Hypotonia with poor suck. |
|
2y–6 y |
1. Hypotonia with history of poor suck. 2. Global developmental delay. |
|
6y–12 y
|
1. History of hypotonia with poor suck (hypotonia often persists). 2. Global developmental delay. 3. Excessive eating (hyperphagia; preoccupation with food) with central obesity if uncontrolled. |
|
13 y through adulthood |
1. Cognitive disabilities; usually mild mental retardation. 2. Excessive eating (hyperphagia; preoccupation with food) with central obesity if uncontrolled. 3. Hypothalamic hypogonadism and/or typical behavior problems (including temper tantrums, perseverative and compulsive-like behaviors). |
TABLE 2. Sensitivities and the Percentages of Documentation of the Published Criteria
|
|
% Affected
|
|
Major criteria |
|
|
Neonatal hypotonia |
88 |
|
Feeding problems in infancy |
79 |
|
Excessive weight gain |
67 |
|
Facial features |
88 |
|
Hypogonadism |
51 |
|
Developmental delay |
99 |
|
Hyperphagia |
84 |
|
Minor criteria |
|
|
Decreased fetal activity |
62 |
|
Behavior problems |
87 |
|
Sleep disturbance/sleep apnea |
76 |
|
Short stature |
63 |
|
Hypopigmentation |
73 |
|
Small hands and/or feet |
88 |
|
Narrow hands/straight |
82 |
|
ulnar borders |
|
|
Eye abnormalities |
68 |
|
Thick viscous saliva |
89 |
|
Articulation defects |
80 |
|
Skin-picking |
83 |
Modified from PEDIATRICS (ISSN 0031 4005) Vol. 108 No. 5, Pages 5, Copyright © 2001 by the AAP
Treatments
Prader-Willi syndrome cannot be cured. But, early intervention can help people build skills for adapting to the disorder. Early diagnosis can also help parents learn about the condition and prepare for future challenges. A health care provider can do a blood test to check for Prader-Willi syndrome.
Exercise and physical activity can help control weight and help with motor skills. Speech therapy may be needed to help with oral skills.
Human growth hormone has been found to be helpful in treating Prader-Willi syndrome. It can help to increase height, decrease body fat, and increase muscle mass. However, no medications have yet been found to control appetite in those with Prader-Willi
IMPRINTING
Prader-Willi syndrome affects between 1/10,000 and 1/30,000 live births. The study of this disease led to the discovery that, for some genes, the origin of the gene may be important. For some loci the gene inherited from the father acts differently from the gene inherited from the mother, even though they may have the same DNA. This phenomenon is called imprinting. About 75% of patients with Prader-Willi syndrome have a small deletion of the long arm of chromosome
Congenital hypothyroidism
The fetal hypothalamic-pituitary-thyroid system develops independently of the mother’s pituitary-thyroid axis. During embryogenesis, primordial thyroid cells arise from epithelial cells on the pharyngeal floor; they then migrate caudally to fuse with the ventral aspect of the fourth pharyngeal pouch by 4 weeks’ gestation. The thyroid continues to develop anteriorly to the third tracheal cartilage. Thyroglobulin is produced by 8 weeks’ gestation. Trapping of iodine occurs by 10-12 weeks’ gestation, followed by the synthesis of iodothyronines. Colloid formation and pituitary secretion of thyrotropin, also termed thyroid-stimulating hormone (TSH), occur by the 12 weeks’ gestation.
Normal physiology
The primary function of the thyroid gland is synthesis of thyroxine (T4) and triiodothyronine (T3). Pituitary thyrotropin regulates thyroid hormone production. TSH synthesis and secretion are stimulated by thyrotropin-releasing hormone (TRH), which is synthesized by the hypothalamus and is secreted into the hypophyseal portal vasculature for transport to the anterior pituitary gland. Serum T4 concentration modulates secretion of both TRH and TSH by means of a classic negative feedback loop.
Circulating T4 is predominantly bound to T4-binding globulin (TBG). T4 is deiodinated in peripheral tissue to T3, the more bioactive thyroid hormone. T3 carries 3-4 times the metabolic potency of T4, freely enters cells, and binds to receptors of the hormone into the cell nucleus. Thyroid hormone exerts profound effects on the regulation of gene transcription. Some major clinical phenomena of thyroid hormone action include differentiation of the CNS and maintenance of muscle mass. Thyroid hormone also controls skeletal growth and differentiation and metabolism of carbohydrates, lipids, and vitamins.
Thyroid hormone synthesis absolutely requires iodine. Dietary iodine deficiency is endemic in several areas of the world, particularly high mountain plateaus. In the
In the thyroid gland, iodide is trapped, transported, and concentrated in the follicular lumen for thyroid hormone synthesis. Before trapped iodide can react with tyrosine residues, it must be oxidized by thyroidal peroxidase. Iodination of tyrosine forms mono-iodotyrosine and di-iodotyrosine. Two molecules of di-iodotyrosine combine to form T4, and one molecule of mono-iodotyrosine combines with one molecule of di-iodotyrosine to form T3. Formed thyroid hormones are stored within thyroglobulin in the lumen of the thyroid follicle until release. TSH stimulates uptake and organification of iodide as well as liberation of T4 and T3 from thyroglobulin.
Pathophysiology
Congenital hypothyroidism most commonly results from agenesis, dysplasia, or ectopy of the thyroid; however, it is also caused by autosomal recessive defects in the organification of iodine (thyroid hormone synthesis) and defects in other enzymatic steps in T4 synthesis and release.
Frequency
Congenital hypothyroidism has a frequency of 1 case per 3500 live births in
.
International
Hypothyroidism can be congenital. Thyroid dysgenesis affects 1 per 4000 newborns worldwide. Hypothalamic or pituitary insufficiency, which results in secondary or tertiary hypothyroidism, respectively, affects 1 per 60,000-140,000 newborns worldwide.
Mortality/Morbidity
Untreated congenital hypothyroidism in early infancy results in profound growth failure and disrupted development of the CNS, leading to developmental cognitive delay (cretinism). Untreated hypothyroidism in older children leads to growth failure as well as slowed metabolism and impaired memory.
Race
In descending order, thyroid dysgenesis occurs more frequently in Hispanics than in whites, followed by blacks.
Sex
Thyroid dysgenesis occurs more frequently in females than in males, with a female-to-male ratio of 2:1. CLT also has a 2:1 female-to-male preponderance.
Age
Congenital hypothyroidism can present with goiter at birth or with the gradual development of symptoms over the first several months of life. The age of symptom onset is unpredictable in a child who has thyroid dysgenesis with a hypoplastic and/or ectopic thyroid gland because initial increases in TSH may be able to initially overcome the relative insufficiency of the thyroid gland. CLT typically presents during adolescence; however, it may present any time in life.
Clinics
Most infants with congenital hypothyroidism are asymptomatic during the neonatal period or display subtle and nonspecific symptoms of thyroid hormone deficiency.
The lack of symptoms initially may result, in part, from an ectopic thyroid gland with clinically significant reserve function, partial defects in thyroid hormone synthesis, or to the moderate amount of maternal T4 that crosses the placenta and is able to boost fetal levels within 25-50% of normal levels observed at birth.
Detection of congenital hypothyroidism based on signs and symptoms alone may be delayed until age 6-12 weeks or older because of the protean clinical presentation and requires a high index of suspicion by the health care provider.
Only about 5% of infants with hypothyroidism are detected by clinical criteria before the biochemical screen alerts the clinician to confirm the diagnosis.
The following are among the earliest signs of hypothyroidism:
o Prolonged gestation
o Elevated birth weight
o Delayed stooling after birth, constipation
o Prolonged indirect jaundice
o Poor feeding, poor management of secretions
o Hypothermia
o Decreased activity level
o Noisy respirations
o Hoarse cry
Acquired hypothyroidism: The clinical features of acquired hypothyroidism are typically insidious in onset.
Goiter: Patients with CLT (ie, Hashimoto thyroiditis) most commonly present with an asymptomatic goiter. Parents may report that their child’s neck looks “full” or “swollen.” Children may complain of local symptoms of dysphagia, hoarseness, or of a pressure sensation in their neck and/or throat. A patient with other causes of hypothyroidism may have an enlarged thyroid gland.
Slow growth, delayed osseous maturation, and increased weight: Mild weight gain despite decreased appetite is characteristic of the child who has a hypothyroid condition. Moderate-to-severe obesity in children is not typical for hypothyroidism. Furthermore, children with hypothyroidism manifest a decreased growth rate, a more constant finding than weight gain. In contrast, children with exogenous obesity typically have an increased growth velocity.
o Lethargy
o Decreased energy, dry skin, and puffiness
o Sleep disturbance, typically obstructive sleep apnea
o Cold intolerance and constipation
Heat intolerance, weight loss, and tremors: These are typical symptoms of hyperthyroidism. However, approximately 5-10% of children with CLT initially present with symptoms of toxic thyroiditis. This clinical picture may suggest a diagnosis of
Sexual pseudoprecocity
Parents may bring their child in for evaluation secondary to concern about testicular enlargement in boys or early breast development or onset of vaginal bleeding in girls.
The exact mechanism of sexual pseudoprecocity is not fully understood.
Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are elevated into the pubertal range. Mounting evidence suggests that increased serum levels of prolactin produce resistance to LH stimulation of the gonads, perhaps leading to hypothalamic gonadotropin-releasing hormone (GnRH) production and stimulation of pituitary LH and FSH release.
The short stature and delayed bone age observed in children with hypothyroidism help distinguish sexual pseudoprecocity from true precocious puberty.
Sexual pseudoprecocity reverses with adequate thyroid replacement.
Galactorrhea: This condition develops in primary hypothyroidism secondary to TRH secretion from the hypothalamus. TRH stimulates the anterior pituitary to release TSH and prolactin. Galactorrhea resolves as prolactin concentrations fall with thyroid replacement.
Physical
If the newborn with congenital hypothyroidism is not identified by newborn screening and receives no replacement therapy, clinical manifestations of congenital hypothyroidism evolve during the first weeks after birth. Note that although the signs listed below are classic for congenital hypothyroidism, they may be subtle or absent. Recognition of this disorder has been enhanced by systematic newborn screening for the past 30 years.
Physical signs of congenital hypothyroidism include the following:
Bradycardia
Elevated weight
Sluggish behavior
Rare cry or hoarse cry (hoarse cry is secondary to myxedema of the vocal cords)
Large fontanelles
Myxedema of the eyelids, hands, and/or scrotum
Large protruding tongue (secondary to accumulation of myxedema in the tongue)
Goiter
Umbilical hernia
Delayed relaxation of deep tendon reflexes (The Achilles tendon reflex appears to be most sensitive to effects of hypothyroidism.)
Cool dry skin
Enlarged cardiac silhouette, usually because of pericardial effusion
Prolonged conduction time and low voltage on electrocardiogram (ECG)
Hypothermia
The signs of acquired hypothyroidism can include many physical findings observed with congenital hypothyroidism, such as the following:
Decreased growth velocity
Bradycardia
Mild obesity (5-
Immature upper-to-lower body proportions
Dry coarse hair
Delayed dentition
Precocious sexual development
Cool, dry, carotenemic skin
Brittle nails
Delayed relaxation phase of deep tendon reflexes
Goiter formation
This may occur secondary to the effects of TSH receptor–stimulating antibodies, inflammatory lymphocytic infiltration, or compensatory hyperplasia because of decreased serum T4 and increased TSH concentrations.
Typically, the thyroid gland is enlarged diffusely, although it may not be enlarged symmetrically.
Upon palpation, the thyroid gland may initially be soft but then takes on a firm feeling with rubbery consistency and a seedlike surface secondary to hyperplasia of the normal lobular architecture
Myxedema (much more rare in children than in adults)
Dull facial expression
Causes
Congenital hypothyroidism: Approximately 75% of infants with congenital hypothyroidism have defects in thyroid gland development, 10% have hereditary defects in thyroid hormone synthesis or uptake, 5% have secondary (pituitary) or tertiary (hypothalamus) hypothyroidism, and 10% have transient hypothyroidism.
Thyroid dysgenesis: Defective thyroid gland development accounts for most instances of congenital hypothyroidism. Thyroid dysgenesis occurs sporadically in most cases but is occasionally familial because of mutations or deletions of genes (PAX8, TTF1, TTF2) that are involved in fetal thyroid formation. Thyroid dysgenesis ranges in severity from thyroid aplasia or hypoplasia to functional ectopic thyroid tissue. Approximately 40-60% of infants with thyroid gland dysgenesis have some functioning tissue. Laboratory and imaging studies facilitate the determination of the degree of dysgenesis. Thyroid agenesis is suggested by a low serum T4 level with an elevated serum TSH level and undetectable serum thyroglobulin. Newborns with ectopic or hypoplastic thyroid glands manifest low serum T4, elevated serum TSH, and measurable levels of circulating thyroglobulin. Imaging aids in confirming the diagnosis of aplastic, hypoplastic, or ectopic thyroid.
Familial thyroid dyshormonogenesis: Rare autosomal recessive inborn errors of thyroid hormone synthesis, secretion, or uptake also cause congenital hypothyroidism. The following 8 inborn errors have been identified:
Failure to respond to TSH secondary to defective activation of the thyroid receptor and related cyclic adenosine monophosphate (cAMP) signal transduction pathway
Defect in trapping of iodide secondary to sodium-iodide symporter failure
Defective oxidation of iodide to iodine secondary to thyroid peroxidase deficiency
Defective coupling of iodotyrosines
Deiodination defects
Defective thyroglobulin synthesis
Defective proteolysis of thyroglobulin
Release of T3 and T4 into the circulation
Partial peripheral resistance to thyroid hormones (autosomal dominant defect): Patients relate a family history of goiter with euthyroidism or hypothyroidism in the face of elevated serum levels of T4 or T3 but nonsuppressed serum TSH concentrations.
Differential Diagnoses
Constipation Malabsorption Syndromes
Constitutional Growth Delay Malnutrition
Growth Hormone Deficiency Mood Disorder: Depression
Hyposomatotropism Short Stature
Laboratory Studies
For all measures of thyroid function, age must be considered to interpret the results. In the term neonate, laboratory tests best reflect true thyroid function when performed in infants older than 24 hours.
Serum thyrotropin (TSH) concentration remains the most sensitive screening test for hypothyroidism and for establishing the diagnosis of primary hypothyroidism. The sample can be obtained at any time of day. A value within the reference range does not exclude TSH deficiency or TRH deficiency.
A physiologic surge of TSH occurs within the first 30 minutes of life and appears to be related to the stress of delivery and exposure to the cold temperature of the extrauterine environment. Serum TSH levels peak at levels as much as 70 mIU/L within the first 24 hours of life and then rapidly drop to less than 10 mIU/L within the first 3 days of life. Beyond the neonatal period, healthy serum levels of TSH are less than 6 mIU/L. Serum TSH levels are elevated in primary hypothyroidism or compensated hypothyroidism and should be low or within the reference range in cases of pituitary (TSH deficiency) or hypothalamic (TRH deficiency) etiologies. Isolated TSH deficiency is far less common than multiple anterior pituitary hormone deficiencies.
Serum TSH is the optimal parameter to guide dosing of thyroid hormone replacement, except in patients with secondary or tertiary hypothyroidism. In these patients, measuring serum free T4 by means of equilibrium dialysis is the superior testing method. Adequate thyroid hormone replacement results iormalization of serum TSH. In the rare syndromes of thyroid hormone resistance, serum TSH levels are elevated in the presence of normal-to-high serum total T4 concentration.
Serum TSH levels are often mildly abnormal (£ 7 mIU/L) in children and adolescents who are morbidly obese (>
T4 is present in both the
Measurement of serum T3 concentration, free or total, is not required to confirm the diagnosis of hypothyroidism.
Newborn screening for congenital hypothyroidism includes the following:
Required by
Infants with abnormal or borderline screening results should have total T4 and TSH obtained for definitive testing. Thyroid hormone replacement may be empirically initiated while awaiting the confirmatory studies.
In infants, if the serum total T4 is less than 85 nmol/L (<7 mg/dL), with TSH more than 40 mIU/L, congenital hypothyroidism is likely. If total T4 is low, and serum TSH is not elevated, TBG deficiency, central hypothyroidism, or euthyroid sick syndrome should be considered, and repeat testing may be needed. Serum free T4 concentration is normal in TBG deficiency. Normal TSH (<20 mIU/L) in the presence of low total T4 and free T4 concentrations suggest secondary or tertiary causes of hypothyroidism. In the latter, signs of associated hypopituitarism (eg, poor feeding, hypoglycemia) and physical findings (eg, midline defects, micropenis) support the diagnosis. All such infants should be screened for other pituitary hormone deficiencies (see Hypopituitarism).
Serum antithyroid antibody test findings do not facilitate the diagnosis of hypothyroidism and only serve to establish a diagnosis of CLT and indicate the risk of subsequent development of hypothyroidism. Antithyroid peroxidase and antithyroglobulin antibody titers are elevated in 90-95% of children with CLT. A small proportion of children with test results that are initially negative become positive later. As many as 20% of individuals who have antibody-positive test results do not develop hypothyroidism or hyperthyroidism.
Serum total T4 levels and serum free T4 levels are both low in patients with hypothyroidism. In compensated hypothyroidism, total T4 may remain within the reference range in the presence of elevated TSH.
Newborns with an elevated TSH should be treated empirically with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits as a result of hypothyroidism.
Low or low-normal serum total T4 levels in the setting of a serum TSH within the reference range suggests TBG deficiency. This congenital disorder causes no pathologic consequence; however, it should be recognized to avoid unnecessary thyroid hormone administration. TBG deficiency affects 1 individual per 3000 population; therefore, occurrence is nearly as frequent as that in congenital hypothyroidism. TBG deficiency results in low serum total T4; however, serum TSH and serum free T4 concentrations are normal. Assessment of the serum TBG concentration, preferably with simultaneous serum free and serum total T4 concentrations, confirms the diagnosis.
Imaging Studies
In vivo radionucleotide studies: The iodide-trapping or concentrating mechanism of normal thyroid tissue can be evaluated by radioisotope (iodine-123 or technetium-99m pertechnetate). In children, technetium-99m is a useful radioisotope because it is trapped by the thyroid but not organified; thus, the child is exposed to lower amounts of radiation.
In congenital organification defects and lymphocytic thyroiditis, the amount of radioisotope uptake is within reference range; however, the half-life of the radioisotope within the thyroid is decreased because of the lack of organification. This can be demonstrated by means of a perchlorate washout study.
Radioisotope-based thyroid scanning is useful to detect the absence or ectopic location of healthy thyroid tissue in congenital hypothyroidism.
Iodine-123 scanning of the thyroid can be used to identify ectopic thyroid tissue, such as lingual thyroid. Absence of a signal on this study confirms athyreosis.
Treatment & Medication
In congenital hypothyroidism, treatment should be initiated as soon as the diagnosis is suggested, immediately after obtaining blood for confirmatory tests. Delaying treatment after 6 weeks of life is associated with a substantial risk of delayed cognitive development. Newborns with elevated TSH should be treated empirically with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits caused by hypothyroidism.
Once treatment is initiated for congenital hypothyroidism, serum total T4 and TSH concentrations should be assessed monthly until the total or free T4 levels normalize, then every 3 months until the patient is aged 3 years. Thereafter, total T4 and TSH should be measured every 6 months.
Bone age may confirm the diagnosis of congenital hypothyroidism or can be used to assess excessive thyroid hormone replacement.
Therapeutic goals are normalization of thyroid function test results and elimination of all signs and symptoms of hypothyroidism.
Therapy should correct growth, pseudoprecocious puberty, and galactorrhea. Goiter may be reduced; however, replacement therapy often does not result in complete normalization of size.
When indicated by an elevated serum TSH, dosage adjustments of 0.0125 mg levothyroxine are usually sufficient. Because the half-life of T4 in the serum is about 6 days, approximately 3.5 weeks are required for serum T4 values to reach a new steady state. Depending on the degree of hypothyroidism and the time spent in the hypothyroid state, suppression of elevated TSH levels may take longer; therefore, repeat measurements of total T4 and TSH should be obtained no sooner than 1 month after any dosage adjustment or change in brand of thyroid hormone.
Levothyroxine tablets are easily crushed and can be given in a spoon with a small amount of water, formula, or cereal. Suspensions are not commercially available and are not recommended because maintaining a consistent concentration of levothyroxine in solution is difficult.
Approximately 20% of children with CLT recover to the euthyroid state and do not require lifelong thyroid hormone replacement. After treatment beyond the completion of puberty, a 6-month trial off thyroid hormone replacement therapy should be considered, with monitoring of serum TSH and total T4 levels every 3 months. If serum TSH levels rise above the reference range, levothyroxine treatment should be resumed and continued for life. Patients with CLT should undergo at least yearly monitoring of thyroid function with serum total T4 and TSH assessment to assure adequate treatment and maintenance of euthyroidism.
Surgical Care
Rarely, a massive goiter may require surgical resection for cosmetic indications. Generally, surgical therapy has no role in the treatment of hypothyroidism. Case reports have documented surgical resection of an enlarged pituitary gland, which subsequently demonstrated physiologic thyrotroph hypertrophy related to primary hypothyroidism. This condition is best treated by adequate T4 replacement.
Consultations
Consultation with a nuclear medicine physician is indicated for performance of radioiodine scan. Surgical consultation is advised during evaluation of a single cold nodule in the adolescent or young adult.
Thyroid Hormone
Levothyroxine is the preferred form of thyroid hormone replacement in all patients with hypothyroidism. Rarely, patients with congenital hypothyroidism display a “reset thyrostat” (ie, the serum TSH is not suppressed to reference range even with supraphysiologic replacement of levothyroxine). The primary therapeutic goal in patients with congenital hypothyroidism is to maintain the free serum T4 level within the high end of the reference range without resulting in symptoms of hyperthyroidism.
Thyroid hormones only should be used as replacement therapy in children with hypothyroidism. In active form, thyroid hormone influences growth and maturation of tissues, metabolism, and development. It does not enhance final adult height in euthyroid children.
Levothyroxine (Levothroid, Levoxyl, Synthroid)
Synthetic drug identical to human T4. Adjust dose on basis of total T4 and TSH (if primary hypothyroidism) or free T4 (if secondary or tertiary hypothyroidism); target range is normal total or free T4, with TSH <5 mcU/mL. Use a single brand to avoid variations in potency between brands. Several commercial preparations are available and share equal efficacy, despite different potency. With age, dose decreases on a weight basis, although daily dose approximates 100 mcg/m2, IV dose is approximately 40-50% of the
Dosing
Pediatric
Neonates: Initial dose 10-15 mcg/kg
Term infants-2 years: 37.5-50 mcg PO every am ac; titrate on basis of thyroid function tests; check serum total T4 and TSH q3mo until 2 y; therapeutic goals are normal total T4 and TSH less than 5 mcU/mL
2-6 years: 5 mcg/kg
6-12 years: 4-5 mcg/kg
Adolescents: 100-150 mcg
Interactions
Absorption can be inhibited by concurrent soy ingestion (eg, soy-based formulas); cholestyramine, iron salts, sucralfate, or aluminum hydroxide may decrease liothyronine absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when administered with liothyronine; activity of some beta-blockers may decrease when hypothyroidism converted to euthyroid state
Contraindications
Documented hypersensitivity; uncorrected adrenal insufficiency; hyperthyroidism
Use cautiously in angina pectoris or cardiovascular disease; in adults with long-standing hypothyroidism, rapid initiation of full thyroid hormone replacement therapy can precipitate heart failure; by contrast, diagnosis of hypothyroidism in infants and children is typically recognized promptly (as a result of growth failure), and pediatric heart usually more resilient to challenge; therefore, full replacement doses in children may be initiated and not gradually titrated ; treatment of compensated hypothyroidism rests the gland and may decrease autoimmune inflammatory process and diminish goiter size; avoid overtreatment, which may advance skeletal maturation and thereby compromise final adult height and decrease ultimate bone mineral density; periodically monitor thyroid status
INBORN ERRORS OF METABOLISM
Many disorders originate in mutational events that alter the genetic constitution of an individual, disrupting normal function. Hundreds of human hereditary biochemical disorders, termed inborn errors of metabolism by Garrod at the turn of the century, have been discovered, and they are continually being discovered.
Now modern biochemical genetics can describe how genetic information is translated into the synthesis of proteins having specific metabolic or structural properties. An inherited mutational event can result in the alteration of either primary protein structure or the amount of the specific protein being synthesized. In either case, the functional ability of the protein, whether it is an enzyme, receptor, transport vehicle, membrane pump, or structural element, may be relatively or seriously compromised.
If the process affected by an inborn error of metabolism is essential for well-being and if the degree of alteration is sufficient to affect the system, clinical consequences may result. Some genetic changes are clinically inconsequential and are responsible only for the many polymorphic differences that set individuals apart. Others produce changes that express themselves only under conditions that may not be encountered during the lifetime of an individual. Still others, however, produce a disease state, which may range from very mild to lethal. Most inborn errors of metabolism exhibiting clinical consequences manifest themselves (or can be detected) in the newborn period or shortly thereafter. It is also now possible to screen and detect many of these disorders in utero
Children with inborn errors of metabolism may present with one or more of a large variety of signs and symptoms. These may include metabolic acidosis, persistent vomiting, failure to thrive, developmental abnormalities, elevated blood or urine levels of a particular metabolite, for example, an amino acid or ammonia, a peculiar odor, or physical changes such as hepatomegaly. Diagnosis is facilitated by considering those presenting in the neonatal period separately from children presenting later in life.
NEONATAL PERIOD. Inborn errors of metabolism causing clinical manifestations in the neonatal period are usually severe and are often lethal if proper therapy is not promptly initiated. Clinical findings are usually nonspecific and similar to those seen in infants with generalized infections. An inborn error of metabolism should be considered in the differential diagnosis of a severely ill neonatal infant, and special studies should be undertaken if the index of suspicion is high.
Neonatal infants with metabolic disorders are usually normal at birth; however, signs and symptoms such as lethargy, poor feeding, convulsions, and vomiting may develop as early as a few hours after birth. A history of clinical deterioration in a previously normal neonate should suggest an inborn error of metabolism. This clinical course contrasts with many other genetic disorders or perinatal insults, which cause abnormalities from the time of birth. Occasionally, vomiting may be severe enough to suggest the diagnosis of pyloric stenosis, which is usually not present, although it has simultaneously occurred in such infants. Lethargy, poor feeding, convulsions, and coma may also be seen in infants with hypoglycemia or hypocalcemia. Response to intravenous injection of glucose or calcium usually establishes these diagnoses. Because most inborn errors of metabolism are inherited as autosomal recessive traits, a history of consanguinity and/or death in the neonatal period in the immediate family should increase suspicion of this diagnosis. Some of these disorders have a high incidence in specific population groups. For instance, tyrosinemia type 1 is more common among French-Canadians of
|
Inborn Error of Metabolism |
Urine Odor |
|
Glutaric acidemia (type II) |
Sweaty feet |
|
Hawkinsinuria |
Swimming pool |
|
Isovaleric acidemia |
Sweaty feet |
|
Maple syrup urine disease |
Maple syrup |
|
Methionine malabsorption |
Cabbage |
|
Multiple carboxylase deficiency |
Tomcat urine |
|
Oasthouse urine disease |
Hops–like |
|
Phenylketonuria |
Mousy or musty |
|
Trimethylaminuria |
Rotting fish |
|
Tyrosinemia |
Rancid, fishy, or cabbage–like |
Diagnosis usually requires a variety of specific laboratory studies. Measuring serum concentrations of ammonia, bicarbonate, and pH is often very helpful in differentiating major causes of metabolic disorders. Elevation of blood ammonia is usually due to defects in urea cycle enzymes. These infants with elevated blood ammonia levels commonly have normal serum pH and bicarbonate, and without measurement of blood ammonia they may remain undiagnosed and succumb to their disease. Elevation of serum ammonia, however, has also been observed in some infants with certain organic acidemias. These infants are severely acidotic because of accumulation of organic acids in body fluids.
When blood ammonia, pH, and bicarbonate are normal, other aminoacidopathies, such as hyperglycinemia and galactosemia, should be considered; galactosemic infants may also manifest cataracts, hepatomegaly, ascites, and jaundice.
Most inborn errors of metabolism presenting in the neonatal period are lethal if specific therapy is not initiated immediately. Specific diagnosis, even in an infant in whom death seems inevitable, is of great importance for genetic counseling of the family. Therefore, every effort should be made to determine the diagnosis while the infant is alive; postmortem examination is usually not helpful.
CHILDREN AFTER THE NEONATAL PERIOD. Most inborn errors of metabolism that cause symptoms in the first few days of life exhibit milder variant forms that have a more insidious onset. These forms may escape detection during the neonatal period, and the diagnosis may be delayed for months or even years. The early clinical manifestations in children with these forms are commonly nonspecific and may be attributed to perinatal insults.
Clinical manifestations, such as mental retardation, motor deficits, and convulsions are the most constant findings in some of these children. There may be an episodic or intermittent pattern with episodes of acute clinical manifestations separated by periods of seemingly disease-free states. The episodes are usually triggered by a stress or a nonspecific insult such as an infection. The child may die during one of these acute attacks. An inborn error of metabolism should be considered in any child with one or more of the following manifestations: (1) unexplained mental retardation, developmental delay, motor deficits, or convulsions; (2) unusual odor, particularly during an acute illness; (3) intermittent episodes of unexplained vomiting, acidosis, mental deterioration, or coma; (4) hepatomegaly; or (5) renal stones.
Inborn errors of metabolism of a given pedigree run true to type. Thus, although symptomatology may vary among siblings, usually if one child in a family, for example, has the form of maple syrup urine disease manifested during the neonatal period, the next affected sibling will have the same defect, not the variant that occurs only intermittently later in childhood.
DEFECTS IN METABOLISM OF AMINO ACIDS
Phenylalanine
Phenylalanine is an essential amino acid. Dietary phenylalanine not utilized for protein synthesis is normally degraded via the tyrosine pathway. Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin causes accumulation of phenylalanine in body fluids. Several clinically and biochemically distinct forms of hyperphenylalaninemia exist.
CLASSIC PHENYLKETONURIA (PKU).
This form of the disorder is caused by the complete or near-complete deficiency of phenylalanine hydroxylase. Excess phenylalanine is transaminated to phenylpyruvic acid or decarboxylated to phenylethylamine. These and subsequent metabolites, along with excess phenylalanine, disrupt normal metabolism and cause brain damage.
Clinical Manifestations. The affected infant is normal at birth. Mental retardation may develop gradually and may not be evident for a few months. It has been estimated that an untreated infant loses about 50 points in IQ by the end of the 1st yr of life. Mental retardation is usually severe, and most patients require institutional care. Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom. Older untreated children become hyperactive with purposeless movements, rhythmic rocking, and athetosis.
On physical examination these infants are blonder than unaffected siblings; they have fair skin and blue eyes. Some may have a seborrheic or eczematoid skin rash, which is usually mild and disappears as the child grows older. These children have an unpleasant odor of phenylacetic acid, which has been described as musty or mousey. There are no consistent findings oeurologic examination. However, most infants are hypertonic with hyperactive deep tendon reflexes. About one fourth of children have seizures, and more than 50% have electroencephalographic (EEG) abnormalities. Microcephaly, prominent maxilla with widely spaced teeth, enamel hypoplasia, and growth retardation are other common findings in untreated children. The clinical manifestations of classic PKU are rarely seen in those countries in which neonatal screening programs for the detection of PKU are in effect.
Diagnosis. Infants with PKU are clinically normal at birth, and tests of their urine for phenylpyruvic acid may be negative in the first few days of life; accordingly, the diagnosis depends on measuring blood levels of phenylalanine. The bacterial inhibition assay method of Guthrie is widely used in the newborn period to screen for PKU. This test requires a few drops of capillary blood, which are placed on a filter paper and mailed to the laboratory for assay. Blood phenylalanine in affected infants may rise to levels necessary to render the Guthrie test positive as early as 4 hr after birth in the absence of any protein feeding. It is recommended, however, that the blood for screening be obtained after 48-72 hr of life and preferably after feeding proteins in order to reduce the possibility of false-negative results. When this test indicates an elevated level of phenylalanine, the phenylalanine and tyrosine concentrations of the plasma should be measured. The criteria for diagnosis of classic PKU are (1) a plasma phenylalanine level above 20 mg/dL (
Treatment. The goal of therapy is to reduce phenylalanine and its metabolites in body fluids in order to prevent or minimize brain damage. This can be achieved by instituting a diet low in phenylalanine; formulas low in this essential amino acid are now available commercially. Administration of the low-phenylalanine diet requires close nutritional supervision and frequent monitoring of the serum concentration of phenylalanine. The optimal serum level to be maintained probably lies between 3 mg/dL (
The duration of diet therapy is controversial. Although rigid diet control may be relaxed after 6 yr of age, some form of restriction in dietary phenylalanine is necessary indefinitely. Dietary management is almost inevitably complicated by emotional problems resulting from dietary restriction and the abnormal eating habits imposed upon child and family. Therefore, parents and childreeed continuous skillful and empathetic support and guidance.
Pregnancy in Mothers with PKU. Pregnant women with PKU who are not on a low-phenylalanine diet have a higher risk of spontaneous abortion than the general population. Infants born to such mothers are often mentally retarded and may have microcephaly and/or a congenital heart anomaly. These complications are related to high maternal levels of blood phenylalanine. Prospective mothers who have PKU should be started on a low-phenylalanine diet before conception, and every effort should be made to keep blood phenylalanine levels below 10 mg/dL throughout pregnancy.
HYPERPHENYLALANINEMIA DUE TO DEFICIENCY OF COFACTOR TETRAHYDROBIOPTERIN (BH4). In about 2% of infants with hyperphenylalaninemia, the defect resides in one of the enzymes necessary for production or recycling of the cofactor BH4. Historically, these infants were diagnosed as having PKU, but they deteriorated neurologically despite adequate control of serum phenylalanine; BH4 was then shown to be a cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. The latter two hydroxylases are essential for biosynthesis of the neurotransmitters dopamine and serotonin. BH4 is also a cofactor for nitric oxide synthase that catalyzes the generation of nitric oxide from arginine. Today, patients with BH4 deficiency are diagnosed very early in life because all patients with hyperphenylalaninemia are tested for the possibility of this cofactor deficiency.
BH4 is synthesized from guanosine triphosphate and is converted to 4a-hydroxytetrahydrobiopterin during the hydroxylation of phenylalanine by phenylalanine hydroxylase. 4a-Hydroxytetrahydrobiopterin is dehydrated to quinonoid dihydrobiopterin by the enzyme carbinolamine dehydratase. The dehydration process may also occur nonenzymatically but at a slower rate. The quinonoid dihydrobiopterin is reduced by the enzyme dihydropteridine reductase to regenerate BH4. Four enzyme deficiencies leading to defective BH4 formation have been described. More than half of the reported patients have had a deficiency of 6-pyruvoyltetrahydropterin synthase (6-PTS). Only a few patients with a deficiency of guanosine triphosphate (GTP) cyclohydratase and carbinolamine dehydratase have been reported. The remaining patients have had a deficiency of dihydropteridine reductase.
The clinical manifestations of these disorders are similar and are usually indistinguishable from those of classic PKU. These patients are identified during screening programs for PKU because of evidence of hyperphenylalaninemia, but neurologic manifestations, such as loss of head control, hypertonia, drooling, swallowing difficulties, and myoclonic seizures, develop after 3 mo of age despite adequate dietary therapy. The exception to this malignant course occurs in patients with carbinolamine dehydratase deficiency in whom the clinical manifestations may be none other than mild hyperphenylalaninemia. This is not surprising because BH2 is formed slowly without the enzyme action. Plasma phenylalanine levels may be as high as those in classic PKU or in the range of benign (persistent) hyperphenylalaninemia (<
Diagnosis of BH4 deficiency and the responsible enzyme defect may be established by performing one of the following tests:
1. Measurement of neopterin (oxidative product of dihydroneopterin triphosphate) and biopterin (oxidative product of dihydro- and tetrahydrobiopterin) in body fluids, especially urine. In patients with 6-pyruvoyltetrahydropterin synthase deficiency, there is a marked elevation of neopterin and a concomitant decrease in biopterin exretion (neopterin-biopterin ratio is high). In patients with GTP cyclohydrolase deficiency, urinary excretion of both neopterin and biopterin is very low, and in patients with dihydropteridine reductase deficiency, neopterin is normal, but biopterin is very high (neopterin-biopterin ratio is low). Excretion of biopterin increases in this enzyme deficiency because the quinonoid dihydrobiopterin cannot be recycled into BH4. Patients with carbinolamine dehydratase deficiency excrete 7-biopterin in their urine.
2. BH4 loading test. An oral or intravenous (more reliable if feasible) dose of BH4 (2{endash}–10 mg/kg) normalizes plasma phenylalanine in patients with BH4 deficiency within 4{endash}–6 hr. This test should be done while the child is receiving normal amounts of phenylalanine in the diet. Some patients with dihydropteridine reductase deficiency may not respond to this loading test.
3. Enzyme assay. The activity of dihydropteridine reductase can be measured in many tissues, including liver, leukocytes, red blood cells, and cultured fibroblasts. 6-Pyruvoyltetrahydropterin synthase can be measured in liver, kidney, and red blood cells. GTP cyclohydrolase can be measured in liver and in phytohemagglutinin-stimulated lymphocytes (the enzyme activity is normally very low in unstimulated lymphocytes). Measurement of the last two enzymes is technically difficult, and assays are not readily available.
4. Gene study. Genes for dihydropteridine reductase and carbinolamine dehydratase have been identified. Identification of mutations in these gene in affected patients and their families is now possible.
Treatment. The long-term efficacy of various therapies is unknown. The various treatment methods include the following:
1. Low-phenylalanine diet. Although phenylalanine does not prevent neurologic damage, such a diet in conjunction with the following therapies is recommended for at least the first 2 yr of life. High levels of phenylalanine inhibit the synthesis of neurotransmitters.
2. Neurotransmitter precursors. Administration of the L-dopa and 5-hydroxytryptophan seems to be the most effective treatment and may prevent neurologic damage if started early in life. Therefore, all patients with PKU and hyperphenylalaninemia should be tested for BH4 deficiency as early as possible. Treatment started after 6 mo of age, although resulting in some improvement, has not reversed existing neurologic damage.
3. BH4 replacement. Oral administration of the cofactor in small daily doses normalizes serum levels of phenylalanine. This compound, unless given at high doses (20{endash}–40 mg/kg/24 hr), does not readily cross the blood-brain barrier, and neurologic damage may continue to progress.
BENIGN HYPERPHENYLALANINEMIA. Infants with hyperphenylalaninemia are occasionally identified whose blood levels of phenylalanine are only slightly elevated; these concentrations are not enough (less than 20 mg/dL or
For infants who have serum phenylalanine concentrations in the range of 10–20 mg/dL, with normal tyrosine values and no PKU, a simple reduction of dietary protein intake may be sufficient to control serum concentrations of phenylalanine; if this is not effective, specific restriction of dietary phenylalanine is indicated. All infants who are not treated with dietary restriction should be systematically monitored with repeated determinations of plasma phenylalanine and developmental evaluations to establish the safety of continuing partial treatment or nontreatment. Periodic challenges with natural protein may be helpful in determining the need for continuing dietary restriction.
TRANSIENT HYPERPHENYLALANINEMIA. Moderately elevated levels of phenylalanine occur in transient tyrosinemia of the newborn infant (see Chapter 71.2). When the infant’s ability to oxidize tyrosine matures, the elevated levels of tyrosine and phenylalanine return to normal.
Absence of or delayed maturation of phenylalanine transaminase can also produce hyperphenylalaninemia if the patient is fed milk with a high protein content. Such infants cannot produce much phenylpyruvic acid, even when their blood levels of phenylalanine approach 30 mg/dL; they have normal blood levels when fed milk products having the protein content of human milk.
GENETICS AND PREVALENCE. All defects causing persistent hyperphenylalaninemia and PKU are inherited as autosomal recessives. They have a collective prevalence of 1:10,000 to 1:20,000 live births, with classic PKU being the most common and GTP cyclohydrolase the rarest. The gene for phenylalanine hydroxylase is located on the long arm of chromosome 12. Many mutations of the gene have been described in different families. The genes for carbinolamine dehydratase and dihydropteridine reductase are located on the long arm of chromosome 10 and the short arm of chromosome 4, respectively. Prenatal diagnosis and carrier detection are possible using specific genetic probes in cells obtained from chorionic villus biopsy.
Tyrosine
Tyrosine, obtained from ingested protein and synthesized endogenously from phenylalanine, is used for protein synthesis and is a precursor of dopamine, norepinephrine, epinephrine, melanin, and thyroxine. Excess tyrosine is metabolized to carbon dioxide and water. At least two distinct clinical entities are associated with a persistent increase in plasma concentrations of tyrosine, but only in tyrosinemia type II are signs and symptoms attributed to high levels of tyrosine in body fluids. In hereditary tyrosinemia type I the causal relationship with increased tyrosine levels remains unclear. There are also patients who present varied clinical findings and tyrosinemia but do not fit into any specific category, and a transient form of tyrosinemia is seen iewborn infants.
TYROSINEMIA TYPE I (Tyrosinosis, Hereditary Tyrosinemia, Hepatorenal Tyrosinemia). In this condition, caused by a deficiency of the enzyme fumarylacetoacetate hydrolase, a moderate elevation of serum tyrosine is associated with severe involvement of the liver, kidney, and central nervous system. These findings are thought to be due to an accumulation of intermediate metabolites of tyrosine in the body, especially succinylacetone. Decreased activities of 4-hydroxyphenylpyruvate dioxygenase and maleylacetoacetate isomerase observed in this condition are presumed to be secondary phenomena.
Clinical Manifestations. There are two main forms of the disease: the neonatal or acute form, which comprises most reported cases, and the chronic or latent form. Intermediate forms also occur. Acute and chronic forms have been observed within the same family.
Infants having the acute form become symptomatic within the first 6 mo of life. Failure to thrive, developmental delay, irritability, vomiting, diarrhea, and fever are among the early manifestations. Hepatomegaly, jaundice, hypoglycemia, and bleeding tendencies as manifested by melena, hematuria, and ecchymosis are common findings. A cabbage-like odor of some infants is related to metabolites of methionine. Death from hepatic failure usually occurs before the 2nd yr of life.
In the chronic form, clinical manifestations may not appear until after the 1st yr of age. Failure to thrive, developmental delay, progressive cirrhosis, renal tubular dysfunction (Fanconi syndrome), and vitamin D–resistant rickets are characteristic. Episodes of acute polyneuropathy resembling acute porphyria have been observed in about 40% of affected infants. These episodes are characterized by severe pains in the legs (occasionally in the abdomen), hypertonia, vomiting, paralytic ileus, and occasionally self-mutilation. Elevation of urinary 5-aminolevulinic acid (presumably due to inhibition of 5-aminolevulinic hydratase by succinylacetone) has been observed in these patients, but the relationship of this abnormality to the polyneuropathic crises is unclear because the urinary excretion of 5-aminolevulinic acid remains elevated between the attacks. Death usually occurs by 10 yr of age from liver failure or hepatoma.
Laboratory findings include normocytic anemia and marked elevations of serum bilirubin (both conjugated and unconjugated), serum transaminases, and a{alpha}-fetoprotein. An increase in serum levels of a{alpha}-fetoprotein has been observed in the cord blood of affected infants, indicating intrauterine liver damage. Plasma levels of tyrosine and other amino acids, especially methionine, are moderately increased. Generalized aminoaciduria occurs. Urinary excretion of 5-aminolevulinic acid may be increased. The presence of succinylacetoacetate and succinylacetone in serum and urine is diagnostic. Liver histology is usually compatible with chronic active hepatitis and nonspecific cirrhosis. Hyperplasia of pancreatic islet cells is also a common finding.
This condition should be differentiated from other causes of hepatitis and hepatic failure in infants, including galactosemia, hereditary fructose intolerance, and giant cell hepatitis. Diagnosis is established by measurement of fumarylacetoacetate hydrolyase activity in liver biopsy specimens or fibroblast cultured cells. The degree of residual enzyme activity dictates the severity of the disease.
Treatment. A diet low in tyrosine, phenylalanine, and methionine may result in some clinical improvement in some patients. However, in most patients the progression of the disease cannot be halted by diet alone. Inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase by 2-(nitro-4-trifluoromethylbenzoyl)-1-3-cyclohexanedione (NTBC) has been shown to cause significant improvement in clinical and biochemical findings in five patients with this condition. The long-term effect of this treatment, however, has not yet been determined. Liver transplantation, especially if performed early in the course of the disease, remains the most effective therapy.
Tyrosinemia type I is an autosomal recessive trait. The gene for fumarylacetoacetate hydrolase has been mapped to the long arm of chromosome 15. Most reported patients have a French-Canadian ancestry. The prevalence of the condition is estimated to be
TYROSINEMIA TYPE II (Richner-Hanhart Syndrome, Oculocutaneous Tyrosinemia). This rare autosomal recessive disorder results in mental retardation, palmar and plantar punctate hyperkeratosis, and herpetiform corneal ulcers. Excessive tearing, redness, pain, and photophobia may occur before skin lesions. Corneal lesions usually occur during the first few months of life and are presumed to be due to tyrosine deposition; skin lesions may develop later in life. Mental retardation is usually mild to moderate and may be associated with self-mutilation.
Significant hypertyrosinemia (20–50 mg/dL) and tyrosinuria are present. The condition is due to the deficiency of the cytosolic fraction of hepatic tyrosine amino transferase (tyrosine transaminase). In contrast to tyrosinemia type I, liver and kidney functions, as well as serum concentrations of other amino acids, are normal.
Treatment with a diet low in tyrosine and phenylalanine has not only corrected the chemical abnormalities but has also resulted in dramatic healing of the skin and eye lesions. Mental retardation may be prevented by early dietary restriction of tyrosine. The gene for tyrosine aminotransferase is located on the long arm of chromosome 16.
TRANSIENT TYROSINEMIA OF THE NEWBORN. In a small number of newborn infants, plasma tyrosine may rise to as high as 60 mg/dL during the first 2 wk of life. Most affected infants are premature and are receiving high-protein diets. Lethargy, poor feeding, and decreased motor activity occur in some of them, but most are asymptomatic and come to medical attention because of a high blood phenylalanine level, rendering the Guthrie test for PKU screening positive. Tyrosinemia usually resolves spontaneously during the 1st mo of life. The condition is presumably due to delayed maturation of 4-hydroxyphenylpyruvate dioxygenase. The condition is often corrected promptly by reducing the amount of protein in the diet (to 2-3 g/kg/24 hr) and by administering vitamin C (200–400 mg/24 hr). Mild intellectual deficits have been reported in some full-term infants with this disorder. Because vitamin C is necessary for optimal functioning of the dioxygenase, it is not surprising that tyrosinemia occurs in patients with scurvy.
HAWKINSINURIA. This rare condition (named after the first affected family) is due to a deficiency of one of the components of the 4-hydroxyphenylpyruvate dioxygenase enzyme complex. This enzyme oxidizes 4-hydroxyphenylpyruvic acid to form an epoxide intermediate first; the epoxide metabolite undergoes a rearrangement to form the final product, homogentisic acid. A block in the rearrangement step leads to an accumulation of the epoxide intermediate, which either is reduced to form 4-hydroxycyclohexylacetic acid (4-HCAA) or reacts with glutathione (or cysteine) to form the unusual organic acid 2-L-cysteine-S-yl-1-4-dihydroxycyclohex-5-en-1-yl-acetic acid (hawkinsin).
Individuals with this disorder become symptomatic only during infancy. The symptoms usually appear after weaning from breast-feeding with the introduction of a high-protein diet. Severe metabolic acidosis, ketosis, failure to thrive, mild hepatomegaly, and an unusual odor (like that of a swimming pool) are common findings. These infants respond well to a diet low in both phenylalanine and tyrosine, and their clinical manifestations resolve spontaneously by 1 yr of age. Adults with this condition are usually asymptomatic despite metabolic abnormalities. Mental development is usually normal.
Affected children and adults excrete 4-hydroxyphenylpyruvic acid and 4-hydroxyphenylacetic acid as well as the two very unusual organic acids 4-HCAA and hawkinsin in their urine.
Treatment consists of a low-protein diet (such as breast milk) or a diet low in phenylalanine and tyrosine. Large doses of vitamin C (up to 1,000 mg/24 hr) are also recommended. No therapy is needed after 1 yr of age. The condition is inherited as an autosomal dominant trait, and all affected patients reported to date have been presumed to be heterozygous for the trait.
ALBINISM. This condition is due to defects in the biosynthesis and distribution of melanin. Melanin is synthesized by melanocytes from tyrosine in a membrane-bound intracellular organelle called the melanosome. Tyrosine is formed in the skin from phenylalanine by the action of phenylalanine hydroxylase and its cofactor, tetrahydrobiopterin (BH4). BH4 seems to be a rate-limiting compound for melanine synthesis because depigmented skin from patients with vitiligo has very low activity of the carbinolamine dehydralase, the enzyme that is necessary for regeneration of BH4. Tyrosine is transported into melanosome, where it is metabolized to dopa and dopaquinolone by the action of a single enzyme, tyrosinase. Dopaquinone either reacts with cysteine to make pheomelanine, a yellow-red pigment, or undergoes several nonenzymatic steps to form eumelanine, which is brown-black. Albinism (all types) has a world-wide prevalence of
Clinical manifestations common in almost all forms of albinism include depigmentation of the skin, iris, and retina. Nystagmus, strabismus, photophobia, decreased visual acuity, and the presence of red reflex are common eye findings. Binocular vision is absent because of a decussation defect in which all optic nerve fibers from one eye completely cross to the other side at the chiasma. Blindness and skin cancer are the two major late sequelae of albinism in its severe forms.
OCULOCUTANEOUS (GENERALIZED) ALBINISM. Two major forms of this condition have been identified, tyrosinase negative (type I) and tyrosinase positive (type II). This classification is based on the ability of a plucked hair bulb to form pigment (melanine) when incubated with tyrosine.
Tyrosinase negative (type I) albinism is the most severe and the second most common form (after tyrosinase positive) of generalized albinism. This is an autosomal recessive condition that is caused by deficiency of the tyrosinase enzyme. The gene for this enzyme is mapped to the long arm of chromosome 11. Many different mutations of the gene have been shown to cause this form of albinism. A milder form of the condition, which is seen predominantly in Amish families (type IB), is now known to be caused by mutations in other loci of the same gene. In fact, some of the patients who were thought to have tyrosinase positive albinism have been found to have a mutation in the tyrosinase gene.
Tyrosinase positive (type II) albinism is the most common form of generalized albinism and is inherited as an autosomal recessive trait. The gene is located on the long arm of chromosome 15.
Ocular Albinism. In these patients albinism is limited to the eyes (iridis and retina). Nystagmus, decreased visual acuity, and photophobia are common findings in all forms. Skin and hair color are withiormal limits but are usually lighter than those ionaffected siblings. Eyes are usually pale blue to light green. Hair bulb tyrosinase is positive in all cases. Four forms of this condition have been identified, differentiated by their mode of inheritance and additional associated anomalies. Partial Albinism (Piebaldism). This disorder is characterized by localized areas of skin and hair devoid of pigment, and is inherited as a dominant trait. In some instances a white forelock or patch of depigmented hair elsewhere may be the sole manifestation.
ALCAPTONURIA
This rare (incidence
Clinical manifestations of alcaptonuria consist of ochronosis and arthritis. These findings may not become evident until midadult life. The only sign of the disorder in the pediatric age group is a darkening of the urine to almost a black color on standing. This is caused by oxidation and polymerization of the homogentisic acid and is enhanced with an alkaline pH. Therefore, an acid urine may not become dark even after many hours of standing. This is one of the reasons why darkening of the urine may never be noted in an affected person, and the diagnosis may be delayed until adulthood, when arthritis or ochronosis occurs. Ochronosis, a term used to describe the darkening of tissue, is due to a slow accumulation of the black polymer of homogentisic acid in cartilage and other mesenchymal tissues. It is manifested clinically as dark, blackened spots in the sclera or as diffuse blackish pigmentation of the conjunctiva, cornea, and ear cartilage. Arthritis is the only disabling effect of this condition, which occurs in almost all affected subjects with advancing age. It involves the large joints (spine, hip, and knee) and is usually more severe in men. The arthritis has the clinical characteristics of rheumatoid arthritis, but the radiologic findings are typical of osteoarthritis. Degenerative changes in the lumbar spine are quite characteristic with narrowing of the joint spaces and fusion of the vertebral bodies. The pathogenesis of arthritic changes remains unclear. High incidences of heart disease (mitral and aortic valvulitis, calcification of the heart valves, and myocardial infarction) have also beeoted.
The diagnosis is confirmed by measurement of homogentisic acid in urine. Affected subjects may excrete as much as 4–8 g of this compound daily. Homogentisic acid is a strong reducing agent that produces a positive reaction with Fehling or Benedict reagent (but not with glucose oxidase). The dark urine of phenol poisoning and that associated with melanotic tumors do not have these reducing properties. The enzyme is expressed only in the liver and kidneys. The gene for alkaptonuria has been mapped to the long arm of chromosome 3.
There is no effective treatment for this disorder.
Methionine
The normal pathway for catabolism of methionine, an essential amino acid, produces S-adenosylmethionine, which serves as a methyl group donor for methylation of a variety of compounds in the body, and cysteine, which is formed through a series of reactions called trans-sulfuration. HOMOCYSTINURIA (Homocystinemia). Most homocysteine, an intermediate compound of methionine degradation, is normally remethylated to methionine. This methionine-sparing reaction is catalyzed by the enzyme methionine synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a substrate and a metabolite of vitamin B12 (methylcobalamin) as a cofactor. Homocysteine (and its dimer homocystine) ordinarily is not detectable in plasma or urine. Three major forms of homocystinemia and homocystinuria have been identified.
Homocystinuria Due to Cystathionine Synthase Deficiency (Homocystinuria Type I, Classic Homocystinuria). This is the most common inborn error of methionine metabolism. The prevalence of this autosomal recessive condition is estimated at
Infants with this disorder are normal at birth. Clinical manifestations during infancy are nonspecific and may include failure to thrive and developmental delay. The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs. This causes severe myopia and iridodonesis (quivering of the iris). Astigmatism, glaucoma, staphyloma, cataracts, retinal detachment, and optic atrophy may develop later in life. Progressive mental retardation is common. Normal intelligence, however, has been reported in about 1/3 of patients. Psychiatric disorders have been observed in more than 50% of affected patients. Convulsions occur in about 20% of patients. Affected individuals with homocystinuria manifest skeletal abnormalities resembling those of Marfan syndrome; they are usually tall and thin with elongated limbs and arachnodactyly. Scoliosis, pectus excavatum or carinum, genu valgum, pes cavus, high arched palate, and crowding of the teeth are commonly seen. These children usually have fair complexions, blue eyes, and a peculiar malar flush. Generalized osteoporosis is the main roentgenographic finding. Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age. Optic atrophy, paralysis, seizure disorders, cor pulmonale, and severe hypertension (due to renal infarcts) are among the serious consequences of thromboembolism, which is due to changes in the vascular walls and increased platelet adhesiveness secondary to elevated homocystine levels. The risk of thromboembolism increases following surgical procedures.
Elevations of both methionine and homocystine (or homocysteine) in body fluids are the diagnostic laboratory findings. Freshly voided urine should be tested for homocystine, since this compound is unstable and may disappear as the urine is stored. Cystine is low or absent in plasma. The diagnosis may be established by assay of the enzyme in liver biopsy specimens, cultured fibroblasts, or phytohemagglutinin-stimulated lymphocytes. Prenatal diagnosis is feasible by performing an enzyme assay of cultured amniotic cells or chorionic villi. An increasing number of mutations have been recognized in different families.
Treatment with high doses of vitamin B6 (200–1,000 mg/24 hr) causes dramatic improvement in patients who are responsive to this therapy, but some patients may not respond because of folate depletion; therefore, a patient should not be considered unresponsive to vitamin B6 until folic acid (1–5 mg/24 hr) has been added to the treatment regimen. Restriction of methionine intake in conjunction with cysteine supplementation is recommended for all patients regardless of their response to vitamin B6. Betaine (trimethylglycine, 6–9 g/24 hr), which also serves as a methyl group donor, lowers homocysteine levels in body fluids by remethylating homocysteine to methionine. This treatment has produced clinical improvement in patients who are unresponsive to vitamin B6 therapy.
Homocystinuria Due to Defects in Methylcobalamin Formation (Homocystinuria Type II). Methylcobalamin is the cofactor for the enzyme methionine synthase, which catalyzes remethylation of homocysteine to methionine. There are at least five distinct defects in the intracellular metabolism of cobalamin that may interfere with the formation of methylcobalamin. The exact nature of these defects is unknown.
The clinical manifestations are similar in patients with all of these defects. Vomiting, poor feeding, lethargy, hypotonia, and developmental delay may occur in the first few months of life. Laboratory studies reveal megaloblastic anemia, homocystinuria, and hypomethioninemia. The presence of hypomethioninemia and megaloblastic anemia differentiates these defects from homocystinuria due to either cystathionine synthase deficiency or methylenetetrahydrofolate reductase deficiency.
Diagnosis is established by complementation studies performed in cultured fibroblasts. Prenatal diagnosis has been accomplished by studies in amniotic cell cultures.
Treatment with vitamin B12 (1–2 mg/24 hr) has been effective in correcting clinical and biochemical findings in these patients.
Homocystinuria Due to Deficiency of Methylenetetrahydrofolate Reductase (Homocystinuria Type III). This enzyme reduces 5–10 methylenetetrahydrofolate to form 5-methyltetrahydrofolate, which provides the methyl group needed for remethylation of homocysteine to methionine The gene for this enzyme has been located on the short arm of chromosome 1. The condition is transmitted as an autosomal recessive trait and as of 1994, 40 cases have been reported.
The severity of the enzyme defect and of the clinical manifestations varies considerably in different families. Complete absence of enzyme activity results ieonatal apneic episodes and myoclonic seizures that may lead rapidly to coma and death. Partial deficiency may result in a more chronic clinical picture, manifested by mental retardation, convulsions, microcephaly, and spasticity. Laboratory studies reveal moderate homocystinemia and homocystinuria. The methionine concentration is low or low normal. This finding differentiates this condition from classic homocystinuria due to cystathionine synthase deficiency. Absence of megaloblastic anemia distinguishes this condition from homocystinuria due to methylcobalamin formation (see earlier). Thromboembolism of vessels has also been observed in these patients. Diagnosis may be confirmed by the enzyme assay in cultured fibroblasts, and leukocytes.
Treatment with a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine has been tried. Of these, early treatment with betaine seems to have the most beneficial effect.
Valine, Leucine, Isoleucine, and Related Organic Acidemias
The early steps in the degradation of these three essential amino acids, the branched-chain amino acids, are similar. Although valine transaminase may be different from leucine-isoleucine transaminase, only one enzyme system (branched-chain a{alpha}-ketoacid dehydrogenase) is involved in the decarboxylation of their three ketoacid derivatives. The intermediate metabolites are all organic acids, and deficiency of any of the degradative enzymes, except for the transaminases, causes acidosis; in such instances, the organic acids before the enzymatic block accumulate in body fluids and are excreted in the urine. These disorders cause severe metabolic acidosis, which usually occurs during the first few days of life. Although most of the clinical findings are nonspecific, some manifestations may provide important clues to the nature of the enzyme deficiency. Definitive diagnosis is usually established by identifying and measuring specific organic acids in body fluids, especially urine, and by the enzyme assay.
MAPLE SYRUP URINE DISEASE (MSUD). Decarboxylation of leucine, isoleucine, and valine is accomplished by a complex enzyme system (branched-chain a{alpha}-ketoacid dehydrogenase) using thiamine pyrophosphate as a coenzyme.
Classic MSUD. This form has the most severe clinical manifestations. Affected infants who are normal at birth develop poor feeding and vomiting during the 1st wk of life; lethargy and coma ensue within a few days. Physical examination reveals hypertonicity and muscular rigidity with severe opisthotonos. Periods of hypertonicity may alternate with bouts of flaccidity. Neurologic findings are often mistaken for generalized sepsis and meningitis. Convulsions occur in most infants, and hypoglycemia is common. However, in contrast to most hypoglycemic states, correcting the blood glucose concentration does not improve the clinical condition. Routine laboratory studies are usually unremarkable, except for severe metabolic acidosis. Death usually occurs in untreated patients within the first few weeks or months of life.
Diagnosis is often suspected because of the peculiar odor of maple syrup found in urine, sweat, and cerumen. It is usually confirmed by amino acid analysis showing marked elevations in plasma levels of leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not normally found in blood) and depression of alanine. Leucine levels are usually higher than those of the other three amino acids. Urine contains high levels of leucine, isoleucine, and valine and their respective ketoacids. These ketoacids may be detected qualitatively by adding a few drops of 2,4-dinitrophenylhydrazine reagent (0.1% in 0.1 N HCl) to the urine; a yellow precipitate of 2-4 diphenylhydrazone is formed in a positive test.
Treatment of the acute state is aimed at quick removal of the branched-chain amino acids and their metabolites from the tissues and body fluids. Because renal clearance of these compounds is poor, hydration alone does not produce a rapid improvement. Peritoneal dialysis is the most effective mode of therapy and should be promptly instituted; significant decreases in plasma levels of leucine, isoleucine, and valine are usually seen within 24 hr of institution of treatment. Attempts should also be made to stop the patient’s catabolic state by providing sufficient calories intravenously or orally.
Treatment after recovery from the acute state requires a low branched-chain amino acid diet. Synthetic formulas devoid of leucine, isoleucine, and valine are now commercially available.* Because these amino acids cannot be synthesized endogenously, small amounts of them should be added to the diet; the amount should be titrated carefully by performing frequent analyses of the plasma amino acids. A clinical condition resembling acrodermatitis enteropathica occurs in affected infants whose plasma isoleucine concentration becomes very low; addition of isoleucine to the diet causes a rapid and complete recovery. Patients with MSUD should remain on the diet for the rest of their lives.
The long-term prognosis of affected children remains guarded. Severe ketoacidosis, cerebral edema, and death may occur during any stressful situation such as infection or surgery. Mental and neurologic deficits are common sequelae.
Intermittent MSUD. In this form of MSUD seemingly normal children develop vomiting, odor of maple syrup, ataxia, lethargy, and coma during stress such as infection or surgery. During these attacks, laboratory findings are indistinguishable from those of the classic form, and death may occur. Treatment of the intermittent variety is similar to that of the classic form. After recovery, although a normal diet is tolerated, a diet low in branched-chain amino acids is recommended. The activity of dehydrogenase in patients with the intermittent form is higher than that in the classic form and may reach 8–16% of the normal activity.
Mild (Intermediate) MSUD. In this form affected children develop milder disease after the neonatal period. They are usually mildly to moderately retarded; have increased plasma levels of leucine, isoleucine, and valine; and excrete ketoacid derivatives of these amino acids in their urine. They usually have the odor of maple syrup. These children are commonly diagnosed during an intercurrent illness when signs and symptoms of classic MSUD occur. The dehydrogenase activity is 2–8% of normal. Since patients with thiamine-responsive MSUD usually have manifestations similar to those seen in the mild form, a trial of thiamine therapy is recommended.
ISOVALERIC ACIDEMIA. This rare condition is due to the deficiency of isovaleryl CoA dehydrogenase, which catalyzes the conversion of isovaleric acid to 3-methylcrotonic acid in the leucine degradative pathway. Isovaleric acidemia is inherited as an autosomal recessive trait. The gene has been mapped to the long arm of chromosome 15. The gene frequency in the general population is not known.
Clinical manifestations in the acute form include vomiting and severe acidosis in the first few days of life. Lethargy, convulsions, and coma ensue, and death may occur if proper therapy is not initiated. The vomiting may be severe enough to suggest pyloric stenosis. The characteristic odor of “sweaty feet” may be present. A milder form of the disease also exists in which the first clinical manifestation (vomiting, lethargy, acidosis, or coma) may not appear until the infant is a few months or a few years old (chronic intermittent form).
Laboratory findings reveal severe ketoacidosis, neutropenia, thrombocytopenia, and occasionally pancytopenia. Hypocalcemia and moderate to severe hyperammonemia may be present in some patients. Increases in plasma ammonia may suggest a defect in the urea cycle. However, in the latter conditions the infant is not acidotic. Hyperglycemia may be present in some patients.
Diagnosis is established by demonstrating marked elevations of isovaleric acid and its metabolites (isovalerylglycine, 3-hydroxyisovaleric acid) in body fluids, especially urine. Isovaleric acid is volatile and may disappear from the urine if the specimen is not handled properly; however, isovalerylglycine is a stable compound that is more reliable for diagnostic purposes. Measuring the enzyme in cultured skin fibroblasts confirms the diagnosis. Intrauterine diagnosis has been accomplished by measuring isovalerylglycine in amniotic fluid.
Treatment of the acute attack is aimed at hydration, correction of metabolic acidosis (by infusing sodium bicarbonate), and removal of the excess isovaleric acid. Because isovalerylglycine has a high urinary clearance, administration of glycine (250 mg/kg/24 hr) is recommended to enhance formation of isovalerylglycine. Carnitine (100 mg/kg/24 hr) also increases removal of isovaleric acid by forming isovalerylcarnitine, which is excreted in the urine. Adequate calories should be provided orally or intravenously to minimize the catabolic state. In patients with significant hyperammonemia (blood ammonia >
Glycine
Glycine is a nonessential amino acid synthesized mainly from serine and threonine. The main catabolic pathway requires the complex glycine cleavage enzyme system to cleave the first carbon of glycine and convert it to carbon dioxide. The second carbon is transferred to tetrahydrofolate (THF) to form hydroxymethyltetrahydrofolate, which may either react with another mole of glycine to form serine or form methyltetrahydrofolate, which serves as a methyl group donor for many reactions in the body. The glycine cleavage system, a mitochondrial multienzyme system, is composed of four proteins: P protein, H protein, T protein, and L protein. The T protein, also known as aminomethyltransferase, is mapped to the short arm of chromosome 3. More than 80% of patients with nonketotic hypoglycinemia have defects in P protein. Defects in T protein account for nearly the rest of the reported cases.
HYPERGLYCINEMIA. Elevated levels of glycine in body fluids occur in patients having a number of inborn errors of metabolism, including propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and b{beta}-ketothiolase deficiency. These disorders have been collectively referred to as ketotic hyperglycinemia because episodes of severe acidosis and ketosis occur. The pathogenesis of hyperglycinemia in these disorders is not fully understood, but inhibition of the glycine cleavage enzyme system by the various organic acids has been shown to occur in some of the affected patients. The term nonketotic hyperglycinemia is reserved for the clinical condition caused by the genetic deficiency of the glycine cleavage enzyme system. In this condition hyperglycinemia is present without ketosis.
Nonketotic Hyperglycinemia. The majority of patients with this disorder become ill during the first few days of life. The clinical manifestations of poor feeding, failure to suck, and lethargy may progress rapidly to a deep coma, apnea, and death. Convulsions, especially myoclonic seizures, and hiccups are common. This disorder is usually fatal; current therapeutic measures may produce only transient improvement. The rare infant who survives this state will have severe mental retardation, repeated myoclonic seizures, and microcephaly. Milder forms of the condition have also been reported; mental retardation, convulsions, and spasticity are frequent findings in these patients. Heterogeneity in clinical severity of the disease has also been observed within a given family.
Laboratory findings reveal moderate to severe hyperglycinemia and hyperglycinuria, and an increased glycine concentration in the spinal fluid. The high ratio of glycine concentration in the spinal fluid to that in blood has been used to differentiate nonketotic hyperglycinemia from other hyperglycinemic states. Plasma serine levels are usually low. Serum pH is usually normal. Organic acidemias that cause hyperglycinemia (propionic and methylmalonic acidemias) should be ruled out by proper urinary assays. Diagnosis of nonketotic hyperglycinemia may be suggested in infants who are receiving the anticonvulsant drug valproic acid because this medication is known to cause moderate increases in blood and urinary glycine concentrations. Repeat assays after removal of the drug should establish the diagnosis. The rare condition D-glyceric acidemia, which may cause hyperglycinemia, should also be ruled out (see later).
No effective treatment is known. Exchange transfusion, dietary restriction of glycine, and administration of sodium benzoate or folate have not altered the neurologic outcome. Drugs that counteract the effect of glycine on the neuronal cells, such as strychnine and diazepam, have been used; beneficial effects have been observed in some patients with the mild form of the condition.
Nonketotic hyperglycinemia appears to be inherited as an autosomal recessive trait and is more common in
Urea Cycle and Hyperammonemia
Catabolism of amino acids results in the production of free ammonia, which is highly toxic to the central nervous system. Ammonia is detoxified to urea through a series of reactions known as the Krebs-Henseleit or urea cycle. Five enzymes are required for the synthesis of urea: carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinate lyase (
GENETIC CAUSES OF HYPERAMMONEMIA. In addition to genetic defects of the urea cycle enzymes, a marked increase in plasma level of ammonia is also observed in other inborn errors of metabolism. In this section only defects of urea cycle enzymes and transient hyperammonemia of the newborn are discussed.
CLINICAL MANIFESTATIONS OF HYPERAMMONEMIA. In the neonatal period, symptoms and signs are mostly related to brain dysfunction and are similar regardless of the cause of the hyperammonemia. In general, the affected infant is normal at birth but becomes symptomatic after a few days of protein feeding. Refusal to eat, vomiting, tachypnea, and lethargy quickly progress to a deep coma. Convulsions are common. Physical examination may reveal hepatomegaly in addition to the neurologic signs of deep coma. In infants and older children, acute hyperammonemia is manifested by vomiting and neurologic abnormalities such as ataxia, mental confusion, agitation, irritability, and combativeness. These manifestations may alternate with periods of lethargy and somnolence that may progress to coma.
Routine laboratory studies show no specific findings when hyperammonemia is due to defects of the urea cycle enzymes. Blood urea nitrogen is usually very low. In infants with organic acidemias, hyperammonemia is commonly associated with severe acidosis. Newborn infants with hyperammonemia are often misdiagnosed as having a generalized infection, and they may succumb to the disease without a correct diagnosis. Autopsy is usually unremarkable. It is therefore imperative to measure plasma ammonia levels in any ill infant whose clinical manifestations cannot be explained by an obvious infection.
DIAGNOSIS. The main criterion for diagnosis is hyperammonemia. The plasma ammonia concentration in the ill infant is usually above
TREATMENT OF ACUTE HYPERAMMONEMIA. Acute hyperammonemia should be treated promptly and vigorously. The goal of therapy is to remove ammonia from the body and provide adequate calories and essential amino acids to halt further breakdown of endogenous proteins. Adequate calories, fluid, and electrolytes should be provided intravenously. Lipids for intravenous use (1 g/kg/24 hr) provide an effective source of calories. Minimal amounts of protein (0.25 g/kg/24 hr), preferably in the form of essential amino acids, should be added to the intravenous fluid to prevent a catabolic state. To supply these essential amino acids without increasing the nitrogen load, ketoacid analogs of essential amino acids have been used by some, but the beneficial effects of these compounds have not been proved clinically. Oral feeding with a low-protein formula (0.5{endash}–1.0 g/kg/24 hr) through a nasogastric tube should be started as soon as sufficient improvement in the clinical condition permits it.
Because ammonia is poorly cleared by the kidneys, its removal from the body must be expedited by formation of compounds with a high renal clearance. Sodium benzoate forms hippuric acid with endogenous glycine; hippurate is cleared from the kidney at 5 times the glomerular filtration rate. Each mole of benzoate removes 1 mole of ammonia as glycine. Phenylacetate conjugates with glutamine to form phenylacetylglutamine, which is readily excreted in the urine. One mole of phenylacetate removes 2 moles of ammonia as glutamine from the body.
Arginine administration is effective in the treatment of hyperammonemia that is due to defects of the urea cycle (except in patients with arginase deficiency) because it supplies the urea cycle with ornithine and N-acetylglutamate. In patients with citrullinemia, 1 mole of arginine reacts with 1 mole of ammonia (as carbamylphosphate) to form citrulline. In patients with argininosuccinic acidemia, 2 moles of ammonia (as carbamylphosphate and aspartate) form argininosuccinic acid with arginine through the urea cycle. Citrulline and argininosuccinic acid are far less toxic and more readily excreted by the kidneys than ammonia. In patients with CPS or ornithine transcarbamylase (OTC) deficiency, arginine administration is indicated because arginine becomes an essential amino acid in these disorders. Patients with OTC deficiency benefit from citrulline supplementation (200 mg/kg/24 hr) because 1 mole of citrulline can accept 1 mole of ammonia (as aspartic acid) to form arginine. In patients whose hyperammonemia is secondary to organic acidemias, treatment with arginine is not indicated because no beneficial effect from such therapy can be expected. However, in a newborn infant with a first attack of hyperammonemia, arginine should be used until the diagnosis is established.
Benzoate, phenylacetate, and arginine may be administered together for maximal therapeutic effect. A priming dose of these compounds is followed by continuous infusion until recovery from the acute state occurs. It should be noted that both benzoate and phenylacetate are supplied as concentrated solutions and should be properly diluted (1–2% solution) for intravenous use. The recommended therapeutic doses of both compounds deliver a substantial amount of sodium to the patient that should be calculated as part of the daily sodium requirement. Benzoate and phenylacetate should be used with caution iewborn infants with hyperbilirubinemia because they may potentiate the risk of hyperbilirubinemia by displacing bilirubin from albumin. In infants at risk, it is advisable to reduce bilirubin to a safe level by exchange transfusion before administering benzoate or phenylacetate.
If the foregoing therapies fail to produce any appreciable change in the blood ammonia level within a few hours, hemodialysis or peritoneal dialysis should be used. Exchange transfusion has little effect on reducing total body ammonia. It should be used only if dialysis cannot be employed promptly or when the patient is a newborn infant with hyperbilirubinemia (see earlier). Hemodialysis, although the most effective measure for removal of ammonia, is technically difficult to perform and may not be readily available in all centers. Peritoneal dialysis, therefore, is the most practical and expeditious method for treatment of patients with severe hyperammonemia; there is usually a dramatic decrease in the plasma ammonia level within a few hours of dialysis, and in most patients the plasma ammonia returns to normal within 48 hr of initiation of peritoneal dialysis. In a patient whose hyperammonemia is due to an organic acidemia, peritoneal dialysis effectively removes both the offending organic acid and ammonia from the body.
To curtail the possible production of ammonia by intestinal bacteria, oral administration of neomycin and lactulose through a nasogastric tube should be initiated very early in the course of therapy. There may be considerable lag between the normalization of ammonia and an improvement in the neurologic status of the patient. Several days may be needed before the infant becomes fully alert.
ARGINASE DEFICIENCY (Hyperargininemia). This defect is inherited as an autosomal recessive trait. There are two genetically distinct arginases in humans. One is cystosolic and is expressed in liver and erythrocytes, and the other is found in the renal mitochondria. The cytosolic enzyme, which is the one deficient in patients with arginase deficiency, is mapped to the long arm of chromosome 6.
The clinical manifestations of this rare condition are quite different from those of other urea cycle enzyme defects. The onset is insidious; the infant usually remains asymptomatic in the first few months or sometimes years of life. A progressive spastic diplegia with scissoring of the lower extremities, choreoathetotic movements, and loss of developmental milestones in a previously normal infant may suggest a degenerative disease of the central nervous system. Two children were followed for several years with the diagnosis of cerebral palsy before the diagnosis of arginase deficiency was confirmed. Mental retardation is progressive; seizures are common, and episodes of severe hyperammonemia are not usually seen in this disorder. Hepatomegaly may be present.
Laboratory findings reveal marked elevation of arginine in plasma and cerebrospinal fluid. Urinary orotic acid is moderately increased. Plasma ammonia levels may be normal or mildly elevated. Urinary excretion of arginine, lysine, cystine, and ornithine is usually increased, which may suggest a diagnosis of cystinuria. However, urinary excretion of these amino acids may be normal. Therefore, determination of amino acids in plasma is a critical step before the diagnosis of argininemia can be ruled out. The guanidino compounds (a{alpha}-keto-guanidinovaleric acid, argininic acid) are markedly increased in urine. The diagnosis is confirmed by assaying arginase activity in erythrocytes. Prenatal diagnosis has not yet been achieved.
Treatment consists of a low-protein diet devoid of arginine. Administration of a synthetic protein made of essential amino acids usually results in a dramatic decrease in plasma arginine concentration and an improvement ieurologic abnormalities. The composition of the diet and the daily intake of protein should be monitored by frequent plasma amino acid determinations. Sodium benzoate (250{endash}–375 mg/kg/24 hr) is also effective in controlling hyperammonemia. One patient developed type I diabetes at age 9 yr while his argininemia was under good control.
HISTIDINEMIA. This disorder is due to a deficiency of histidase, which normally converts histidine to urocanic acid. The disorder is inherited as an autosomal recessive trait; its overall prevalence is estimated at
Clinical manifestations include impaired speech, growth retardation, or mental retardation. However, the relationship of these findings to histidinemia remains unclear; routine amino acid screening has uncovered a significant number of asymptomatic subjects with histidinemia.
Laboratory studies reveal marked increases in plasma and cerebrospinal fluid concentrations of histidine. There is also an unexplained elevation in the blood level of alanine. Urine contains large amounts of histidine and its transaminated product imidazolepyruvate. The latter compound, like phenylpyruvate, reacts with ferric chloride to produce an intense blue-green color. The diagnosis of histidinemia may be confirmed by assay of histidase in liver or skin. Prenatal diagnosis has not yet been achieved because histidase is not present in amniotic cells.
Treatment with a diet low in histidine has produced excellent biochemical control. However, no clinical improvement in symptomatic patients has been observed. Unlike phenylketonuria, maternal histidinemia does not cause any ill effect in the offspring.
Aspartic Acid (Canavan Disease)
N-Acetylaspartic acid is a derivative of aspartic acid that is synthesized in the brain and is found in a high concentration, similar to that of glutamic acid. Its function is unknown, but excessive amounts of N-acetylaspartic acid in urine and a deficiency of the enzyme aspartoacylase that cleaves the N-acetyl group from N-acetylaspartic acid are associated with Canavan disease.
CANAVAN DISEASE. Canavan disease is an autosomal recessive disorder characterized by spongy degeneration of the white matter of the brain, leading to a severe form of leukodystrophy. It is more prevalent in individuals of Ashkenazi Jewish descent than in other ethnic groups.
Etiology and Pathology. The basic defect is a deficiency of the enzyme aspartoacylase, which leads to the accumulation of N-acetylaspartic acid in brain, especially in white matter, and massive urinary excretion of this compound. Excessive amounts of N-acetylaspartic acid are also present in the blood and cerebrospinal fluid. There is striking vacuolization and astrocytic swelling in white matter. Electron microscopy reveals distorted mitochondria. As the disease progresses, the ventricles tend to enlarge, leading to brain atrophy.
Clinical Manifestations. The severity of Canavan disease comprises a wide spectrum of manifestations. In general, infants appear normal at birth and may not manifest symptoms of the disease until 3–6 mo of age, when they develop progressive macrocephaly, severe hypotonia, and persistent head lag. As the infant grows older, delayed milestones become evident. These children are usually hyper-reflexic and hypotonic, although joint stiffness may be encountered because of disuse. Seizures and optic atrophy develop as they grow older. Feeding difficulties, poor weight gain, and gastroesophageal reflux may occur in the 1st yr of life; swallowing deteriorates during the 2nd and 3rd yr of life, and nasogastric feeding or permanent gastrostomy may be required. Most patients die in the 1st decade of life; however, with improved nursing care they may survive through the second decade.
Diagnosis. Computed tomography (CT) scans and magnetic resonance imaging (MRI) suggest diffuse white matter degeneration, primarily in the cerebral hemispheres with less involvement in the cerebellum and brain stem. Repeated evaluations may be required. The differential diagnosis of Canavan disease should include Alexander disease, which is another leukodystrophy with macrocephaly. Progression is usually slow in Alexander disease, and hypotonia is not as pronounced as it is in Canavan disease. Brain biopsy shows spongy degeneration of the myelin fibers, astrocytic swelling, and elongated mitochondria. Definite diagnosis can be established by finding elevated amounts of N-acetylaspartic acid in the urine and a deficiency of aspartoacylase in cultured skin fibroblasts. The biochemical and enzyme diagnosis is the method of choice for diagnosis; brain biopsy is no longer required. Levels of N-acetylaspartic acid iormal urine are only trace amounts (less than 25 mmol/mmol creatinine), whereas in patients with Canavan disease they are in the range of 3,000 ± 1,800 mmol/mmol creatinine. High levels of N-acetylaspartic acid in plasma, cerebrospinal fluid (CSF), and brain tissue can also be detected. The activity of aspartoacylase in the fibroblasts of obligate carriers is about half or less of the activity found iormal individuals.
The gene for aspartoacylase has been cloned and mutations leading to Canavan disease have been identified. There are two mutations predominant in the Ashkenazi Jewish population. The first is an amino acid substitution (E285A) in which glutamic acid is substituted to alanine. This mutation is the most frequent and encompasses 83% of 100 mutant alleles examined in Ashkenazi Jewish patients. The second common mutation is a change from tyrosine to a nonsense mutation, leading to a stop in the coding sequence (Y231X). This mutation accounts for 13% of the 100 mutant alleles. In the non-Jewish population more diverse mutations have been observed and the two mutations common in Jewish people are rare. A different mutation (A305E), substitution of alanine for glutamic acid, accounts for 40% of 62 mutant alleles ion-Jewish patients. When the diagnosis of Canavan disease is reached, it is important to obtain a molecular diagnosis because this will lead to accurate counseling and prenatal diagnosis for the family. If the mutations are not known, prenatal diagnosis relies on the level of N-acetylaspartic acid in the amniotic fluid. In Ashkenazi Jewish patients the carrier frequency may be as high as
Treatment and Prevention. No specific treatment is available. Feeding problems and seizures should be treated on an individual basis. Genetic counseling, carrier testing, and prenatal diagnosis are the only methods of prevention.
DEFECTS IN METABOLISM OF LIPIDS
Lipid Storage Disorders (Lipidoses)
The lipidoses are lysosomal lipid storage diseases, each caused by deficiency of a specific hydrolase. The lipid material stored within the lysosomes, usually a glycosphingolipid, leads to the pathophysiology characteristic of the specific lipid storage disease. For example, if the sphingolipid is stored only in the peripheral tissues, sparing the central nervous system (CNS), then hepatosplenomegaly may be noted and the disease suspected, as in Gaucher disease. On the other hand, if the glycosphingolipid is stored in the CNS only and not in peripheral tissues, there is no hepatosplenomegaly, and the storage disease may not be suspected, as in Tay-Sachs disease. When the CNS is involved, mental retardation and neurologic deterioration are major components of the storage disease. In lipidoses in which storage material accumulates in the periphery and in the CNS, mental retardation together with hepatosplenomegaly is characteristic of the disease, as in Niemann-Pick disease.
The sphingolipids, which are components of the cell membrane, are found in every cell of the body. The structure of sphingosine is achieved by the condensation of the amino acid serine with palmitic acid. This compound combines the C18 nonpolar region of palmitate and the polar region of serine, which contains an amino group and two hydroxyl groups. Another fatty acid is added to sphingosine through the amino group of serine, forming ceramide. The first hydroxyl group (C1) of ceramide can become a recipient to sugars, for example, ceramide-glucose, which is also called glucocerebroside. Ceramide-galactose is another ceramide-monohexoside, also known as galactocerebroside. Phosphocholine may substitute for the sugars, forming sphingomyelin. More than one sugar can be added to ceramide, and branches of sialic acid (neuraminic acid [NANA]) may be added, resulting in a rather complex compound. Wheeuraminic acid is added to the sphingolipid, the resulting compound is called a ganglioside. Despite their complexity, such membrane-associated compounds have similar building blocks and must be degraded or recycled by lysosomal enzymes. A defect in any step results in a lysosmal storage disease. The storage of a specific compound in a specific tissue depends on the distribution of that compound in the body.
GM1 GANGLIOSIDOSIS. This is a group of lysosomal disorders with variable clinical findings. GM1 ganglioside is a monosialoganglioside found iormal cerebral gray and white matter and in peripheral tissues. There are two major forms of GM1 gangliosidosis, infantile (type 1) and juvenile (type 2). There is also an adult form, type 3.
Etiology. The biochemical defect of both forms of GM1 gangliosidosis is a deficiency of the lysosomal enzyme b{beta}-galactosidase, which hydrolyzes the terminal galactose from GM1 ganglioside. The diagnosis is confirmed by demonstrating deficiency of b{beta}-galactosidase in white blood cells or cultured skin fibroblasts.
Clinical Manifestations. The infantile form of GM1 gangliosidosis may be noted at birth by the presence of hepatosplenomegaly, edema of the extremities, and rashes that cannot be explained by the usual newborn skin eruptions. Psychomotor retardation soon becomes evident. A cherry-red spot in the macula is present in 50% of the patients. Umbilical and inguinal hernias with edema of the scrotum are usually present at birth. Because of the coarse facial features and macroglossia these children may be suspected of having Hurler disease. Enlargement of the heart and signs of ventricular hypertrophy occur in most patients with GM1 gangliosidosis. Lumbar kyphosis and some stiffening of the joints are also characteristic of GM1 gangliosidosis as well as of Hurler disease. However, rapid mental deterioration, macular cherry-red spot, and early onset of seizures are more characteristic of GM1 gangliosidosis. The patient becomes dysphagic, deaf, and blind, and death occurs at 3–4 yr of age.
Radiologic changes are those of dysostosis multiplex. Vertebral changes occur with anterior beaking, the sella turcica is large, and the calvarium may be thickened. Although these changes are similar to those seen in the mucopolysaccharidoses, they are less severe. CT scans and MRI of the brain show ventricular dilatation and generalized brain atrophy.
Late-onset GM1 gangliosidosis is clinically distinct. The age of onset varies, and such patients may present with ataxia, dysarthria, and cerebral palsy–like spasticity. Deterioration is slow, and patients may survive through the 4th decade of life. These patients lack visceral involvement, do not have coarse facial features, and do not have dysostosis multiplex.
Biochemical and Pathologic Findings. There are foam cells in bone marrow aspirates and in histologic preparations of tissues such as the lungs and liver. GM1 ganglioside accumulates in the brain and peripheral tissues. In addition, keratan sulfate, a mucopolysaccharide, accumulates in liver and is excreted in the urine of patients with GM1 gangliosidosis.
Diagnosis. GM1 gangliosidosis is suspected clinically by developmental delay, coarse facial features, enlarged tongue, hepatosplenomegaly, and a cherry-red spot of the macula. Hurler disease, I-cell disease, and Niemann-Pick disease should be considered. Radiologic evaluation should rule out Niemann-Pick disease because it is the only one of these conditions that does not show dysostosis multiplex. Urinary mucopolysaccharides that include excessive keratan sulfate are characteristic of GM1 gangliosidosis. The diagnosis is confirmed by enzymatic assay of white blood cells or cultured skin fibroblasts showing a deficiency of b{beta}-galactosidase. Prenatal diagnosis can be accomplished by assaying amniocytes or chorionic villi for b{beta}-galactosidase.
Genetics and Treatment. GM1 gangliosidosis is inherited as an autosomal recessive trait. Carriers can be detected using white blood cells or cultured skin fibroblasts to assay for b{beta}-galactosidase. The gene for GM1 gangliosidosis has been isolated and localized to the short arm of chromosome 3 (3p21.33). Several mutations have been identified for the severe and the late-onset variants of GM1 gangliosidosis. The more severe mutations lead to more profound loss of b{beta}-galactosidase activity. There is no specific treatment for either form of GM1 gangliosidosis other than symptomatic care.
TAY-SACHS (GM2 GANGLIOSIDOSIS I). Because this lysosomal storage disease primarily involves the central nervous system, no evidence of peripheral storage is evident on physical examination. Tay-Sachs disease is the most devastating of the lipid storage diseases and occurs frequently among individuals of Ashkenazi Jewish descent.
Etiology. The basic defect is a deficiency of the heat-labile lysosomal enzyme b{beta}-hexosaminidase A; two isoenzymes, A and B, are responsible for the total activity. Two polypeptide chains, a{alpha} and b{beta}, are required for the formation of b{beta}-hexosaminidase A and B. Isoenzyme A is formed with a{alpha} and b{beta} chains, whereas isoenzyme B is composed of b{beta} chains only. Therefore, a defect in the a{alpha} chain results in deficient activity in b{beta}-hexosaminidase A, as occurs in both forms of Tay-Sachs disease. Several mutations at the gene locus affecting the production of the a{alpha} chain of b{beta}-hexosaminidase have been identified. A defect in the b{beta} chain affects the activity of both isoenzymes A and B, thus causing a deficiency of the total activity of b{beta}-hexosaminidase (see later discussion of Sandhoff Disease). The enzyme b{beta}-hexosaminidase A requires for its hydrolytic activity an activator that binds to the enzyme and to the natural substrate GM2 ganglioside. Very rarely, patients with Tay-Sachs disease may have normal activity of b{beta}-hexosaminidase A when it is assayed in a test tube. In such cases the disease is caused by activator deficiency, and an assay for the activator should be performed.
Clinical Manifestations. Infants develop normally until about 5 mo of age. Usually decreased eye contact and focusing are noted first, along with an exaggerated startle response to noise, hyperacusis. By the end of the 1st yr an infant with Tay-Sachs disease becomes severely hypotonic. Physical examination is often characterized by severe hypotonia, blindness, and hyperacusis. Funduscopic examination of the eye may reveal a cherry-red spot of the macula. Such infants assume a froglike position and interact very little with their surroundings. The head size may enlarge more than 50%, but this enlargement is not associated with hydrocephalus. Seizures may complicate the disease in the 2nd yr of life, and death usually occurs between the 2nd and 4th yr of age.
Late-onset or juvenile Tay-Sachs disease (GM2 gangliosidosis III) is a variant of Tay-Sachs disease. Onset may occur as early as 2nd yr of life but can also occur in the 2nd or 3rd (adult GM2 gangliosidosis) decade of life. Mental retardation is not associated in the early phase of this condition, and the major manifestations are those of ataxia, choreoathetosis, and dysarthria. Blindness and spasticity may occur prior to death. Juvenile Tay-Sachs disease is not associated with cherry-red spot of the macula, and there is no organomegaly. Tay-Sachs disease is not associated with bony changes. CT scan and MRI of the brain reveal enlarged ventricles and brain atrophy with gray matter degeneration.
Diagnosis. Tay-Sachs disease is usually suspected in a severely retarded infant with a cherry-red spot of the macula and lack of visceral storage. Several sphingolipidoses are associated with cherry-red spot, but only patients with Tay-Sachs disease lack hepatosplenomegaly. The juvenile form of Tay-Sachs disease should be suspected in a child whose ataxia and dysarthria become progressive. The assay for b{beta}-hexosaminidase A is diagnostic and can be carried out on plasma, cultured skin fibroblasts, or white blood cells. Carriers for Tay-Sachs disease and juvenile Tay-Sachs disease can be detected by performing an assay for the specific activity of hexosaminidase A.
Genetics and Prevention. There is considerable heterogeneity at the gene level, and the major group of mutations responsible for Tay-Sachs disease in the Jewish population is different from that ion-Jewish people. The mutation for the infantile form of Tay-Sachs disease is different from that for the juvenile form. The gene for hexosaminidase A (Hex A) has been isolated. The most frequent DNA defect in Ashkenazi Jewish people is a four base pair insertion in exon 11. This change results in termination signal and deficiency of mRNA. Another mutation common among Ashkenazi Jews has been located at the first nucleotide of intron 12, where there is a G to C substitution. This mutation also results in loss of activity of Hex A. Other ethnic groups carry a variety of different mutations. The gene for Hex A has been localized to chromosome 15 (15q23–q24).
Both forms of Tay-Sachs disease are inherited as autosomal recessive traits, and both are more frequent among Ashkenazi Jews. The frequency of Tay-Sachs disease is
Treatment. There is no treatment for either form of Tay-Sachs disease.
SANDHOFF DISEASE (GM2 Gangliosidosis II). This autosomal recessive disease is associated with total b{beta}-hexosaminidase deficiency because both A and B isoenzymes are deficient. Clinical manifestations vary but usually mimic those of Tay-Sachs disease in its infantile form. However, Sandhoff disease is associated with hepatosplenomegaly, indicating peripheral storage of GM2 ganglioside, an N-acetylglucosamine containing oligosaccharide. Foam cells are found in bone marrow aspirates. The cherry-red spot of the macula is also seen in Sandhoff disease. A juvenile form of Sandhoff disease presents in the latter half of the 1st decade of life with ataxia, dysarthria, and mental deterioration. No visceral enlargement or macular cherry-red spot is associated with this form of the disease. There is no preponderance of Sandhoff disease among Ashkenazi Jews.
The basic defect is an abnormal b{beta} chain in b{beta}-hexosaminidase that affects both the A and B isoenzymes. Diagnosis of Sandhoff disease is achieved by demonstrating a total deficiency of b{beta}-hexosaminidase on assay of plasma white blood cells or cultured fibroblasts.
Genetics. The b{beta} chain for b{beta} hexosaminidase (Hex B) gene has been localized to chromosome 5 (5q11). Several mutations have been identified that can be correlated with the clinical severity of the disease.
NIEMANN-PICK DISEASE
Type A. This is an autosomal recessive disorder of sphingomyelin and cholesterol storage within the lysosomes. Niemann-Pick disease is found more frequently among Jewish individuals of Ashkenazi descent.
Etiology. There are increased levels of sphingomyelin and cholesterol in bone marrow cells, liver, spleen, and brain. The enzyme defect is sphingomyelinase deficiency. Failure to cleave phosphocholine from sphingomyelin results in the storage of sphingomyelin. Storage of cholesterol is not well understood, but there seems to be a close relationship between the metabolism of sphingomyelin and that of cholesterol.
Clinical Manifestations. These begin at 3–4 mo of age with feeding difficulties and failure to thrive. Neurologic deterioration may not be overt because these children are able to sit, stand, and learn other skills, although their development is globally delayed. Physical examination is characterized by hepatosplenomegaly. The liver may be enlarged earlier than the spleen. Bone marrow aspirates show characteristic foam cells containing sphingomyelin and cholesterol. As the disease progresses, children with Niemann-Pick disease begin to look more severely malnourished and have protruding abdomens. Mental retardation becomes more pronounced as new skills are not achieved and existing skills regress. Muscle strength diminishes, and the children become hypotonic. Hearing and vision deteriorate, and blindness occurs in the advanced stages of the disease. Hypoacusis is present. A cherry-red spot on the macula is seen in 50% of cases. Death occurs before the 4th yr of life.
Major bony abnormalities are not associated with Niemann-Pick disease, although some widening of the medullary cavity and thinning of the cortex are observed. CT scan and MRI of the brain show gray matter degeneration, demyelination, and cerebellar atrophy.
Late-onset variants of Niemann-Pick disease are associated with dystonic movements, athetosis, and seizures. Hepatosplenomegaly and sphingomyelinase deficiency are diagnostic.
Diagnosis. Hepatosplenomegaly, mental retardation, foam cells in bone marrow or peripheral blood smears, and a cherry-red spot suggest the diagnosis. Sphingomyelinase deficiency in white blood cells, cultured skin fibroblasts, or other tissues is diagnostic. Carrier detection and prenatal diagnosis are available using a sphingomyelinase assay.
Genetics. The gene for sphingomyelinase has been localized to the short arm of chromosome 11 (11p15) and several mutations have been identified that cause sphingomyelinase deficiency.
Treatment. There is no therapy.
Niemann-Pick Disease (Type B). This is a benign form of sphingomyelinase deficiency that is associated with hepatosplenomegaly and the presence of foam cells in the bone marrow but minor or no neurologic involvement. This disease has an autosomal recessive mode of inheritance but is not associated with any particular ethnic group. It is compatible with a normal life span.
Niemann-Pick Disease (Types C and D). These two autosomal recessive disorders are the same disease with different severity. They are not caused by sphingomyelinase deficiency, although the enzyme activity may be reduced. Hepatosplenomegaly exists and foam cells are present in the bone marrow. There are several forms of Niemann-Pick type C. The neonatal form of the disease can be associated with jaundice and hepatosplenomegaly. More commonly type C is associated with normal development until the age of 2–3 yr, when extrapyramidal symptoms develop, with vertical gaze disturbance. Type D is similar to type C but is found more frequently in
The diagnosis of Niemann Pick type C should be suggested by the triad of gaze paresis, hepatosplenomegaly, and foam cells in the bone marrow. The diagnosis should be confirmed by increased cholesterol in cultured fibroblasts and decreased cholesterol ester synthesis when fibroblasts are incubated with low density lipoprotein (LDL).
GAUCHER DISEASE
In this disorder glucosylceramide (glucocerebroside) is stored in the reticuloendothelial system. The classic form of Gaucher disease, sometimes referred to as the chronic or adult form, is common among Ashkenazi Jews and does not involve the central nervous system. There is an infantile form that is neuropathic and also a juvenile form that is associated with late-onset neurologic deterioration.
Etiology. The enzyme defect is deficiency of beta-glucosidase. Enzyme determination can be performed on white blood cells or cultured skin fibroblasts.
Clinical Manifestations. The chronic form of Gaucher disease is characterized by reticuloendothelial system involvement resulting in splenomegaly. Splenomegaly is usually the first clinical sign of Gaucher disease, but symptoms of hypersplenism and bone marrow failure may occur as early as birth and as late as 80 yr of age. Splenomegaly can be striking, and the spleen may occupy a major portion of the abdomen. In the Ashkenazi Jewish population Gaucher disease may not be identified until the 2nd or 3rd decade of life. The storage of glucocerebroside in the spleen and bone marrow leads to anemia, leukopenia, and thrombocytopenia. In rare cases, thrombocytopenia leads to bleeding. Involvement of the liver is minimal, although moderate hepatomegaly may be encountered. Bone marrow aspirates and cells from the spleen show the characteristic Gaucher cells engorged with glucocerebroside. Radiologic changes include the Erlenmeyer flask shape of the long bones, especially the distal femora.
Diagnosis. Splenomegaly with mild anemia that is unexplained should lead to suspicion of Gaucher disease. Bone marrow aspirates showing Gaucher cells strengthen the suspicion. Gaucher disease is confirmed by the demonstration of a deficiency of b{beta}-glucosidase.
Genetics. Gaucher disease is inherited as an autosomal recessive disease. It is very common among Ashkenazi Jews, with a frequency as high as
Treatment. Splenectomy, which used to be the treatment for Gaucher disease, is now rarely used. Enzyme replacement therapy is the treatment of choice. Glucocerebrosidase isolated from human placenta (Ceredase) or genetically engineered enzyme (Cerezyme) are available. These enzymes are targeted for the lysosomes. The more commonly used therapy is 15–60 units of enzyme per kilogram per 4 wk. The dose is divided and given intravenously every 2 wk. This treatment reduces the size of the spleen dramatically, improves the blood count, and reverses bony changes. Another regimen uses much less enzyme, 1–3 units per kilogram per 4 wk. The dose is divided and given three times weekly. Allergic reactions may occur and patients should be monitored; these are usually not serious.
Ceredase or Cerezyme has not been successful in treating infantile or juvenile Gaucher disease.
Infantile Gaucher Disease. This form of the disease involves the central nervous system. The disease may present with splenomegaly, strabismus, trismus, and dorsiflexion of the head. Seizures are common, and such children usually die around 3{endash}–4 yr of age. The diagnosis is made by demonstrating a deficiency of glucocerebrosidase in the tissues.
Juvenile Gaucher Disease. This form of disease has variable age of onset, with neurologic signs occurring in the 1st or 2nd decade of life. Neurologic symptoms include ataxia, peripheral neuropathy, myoclonus, ophthalmoplegia, and dementia. The diagnosis is made by documenting a deficiency of glucocerebrosidase (b{beta}-glucosidase). This autosomal recessive disorder is panethnic in distribution.
Defects in Intermediary Carbohydrate Metabolism
The intracellular conversion of glucose, fructose, and galactose proceeds as shown schematically in Figure 73–{endash}1 Figure 73–{endash}1. The demonstration of defective enzyme activity must serve as the basis of diagnosis and therapy in inborn errors of metabolism. However, an enzymatic defect affecting one tissue may not be demonstrable in another tissue for several reasons:
1. The defective enzyme may normally be absent as is glucose-6-phosphatase from muscle. Therefore, the deficiency of this enzyme in liver, kidney, and intestine of glycogen storage disease type I (GSD I) does not affect the skeletal muscle.
2. An enzymatic activity may reflect different enzyme proteins in different tissues. This is the case for glycogen synthetase, phosphorylase, or phosphorylase kinase. Thus, the deficiency of these enzymes in the livers of patients with GSD 0, GSD VI, or GSD IX does not affect their activity in skeletal muscle.
3. There may not have been the opportunity to measure a defective activity in more than one tissue of the patient. Galactokinase deficiency of erythrocytes is likely to affect the liver. However, galactokinase has not been assayed in hepatic tissue of a patient with the defect of this enzyme in erythrocytes.
4. An enzyme may not be effective in vivo, although the usual assay indicates in vitro activity. For example, GSD Ia has clinical and biochemical manifestations similar to those of GSD Ib. Glucose-6-phosphatase activity measured in frozen liver homogenates is deficient in GSD Ia but normal in GSD Ib. Hepatocytes of GSD Ib have a defect in the transport of glucose-6-phosphate to glucose-6-phosphatase across the microsomal membranes that normally separate substrate from enzyme in intact liver cells. In vivo, the result of the transport defect is similar to that of the actual defect of the enzyme. However, in homogenates of frozen liver tissue, normal intracellular topography is destroyed, and membrane barriers are broken down. Substrate added to GSD Ib homogenate can reach the enzyme, although the transport system is defective. Therefore, in GSD Ib, glucose-6-phosphatase is demonstrable in vitro but remains separated from its substrate in vivo.
5. An apparent enzymatic deficiency revealed by tissue analysis may be an artifact of suboptimal tissue handling. For example, liver phosphorylase activity is low or not demonstrable in autopsy liver, and it is altered nonpredictably in hepatic biopsy specimens unless they are frozen at once after removal from the body.
GALACTOSEMIA: DEFICIENCY OF GALACTOKINASE. This disorder is characterized by galactosemia, galactosuria, and cataracts without mental deficiency or aminoaciduria. Cataracts begin to form after birth when the diet contains galactose derived from the lactose in milk. By the time the diagnosis is made, elimination of dietary galactose may come too late to reverse cataract formation, although younger siblings of the patient may be helped and should be tested at birth.
Galactokinase catalyzes the initial phosphorylation of galactose. If its activity is deficient, the ingestion of galactose leads to increased concentration of galactose in blood and in urine, where it can be found as a reducing substance that is not glucose. Urine specimens tested for galactose should be collected following ingestion of a galactose-containing formula. If an affected infant is receiving a diet without galactose such as glucose water prior to the urine collection, galactose may be absent from the urine and the diagnosis will be missed.
Postnatal institution of a galactose-free diet should prevent cataract formation. Because the children are otherwise normal, the prognosis can be good.
Definitive diagnosis is made by showing that erythrocytes are deficient in galactokinase activity, but the defect is assumed to involve the liver. Some galactose is converted into galactitol, which may be responsible for the cataract formation. Erythrocytic galactokinase activity in affected patients is below the limits of measurement; heterozygous parents and siblings have intermediate activity values. Inheritance is autosomal recessive. The incidence of the condition is about
GALACTOSEMIA: DEFICIENCY OF GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE. “Classic” galactosemia is a serious disease with early onset of symptoms; the incidence is
The transferase gene codes for a 379 amino acid peptide. This missence mutation Q188R is one of nine polymorphisms and accounts for 70% of affected Caucasian patients. Severity may not correlate with the genotype in classical galactosemia but may relate to residual enzyme activity in variants (
The diagnosis of uridyl transferase deficiency should be considered iewborn infants or older infants or children with any of the following clinical manifestations: jaundice, hepatomegaly, vomiting, hypoglycemia, convulsions, lethargy, irritability, feeding difficulties, poor weight gain, aminoaciduria, cataracts, hepatic cirrhosis, ascites, splenomegaly, or mental retardation. Patients with galactosemia are at increased risk for E. coli neonatal sepsis; the onset of sepsis often precedes the diagnosis of galactosemia. When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (mental retardation) becomes increasingly severe and irreversible. Therefore, galactosemia should be considered for the newborn or young infant who is not thriving or who has any of the above findings.
Because galactose is injurious to persons with galactosemia, diagnostic tests dependent on administering galactose orally or intravenously cannot be used. Galactose administration results in high concentrations of intracellular galactose-1-phosphate, which can function as a competitive inhibitor of phosphoglucomutase. This inhibition transiently impairs the conversion of glycogen to glucose and produces hypoglycemia. Galactose-1-phosphate is responsible for hepatotoxicity and mental retardation, but galactitol causes cataracts. Deficiency of either galactokinase or uridyl transferase produces elevations of galactitol.
Light and electron microscopy of hepatic tissue reveals fatty infiltration, the formation of pseudoacini, and eventual macronodular cirrhosis. These changes are consistent with a metabolic disease but do not indicate the precise enzymatic defect.
The preliminary diagnosis of galactosemia is made by demonstrating a reducing substance in several urine specimens collected while the patient is receiving human or cow’s milk or another formula containing lactose. The reducing substance found in urine by Clinitest can be identified by chromatography or by an enzymatic test specific for galactose. Clinistix or Testape urine tests are negative because these test materials rely on the action of glucose oxidase, which is specific for glucose and nonreactive with galactose. Deficient activity of galactose-1-phosphate uridyl transferase is demonstrable in hemolysates of erythrocytes, which also exhibit increased concentrations of galactose-1-phosphate. Heterogeneity of the defective enzyme can be shown by electrophoretic techniques using hemolysates. In the complete absence of uridyl transferase activity, very small amounts of galactose may still be metabolized by alternate pathways that are of no clinical significance in most patients.
Primary or secondary amenorrhea was reported in 12 of 18 galactosemic women with transferase deficiency who had laboratory evidence of hypergonadotropic hypogonadism. This condition may result from ovarian toxicity due to galactose and its metabolites, in particular, galactose-1-phosphate, which in patients with galactosemia is present in concentrations toxic to the brain, liver, and kidney. A similar effect is not apparent on the male gonads. This interpretation is consistent with the report of reduced oocytes in offspring of pregnant rats on a high-galactose diet and also with the report that risk factors for ovarian cancer may include increased dietary galactose and decreased transferase activity.
The term galactosemia, though adequate for the deficiencies of both galactokinase and uridyl transferase, generally designates the latter for historical reasons.
An occasional infant with galactosemia may tolerate an unexpectedly large amount of food containing lactose, but this is rare. Usually galactose must be excluded from the diet early in life to avoid severe cirrhosis of the liver, mental retardation, cataracts, and recurrent hypoglycemia.
With good dietary control the prognosis is variable. On long-term follow-up, patients may manifest developmental delay and learning disabilities, which increase in severity with age. In addition, most will manifest speech disorders, while a smaller number demonstrate poor growth and impaired motor function and balance (with or without overt ataxia). The relative control of galactose-1-phosphate levels does not always correlate with long-term outcome, leading to the belief that other factors, such as UDP-galactose deficiency (a donor for galacto-lipids and proteins), may be responsible.
DEFICIENCY OF URIDYL DIPHOSPHOGALACTOSE-4-EPIMERASE. There are two forms of this defect. Depending on the tissue distribution, the condition can be either completely asymptomatic or clinically identical to that of the classic form of galactosemia in which there is a deficiency of transferase activity.
In the benign form the defect is an incidental finding in an otherwise healthy individual without clinical manifestations. The liver is not enlarged, nor are there cataracts or abnormal neurologic findings. Growth and development are normal on an unrestricted normal diet. Patients may be discovered during a newborn screening examination to have an increased concentration of erythrocyte galactose-1-phosphate; galactokinase and uridyl transferase activity is normal. Inheritance is autosomal recessive. The epimerase deficiency affects leukocytes, lymphocytes, and erythrocytes, but its normal activity in tissues other than blood cells may explain the normal tolerance for galactose and the absence of clinical symptoms. No treatment is required.
In patients with generalized epimerase deficiency, the epimerase activity is less than 10% of normal in fibroblasts, in addition to decreased activity in leukocytes and erythrocytes. Parents have about 50% of normal activity in their fibroblasts, consistent with an autosomal recessive mode of inheritance. The clinical manifestations and course are indistinguishable from those of classic galactosemia and include cataracts, hepatomegaly, jaundice, proteinuria, and the presence of a non-glucose-reducing substance in the urine. Treatment is accomplished with a galactose-free diet. Although this form of galactosemia is very rare, it must be considered in a symptomatic patient who has normal transferase activity.
73.3 Defects in Fructose Metabolism
DEFICIENCY OF FRUCTOKINASE (BENIGN FRUCTOSURIA). This condition is not associated with any clinical manifestations. It is an accidental finding usually made because the asymptomatic patient’s urine contains a reducing substance. No treatment is necessary. Inheritance is autosomal recessive with an incidence of
Fructokinase deficiency is present in liver, intestine, and kidney. Ingested fructose is not metabolized. Its level is increased in the blood, and it is excreted in urine, there being practically no renal threshold for fructose. Positive Clinitest tests and negative Clinistix tests reveal the urinary-reducing substance to be something other than glucose. It can be identified as fructose by chromatography.
DEFICIENCY OF FRUCTOSE 1,6-BISPHOSPHATE ALDOLASE (ALDOLASE B) (HEREDITARY FRUCTOSE INTOLERANCE). This severe disease of infants appears with the ingestion of fructose-containing food. Either fructose or sucrose (table sugar), the disaccharide of glucose and fructose, may be added as a sweetener to baby foods or formulas. Symptoms may occur quite early in life, soon after birth if foods or formulas containing sucrose or fructose are then introduced into the diet. Early clinical manifestations may resemble those of galactosemia and include jaundice, hepatomegaly, vomiting, lethargy, irritability, and convulsions. A urinary-reducing substance that is not glucose can be identified as fructose by chromatography. Acute fructose ingestion produces symptomatic hypoglycemia; chronic ingestion results in hepatic disease.
The deficiency of 1-phosphofructaldolase is practically complete in the liver. Fructose-1-phosphate accumulates in hepatocytes and acts as a competitive inhibitor for phosphorylase in concentrations similar to those of intracellular glucose-1-phosphate. The resulting transient inhibition of the conversion of glycogen to glucose leads to severe hypoglycemia. Some affected children show reduced hepatic conversion of fructose-1,6-diphosphate into the respective trioses in addition to that of fructose-1-phosphate. The concentration of fructose-1-phosphate may be reduced in body tissues by dietary elimination of fructose. However, fructose-1,6-diphosphate is an obligatory metabolite of glycolysis and gluconeogenesis and cannot be eliminated from the body by dietary means.
The severe reduction in the conversion of fructose-1,6-diphosphate in some children may result in progressive liver disease despite a fructose-free diet in patients who appear clinically well except for hepatomegaly and elevated levels of serum transaminases. Successive liver biopsies show increasing fatty infiltration and fibrosis, with focal cytoplasmic dissolution, and abnormal appearance of glycogen and mitochondria, and unusual platelike and needle-like crystals in hepatocytes. The prognosis of fructose intolerance must be guarded in some patients, even with good dietary control. Without such control, the disease can result in death during infancy or early childhood. Some infants with hereditary fructose intolerance show fewer and relatively milder symptoms. Owing to dietary avoidance of sucrose, affected patients have few dental caries.
Fructose tolerance tests are contraindicated because they may be followed by hypoglycemia, shock, and death.
Treatment requires completely eliminating fructose from the diet. This may be difficult because fructose is a widely used additive, found even in some aspirin preparations. Inheritance is autosomal recessive, and the incidence (including a mild form in adults) is about
DEFICIENT MUSCLE PHOSPHOGLYCERATE MUTASE. This deficiency has occurred in an otherwise healthy adult exhibiting myoglobinuria and cramps after exercise. The patient was unable to increase blood lactic acid concentration after ischemic exercise, and a muscle biopsy showed normal glycogen concentration and enzyme activities except for low phosphoglycerate mutase activity due to the presence of small normal amounts of B (brain type) isozyme and absence of the M (muscle type) isozyme.
DEFICIENT MUSCLE TYPE LACTATE DEHYDROGENASE. The inability to synthesize the M unit of lactate dehydrogenase (LDH) is inherited as an autosomal recessive disorder and resides on chromosome 11. Affected patients still possess the ability to make the H unit of the enzyme.
The main complaints are fatigue and myoglobinuria after strenuous exercise. There is slightly below normal activity of erythrocyte LDH with a disproportionately high ratio of creatine kinase to LDH activity. Ischemic work results in venous lactate below that of control subjects, and venous pyruvate concentration is at least twice that of normal controls. Patients with deficient M type lactate dehydrogenase can convert muscle glycogen to pyruvate, which is then released into the bloodstream rather than converted to lactate.
73.4 Defects in Intermediary Carbohydrate Metabolism Associated with Lactic Acidosis
The defects in carbohydrate metabolism associated with lactic acidosis are discussed here; Figure 73–{endash}2 Figure 73–{endash}2 depicts the relevant metabolic pathways.
The normal lactic acid blood concentration is less than 18 mg/dL or
Deep sighing respirations of the Kussmaul variety should suggest acute metabolic acidosis from hyperlactic acidemia (see Chapter 53). If not corrected, the acidosis can lead to coma, respiratory failure, cardiovascular collapse, renal insufficiency, and death (see Chapter 53).
Hyperlactic acidemia occurs with those defects of carbohydrate metabolism that interfere with the conversion of pyruvate to glucose via the pathway of gluconeogenesis or to CO2 and water via the mitochondrial enzymes of the citric acid cycle. The concentration of blood lactic acid should be determined in infants and children with unexplained acidosis, especially if the anion gap (see Chapter 53) in blood is greater than
DEFICIENCY OF GLUCOSE-6-PHOSPHATASE. GSD I is the only one of the 12 types of glycogenesis associated with significant lactic acidosis. In most patients the resultant recurrent metabolic acidosis is of minor clinical importance, but in some children it is a life-threatening condition. GSD I is discussed further in Chapter 73.5.
DEFICIENCY OF FRUCTOSE-1,6-DIPHOSPHATASE. These infants are symptom free as long as their diet is limited to human milk. If they receive formulas or food containing fructose or sucrose, they develop intermittent attacks of hypoglycemia, shock, coma, convulsions, and a metabolic acidosis due to hyperlacticacidemia. In symptom-free intervals, physical examination may be normal except for hepatomegaly. If untreated, the disease can lead to psychomotor retardation or death. Inheritance is autosomal recessive.
Fructose-1,6-diphosphatase is one of the four key enzymes of gluconeogenesis. Its activity is markedly reduced or undetectable in hepatic biopsy specimens that show fatty infiltration and reduced glycogen concentration. Other enzymes of fructose metabolism, gluconeogenesis, or glycogen degradation are normal. After glucagon administration, the normal rise in blood glucose concentration may not occur or is abolished after a few hours of fasting. These observations are consistent with reduced stores of liver glycogen. Biochemical analysis of hepatic biopsy tissue indicates that less than 1.5% of wet liver weight may be glycogen (normal: 2{endash}–6%).
Administering galactose produces a normal increase in concentration of blood glucose that is not observed after administering fructose, glycerol, or alanine. The latter substances may produce acute hypoglycemia and lactic acidosis; tolerance tests using them should be avoided. Fasting for more than 10 hr may cause hypoglycemia and lactic acidosis. The clinical presentation may resemble “ketotic hypoglycemia” (see Chapter 77). Untreated fructose-1,6-diphosphatase deficiency is a serious disease with a poor prognosis. Growth and development are normal if the diet is kept free of fructose, sucrose, and sorbitol and is reasonably restricted in fat and protein.
DEFICIENCY OF PYRUVATE DECARBOXYLASE. This enzyme has also been designated the pyruvate dehydrogenase component or the first enzyme (E1) of the pyruvate dehydrogenase complex. Neonatal onset is associated with lethal lactic acidosis, white matter cystic lesions, agenesis of the corpus callosum, and the most severe enzyme deficiency. Infantile onset may be lethal or associated with psychomotor retardation and chronic lactic acidosis, brain anomalies and cystic lesions, brain stem and basal ganglia pathology typical of Leigh disease, and a greater amount of enzyme activity than that ieonatal disease. Older children, usually boys, may have less acidosis, greater enzyme activity, and manifest ataxia with high carbohydrate diets. Intelligence may be normal. All age patients may have facial dysmorphology similar to fetal alcohol syndrome.
DEFICIENCY OF DIHYDROLIPOYL TRANSACETYLASE. This enzyme is designated the second enzyme (E2) in the pyruvate dehydrogenase complex, and the only reported patient who might have had this defect was a 9-yr-old boy with profound motor and mental retardation. Blood concentrations of pyruvate and lactate were normal when the patient was fasting but rose to twice the level of controls by 2 hr after a normal meal. A diet high in carbohydrates but not fat (65% and 15%, respectively) precipitated severe lactic acidosis. Dietary thiamine had no effect. Two sisters of the patient had died with severe lactic acidosis; their brains were severely deficient in myelin, but there were no signs of active demyelination. The boy’s cultured skin fibroblasts had reduced activity of the pyruvate dehydrogenase complex; activity of the pyruvate decarboxylase was normal. Because the a{alpha}-ketoglutarate dehydrogenase complex was not defective and because there is evidence that this complex includes an enzyme similar if not identical to E3 of the pyruvate dehydrogenase complex, it can be inferred that E2 may have been defective.
DEFICIENCY OF DIHYDROLIPOYL DEHYDROGENASE. The clinical manifestations of a deficiency of this third enzyme (E3) of the pyruvate dehydrogenase complex are severe and include lethargy, hypertonia, irritability, optic atrophy, hyperactive reflexes with muscular hypotonia, lower extremity spasticity, irregular respirations, and laryngeal stridor. Persistent lactic acidosis was not corrected by a diet high in thiamine or fat. Episodes of hypoglycemia may be relieved by alanine. There has been a history of consanguinity.
Laboratory findings include elevations of blood concentrations of pyruvate, lactase, and a{alpha}-ketoglutarate. Liver function tests may be normal. Dihydrolipoyl dehydrogenase activity in tissues may be as low as 5% of normal. Activities of the pyruvate dehydrogenase complex (but not E1) and the a{alpha}-ketoglutarate dehydrogenase complex in liver, muscle, brain, kidney, and skin fibroblasts have also been decreased.
Pathology of the brain in one infant revealed cavitation and lack of myelination in the basal ganglia, thalamus, and brain stem resembling Leigh syndrome.
DEFICIENCY OF PYRUVATE CARBOXYLASE. Clinical manifestations of this deficiency have varied from hypoglycemia in infancy to absence of clinical signs and symptoms during the 1st yr of life. Usually psychomotor retardation becomes evident in the 1st yr and may be severe and progressive, culminating in death. Clinical findings have included vomiting, irritability, lethargy, progressive motor and mental retardation, hypotonia, hyporeflexia, abnormal eye movements, optic atrophy, ataxia, and convulsions. There may be a history of psychomotor retardation and death of siblings whose clinical or pathologic findings suggested Leigh syndrome or who were undiagnosed.
Laboratory findings are characterized by elevated concentrations of blood lactate, pyruvate, and alanine. Cerebrospinal fluid protein may be elevated. In one patient, although liver size was normal, glycogen in liver and muscle was increased; there was a normal increase of blood glucose concentration following glucagon administration.
Diagnosis is based upon demonstration of a pyruvate carboxylase deficiency in the liver; a partial defect has been reported in one of two liver pyruvate carboxylases. Activities of the three other gluconeogenic enzymes have beeormal.
Treatment with thiamine has prevented episodes of acute metabolic acidosis and controlled the biochemical defect in some patients but has not affected the clinical outcome. Therapy with biotin and lipoic acid is ineffective.
DEFICIENCY OF PYRUVATE CARBOXYLASE SECONDARY TO DEFICIENCY OF HOLOCARBOXYLASE SYNTHETASE OR BIOTINIDASE. See also Chapter 71.6
Deficiency of either of these enzymes of biotin metabolism results in a secondary deficiency of pyruvate carboxylase (and other biotin-requiring carboxylases and metabolic reactions) and in the symptoms associated with the respective deficiencies as well as in skin rash, lactic acidosis, and alopecia. The course of biotinidase deficiency can be protracted, with intermittent exacerbation of chronic lactic acidosis, failure to thrive, and hypotonia leading to spasticity, lethargy, coma, and death. Initial symptoms of this kind in one patient with biotinidase deficiency were reversed by oral biotin, 10 mg/24 hr. In a subsequent sibling the diagnosis was apparent by the finding of less than 5% normal biotinidase activity in serum of cord blood. Biotin therapy prevented the development of discernible symptoms. Because of the curative effect of biotin in an otherwise fatal condition, children with compatible symptomatology, especially children with lactic acidosis and/or unexplained skin rash, should have an assay of serum biotinidase despite the fact that the disease may be rare. The disease can be thought of as biotin dependency. Biotin therapy must be maintained indefinitely.
CARNITINE DEFICIENCY STATES (see also Chapter 72.1). These states may present with recurrent attacks of severe metabolic acidosis (lactic and pyruvic acidemia), hypoglycemia, and hepatomegaly. Cardiomegaly may be present. Untreated, the patient may die during an attack or develop persistent psychomotor retardation, but correction of acidosis and intravenous glucose may terminate the crisis, usually within 12{endash}–24 hr. Carnitine concentration may be reduced in serum, liver, muscle, and/or heart. Administration of L-carnitine, the naturally occurring isomer, benefits some but not all patients. Administration of DL-carnitine is without benefit and may be harmful.
L-Carnitine is synthesized in the liver from lysine in four enzymatic steps. The first three steps can also be executed in muscle and heart. The resulting carnitine precursor is transported through blood to the liver, where the synthesis is completed. The finished L-carnitine is returned into cells of muscle and heart. At the outer side of the inner membrane of the mitochondria, the enzyme carnitine palmitoyl transferase I (CPT I) forms fatty acid{endash}–carnitine esters. These esters are transferred into the mitochondria, where CPT II cleaves the esters, freeing fatty acid for energy production by b{beta} oxidation. Carnitine exits from the mitochondria to begin the next cycle of fatty acid transfer. Carnitine is indispensable in the transport of fatty acids from the cytoplasm into the mitochondria. A newborn girl with CPT II deficiency demonstrated in heart, liver, muscle, and fibroblasts died at age 5 days of encephalocardiomyopathy, hepatomegaly, hypoglycemia, carnitine deficiency, and acidosis. She had appeared normal for the first 2 days of life, probably living off her tissue glycogen stores. However, entry of fatty acids into mitochondria was impaired and energy production could not be sustained once glycogen was depleted. An infant boy with CPT II deficiency demonstrated in fibroblasts appeared healthy until 3 mo of age when he had an episode of lethargy, seizures, hypoglycemia, and respiratory arrest from which he recovered. He died suddenly at age 17 mo.
Carnitine deficiency states can exist either as primary carnitine deficiency, which is the result of a defect within the metabolism of carnitine itself, or more often as secondary carnitine deficiency, which is acquired as the result of some other condition. In primary carnitine deficiency the concentration of carnitine in serum and tissues such as liver, muscle, or heart is usually markedly reduced. Carnitine deficiency can occur with CPT II deficiency, in which acylcarnitine ester is formed normally by CPT I but then is not cleaved by the defective CPT II and is excreted with the loss of the carnitine moiety (see Chapter 72.1).
In secondary carnitine deficiency the concentration of carnitine is reduced in serum and/or tissues because of a carnitine loss that may be associated with many different conditions. These conditions are separable into two groups: (1) those with increased loss or decreased intake of carnitine, and (2) those with an accumulation of carnitine esters that are excreted in the urine, draining the body of carnitine. Group 1 includes renal Fanconi syndrome, type XI glycogenosis, cystinosis, Lowe syndrome, suboptimal diet, and renal dialysis. Group 2 includes defects in b{beta} oxidation of fatty acids, various types of organic acidemia, and treatment with the anticonvulsant drug valproic acid, which is excreted in urine as valproylcarnitine ester.
The main danger posed by primary and secondary carnitine deficiencies is the threat to the transfer of fatty acids into the mitochondria and therefore to b{beta} oxidation and energy production. The extent to which this threat can be alleviated by carnitine treatment depends on the defective site and mechanism underlying the carnitine reduction. To date, side effects of carnitine treatment are rare and are limited to diarrhea and a fishy body odor. Therefore, after reduced carnitine has been found in serum and/or tissue biopsies, one may consider treatment of children with primary as well as secondary carnitine deficiency with oral L-carnitine in divided doses of up to 200 mg/kg/24 hr.
DEFICIENCY OF PYRUVATE DEHYDROGENASE PHOSPHATASE. This deficiency has been found in a newborn boy who had a metabolic acidosis with high serum concentrations of lactate (up to 7 times normal), pyruvate (2 times normal), and free fatty acids (3 times normal). There was no hypoglycemia or hepatomegaly. The acidosis improved when the intake of glucose was increased and that of fat decreased. Periods of clinical stability and moderate hyperlactic acidemia were interrupted every few days by episodes of severe lactic acidosis. Neurologic damage was evident, with lethargy, convulsions, hypotonia, and irritability. The patient died at 6 mo of age.
The pyruvate dehydrogenase component E1 of the pyruvate dehydrogenase complex exists in both active and inactive forms. E1 is inactivated when it is phosphorylated by pyruvate dehydrogenase kinase in the presence of ATP. E1 is stimulated by calcium. Pyruvate dehydrogenase phosphatase activity was reported deficient in liver and muscle but not in the brain of this child based on the observation that the addition of calcium to a homogenate of liver increased the activity of pyruvate decarboxylase in the patient by 4% and in a control by 50%. Deficiency of this activating phosphatase has been reported in another 7-mo-old boy in whom brain autopsy findings were consistent with Leigh syndrome.
CONGENITAL IDIOPATHIC LACTIC ACIDOSIS. This diagnosis should be considered when there is labored respiration in infancy associated with metabolic acidosis from hyperlactic acidemia. Liver and spleen may be enlarged. Convulsions, hypoglycemia, psychomotor retardation, and neurologic damage usually lead to death in infancy despite dietary administration of thiamine, biotin, steroids, lipoic acid, and other agents. Long-term survival in a few instances is possible.
There are increased serum concentrations of pyruvate, lactate, and alanine, as well as of other amino acids. Cerebral autopsy findings may show severe spongy degeneration and lack of myelination, or there may be only moderate or mild abnormalities.
A variety of deficiencies in enzymatic activities, including those reported and defects in mitochondrial respiratory chain complexes may lead to lactic acidosis. The respiratory chain produces ATP from NADH or FADH2 and includes five specific complexes (I—{emdash}NADH-coenzyme Q reductase; II—{emdash}succinate-coenzyme Q reductase; III—{emdash}coenzyme QH2 cytochrome C reductase; IV—{emdash}cytochrome C oxidase; V—{emdash}ATP synthase). Each complex is composed of 9{endash}–25 individual proteins, encoded by nuclear or mitochondrial DNA (inherited only from the mother by mitochondrial inheritance). Such defects produce chronic lactic acidosis in children or adults and are usually diagnosed by muscle biopsy analysis of oxidative mitochondrial function. Some deficiencies resemble Leigh syndrome, while others cause infantile myopathies such as MELAS (mitochondrial encephalopathy, myopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonus epilepsy, with ragged-red fibers), and Kearns-Sayre syndrome (external ophthalmoplegia, acidosis, retinal degeneration, heart block, myopathy, high CSF protein). In patients who have not been examined in a systematic way, excluding the defects described earlier, the diagnosis of congenital idiopathic lactic acidosis should probably not be made.
LEIGH SUBACUTE NECROTIZING ENCEPHALOPATHY (SNE). This condition is characterized by seizures, psychomotor retardation, optic atrophy, hypotonia, vomiting, abnormal movements, lethargy, and lactic acidosis (also see Chapter 548). It is difficult to distinguish this syndrome reliably from many of the enzymatic deficiencies that are associated with lactic acidosis. Gliosis, cavitation, and capillary proliferation in the brain stem, basal ganglia, and thalamus, which are critical criteria for a pathologic diagnosis, may be visible on CT scan. Similar lesions viewed as characteristic have been encountered in patients shown to have pyruvate carboxylase deficiency, or, in one case, defective pyruvate decarboxylase activity in skin fibroblasts. Another boy shown to have SNE by brain autopsy also had a deficiency of pyruvate dehydrogenase phosphatase. The assessment of patients presenting symptoms and signs consistent with Leigh syndrome must include assays of enzymatic activities that result in lactic acidosis. These activities were normal in a 22-mo-old boy who had the cerebral findings of Leigh syndrome associated with increased concentration of endorphin and norepinephrine in cerebrospinal fluid (CSF) and of enkephalins in cerebral cortex.
Thiamine is transiently effective in some patients with Leigh syndrome but not in others. Its use was suggested by the report that extracts of blood, CSF, and urine of patients with SNE inhibited thiamine pyrophosphate{endash}–adenosine triphosphate phosphoryl transferase. Thiamine in pharmacologic doses might have over-ridden this inhibitor, which has also been found in the urine of as many as 10% of clinically normal persons.
Attempts to correct hyperlactic acidemia with dichloroacetate, which inhibits the inactivating kinase for pyruvate dehydrogenase (E1; see Fig. 73–{endash}2 Fig. 73–{endash}2), thereby maintaining dehydrogenase (E1) activity, have been ineffective in a child with fatal lactic acidosis of unknown cause.
Acute, life-threatening hyperlactic acidemia can be corrected by the intravenous infusion of tris-hydroxymethyl aminomethane (THAM), which avoids the sodium overload of sodium bicarbonate administration. This treatment does not alter the poor prognosis for the majority of conditions that are associated with increased concentrations of lactic and pyruvic acid.
73.5 Glycogen Storage Diseases
These diseases are the result of metabolic errors leading to abnormal concentrations or structure of glycogen. The glycogen storage diseases (GSD) or glycogenosis can be classified according to the identified enzymatic defects or sometimes by the distinctive clinical features (Table 73–{endash}1 Table 73–{endash}1). The separation of a new type of GSD is useful to the clinician if the clinical or biochemical characteristics are sufficiently distinctive to permit their recognition in future patients. Figure 73–{endash}3 Figure 73–{endash}3 depicts the relevant metabolic pathways.
DEFICIENCY OF GLYCOGEN SYNTHETASE (GSD 0). Early morning convulsions associated with hypoglycemia are typical symptoms of this condition. There is an associated hyperketonemia but no hepatomegaly. Hypoglycemia appears during periods without food and is not responsive to glucagon administration. After administration of glucose the blood glucose level remains elevated for longer than usual. The diagnosis should be made expeditiously, because hypoglycemic episodes and mental retardation can be avoided if the patient is given frequent meals rich in protein. The clinical picture is similar to that of ketotic hypoglycemia (see Chapter 77), and patients with the latter diagnosis may benefit from an assay of hepatic glycogen synthetase. Persistent hyperglycemia and an increase in serum lactate concentration after administration of glucose should reveal those with a possible deficiency of glycogen synthetase.
Glycogen synthetase activity is deficient in liver but normal in muscle and in white and red blood cells. Glycogen concentration is low (less than 2%) but not absent in liver and normal in muscle. Differential involvement of tissues reflects the fact that different isozymes of glycogen synthetase exist for various tissues. The activation system for glycogen synthetase is normal.
DEFICIENCY OF GLUCOSE-6-PHOSPHATASE (GSD Ia). In GSD Ia, glucose-6-phosphatase activity is defective, and glycogen concentration is increased in liver, kidney, and intestine. Clinical manifestations are summarized in Table 73–{endash}1 Table 73–{endash}1. Mild hypotonia is sometimes also reported in GSD Ia, but the disease does not have a primary effect on muscle, because muscle does not normally contain glucose-6-phosphatase. Marked hypoglycemia may be well tolerated; patients with blood glucose levels as low as 10 mg/dL may display normal behavior. Hyperlipidemia (producing xanthomas) and hyperuric acidemia are marked. In adults the latter produces gout, which must be appropriately treated. There is a secondary impairment of platelet function, which may make bleeding a problem when biopsies are done. Young children with GSD Ia have impressive hepatomegaly, but liver involvement may be easily overlooked in the affected adult. In patients with GSD Ia, the kidneys are moderately but consistently enlarged on roentgenographic examination, which helps to differentiate GSD Ia from GSD III, in which renal size is normal.
Administering galactose or fructose does not produce an elevation of blood glucose concentration; tolerance tests with these sugars should not be done because they can lead to severe acidosis. Intravenous administration of glucagon is not followed by a normal rise in blood glucose, regardless of how recently the patient may have eaten. The glucagon tolerance test can, therefore, differentiate between GSD Ia and GSD III; in the latter the concentration of blood glucose will increase if glucagon is given 2 hr after a meal. Subcutaneous administration of epinephrine has no advantage over the glucagon tolerance test and may produce unpleasant side effects.
Acute lactic acidosis may be a recurrent and life-threatening problem. Portacaval shunt has been advocated for its prevention or control, but no patients have benefited from the operation, which has been complicated by closure of the anastomosis and by development of cirrhosis or encephalopathy. Patients in whom this condition is difficult to control can be managed successfully with continuous nighttime feedings by nasopharyngeal or gastrostomy tube. Therapeutic success also has been reported with repeated daily drinking of a solution of uncooked cornstarch. With such dietary regimens, children grow satisfactorily, hepatomegaly and renal disease (hyperfiltration, focal segmental sclerosis, and interstitial fibrosis) recede, and hypoglycemia and lactic acidosis become manageable. However, when the gastric tube feedings are discontinued, the pretreatment tolerance of hypoglycemia may have been lost. Disease-related post-treatment hypoglycemia may result in convulsions. Frequent meals have effects similar to those of gastric tube feedings and may suffice for clinical control. As patients grow older, their metabolic problems become less severe and are more easily manageable.
In GSD Ia, hepatocytes contain many lipid droplets ranging in size from smaller than mitochondria to several times that of the nucleus, and the nuclei themselves frequently contain glycogen. Nuclear glycogenosis can also occur in GSD III, in diabetes mellitus, and in
GSD Ib (Pseudo-GSD I). Clinically, GSD Ib is indistinguishable from GSD Ia except that children with GSD Ib have an increased incidence of neutropenia, inflammatory bowel disease, and infections. Neutropenia responds to G-CSF. Hepatic glycogen concentration is increased but glucose-6-phosphatase activity is normal in hypotonic homogenates made of frozen liver tissue. The activity is decreased, however, in isotonic homogenates made from fresh liver tissue, which is consistent with a defect in GSD Ib of enzymes that transport glucose-6-phosphate across microsomal membranes. Further evidence that this variant of GSD I is associated with an intracellular transport defect is the finding that when fresh liver homogenates from affected patients are treated with deoxycholate, the activity of glucose-6-phosphatase is normal; deoxycholate is known to break up microsomal membranes.
GSD Ic. Transport of glucose-6-phosphate into microsomes (which is defective in GSD Ib) is normally associated with transport of inorganic phosphates in the opposite direction. A deficiency in this phosphate transfer has been described in an 11-yr-old girl with insulin-dependent diabetes (GSD Ic). Liver glycogen concentration was 9.4%, but because the patient had frequent hypoglycemic attacks, the increased glycogen concentration could have resulted from therapeutic glucose administration. The patient’s clinical picture appeared to be similar to that of Mauriac syndrome in diabetic children (see Part XXVI, Section 6).
DEFICIENCY OF LYSOSOMAL ACID a{alpha}-GLUCOSIDASE (GSD II). This disease, whose clinical manifestations are summarized in Table 73–{endash}1 Table 73–{endash}1, occurs in at least two varieties, one affecting infants (GSD IIa), the other affecting older children and adults (GSD IIb). Both varieties have not occurred in members of the same family. Fibroblast studies indicate that in a patient with GSD IIa, the lysosomal acid a{alpha}-glucosidase is structurally altered, whereas in a patient with GSD IIb, the amount of the enzyme is reduced. Abnormal lysosomes are the morphologic hallmark of GSD II, although on rare occasions similar intracellular vacuoles in liver and muscle of patients with GSD III or GSD IV are seen. The gene for acid a{alpha}-glucosidase is localized on chromosome 17.
GSD IIa. This is the classic form of generalized glycogenosis and is always fatal, usually within 2 yr after birth. Affected children appear clinically healthy at birth with normal muscle tone and liver size. Heart size and electrocardiographic results (shortened PR interval, ventricular hypertrophy) are marginally abnormal. However, after a few weeks or months at home, the infant becomes completely flaccid. Sucking becomes weak, respirations shallow, and the cardiac silhouette huge. The liver is typically only moderately enlarged. The patients are alert and normally intelligent. The mouth is kept open and the tongue thrust forward, perhaps more because of air hunger than the associated macroglossia; the resulting facial expression is characteristic. Aspiration pneumonia leads to chronic pulmonary infiltrates, and bronchial compression by the large heart leads to atelectasis. Death is due to failure of respiratory muscles. There is hardly any other condition in which such extreme cardiomegaly and muscular weakness occur in an infant who appears normal at birth. Blood glucose concentrations are normal, as are tolerance tests with glucagon and other carbohydrate test substances.
GSD II is the only lysosomal disease among the glycogenoses; the other types of GSD are associated with defects of enzymes located in the cytoplasm. The deficient acid a{alpha}-glucosidase is a glycogen-degrading enzyme associated with the lysosomal fraction of tissue homogenates. Fusion of a primary lysosome with an autophagic vacuole normally creates a secondary lysosome. If the primary lysosome is deficient in a lysosomal enzyme (such as a{alpha}-glucosidase), then the secondary lysosome may become engorged with the material (such as glycogen) that should have been degraded by the defective enzyme. Besides deficiencies of enzymes, other errors in lysosomal mechanisms may be present, such as membrane defects. In GSD IIa the deficiency of lysosomal acid a{alpha}-glucosidase produces intracellular vesicles (so-called abnormal lysosomes) engorged with glycogen (Fig. 73–{endash}4 Fig. 73–{endash}4) in cells of liver, muscle, heart and most other tissues of the body. Deficient acid a{alpha}-glucosidase activity is also associated with the formation of glycogen-filled “abnormal lysosomes” in the cells of placenta and skin of children with I-cell disease (mucolipidosis type II, ML II; see Chapter 72.3).
Increased glycogen concentrations are found in many tissues of affected children. The deficiency of the lysosomal enzyme for glycogen degradation explains the membrane-bound accumulations of glycogen in lysosomes, but it does not explain the excessive accumulation of glycogen in the cytoplasm of heart and muscle cells.
The excessive tissue glycogen as such may not be a cause of death. The normalization of the hepatic ultrastructure is not clinically beneficial for the patient. Bone marrow transplantation in a boy with GSD IIa resulted in engraftment of blood cell lines, but the patient died of GSD IIa 5 mo after the procedure.
The prenatal diagnosis of GSD IIa can be made by electron microscopic examination of cells obtained by chorionic villus biopsy or at amniocentesis (see later).
GSD IIb. Weakness of skeletal muscle begins later in life than in those with GSD IIa. In some the disease is compatible with a normal life span, though it may demand a sedentary life-style. In other patients, death from respiratory failure can occur during the 3rd or 4th decade. Cardiomegaly is absent, and the electrocardiogram is normal. The diagnosis is based on electron microscopic examination of skin biopsy showing abnormal lysosomes packed with glycogen particles.
Some cases cannot be explained on the basis of defective activity of lysosomal acid a{alpha}-glucosidase. For example, a patient who died of unrelated hypertension at 24 yr of age had a deficiency of acid a{alpha}-glucosidase consistent with GSD IIa. Glycogen concentration was increased in all tissues except heart, though cardiac a{alpha}-glucosidase activity was deficient. Heart muscle appeared normal on light microscopy; electron microscopy revealed occasional abnormal lysosomes but no excess of glycogen in cytoplasm.
DEFICIENCY OF “DEBRANCHER” ACTIVITY (GSD III). Clinical manifestations are summarized in Table 73–{endash}1 Table 73–{endash}1. In GSD III, hepatomegaly can be as impressive as in GSD I. When generalized, this disorder also affects muscle and heart, but either organ may be clinically involved to a varying degree. Some patients resemble children with muscular dystrophy. Electrocardiographic abnormalities and moderate cardiomegaly are usually found; the size of the kidneys is normal. Patients with GSD III restricted to the liver usually do well. Hypoglycemia is rare and does not present a clinical problem. There may be recurrent pneumonia, but the long-term prognosis is usually good. The serum concentrations of uric acid, lactate, ketones, and lipids are normal. Blood glucose concentration increases if glucagon is given 2 hr after a meal in patients with GSD III but not in those with GSD I, whereas blood glucose levels remain flat in both glycogenoses when glucagon is administered after overnight fasting. These clinical and laboratory findings distinguish GSD III from GSD I.
For “debranching” of the glycogen molecule, two enzymatic reactions need to occur in sequence after phosphorylase activity has reduced the outer chains of the glycogen molecule to within 4 glucose units of the 1,6 branch point. The first reaction is that of a transferase that transfers 3 glucose units of the branched outer chain onto the straight outer chain. The glucose molecule at the branch point becomes exposed and accessible to the subsequent action of a{alpha}-1,6-glucosidase, which removes it. Both the transferase and the a{alpha}-1,6-glucosidase activities are deficient in the livers of patients with GSD III. In some patients the activity of transferase in muscle may be low, whereas that of a{alpha}-1,6-glucosidase remains normal. The overall effect in either liver or muscle is a loss of debrancher activity. Both enzymatic activities may be retained in muscle, the defect being limited to the liver.
Frequently GSD III is a generalized disease, and glycogen concentrations are found to be increased and debranching activity deficient in every (examined) tissue. In generalized GSD III, the concentration of glycogen in muscle may reach the same levels as in GSD II, although patients with the former may be symptom free and those with the latter are markedly hypotonic. In GSD III, starvation induces the degradation of glycogen to within 4 units of the branch point. Glycogen with such short outer chains is called a limit dextrin; hence limit dextrinosis is an alternative designation for GSD III. Light microscopic appearance of liver in GSD III is similar to that of GSD I except that GSD III exhibits formation of fibrous septa, more extensive nuclear glycogenosis, and a paucity of intracellular lipid droplets. Hepatic cirrhosis does not usually develop in GSD III; the fibrous septa usually remain stable.
DEFICIENCY OF “BRANCHER” ACTIVITY (GSD IV). This defect is characterized clinically by hepatomegaly and splenomegaly. Progressive portal fibrosis leads to hepatic cirrhosis, ascites, and death in childhood from liver failure. Treatment with corticosteroids may induce temporary remission. Affected children are candidates for liver transplantation.
Hepatic symptoms are associated with reduced rather than increased concentrations of tissue glycogen. The glycogen resembles amylopectin, because it has fewer than the normal number of branch points. This may be the consequence of deficiency of branching enzyme, though one would expect a defect of this enzyme to result in the synthesis of amylose, the glucose polymer with no branch points. The cirrhosis may be the result of the amylopectin-like glycogen, because this glucose polymer is not normally present even transiently in the liver. The limit dextrin of GSD III may not have this effect because it is a transient form normally encountered during synthesis and degradation of glycogen.
DEFICIENCY OF MUSCLE PHOSPHORYLASE (GSD V) (MCARDLE SYNDROME). This disorder has a wide clinical spectrum, varying from almost no symptoms to recurrent myoglobinuria, attacks of rhabdomyolysis, and unremitting muscle pain. The muscular pains and cramps after exercise that characterize GSD V can be differentiated from muscle cramps related to more common causes by the ischemic exercise test.
The test requires inflation of a blood pressure cuff on the upper arm to above the arterial pressure. The patient is then asked to squeeze a rubber ball with the hand of the same arm about once every second. The healthy person will easily squeeze 70{endash}–110 times, with some discomfort but without cramping of the muscle or residual symptoms after deflation of the blood pressure cuff. In the patient with GSD V, muscle cramps may limit the squeeze to 20{endash}–30 movements. When the cuff is released, the cramps persist, with the hand in a tetanic position (wrist bent, fingers extended) that cannot be corrected by the patient or by the examiner. After several minutes there is gradual release of the cramp, but pain may persist for 24{endash}–48 hr. In the healthy person, blood samples taken from the antecubital vein of the ischemic arm during exercise show a rise in serum lactate, a rise that does not occur in patients with GSD V because of their inability to produce lactate from glycogen. The diagnosis of GSD V also has been made using magnetic resonance spectroscopy by measuring pH, ATP, and phosphocreatine concentration following both aerobic and ischemic exercise. Molecular diagnosis of DNA from chromosome II reveals characteristic restriction endonuclease mutations; despite genetic heterogeneity, a diagnosis is possible in 90% of cases. A clinical picture consistent with McArdle syndrome, including recurrent rhabdomyolysis, has also occurred in patients with carnitine palmityl transferase deficiency.
Skeletal muscle is without phosphorylase activity. The activity in liver and smooth muscle is normal. The system of phosphorylase activation is intact; patients may have 3 times the normal activity of muscle phosphorylase kinase. Glycogen concentration is increased in muscle but usually not above 4%. Histologically, much of the excessive glycogen is deposited in the cytoplasm beneath the sarcolemma. In patients with phosphorylase deficiency, the energy for muscle contraction can still be provided by glucose entering the myocyte, which may suffice for energy requirements at rest when there are no symptoms. Peak demands for energy, however, which ordinarily are met by supplemental breakdown of muscle glycogen, cannot be satisfied in GSD V because of the phosphorylase defect. The result is pain and cramping during and after exercise, with little or no production of lactic acid. Ischemic exercise tests worsen the situation by interrupting the normal supply of oxygen and glucose.
Treatment includes avoidance of excessive exercise and a high-protein diet.
DEFICIENCY OF LIVER PHOSPHORYLASE (GSD VI). In GSD VI, hepatomegaly may be massive. Otherwise, the affected children are without symptoms and lead normal lives, though there may be some elevation of serum lipids and transaminases (see Table 73–{endash}1 Table 73–{endash}1). Most patients do not have hypoglycemia. The blood glucose concentration does not increase after glucagon administration; this finding can be used to separate GSD VI from GSD IX, in which glucagon tolerance curves are normal. Separation from GSD I also can be made on clinical evidence. The hepatomegaly may recede as the children grow older. Some patients with GSD VI have subtle and unexplained cardiomyopathy.
The low activity of the hepatic phosphorylase system is consistent with but not diagnostic of GSD VI, because low activity may result from a number of defects within the phosphorylase activation system. The diagnosis rests on demonstration of a deficiency in the liver phosphorylase enzyme itself. Leukocyte phosphorylase may also be affected but cannot be relied upon for diagnosis. By light microscopy, formation of fibrous septa is seen in portal areas of the liver. Whether this change remains stationary or progresses to cirrhosis in adulthood is unknown. Phosphorylase activity, glycogen concentration, and histologic appearance are normal in muscle.
DEFICIENCY OF MUSCLE PHOSPHOFRUCTOKINASE (GSD VII). The symptoms of GSD VII resemble those of GSD V, but the muscle pain and cramping after exercise may be more severe. The disease has been tolerated by a young man who plays tennis for pleasure.
Phosphofructokinase is deficient in skeletal muscle but not in the liver; it is only partially defective in erythrocytes. Because this key glycolytic enzyme affects the use of both glycogen and glucose in muscle, it is surprising that the deficiency may cause fewer symptoms than a deficiency in phosphorylase, which affects only the utilization of glycogen. The concentration of glycogen in muscle is moderately elevated, and its distribution is subsarcolemmal, like that observed in GSD V and GSD X.
PROGRESSIVE BRAIN DISEASE AND DEACTIVATED LIVER PHOSPHORYLASE WITHOUT DEMONSTRATED ENZYME DEFECT (GSD VIII). Hepatomegaly without hypoglycemia was apparent soon after birth in one of the four patients in whom the disease has been described. However, the clinical manifestations, which are unique for GSD VIII among the glycogenoses and are present in all four patients, are related primarily to the central nervous system (see Table 73–{endash}1 Table 73–{endash}1). The infant may develop nystagmus and rolling of the eyes, ataxia, and truncal tremor. The patient becomes hypotonic and then spastic; spasticity may become severe. Gradually the patient loses rapport with the environment, becomes unresponsive and bedridden, develops swallowing difficulties, and may die of aspiration pneumonia. Urinary excretion of epinephrine and norepinephrine may be increased. The glucagon tolerance test is normal.
Glycogen concentration was increased in hepatic and cerebral biopsies; in muscle, it may be normal or increased. In all patients, electron microscopy of cerebral biopsies revealed increased amounts of glycogen in the form of a{alpha} particles that are about 10 times wider than the b{beta} particles usually found in brain. Liver phosphorylase activity may be low. Cerebral enzymes have not been assayed. The low activity of the hepatic phosphorylase system does not reflect a deficiency of phosphorylase enzyme or of any other enzyme in the hepatic system of phosphorylase activation. This is demonstrated by the normal glucagon tolerance curve and also by the fact that in vivo the phosphorylase activity increases to normal within 2 min after the administration of glucagon or epinephrine to the patient. The low phosphorylase activity observed in a liver specimen obtained before glucagon administration could be increased to normal in vitro by the patient’s own liver homogenate. Accordingly, the affected child appears to suffer from impaired control of phosphorylase activation.
DEFICIENCY OF LIVER PHOSPHORYLASE KINASE (GSD IX). This defect occurs in three forms that differ in their pattern of inheritance and tissue distribution. GSD IXa follows an autosomal recessive pattern of inheritance, and GSD IXb is sex-linked recessive. Otherwise, these two forms are indistinguishable. Skeletal muscle is not affected and is normal biochemically (see Table 73–{endash}1 Table 73–{endash}1) and morphologically. In GSD IXc, with autosomal recessive inheritance, the phosphorylase kinase activity of liver and muscle is deficient. Hepatomegaly is massive in early life but recedes as the children grow older; it may disappear completely in teenagers or adults, though the liver can remain somewhat large. Hypoglycemia is unusual. Transaminases are minimally elevated. GSD IX can be classified as a benign hepatomegaly, except in patients who also have defective debrancher activity. Glucagon produces a normal rise in blood glucose concentration that serves to distinguish it from GSD VI, in which the glucagon tolerance curve remains flat. Affected children require no treatment, except perhaps in rare instances of combined deficiencies.
The concentration of liver glycogen is increased and phosphorylase activity is low, as is the case in GSD VI. In GSD IX, however, the low activity of phosphorylase results from a deficiency in phosphorylase kinase. Other enzymes of the activating system, including phosphorylase, are normal. Cultured skin fibroblasts and leukocytes have been reported to be affected but are undependable for diagnosis. The defect persists in adulthood, as demonstrated by rebiopsy of the original patient 25 yr later. In the liver, glycogen remained elevated at 11%, phosphorylase kinase activity was still less than 10% of normal, and some fibrous septa were present.
DEFICIENCY OF CYCLIC 3´{prime}5´{prime}-AMP-DEPENDENT KINASE (GSD X). The patient with this condition had marked hepatomegaly at 6 yr of age, when the clinical picture was indistinguishable from that of GSD IX except that the blood sugar curve remained flat after intravenous administration of glucagon (see Table 73–{endash}1 Table 73–{endash}1). She had no skeletal muscular symptoms at this time, but 6 yr later she complained of muscular pain, cramping after exercise, and a minimal degree of persistent muscular weakness. The ischemic exercise test was normal, and hepatomegaly was persistent. The patient is doing well without specific therapy.
Liver glycogen concentration was high, and hepatic phosphorylase activity was low. Concentration of glycogen in muscle was increased to 2{endash}–4%. Light and electron microscopy showed increased glycogen deposition in liver and skeletal muscle cells. Muscle phosphorylase was present only in the inactive form, whereas normally 60{endash}–80% of total phosphorylase is in the active form. GSD X reflects a deficiency in activity of cyclic 3´{prime}5´{prime}-AMP-dependent kinase. The complete inactivation of muscle phosphorylase in GSD X is clinically well tolerated, whereas the complete lack of muscle phosphorylase in GSD V is characterized by cramps and pains. This difference may be due to the ability of inactive phosphorylase b to degrade glycogen in the presence of adenylic acid (5´{prime}-AMP), which is normally found in muscle tissue.
HEPATIC GLYCOGENOSIS WITH STUNTED GROWTH (GSD XI). This disorder is characterized by a greatly enlarged liver and markedly stunted growth (see Table 73–{endash}1 Table 73–{endash}1). Serum transaminase and lipid levels may be elevated. Affected children develop severe hypophosphatemic rickets early in life unless they receive oral phosphate supplementation. Orally administering phosphate alone to the extent necessary for correction of the hypophosphatemia may heal the florid rickets, but adequate growth is not attained through this regimen. The marked rachitic bone changes are due to Fanconi syndrome characterized by urinary loss of phosphate, amino acids, glucose, and galactose that can occur in these children. After puberty the hepatomegaly may recede (although hepatic glycogen concentration remains increased) and the growth rate may increase (although the ultimate body height remains far below normal). However, after puberty the serum phosphate concentration remains normal without supplementation with phosphate.
Glycogen concentration is markedly increased in liver and kidney but normal in muscle. All measured hepatic glycolytic enzyme activities are normal. Administering glucagon does not increase the blood glucose concentration but does increase urinary excretion of cyclic AMP that is usually induced by glucagon administration. Glucose concentration decreases after the oral administration of 1.75 g/kg of galactose, an amount that normally is followed by a significant increase in blood glucose. Conversely, oral administration of an equivalent amount of fructose is followed by the normal increase in blood glucose concentration. On the basis of these findings, it is reasonable to postulate that patients with GSD XI have a functional deficiency of hepatic phosphoglucomutase.
PRENATAL DIAGNOSIS OF GSD
The glycogenoses generally follow an autosomal recessive pattern of inheritance except for GSD IXb, in which inheritance is sex-linked recessive. They should be detectable in the fetus through assay of cultured amniotic fluid cells when these cells normally produce the particular enzyme under study. This criterion is not fulfilled for GSD I because glucose-6-phosphate is not found iormal cultured amniotic fluid cells. Prenatal diagnosis of GSD I is possible by fetal liver biopsy. GSD I, GSD III, GSD VI, GSD IX, and GSD X may not be candidates for prenatal diagnosis because most of the affected children with these conditions lead near-normal lives. In GSD IIa and GSD IV, on the other hand, antenatal diagnosis has been made through assay of cultured amniotic fluid cells. Acid a{alpha}-glucosidase activity has been present in all amniotic fluid specimens tested, even in GSD IIa. Several weeks may be needed to culture the amniotic fluid cells. Prenatal diagnosis of GSD IIa is feasible within 3 days after amniocentesis through electron microscopic examination of uncultured amniotic fluid cells, which show abnormal intracellular lysosomes that are not present in heterozygous or normal fetuses. These cellular inclusions are also seen by electron microscopy of chorionic villus biopsy specimens in fetal GSD IIa.
DISORDERS OF MUCOPOLYSACCHARIDE METABOLISM
The mucopolysaccharidoses are a group of inherited disorders caused by incomplete degradation and storage of acid mucopolysaccharides (glycosaminoglycans). The clinical manifestations result from the accumulation of mucopolysaccharides in various organs. Specific degradative lysosomal enzyme deficiencies have been identified for all the mucopolysaccharidoses.
The mucopolysaccharides are polyanionic polymers, most of which contain alternating carbohydrate residues of N-acetylhexosamine and uronic acid. Although the acid mucopolysaccharides are closely related as a group, individual compounds differ in their distribution in body tissues. Dermatan sulfate, heparan sulfate, and keratan sulfate are the major mucopolysaccharides involved in the pathogenesis of the mucopolysaccharidoses. The structural differences of the mucopolysaccharides explain the need for various lysosomal enzymes required for their degradation.
Because the mucopolysaccharides are major components of the intercellular substance of connective tissue, bony changes are characteristic of the mucopolysaccharidoses. The skeletal deformities seen in roentgenograms are referred to as dysostosis multiplex. The central nervous system also may be affected, leading to progressive mental retardation. In addition, the cardiovascular system, liver, spleen, tendons, joints, and skin may be involved. The degree of disability and overall prognosis in each of the mucopolysaccharidoses are determined by the extent of the physical and mental involvement.
The mucopolysaccharidoses follow an autosomal recessive mode of inheritance, with the exception of Hunter syndrome, which is inherited as an X-linked recessive trait. They are suspected on the basis of clinical and radiologic manifestations, and the diagnosis is confirmed by the finding of increased urinary excretion of mucopolysaccharides and deficiency of a specific enzyme.
HURLER SYNDROME (MPS IH). This syndrome is the most severe of the mucopolysaccharidoses. Its relentless progression usually results in death by the early teenage years.
Etiology and Pathology. The basic defect in Hurler disease is a deficiency of a{alpha}-L-iduronidase, which leads to accumulation of the dermatan and heparan sulfates in tissues and their urinary excretion. Almost every tissue in the body is affected, with widespread occurrence of vacuolated, or “gargoyle,” cells, which contain lysosomes engorged with mucopolysaccharide. In the brain, lipid storage also occurs with the mucopolysaccharide accumulation. There is unusual hyalinization of collagen and separation of the collagen bundles. These changes lead to joint deformities and stiffness, thickened meninges, hydrocephalus, peripheral nerve compression, and a tendency to develop hernias. As the disease progresses, narrowing of the coronary arteries, thickening of the cardiac valves and endocardium, and stiffening of the myocardium may lead to congestive heart failure. The constricted thorax contributes to the clinical deterioration of these patients.
Clinical Manifestations. Infants with Hurler syndrome appear normal at birth, and during the 1st yr of life only slight developmental delays are noted. Physical examination, however, reveals hepatosplenomegaly, exaggerated kyphosis, persistent nasal discharge, and noisy breathing. The facial features become progressively coarser after the 1st yr of life (Fig. 74–{endash}1 Fig. 74–{endash}1). The head is large and dolichocephalic, with frontal bossing and prominent sagittal and metopic sutures. The bridge of the nose is depressed, and the nose is broad and flat. Clouding of the corneas becomes evident at about 1 yr of age. Umbilical and inguinal hernias are common. Children afflicted with this disease regress developmentally, and mental retardation becomes obvious. The downhill course continues rapidly after the 2nd or 3rd yr of life. These children become immobile, their joints become progressively stiff and contracted, and they usually die by their early teens.
Roentgenographic Changes. Roentgenograms of patients with Hurler syndrome reveal dysostosis multiplex, which includes a large dolichocephalic skull and thickened calvarium. There may be hyperostosis of the cranium, and the sella turcica may be boot or J shaped. The medial third of the clavicle is thickened. The vertebral bodies are ovoid in the lower thorax and upper lumbar regions. They develop beaklike projections on their lower anterior margins, while their upper portions remain hypoplastic (Fig. 74–{endash}2 Fig. 74–{endash}2). This results in the gibbus deformity commonly seen in these patients. The ribs are spatulated or oar shaped, and the pelvis shows flaring of the iliac bones, with shallow acetabulae. Roentgenograms of the hips show progressive coxa valga deformity, sometimes resembling the findings of aseptic necrosis. Roentgenograms of the hands show tapering of the terminal phalanges and widening at the distal ends and tapering at the proximal ends of the metacarpals. The 5th metacarpal is the first to show these changes (Fig. 74–{endash}3 Fig. 74–{endash}3). In the long bones, particularly those of the upper extremities, irregular widenings associated with areas of cortical thinning and expansion of the medullary cavity are seen. Occasionally, there may be cortical thickening. The radius curves toward the ulna, and the articular surfaces of the radius and the ulna face one another, forming a V (see Fig. 74–{endash}3 Fig. 74–{endash}3). The humerus may be angulated, and the glenoid fossa, like the acetabulum, may be shallow. Severe growth retardation is common in these children.
Diagnosis. The diagnosis of Hurler syndrome is suggested by the presence of the relevant clinical and roentgenographic findings. Urinary excretion of dermatan and heparan sulfates provides further support. Although there are helpful screening methods for quantifying the mucopolysaccharides in the urine, definitive diagnosis requires detection of a{alpha}-L-iduronidase deficiency in white blood cells, serum, or cultured skin fibroblasts.
Genetics. Hurler disease is an autosomal recessive disorder. The human a{alpha}-L-iduronidase cDNA and gene have been isolated, and the genomic organization has been elucidated. The coding sequence for a{alpha}-L-iduronidase comprises 14 exons. Chromosomal localization of the iduronidase gene has been assigned to the short arm of chromosome 4 (4p16.3), distal to the
SCHEIE SYNDROME (MPS IS). This syndrome is the mildest of the mucopolysaccharidoses. It is a distinct clinical and genetic entity; the enzyme deficiency, a{alpha}-L-iduronidase, is the same as in Hurler syndrome but is specific for dermatan sulfate, which accumulates in tissues and is excreted in excessive amounts in urine.
Clinical Manifestations. Patients with this disease have normal intelligence, mild facial coarsening with striking prognathism, joint stiffness typified by claw hands, and carpal tunnel syndrome. Corneal clouding is a constant feature that leads to loss of visual acuity. Aortic regurgitation is common. The clinical features do not appear until after 5 yr of age, and the disease is compatible with close-to-normal life expectancy. The patient with Scheie syndrome reaches normal height.
Roentgenographic Changes. Findings on roentgenography include mild dysostosis multiplex, without the vertebral changes or the gibbus deformity seen in Hurler disease. There is coxa valga and slight radial and ulnar obliquity with V formation of their articular surfaces.
Diagnosis. Early clinical diagnosis is more difficult in Scheie than in Hurler syndrome because the somatic changes are mild and mental retardation is not present. Detection of urinary dermatan sulfate is helpful, but the diagnosis is confirmed by demonstrating a deficiency of a{alpha}-L-iduronidase in white blood cells or in cultured skin fibroblasts.
Genetics. Scheie syndrome is the mildest form of iduronidase deficiency diseases. Examples of mutations that lead to a mild form of iduronidase deficiency are substitution of arginine in position 89 for glutamine (R89Q) and an intronic mutation iucleotide position 678. It is possible, by using molecular tools, to correlate the phenotype of iduronidase deficiency with the genotype.
HURLER-SCHEIE SYNDROME (MPS IH/IS). Few reports exist of patients with this syndrome.
Etiology. The basic defect is a{alpha}-L-iduronidase deficiency specific for dermatan sulfate, which is excreted in urine and stored in the liver, spleen, and other tissues. It has been suggested that the Hurler-Scheie syndrome is a genetic compound of two recessive genes, analogous to hemoglobin SC disease, but recent work indicates it is best explained as an allelic mutation of the iduronidase gene.
Clinical Manifestations. Patients develop mild coarseness of facial features, corneal clouding, shortness of stature, joint contractures, hepatosplenomegaly, hernias, and cardiac valvular lesions, primarily mitral insufficiency (Fig. 74–{endash}4 Fig. 74–{endash}4). Mental development is normal. The clinical features, which usually develop in the first 2 yr of life and in early childhood, are often mistaken for manifestations of a variety of skeletal defects causing growth retardation. The disease is compatible with long life.
Roentgenographic Features. Roentgenograms of patients with this syndrome reveal severe dysostosis multiplex with findings identical to those seen in Hurler syndrome, except that there is no gibbus.
Diagnosis. Diagnosis is based upon the findings of dermatan sulfate in the urine and a{alpha}-L-iduronidase deficiency. The clinical pattern of onset of joint involvement and the severity of skeletal deformities distinguish Hurler-Scheie from Scheie disease.
Genetics. The cloning and the elucidation of mutations on the iduronidase gene indicate that the Hurler-Scheie form is caused by mutations with moderate phenotype severity. The mutation R89Q, in which arginine is substituted for glutamine, which causes Scheie syndrome, can under certain circumstances lead to the intermediate phenotype, Hurler-Scheie.
HUNTER SYNDROME (MPS II). This syndrome is the only X-linked disorder among the mucopolysaccharidoses. It is milder than Hurler syndrome with respect to the skeletal and mental defects, although the mucopolysaccharides, dermatan and heparan sulfate, stored in tissues and excreted in the urine are similar in the two diseases. The enzyme deficient in tissues is iduronosulfate sulfatase, but there is a considerable phenotypic heterogeneity; there is no biochemical or enzymatic difference between the severe form of the disease, designated type A, and the mild disease, type B.
Type A. This is the “classic” form of Hunter syndrome. Coarseness of facial features, short stature, joint stiffness, hepatosplenomegaly, and hernias are common clinical manifestations. Mental retardation is severe. Progression of the disease process is slower and the dysostosis multiplex is milder than in Hurler syndrome. Corneal clouding is usually absent, but hearing loss is very common. Skin changes also are frequent, including small raised papules over the skin of the shoulders, the scapulas, and the lower back. Cardiac involvement often occurs. Patients usually do not have gibbus deformity, although mild kyphosis may be present in some. Life expectancy for these patients usually extends into the late teens or early 20s.
Type B. This syndrome is a milder disease than type A, even though the enzyme deficiency and urinary mucopolysaccharides are the same. Retardation is usually lacking or very minimal. The physical features are similar to, but milder than, those in type A, and patients have a longer life expectancy. Airway obstruction caused by mucopolysaccharide accumulation in the trachea and bronchi is a complicating feature of type B.
Diagnosis. The physical features, dysostosis multiplex, and dermatan and heparan sulfaturia suggest either Hurler or Hunter syndrome, but sex-linked inheritance is specific to the latter. Enzyme studies showing iduronosulfate sulfatase deficiency in serum, white blood cells, or cultured fibroblasts confirm the diagnosis of Hunter syndrome. Other sulfatases should be examined, since multiple sulfatase deficiency can be confused with Hunter syndrome.
Genetics. Hunter syndrome is an X-linked disease. The cDNA for iduronosulfatase has been cloned, and the gene has been localized to the Xq28 region close to the fragile X site. The gene for iduronosulfatase is coded for by nine exons. Southern blot analyses of genomic DNA from Hunter patients show that many patients have gross deletions in the iduronosulfatase gene. More than a dozen mutations in the human iduronosulfatase gene in Hunter patients have been reported. These mutations vary from being point mutations to small insertion or deletions in the coding region of the iduronosulfatase gene. There may be a correlation in the nature of mutation and the phenotype observed in patients. For example, patients showing a major change in the gene, such as an insertion of 22 base pairs (nucleotide 1129), are severely affected, type A. Patients with deletions are also severely affected, while patients with point mutations may have a mild phenotype, type B. An example of a mutation causing mild Hunter phenotype is the substitution of lysine for arginine in position 135.
SANFILIPPO SYNDROME (MPS III). This syndrome is a distinct entity and is based on clinical findings and excessive urinary excretion of exclusively heparan sulfate. The coarse facial appearance and skeletal involvement are milder than those seen in the Hurler and Hunter syndromes. There are four enzymatic variants, distinct deficiencies all leading to the same phenotype and mucopolysacchariduria. Heparan sulfate is stored in tissues, and its accumulation is responsible for the neuronal damage and atrophy underlying the profound mental retardation associated with the disease.
Clinical Manifestations. The clinical features of the Sanfilippo syndrome in early life are not very striking. Affected children have delayed developmental milestones and are usually very hyperactive. By the end of the 1st decade there is rapid neurologic deterioration; their gait becomes unsteady, and they become bedridden. Most of the children die in their middle teens. Mental retardation, some joint stiffening, hepatosplenomegaly, hernias, and dysostosis multiplex are common, but dwarfism and corneal clouding are rare.
Patients manifest dysostosis multiplex typical of the mucopolysaccharidoses. The large bones are not as severely involved; the obliquity of the radius and ulna and the tapering of the proximal ends of the metacarpals are very mild.
Diagnosis. Sanfilippo syndrome should be considered in the presence of heparan sulfaturia, hepatosplenomegaly, mental retardation, and dysostosis multiplex. Screening tests for urinary mucopolysaccharides usually give positive results but not as consistently as in the Hurler or Hunter syndrome. The different enzymatic variants can be confirmed by specific enzyme assays provided by special laboratories.
Sanfilippo A Syndrome (MPS III A). Sulfamidase is deficient in this disease and can be assayed using cultured skin fibroblasts or peripheral blood leukocytes. This enzyme is specific for the hydrolysis of the sulfate linked to the amino groups of glucosamine.
Sanfilippo B Syndrome (MPS III B). This form is characterized by a{alpha}-N-acetylhexosaminidase deficiency and can be assayed on serum, white blood cells, or cultured skin fibroblasts. This enzyme is required for the hydrolysis of N-acetylglucosamine residues from heparan sulfate.
Sanfilippo C Syndrome (MPS III C). This syndrome is caused by a deficiency of acetyl CoA:a{alpha}-glucosaminide N-acetyltransferase. This enzyme catalyzes the acetylation of the free glucosamine on the polysaccharide terminus. The assay requires cultured fibroblasts or white blood cells.
Sanfilippo D Syndrome (MPS III D). This deficiency of N-acetylglucosamine-6-sulfatase is specific for heparan sulfate. The enzyme is assayed using a substrate prepared from heparin.
Genetics. All four Sanfilippo syndromes are autosomal recessive disorders caused by four different enzyme defects. The enzymes are involved in the degradation of heparan sulfate. Therefore, the phenotypes are similar because of the accumulation of heparan sulfate. Cloning of cDNA for glucosamine-6-sulfatase, which is deficient in Sanfilippo D, has been achieved. The sequence analysis of the cDNA has revealed a strong homology with steroid sulfatase as well as with other cloned sulfatases. This gene has been localized to the long arm of chromosome 12 (12q14). The genes for the three other enzymes have not been cloned.
MORQUIO SYNDROME (MPS IV). This disorder is characterized by keratan sulfaturia and skeletal dysplasia. Keratan sulfate is stored in tissues together with chondroitin-6-sulfate. The keratan sulfaturia may decrease with age, but it is always above the normal range. There are two enzyme defects that lead to identical phenotypes in this syndrome.
Clinical Manifestations. The syndrome is associated with severe somatic manifestations and lack of mental involvement. At birth it may not be recognized. Joint laxity and shortness of stature first appear at about 1 yr of age. Skeletal abnormalities include flat vertebrae (platyspondyly universalis), short neck, genu valgum, flat feet, large and unstable knee joints, large elbow joints, and large wrists with ulnar deviation. The platyspondyly leads to short trunk and short stature. The odontoid process is underdeveloped; early on, this may cause atlantoaxial subluxation or translocation, with spinal cord compression. Corneal clouding also may be apparent at an early age. There is midface hypoplasia with a depressed nasal bridge and protrusion of the mandible, which give these patients a permanent grin. Hepatosplenomegaly is not as pronounced as in the other mucopolysaccharidoses, but it is usually present. Cardiac manifestations are secondary to respiratory failure caused by kyphoscoliosis and restricted chest movements, although aortic regurgitation may complicate the Morquio syndrome. Teeth are severely affected and have very thin enamel. Hearing loss may result from recurrent otitis media. Variation in the clinical manifestations is common, and very mild cases may be encountered. Patients usually die in their 3rd or 4th decade of life from cor pulmonale caused by the severe abnormalities of the chest and spine.
Roentgenographic Changes. In the 1st yr of life, roentgenograms may reveal only mild changes in patients with Morquio syndrome. The vertebral bodies show height loss and anterior tonguelike projections. At 2 yr the platyspondyly becomes evident. The hypoplasia of the odontoid process can be clearly seen in tomographic studies. The skull and sella turcica are mildly involved. The long bones are shortened, and the metaphyses appear irregular. There is progressive distortion of the epiphyseal metaphyseal plates. The pelvis shows wide acetabulae with progressive subluxation or dislocation of the femoral heads. The metacarpal bones are short and wide with conical tapering of their proximal ends. The distal ends of the radius and ulna face one another, similar to the obliquity seen in other mucopolysaccharidoses. These changes, especially the coxa valga and the changes in the wrists and lumbar spine, should differentiate Morquio syndrome from other skeletal dysplasias.
Diagnosis. The spondyloepiphyseal dysplasias may mimic the signs of Morquio syndrome both clinically and roentgenographically. Screening tests for acid mucopolysaccharides in the urine of these patients can be negative; therefore, quantitative rather than qualitative isolation methods are preferred. The urinary finding of keratan sulfaturia, moreover, is also found in the Kneist syndrome. Therefore, enzyme determinations are essential for differentiating Morquio syndrome from other conditions. There are two enzyme deficiencies:
MORQUIO SYNDROME, TYPE A (MPS IV A). This syndrome is caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, an enzyme that also degrades galactose-6-sulfate.
MORQUIO SYNDROME, TYPE B (MPS IV B). In this syndrome b{beta}-galactosidase is deficient. An important clinical difference between the two syndromes is the lack of enamel hypoplasia in type B. In other respects, including roentgenograms of the spine, the two forms may be indistinguishable. Morquio syndrome type B should not be confused with GM1 gangliosidosis, which also is associated with b{beta}-galactosidase deficiency but resembles Hurler syndrome clinically.
Genetics. The two forms of Morquio syndrome are autosomal recessive. Galactosamine-6-sulfate sulfatase, the enzyme that hydrolyzes sulfate from galactose-6-sulfate and galactosamine-6-sulfate, has been purified and found to be specific for the galactose-galactosamine configuration. Deficiency of this enzyme leads to Morquio type A and to the accumulation in tissues and excretion in urine of keratan sulfate and chondroitin-6-sulfate. A full-length cDNA clone for N-acetylgalactosamine-6-sulfatase has been isolated and expressed in deficient fibroblasts. The gene has been localized to the long arm of chromosome 16 (16q24.3). Two different mutations in the coding sequence have been reported in Morquio type A patients. In one patient with severe clinical phenotype, a 2 bp deletion (1342delCA) was observed that would shift the reading frame. In another instance, two probands with a mild clinical phenotype had a point mutation, creating a missense mutation substituting asparagine for lysine in position 204. Thus there seems to be a correlation of clinical phenotype with the nature of the coding sequence mutation.
b{beta}-Galactosidase is also required for the sequential degradation of keratan sulfate. Deficiency of this enzyme leads to Morquio type B. The cDNA clone for b{beta}-galactosidase has been isolated and characterized. Several point mutations have been reported in the b{beta}-galactosidase gene. The gene has been assigned to the short arm of chromosome 3 (3p21.33). b{beta}-Galactosidase deficiency can also be caused by a protective protein. This disease causes deficiency of sialidase and b{beta}-galactosidase (mucolipidosis I).
KERATAN AND HEPARAN SULFATURIA (MPS VIII). A single case of this unusual form of mucopolysacchariduria has been described. The patient was a boy who was noted to have developmental delay at 18 mo of age. At 2 1/2 yr he was severely retarded, bedridden, and blind. He had scaphocephaly and mild pectus excavatum but no organomegaly; corneal clouding was not noted. Roentgenographic studies showed dysostosis multiplex without the platyspondyly seen in Morquio syndrome.
Urinary studies showed excessive excretion of both keratan and heparan sulfates. Enzymatic assays revealed normal activity for both of the known Morquio enzyme defects. N-acetylglucosamine-6-sulfate sulfatase specific for a substrate prepared from keratan sulfate was deficient. This enzyme defect is different from that of Sanfilippo D, in which N-acetylglucosamine-6-sulfate sulfatase deficiency is specific for heparan sulfate only.
MAROTEAUX-LAMY SYNDROME (MPS VI). The Maroteaux-Lamy syndrome resembles Hurler disease clinically but does not involve mental retardation. There are two clinical types: the severe form is designated type A, and the milder form, with less pronounced skeletal deformities, is designated type B.
Clinical Manifestations. Coarse facial features are typical of this syndrome. The head is enlarged, and the neck and trunk are short. The chest shows pectus carinatum deformity. Claw hands and other joint contractures are common. The abdomen protrudes owing to hepatosplenomegaly (Fig. 74–{endash}5 Fig. 74–{endash}5). Umbilical hernias and corneal opacities are frequent. Mental ability is usually not impaired, although hydrocephalus and increased intracranial pressure are sometimes associated with Maroteaux-Lamy disease. Cardiac involvement includes mitral insufficiency and aortic regurgitation. The roentgenographic findings are those of dysostosis multiplex seen in Hurler syndrome.
Diagnosis. The elevated urinary mucopolysaccharide in Maroteaux-Lamy syndrome is almost exclusively dermatan sulfate, and N-acetylglucosamine-4-sulfate sulfatase (arylsulfatase B) is the deficient enzyme. Types A and B have the same mucopolysacchariduria and the same enzyme deficiency. The findings of somatic changes resembling those of Hurler syndrome, normal mental development, and dermatan sulfaturia suggest either Maroteaux-Lamy or Hurler-Scheie syndrome. Deficiency of arylsulfatase B in white blood cells or cultured fibroblasts confirms the diagnosis of Maroteaux-Lamy syndrome.
Genetics. The Maroteaux-Lamy syndrome is an autosomal recessive disorder. The cDNA for human N-acetylgalactosamine-4-sulfatase (arylsulfatase B) has been isolated. The gene has been localized on the long arm of chromosome 5 (5q13{endash}–5q14). Expression of the cDNA in the deficient fibroblasts corrected the N-acetylgalactosamine-4-sulfatase deficiency in these fibroblasts. Several mutations have been identified, indicating a broad heterogeneity in the mutations. There are deletions, stop codons, and point mutations. The heterogeneity of the mutations can explain the clinical heterogeneity of this disease.
b{beta}-GLUCURONIDASE DEFICIENCY (MPS VII). Patients with this disease have clinical and skeletal features of mucopolysaccharidoses with hepatosplenomegaly, umbilical hernia, thoracolumbar gibbus, and mental retardation. Variations in the phenotypic expression of this enzyme defect have been reported; some patients have a clinical course similar to that of Hurler disease, whereas others have had no mental retardation and a very mild course. The roentgenographic changes are those of dysostosis multiplex. The severity of the bony changes may vary but at times they are indistinguishable from those seen in Hurler disease.
The biochemical findings are characterized by the mucopolysacchariduria of chondroitin 4/6 sulfate. The definitive diagnosis is made by establishing b{beta}-glucuronidase deficiency in white blood cells or in cultured skin fibroblasts.
Genetics. b{beta}-Glucuronidase deficiency is an autosomal recessive disorder. b{beta}-Glucuronidase has been purified and the human gene has been cloned and contains 12 exons. The gene has been localized to chromosome 7 (7q 21.11). Two different mutations have been reported. One of these results in substitution of arginine 382 for cystine and the other in substitution of alanine 619 for valine. Both of these mutations disrupt two highly conserved domains of the b{beta}-glucuronidase gene. Introduction of either of these two mutations iormal cDNAs produced deficient b{beta}-glucuronidase similar to that obtained from mutant gene products.
DIFFERENTIAL DIAGNOSIS OF THE MUCOPOLYSACCHARIDOSES
Diseases with dysostosis multiplex and physical features of the mucopolysaccharidoses are summarized in Table 74–{endash}1 Table 74–{endash}1.
Multiple sulfatase deficiency (see Chapter 72.3) may mimic the mucopolysaccharidoses in its clinical manifestations, roentgenographic findings, and the presence of mucopolysacchariduria. The mental and neurologic deterioration is usually more rapid than that seen in the Hurler or Hunter disease and often resembles metachromatic leukodystrophy. Severe ichthyosis, a constant feature, and hepatomegaly should raise the suspicion of multiple sulfatase deficiency in a patient suspected of having a mucopolysaccharidosis. Urinary screening for mucopolysaccharides and sulfatides is usually positive.
GM1 gangliosidosis (generalized gangliosidosis) (see Chapter 72.3) shares the clinical features of lipid and mucopolysaccharide storage diseases. Clinically, patients with the infantile severe form of generalized gangliosidosis are mentally retarded and hypotonic and have hepatosplenomegaly. In more than 50% there is a macular cherry-red spot.
Mannosidosis (see Chapter 73) is characterized by psychomotor retardation, hearing loss, coarse features with Hurler-like facial appearance, hepatosplenomegaly, muscular hypotonia, and mild dysostosis multiplex. There is no mucopolysacchariduria, but mannose-rich oligosaccharide is found in the urine.
Patients with fucosidosis (see Chapter 72.3) show coarse facial features, hepatosplenomegaly, severe psychomotor retardation, and dysostosis multiplex. There is no mucopolysacchariduria, and fucose-containing oligosaccharide is stored in tissues and
TREATMENT OF THE MUCOPOLYSACCHARIDOSES
Bone marrow transplantation as a specific therapy to replace the defective enzymes in the various mucopolysaccharidoses is being evaluated. Patients with Hurler disease benefit the most both in terms of peripheral disappearance of mucopolysaccharides and improvement in intellectual abilities. Usually the corneas clear, the liver and spleen get smaller, and mucopolysacchariduria normalizes. Skeletal changes do not improve. However, when the transplant is done early in life, skeletal deterioration may be minimal. Hunter syndrome patients and Sanfilippo patients do not seem to benefit intellectually from bone marrow transplantation. There is some experience with other mucopolysaccharidoses, but the number of cases are few.
Down syndrome
Boy with Down syndrome assembling a bookcase
Down syndrome (the most common term in US English) , Down’s syndrome (standard in British English), or trisomy 21 is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who described the syndrome in 1866. The disorder was identified as a chromosome 21 trisomy by Jérôme Lejeune in 1959. The condition is characterized by a combination of major and minor differences in structure. Often Down syndrome is associated with some impairment of cognitive ability and physical growth as well as facial appearance. Down syndrome in a baby can be identified with amniocentesis during pregnancy or at birth.
Individuals with Down syndrome tend to have a lower than average cognitive ability, often ranging from mild to moderate developmental disabilities. A small number have severe to profound mental disability. The incidence of Down syndrome is estimated at 1 per 800 to 1,000 births, although these statistics are heavily influenced by older mothers. Other factors may also play a role.
Many of the common physical features of Down syndrome may also appear in people with a standard set of chromosomes, including microgenia (an abnormally small chin), an unusually round face, macroglossia (protruding or oversized tongue), an almond shape to the eyes caused by an epicanthic fold of the eyelid, upslanting palpebral fissures (the separation between the upper and lower eyelids), shorter limbs, a single transverse palmar crease (a single instead of a double crease across one or both palms, also called the Simian crease), poor muscle tone, a larger thaormal space between the big and second toes. Health concerns for individuals with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid dysfunctions.
Early childhood intervention, screening for common problems, medical treatment where indicated, a conducive family environment, and vocational training can improve the overall development of children with Down syndrome. Although some of the physical genetic limitations of Down syndrome cannot be overcome, education and proper care will improve quality of life.
Characteristics
Example of white spots on the iris known as Brushfield spots
Individuals with Down syndrome may have some or all of the following physical characteristics: microgenia (abnormally small chin), oblique eye fissures with epicanthic skin folds on the inner corner of the eyes (formerly known as a mongoloid fold), muscle hypotonia (poor muscle tone), a flat nasal bridge, a single palmar fold, a protruding tongue (due to small oral cavity, and an enlarged tongue near the tonsils) or macroglossia, a short neck, white spots on the iris known as Brushfield spots,excessive joint laxity including atlanto-axial instability, congenital heart defects, excessive space between large toe and second toe, a single flexion furrow of the fifth finger, and a higher number of ulnar loop dermatoglyphs. Most individuals with Down syndrome have mental retardation in the mild (IQ 50–70) to moderate (IQ 35–50) range,with individuals having Mosaic Down syndrome typically 10–30 points higher. In addition, individuals with Down syndrome can have serious abnormalities affecting any body system. They also may have a broad head and a very round face.
The medical consequences of the extra genetic material in Down syndrome are highly variable and may affect the function of any organ system or bodily process. The health aspects of Down syndrome encompass anticipating and preventing effects of the condition, recognizing complications of the disorder, managing individual symptoms, and assisting the individual and his/her family in coping and thriving with any related disability or illnesses.
Down syndrome can result from several different genetic mechanisms. This results in a wide variability in individual symptoms due to complex gene and environment interactions. Prior to birth, it is not possible to predict the symptoms that an individual with Down syndrome will develop. Some problems are present at birth, such as certain heart malformations. Others become apparent over time, such as epilepsy.
The most common manifestations of Down syndrome are the characteristic facial features, cognitive impairment, congenital heart disease (typically a ventricular septal defect), hearing deficits (maybe due to sensory-neural factors, or chronic serous otitis media, also known as Glue-ear), short stature, thyroid disorders, and Alzheimer’s disease. Other less common serious illnesses include leukemia, immune deficiencies, and epilepsy.
However, health benefits of Down syndrome include greatly reduced incidence of many common malignancies except leukemia and testicular cancer — although it is, as yet, unclear whether the reduced incidence of various fatal cancers among people with Down syndrome is as a direct result of tumor-suppressor genes on chromosome 21 (such as Ets2), because of reduced exposure to environmental factors that contribute to cancer risk, or some other as-yet unspecified factor. In addition to a reduced risk of most kinds of cancer, people with Down syndrome also have a much lower risk of hardening of the arteries and diabetic retinopathy.
Cognitive development
Cognitive development in children with Down syndrome is quite variable. It is not currently possible at birth to predict the capabilities of any individual reliably, nor are the number or appearance of physical features predictive of future ability. The identification of the best methods of teaching each particular child ideally begins soon after birth through early intervention programs. Since children with Down syndrome have a wide range of abilities, success at school can vary greatly, which underlines the importance of evaluating children individually. The cognitive problems that are found among children with Down syndrome can also be found among typical children. Therefore, parents can use general programs that are offered through the schools or other means.
Language skills show a difference between understanding speech and expressing speech, and commonly individuals with Down syndrome have a speech delay, requiring speech therapy to improve expressive language. Fine motor skills are delayed and often lag behind gross motor skills and can interfere with cognitive development. Effects of the disorder on the development of gross motor skills are quite variable. Some children will begin walking at around 2 years of age, while others will not walk until age 4. Physical therapy, and/or participation in a program of adapted physical education (APE), may promote enhanced development of gross motor skills in Down syndrome children.
Individuals with Down syndrome differ considerably in their language and communication skills. It is routine to screen for middle ear problems and hearing loss; low gain hearing aids or other amplification devices can be useful for language learning. Early communication intervention fosters linguistic skills. Language assessments can help profile strengths and weaknesses; for example, it is common for receptive language skills to exceed expressive skills. Individualized speech therapy can target specific speech errors, increase speech intelligibility, and in some cases encourage advanced language and literacy. Augmentative and alternative communication (AAC) methods, such as pointing, body language, objects, or graphics are often used to aid communication. Relatively little research has focused on the effectiveness of communications intervention strategies.
In education, mainstreaming of children with Down syndrome is becoming less controversial in many countries. For example, there is a presumption of mainstream in many parts of the UK. Mainstreaming is the process whereby students of differing abilities are placed in classes with their chronological peers. Children with Down syndrome may not age emotionally/socially and intellectually at the same rates as children without Down syndrome, so over time the intellectual and emotional gap between children with and without Down syndrome may widen. Complex thinking as required in sciences but also in history, the arts, and other subjects can often be beyond the abilities of some, or achieved much later than in other children. Therefore, children with Down syndrome may benefit from mainstreaming provided that some adjustments are made to the curriculum.
Some European countries such as Germany and Denmark advise a two-teacher system, whereby the second teacher takes over a group of children with disabilities within the class. A popular alternative is cooperation between special schools and mainstream schools. In cooperation, the core subjects are taught in separate classes, which neither slows down the typical students nor neglects the students with disabilities. Social activities, outings, and many sports and arts activities are performed together, as are all breaks and meals.
Fertility
Fertility amongst both males and females is reduced; males are usually unable to father children, while females demonstrate significantly lower rates of conception relative to unaffected individuals.[citatioeeded] Approximately half of the offspring of someone with Down syndrome also have the syndrome themselves. There have been only three recorded instances of males with Down syndrome fathering children.
Genetics
Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21
Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The effects of the extra copy vary greatly among people, depending on the extent of the extra copy, genetic history, and pure chance. Down syndrome occurs in all human populations, and analogous effects have been found in other species such as chimpanzees and mice. Recently, researchers have created transgenic mice with most of human chromosome 21 (in addition to the normal mouse chromosomes). The extra chromosomal material can come about in several distinct ways. A typical human karyotype is designated as 46,XX or 46,XY, indicating 46 chromosomes with an XX arrangement typical of females and 46 chromosomes with an XY arrangement typical of males.
Trisomy 21
Trisomy 21 (47,XX,+21) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 21; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo now has 47 chromosomes, with three copies of chromosome 21. Trisomy 21 is the cause of approximately 95% of observed Down syndromes, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete.
Mosaicism
Trisomy 21 is usually caused by nondisjunction in the gametes prior to conception, and all cells in the body are affected. However, when some of the cells in the body are normal and other cells have trisomy 21, it is called mosaic Down syndrome (46,XX/47,XX,+21). This can occur in one of two ways: a nondisjunction event during an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21; or a Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement. There is considerable variability in the fraction of trisomy 21, both as a whole and among tissues. This is the cause of 1–2% of the observed Down syndromes.
Robertsonian translocation
The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation in the karyotype of one of the parents. In this case, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14 (45,XX, t(14;21q)) or itself (called an isochromosome, 45,XX, t(21q;21q)). A person with such a translocation is phenotypically normal. During reproduction, normal disjunctions leading to gametes have a significant chance of creating a gamete with an extra chromosome 21, producing a child with Down syndrome. Translocation Down syndrome is often referred to as familial Down syndrome. It is the cause of 2–3% of observed cases of Down syndrome. It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.
Duplication of a portion of chromosome 21
Rarely, a region of chromosome 21 will undergo a duplication event. This will lead to extra copies of some, but not all, of the genes on chromosome 21 (46,XX, dup(21q)). If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics. This cause is very rare and no rate estimates are available.
Screening
Ultrasound of fetus with Down syndrome and megacystis
Pregnant women can be screened for various complications during pregnancy. Many standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical cord blood sampling (PUBS) are usually offered to families who may have an increased chance of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. ACOG guidelines recommend that non-invasive screening and invasive testing be offered to all women, regardless of their age, and most likely all physicians currently follow these guidelines. However, some insurance plans will only reimburse invasive testing if a woman is >34 years old or if she has received a high-risk score from a non-invasive screening test.
Amniocentesis and CVS are considered invasive procedures, in that they involve inserting instruments into the uterus, and therefore carry a small risk of causing fetal injury or miscarriage. The risks of miscarriage for CVS and amniocentesis are often quoted as 1% and 0.5% respectively. There are several commoon-invasive screens that can indicate a fetus with Down syndrome. These are normally performed in the late first trimester or early second trimester. Due to the nature of screens, each has a significant chance of a false positive, suggesting a fetus with Down syndrome when, in fact, the fetus does not have this genetic abnormality. Screen positives must be verified before a Down syndrome diagnosis is made.
Common screening procedures for Down syndrome are given in Table 1.
|
Screen
|
When performed (weeks gestation) |
Detection rate |
False positive rate |
Description |
|
Quad screen |
15–20 |
81% |
5% |
This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), human chorionic gonadotropin (hCG, a pregnancy hormone), and inhibin-Alpha (INHA). |
|
Nuchal translucency/free beta/PAPPA screen (aka “1st Trimester Combined Test”) |
10–13.5 |
85% |
5% |
Uses ultrasound to measure Nuchal Translucency in addition to the freeBeta hCG and PAPPA (pregnancy-associated plasma protein A). NIH has confirmed that this first trimester test is more accurate than second trimester screening methods. Performing an NT ultrasound requires considerable skill; a Combined test may be less accurate if there is operator error, resulting in a lower-than-advertised sensitivity and higher false-positive rate, possibly in the 5-10% range. |
|
Integrated Test |
10-13.5 and 15–20 |
95% |
5% |
The Integrated test uses measurements from both the 1st Trimester Combined test and the 2nd trimester Quad test to yield a more accurate screening result. Because all of these tests are dependent on accurate calculation of the gestational age of the fetus, the real-world false-positive rate is >5% and maybe be closer to 7.5%. |
Even with the best non-invasive screens, the detection rate is 90%–95% and the rate of false positive is 2%–5%. Inaccuracies can be caused by undetected multiple fetuses (very rare with the ultrasound tests), incorrect date of pregnancy, or normal variation in the proteins.
Confirmation of screen positive is normally accomplished with amniocentesis or chorionic villus sampling (CVS). Amniocentesis is an invasive procedure and involves taking amniotic fluid from the amniotic sac and identifying fetal cells. The lab work can take several weeks but will detect over 99.8% of all numerical chromosomal problems with a very low false positive rate.
Plastic surgery
Plastic surgery has sometimes been advocated and performed on children with Down syndrome, based on the assumption that surgery can reduce the facial features associated with Down syndrome, therefore decreasing social stigma, and leading to a better quality of life. Plastic surgery on children with Down syndrome is uncommon, and continues to be controversial. Researchers have found that for facial reconstruction, “…although most patients reported improvements in their child’s speech and appearance, independent raters could not readily discern improvement….” For partial glossectomy (tongue reduction), one researcher found that 1 out of 3 patients “achieved oral competence,” with 2 out of 3 showing speech improvement. Len Leshin, physician and author of the ds-health website, has stated, “Despite being in use for over twenty years, there is still not a lot of solid evidence in favor of the use of plastic surgery in children with Down syndrome.” The National Down Syndrome Society has issued a “Position Statement on Cosmetic Surgery for Children with Down Syndrome” which states that “The goal of inclusion and acceptance is mutual respect based on who we are as individuals, not how we look.”
Alternative treatment
The Institutes for the Achievement of Human Potential is a non-profit organization which treats children who have, as the IAHP terms it, “some form of brain injury,” including children with Down syndrome. The approach of “Psychomotor Patterning” is not proven, and is considered alternative medicine.
Prognosis
These factors can contribute to a shorter life expectancy for people with Down syndrome. One study, carried out in the United States in 2002, showed an average lifespan of 49 years, with considerable variations between different ethnic and socio-economic groups. However, in recent decades, the life expectancy among persons with Down syndrome has increased significantly up from 25 years in 1980. The causes of death have also changed, with chronic neurodegenerative diseases becoming more common as the population ages. Most people with Down Syndrome who survive into their 40s and 50s begin to suffer from an alzheimer’s-like dementia.
Epidemiology
The incidence of Down syndrome is estimated at one per 800 to one per 1000 births. In 2006, the Centers for Disease Control and Prevention estimated the rate as one per 733 live births in the United States (5429 new cases per year). Approximately 95% of these are trisomy 21. Down syndrome occurs in all ethnic groups and among all economic classes.
Maternal age influences the chances of conceiving a baby with Down syndrome. At maternal age 20 to 24, the probability is one in 1562; at age 35 to 39 the probability is one in 214, and above age 45 the probability is one in 19. Although the probability increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35, reflecting the overall fertility of that age group. Recent data also suggest that paternal age, especially beyond 42, also increases the risk of Down Syndrome manifesting in pregnancies in older mothers.
Current research (as of 2008) has shown that Down syndrome is due to a random event during the formation of sex cells or pregnancy. There has beeo evidence that it is due to parental behavior (other than age) or environmental factors.
Edwards syndrome
Chromosome 18
Trisomy 18 (T18) (also known as Trisomy E or Edwards Syndrome) is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. It is named after John H. Edwards, who first described the syndrome in 1960. It is the second most common autosomal trisomy, after Down Syndrome, that carries to term.
Trisomy 18 is caused by the presence of three—as opposed to two—copies of chromosome
Prognosis
The survival rate of Edwards Syndrome is very low. About 95% die in utero. Of liveborn infants, only 50% live to 2 months, and only 5–10% will survive their first year of life. Major causes of death include apnea and heart abnormalities. It is impossible to predict the exact prognosis of an Edwards Syndrome child during pregnancy or the neonatal period. The median life span is five to fifteen days. One percent of children born with this syndrome live to age ten, typically in cases of the less severe mosaic Edwards syndrome.
Incidence/prevalence
The rate of occurrence for Edwards Syndrome is approximately one in 3,000 (for conception) and approximately one in 6,000 (for live births), as 50% of those diagnosed prenatally with the condition will not survive the prenatal period. Although women in their 20s and early 30s may conceive Edwards Syndrome babies, there is an increased risk of conceiving a child with Edwards Syndrome as a woman’s age increases, with the average age for this disorder being 32½.
Genetics
Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly among people, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in females.
A healthy egg or sperm cell contains individual chromosomes — one to contribute to each of the 23 pairs of chromosomes needed to form a normal cell with typical human karyotype of 46 chromosomes. Numerical errors arise at either of the two meiotic divisions and cause the failure of segregation of a chromosome into the daughter cells (nondisjunction). This results in an extra chromosome making the haploid number 24 rather than 23. Fertilization of these eggs or sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.
Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo now has 47 chromosomes, with three copies of chromosome 18.
A small percentage of cases occur when only some of the body’s cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected people have two copies of chromosome 18, plus extra material from chromosome 18 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 18 and the abnormalities are often less than for the typical Edwards syndrome.
Features and characteristics
Infants born with Edwards syndrome may have some or all of the following characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, mental retardation, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).
Some physical malformations associated with Edwards syndrome include: a small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid folds (palpebral fissures), widely-spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, underdeveloped thumbs and or nails, absent radius, webbing of the second and third toes, clubfoot or Rocker bottom feet, and undescended testicles in males.
In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common head shape anomaly is the presence of choroid plexus cysts, which is a pocket of fluid on the brain that is not problematic in itself but may be a marker for Trisomy 18. Sometimes excess amniotic fluid or polyhydramnios is exhibited.
Klinefelter’s Syndrome
Klinefelter’s Syndrome, genetic disease affecting
Both men and womeormally have 23 pairs of chromosomes. One of these pairs is the sex chromosome. A female normally inherits an X chromosome from each parent so that her chromosomal complement is XX. A male inherits an X chromosome from his mother and a Y chromosome from his father so that his chromosomal complement is XY. It is the presence of the Y chromosome that determines maleness. A male with Klinefelter’s syndrome inherits an extra X chromosome, giving him an abnormal chromosomal complement of XXY. In some cases, more than one extra X chromosome is inherited. The cause of Klinefelter’s syndrome is unknown, although it occurs slightly more often in boys born to older mothers.
In most cases, a boy with Klinefelter’s syndrome has a normal physical appearance until he reaches puberty. Diagnosis of the disorder may be delayed until physical symptoms develop, or until the adult male is tested for infertility. Diagnosis of the disorder is made by performing a chromosomal analysis in which body cells are studied in the laboratory to identify any chromosomal irregularities.
There is no treatment for Klinefelter’s syndrome, although regular injections of the male sex hormone testosterone may increase muscle size and strength, stimulate the growth of facial and body hair, and produce a normal sex drive in some cases. Enlarged breasts may be reduced surgically. Reversing infertility associated with Klinefelter’s syndrome may not be possible. Some men with the disorder may produce a small number of sperm, and they may benefit from modern fertility techniques in which a single sperm is injected into an egg to achieve fertilization
, 47, XXY or XXY syndrome is a condition in which males have an extra X sex chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome. Klinefelter’s syndrome is the most common sex chromosome disorder and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 1000 males. One in every 500 males have an extra x chromosome but do not have the syndrome.
The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. Named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, Boston, Massachusetts, who first described it in 1942[4]. Because of the extra chromosome, individuals with the condition are usually referred to as “XXY Males”, or “47, XXY Males”.
Signs and symptoms
Affected males are almost always effectively infertile although advanced reproductive assistance is sometimes possible. Some degree of language learning impairment may be present, and neuropsychological testing often reveals deficits in executive functions. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males’ gynecomastia is noticeable enough to require surgery.
The term “hypogonadism” in XXY symptoms is often misinterpreted to mean “small testicles” or “small penis”. In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men often also have “microorchidism” (i.e. small testicles).
The more severe end of the spectrum of symptom expression is also associated with an increased risk of germ cell tumors, breast cancer, and osteoporosis, risks shared to varying degrees with females. Additionally, medical literature shows some individual case studies of Klinefelter’s syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis, but possible correlations between Klinefelter’s and these other conditions are not well characterized or understood.
In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur even less frequently in XXY males than iormal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.
There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype testing.
Diagnosis
A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
Diagnosis can also be made prenatally via chorionic villus sampling or amniocentesis, tests in which fetal tissue is extracted and the fetal DNA is examined for genetic abnormalities. A 2002 literature review of elective abortion rates found that approximately 50% of pregnancies in the United States with a diagnosis of Klinefelter’s syndrome were terminated.
Cause
The extra X chromosome is retained because of a nondisjunction event during meiosis (sex cell division). The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about
In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females.However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes, have corresponding genes on their Y chromosome and are capable of being expressed.These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter’s syndrome.
The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital in Edinburgh, Scotland in 1959. This karyotype was found in a 24-year-old man who had signs of Klinefelter’s syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.
Treatment
The genetic variation is irreversible. Testosterone treatment is an option for some individuals who desire a more masculine appearance and identity. Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial morbidity. At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.
Variations
The 48, XXYY (male) syndrome occurs
Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.
Trisomy 18 Edwards’ Syndrome
Introduction
Trisomy 18 syndrome (also known as Edwards’ syndrome, after Dr. John Edwards) is a rare chromosomal disorder in which there are three copies of chromosome 18 (trisomy) rather than the usual two. It is characterized by specific dysmorphic features and organ malformations. While the majority of Trisomy 18 cases are “full” trisomy (where there are three copies of chromosome
Features and Characteristic
Symptoms and findings may be extremely variable from case to case. However, in many affected infants, the following may be found:
Growth deficiency
Feeding difficulties
Breathing difficulties
Developmental delays
Mental Retardation
Undescended testicles in males
Prominent back portion of the head
Small head (microcephaly)
Low-set, malformed ears
Abnormally small jaw (micrognathia)
Small mouth
Cleft lip/palate
Upturned nose
Narrow eyelid folds (palpebral fissures)
Widely-spaced eyes (ocular hypertelorism)
Dropping of the upper eyelids (ptosis)
Overlapped, flexed fingers
Underdeveloped or absent thumbs
Underdeveloped nails
Webbing of the second and third toes
Clubfeet
Small pelvis with limited movements of the hips
Short breastbone
Kidney malformations
Structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus)
Diagnosis
Intrauterine diagnosis is possible with an amniocentesis and chromosome studies. Chromosome studies may be indicated when the mother’s uterus appears unusually large during pregnancy, there is feeble fetal activity, there is an excess of fluid in the fetal sac, a small placenta is noted, and there is a single umbilical artery.
For those cases who are not diagnosed prenatally, the first sign of Trisomy 18 may be seen at birth when the baby appears thin and frail, he or she fails to thrive, has a weak cry, and is small for his or her gestational age. Various other features (as mentioned above) may be indicative of the syndrome as well. Chromosome studies, however, are performed to verify the diagnosis.
Treatment
There is no cure for Trisomy 18, therefore, treatment is based on managing symptoms. For example, many babies with Trisomy 18 have feeding problems that involve breathing, sucking, and swallowing difficulties. Others may have clefts, reflux, or problems with aspiration. For these children, a dysphagia clinic or feeding specialist (i.e., an occupational therapist) may be able to help improve feeding skills. In other cases, a G-tube may be necessary.
Some children with heart problems have difficulty gaining weight. For babies with this problem, parents may work with a nutritionist to devise ways to increase the baby’s caloric intake.
Many children with Trisomy 18 suffer from irritability due to constipation. To help with this, special formula may be needed to form a softer stool or a stool softener medication may be needed. Parents should always seek the advice of their child’s doctor before trying any medication to treat constipation or other health concerns.
Problems with muscle tone and other nervous system abnormalities are common in children with Trisomy 18. Motor skills are often affected and can lead to other problems, such as scoliosis. Physical and occupational therapy should be provided to improve fine and gross motor skills.
Some children have hearing and vision impairments. Hearing aides and glasses should be considered for such children.
Turner syndrome
Turner syndrome or Ullrich-Turner syndrome (also known as “Gonadal dysgenesis”:550) encompasses several conditions, of which monosomy X (deletion of an entire X chromosome) is most common. It is a chromosomal disorder in which all or part of one of the sex chromosomes is absent (unaffected humans have 46 chromosomes, of which 2 are sex chromosomes). Typical females have 2 X chromosomes, but in Turner syndrome, one of those sex chromosomes is missing or has other abnormalities. In some cases, the missing chromosome is present in some cells but not others, a condition referred to as mosaicism.
Occurring in 1 out of every 2500 girls, the syndrome manifests itself in a number of ways. There are characteristic physical abnormalities, such as short stature, swelling, broad chest, low hairline, low-set ears, and webbed necks. Girls with Turner syndrome typically experience gonadal dysfunction (non-working ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Concurrent health concerns are also frequently present, including congenital heart disease, hypothyroidism (reduced hormone secretion by the thyroid), diabetes, vision problems, hearing concerns, and many other autoimmune diseases. Finally, a specific pattern of cognitive deficits is often observed, with particular difficulties in visuospatial, mathematic, and memory areas.
Symptoms
The arrows point to some of the classical features of Turner’s syndrome: (A) short webbed neck; (B) cubitus valgus; (C) lymphedema.
Common symptoms of Turner syndrome include:
Short stature
Lymphedema (swelling) of the hands and feet
Broad chest (shield chest) and widely-spaced nipples
Low hairline
Low-set ears
Reproductive sterility
Rudimentary ovaries gonadal streak (underdeveloped gonadal structures)
Amenorrhea, or the absence of a menstrual period
Increased weight, obesity
Shield shaped thorax of heart
Shortened metacarpal IV (of hand)
Small fingernails
Characteristic facial features
Webbed neck from cystic hygroma in infancy
Coarctation of the aorta
Poor breast development
Horseshoe kidney
Visual impairments sclera, cornea, glaucoma, etc.
Ear infections and hearing loss
Other symptoms may include a small lower jaw (micrognathia), cubitus valgus (turned-out elbows), soft upturned nails, palmar crease and drooping eyelids. Less common are pigmented moles, hearing loss, and a high-arch palate (narrow maxilla). Turner syndrome manifests itself differently in each female affected by the condition, and no two individuals will share the same symptoms.
Risk factors
Risk factors for Turner syndrome are not well known. Nondisjunctions increase with maternal age, such as for Down syndrome, but that effect is not clear for Turner syndrome. It is also unknown if there is a genetic predisposition present that causes the abnormality, though most researchers and doctors treating Turners women agree that this is highly unlikely. There is currently no known cause for Turner syndrome, though there are several theories surrounding the subject. The only solid fact that is known today, is that during conception part or all of the X chromosome is not transferred to the fetus.
Incidence
Approximately 98% of all fetuses with Turner syndrome result in miscarriage.[citatioeeded] Turner syndrome accounts for about 10% of the total number of spontaneous abortions in the
History
The syndrome is named after Henry Turner, an
Diagnosis
Turner syndrome may be diagnosed by amniocentesis during pregnancy. Sometimes, fetuses with Turner syndrome are identified by abnormal ultrasound findings (i.e. heart defect, kidney abnormality, cystic hygroma, ascites). Although the recurrence risk is not increased, genetic counseling is often recommended for families who have had a pregnancy or child with Turner syndrome.
A test, called a karyotype or a chromosome analysis, analyzes the chromosomal composition of the individual. This is the test of choice to diagnose Turner syndrome.
Prognosis
While most of the physical findings in Turner syndrome are harmless, there can be significant medical problems associated with the syndrome.
Cardiovascular
Price et al. (1986 study of 156 female patients with Turner syndrome) showed a significantly greater number of deaths from diseases of the circulatory system than expected, half of them due to congenital heart disease—mostly preductal coarctation of the aorta. When patients with congenital heart disease were omitted from the sample of the study, the mortality from circulatory disorders was not significantly increased.
Cardiovascular malformations are a serious concern as it is the most common cause of death in adults with Turner syndrome. It takes an important part in the 3-fold increase in overall mortality and the reduced life expectancy (up to 13 years) associated with Turner syndrome.
Cause
According to Sybert, 1998 the data is inadequate to allow conclusions about phenotype-karyotype correlations in regard to cardiovascular malformations in Turner syndrome because the number of individuals studied within the less common karyotype groups is too small. Other studies also suggest the presence of hidden mosaicisms that are not diagnosed on usual karyotypic analyses in some patients with 45,X karyotype.
In conclusion, the associations between karyotype and phenotypic characteristics, including cardiovascular malformations, remain questionable.
Prevalence of cardiovascular malformations
The prevalence of cardiovascular malformations among patients with Turner syndrome ranges from 17% (Landin-Wilhelmsen et al., 2001) to 45% (Dawson-Falk et al., 1992).
The variations found in the different studies are mainly attributable to variations in non-invasive methods used for screening and the types of lesions that they can characterize (Ho et al., 2004). However Sybert, 1998 suggests that it could be simply attributable to the small number of subjects in most studies.
Different karyotypes may have differing prevalence of cardiovascular malformations. Two studies found a prevalence of cardiovascular malformations of 30% and 38% in a group of pure 45,X monosomy. But considering other karyotype groups, they reported a prevalence of 24.3% and 11% in patients with mosaic X monosomy , and a prevalence of 11% in patients with X chromosomal structural abnormalities.
The higher prevalence in the group of pure 45,X monosomy is primarily due to a significant difference in the prevalence of aortic valve abnormalities and aortic coarctation, the two most common cardiovascular malformations.
Congenital heart disease
The most commonly observed are congenital obstructive lesions of the left side of the heart, leading to reduced flow on this side of the heart. This includes bicuspid aortic valve and coarctation of the aorta. Sybert, 1998 found that more than 50% of the cardiovascular malformations observed in her study of individuals with Turner syndrome were bicuspid aortic valves or coarctation of the aorta, alone or in combination.
Other congenital cardiovascular malformations such partial anomalous venous drainage and aortic stenosis or aortic regurgitation are also more common in Turner syndrome than in the general population. Hypoplastic left heart syndrome represents the most severe reduction in left-sided structures.
Bicuspid aortic valve. Up to 15% of adults with Turner syndrome have bicuspid aortic valves, meaning that there are only two, instead of three, parts to the valves in the main blood vessel leading from the heart. Since bicuspid valves are capable of regulating blood flow properly, this condition may go undetected without regular screening. However, bicuspid valves are more likely to deteriorate and later fail. Calcification also occurs in the valves, which may lead to a progressive valvular dysfunction as evidenced by aortic stenosis or regurgitation.
With a prevalence from 12.5% to 17.5% (Dawson-Falk et al., 1992), bicuspid aortic valve is the most common congenital malformation affecting the heart in this syndrome. It is usually isolated but it may be seen in combination with other anomalies, particularly coarctation of the aorta.
Coarctation of the aorta. Between 5% and 10% of those born with Turner syndrome have coarctation of the aorta, a congenital narrowing of the descending aorta, usually just distal to the origin of the left subclavian artery and opposite to the duct (and so termed “juxtaductal”). Estimates of the prevalence of this malformation in patients with Turner syndrome ranges from 6.9%[8] to 12.5% (Dawson-Falk et al., 1992). A coarctation of the aorta in a female is suggestive of Turner syndrome, and suggests the need for further tests, such as a karyotype.
Partial anomalous venous drainage. This abnormality is a relatively rare congenital heart disease in the general population. The prevalence of this abnormality also is low (around 2.9%) in Turner syndrome. However, its relative risk is
In the management of a patient with Turner syndrome it is essential to keep in mind that these left-sided cardiovascular malformations in Turner syndrome result in an increased susceptibility to bacterial endocarditis. Therefore prophylactic antibiotics should be considered when procedures with high risk endocarditis are performed, such as dental cleaning.
Turner syndrome is often associated with persistent hypertension, sometimes in childhood. In the majority of Turner syndrome patients with hypertension, there is no specific cause. In the remainder, it is usually associated with cardiovascular or kidney abnormalities, including coarctation of the aorta.
Aortic dilation, dissection, and rupture
Two studies have suggested aortic dilatation in Turner syndrome, typically involving the root of the ascending aorta and occasionally extending through the aortic arch to the descending aorta, or at the site of previous coarctation of the aorta repair.
Allen et al., 1986 who evaluated 28 girls with Turner syndrome, found a significantly greater mean aortic root diameter in patients with Turner syndrome than in the control group (matched for body surface area). Nonetheless, the aortic root diameter found in Turner syndrome patients were still well within the limits.
This has been confirmed by the study of Dawson-Falk et al., 1992 who evaluated 40 patients with Turner syndrome. They presented basically the same findings: a greater mean aortic root diameter, which nevertheless remains within the normal range for body surface area.
Sybert, 1998 points out that it remains unproven that aortic root diameters that are relatively large for body surface area but still well withiormal limits imply a risk for progressive dilatation.
Prevalence of aortic abnormalities
The prevalence of aortic root dilatation ranges from 8.8% to 42% in patients with Turner syndrome. Even if not every aortic root dilatatioecessarily goes on to an aortic dissection (circumferential or transverse tear of the intima), complications such as dissection, aortic rupture resulting in death may occur. The natural history of aortic root dilatation is still unknown, but it is a fact that it is linked to aortic dissection and rupture, which has a high mortality rate.
Aortic dissection affects 1% to 2% of patients with Turner syndrome. As a result any aortic root dilatation should be seriously taken into account as it could become a fatal aortic dissection. Routine surveillance is highly recommended.
Risk factors for aortic rupture
It is well established that cardiovascular malformations (typically bicuspid aortic valve, coarctation of the aorta and some other left-sided cardiac malformations) and hypertension predispose to aortic dilatation and dissection in the general population. At the same time it has been shown that these risk factors are common in Turner syndrome. Indeed these same risk factors are found in more than 90% of patients with Turner syndrome who develop aortic dilatation. Only a small number of patients (around 10%) have no apparent predisposing risk factors. It is important to note that the risk of hypertension is increased 3-fold in patients with Turner syndrome. Because of its relation to aortic dissection blood pressure needs to be regularly monitored and hypertension should be treated aggressively with an aim to keep blood pressure below 140/80 mmHg. It has to be noted that as with the other cardiovascular malformations, complications of aortic dilatation is commonly associated with 45,X karyotype.
Pathogenesis of aortic dissection and rupture
The exact role that all these risk factors play in the process leading to such fatal complications is still quite unclear. Aortic root dilatation is thought to be due to a mesenchymal defect as pathological evidence of cystic medial necrosis has been found by several studies. The association between a similar defect and aortic dilatation is well established in such conditions such as Marfan Syndrome. Also, abnormalities in other mesenchymal tissues (bone matrix and lymphatic vessels) suggests a similar primary mesenchymal defect in patients with Turner syndrome. However there is no evidence to suggest that patients with Turner syndrome have a significantly higher risk of aortic dilatation and dissection in absence of predisposing factors. So the risk of aortic dissection in Turner syndrome appears to be a consequence of structural cardiovascular malformations and hemodynamic risk factors rather than a reflection of an inherent abnormality in connective tissue (Sybert, 1998). The natural history of aortic root dilatation is unknown, but because of its lethal potential, this aortic abnormality needs to be carefully followed.
Pregnancy
As more women with Turner syndrome complete pregnancy thanks to the new modern techniques to treat infertility, it has to be noted that pregnancy may be a risk of cardiovascular complications for the mother. Indeed several studies had suggested an increased risk for aortic dissection in pregnancy. Three deaths have even been reported. The influence of estrogen has been examined but remains unclear. It seems that the high risk of aortic dissection during pregnancy in women with Turner syndrome may be due to the increased hemodynamic load rather than the high estrogen rate. Of course these findings are important and need to be remembered while following a pregnant patient with Turner syndrome.
Cardiovascular malformations in Turner syndrome are also very serious, not only because of their high prevalence in that particular population but mainly because of their high lethal potential and their great implication in the increased mortality found in patients with Turner syndrome. Congenital heart disease needs to be explored in every female newly diagnosed with Turner syndrome. As adults are concerned close surveillance of blood pressure is needed to avoid a high risk of fatal complications due to aortic dissection and rupture.
Skeletal
Normal skeletal development is inhibited due to a large variety of factors, mostly hormonal. The average height of a woman with Turner syndrome, in the absence of growth hormone treatment, is 4’7″, about
The fourth metacarpal bone (fourth toe and ring finger) may be unusually short, as may the fifth.
Due to inadequate production of estrogen, many of those with Turner syndrome develop osteoporosis. This can decrease height further, as well as exacerbate the curvature of the spine, possibly leading to scoliosis. It is also associated with an increased risk of bone fractures.
Kidney
Approximately one-third of all women with Turner syndrome have one of three kidney abnormalities:
A single, horseshoe-shaped kidney on one side of the body.
An abnormal urine-collecting system.
Poor blood flow to the kidneys.
Some of these conditions can be corrected surgically. Even with these abnormalities, the kidneys of most women with Turner syndrome functioormally. However, as noted above, kidney problems may be associated with hypertension.
Thyroid
Approximately one-third of all women with Turner syndrome have a thyroid disorder. Usually it is hypothyroidism, specifically Hashimoto’s thyroiditis. If detected, it can be easily treated with thyroid hormone supplements.
Diabetes
Women with Turner syndrome are at a moderately increased risk of developing type 1 diabetes in childhood and a substantially increased risk of developing type 2 diabetes by adult years. The risk of developing type 2 diabetes can be substantially reduced by maintaining a normal weight.
Cognitive
Turner syndrome does not typically cause mental retardation or impair cognition. However, learning difficulties are common among women with Turner syndrome, particularly a specific difficulty in perceiving spatial relationships, such as Nonverbal Learning Disorder. This may also manifest itself as a difficulty with motor control or with mathematics. While it is non-correctable, in most cases it does not cause difficulty in daily living.
There is also a rare variety of Turner Syndrome, known as “Ring-X Turner Syndrome”, which has an approximate 60% association with mental retardation. This variety accounts for approximately 2 – 4% of all Turner Syndrome cases.
Reproductive
Women with Turner syndrome are almost universally infertile. While some women with Turner syndrome have successfully become pregnant and carried their pregnancies to term, this is very rare and is generally limited to those women whose karyotypes are not 45,X. Even when such pregnancies do occur, there is a higher than average risk of miscarriage or birth defects, including Turner Syndrome or Down Syndrome. Some women with Turner syndrome who are unable to conceive without medical intervention may be able to use IVF or other fertility treatments.
Usually estrogen replacement therapy is used to spur growth of secondary sexual characteristics at the time when puberty should onset. While very few women with Turner Syndrome menstruate spontaneously, estrogen therapy requires a regular shedding of the uterine lining (“withdrawal bleeding”) to prevent its overgrowth. Withdrawal bleeding can be induced monthly, like menstruation, or less often, usually every three months, if the patient desires. Estrogen therapy does not make a woman with nonfunctional ovaries fertile, but it plays an important role in assisted reproduction; the health of the uterus must be maintained with estrogen if an eligible woman with Turner Syndrome wishes to use IVF.
Treatment
As a chromosomal condition, there is no cure for Turner syndrome. However, much can be done to minimize the symptoms. For example:
Growth hormone, either alone or with a low dose of androgen, will increase growth and probably final adult height. Growth hormone is approved by the U.S. Food and Drug Administration for treatment of Turner syndrome and is covered by many insurance plans. There is evidence that this is effective, even in toddlers.
Estrogen replacement therapy has been used since the condition was described in 1938 to promote development of secondary sexual characteristics. Estrogens are crucial for maintaining good bone integrity and tissue health. Women with Turner Syndrome who do not have spontaneous puberty and who are not treated with estrogen are at high risk for osteoporosis.
Modern reproductive technologies have also been used to help women with Turner syndrome become pregnant if they desire. For example, a donor egg can be used to create an embryo, which is carried by the Turner syndrome woman.
Uterine maturity is positively associated with years of estrogen use, history of spontaneous menarche, and negatively associated with the lack of current hormone replacement therapy.
Basic:
1. Medical Genetics + Student Consult, 4th Edition. Lynn B. Jorde, John C. Carey, MPH and Michael J. Bamshad, 2010, p. 368. ISBN: 978-032-305-373-0
2. Essential Medical Genetics, 6 edition. Edward S. Tobias, Michael Connor, Malcolm Ferguson Smith. Published by Wiley-Blackwell, 2011, p. 344. ISBN: 978-140-516-974-5
3. Emery’s Elements of Medical Genetics + Student Consult, 14th Edition Peter D Turnpenny, 2012 p. 464. ISBN: 978-070-204-043-6
4. Genes, Chromosomes, and Disease: From Simple Traits, to Complex Traits, to Personalized Medicine. Nicholas Wright Gillham. Published by FT Press Science, 2011. p. 352.
5. Management of Genetic Syndromes. Suzanne B. Cassidy, Judith E. Allanson; 3 edition. Published by Wiley-Blackwell. 2010 p. 984 ISBN: 978-047-019-141-5.
6. Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment (Milunsky, Genetic Disorders and the Fetus) 6 edition. Aubrey Milunsky and Jeff Milunsky. Published by Wiley-Blackwell, 2010 p. 1184 ISBN: 978-140-519-087-9
7. Molecular Diagnostics: Fundamentals, Methods, & Clinical Applications. 1st edition. Buckingham L, Flaws ML. F.A. Davis. 2007.
8. Passarge E. Color Atlas of Genetics – Thieme, 2007 Р. 497
Additional:
1. Atlas of Inherited Metabolic Diseases 3 edition William L Nyhan Bruce A Barshop, Aida I Al-Aqeel. Published by CRC. Press 2011, p 888. ISBN: 978-144-411-225-2.
2. Inborn Metabolic Diseases: Diagnosis and Treatment Jean-Marie Saudubray, Georges van den Berghe, John H. Walter. 5th ed. Published by Springer, 2012, p. 684. ISBN: 978-364-215-719-6.
3. Chromosome Abnormalities and Genetic Counseling (Oxford Monographs on Medical Genetics). 4 edition R. J. M. Gardner, Grant R Sutherland and Lisa G. Shaffer. Published by Oxford University Press, USA; 2011 p.648. ISBN: 978-019-537-533-6.
4. Mitochondrial Medicine: Mitochondrial Metabolism, Diseases, Diagnosis and Therapy Editored by Anna Gvozdjáková. Published by Soringer, 2008, p. 409 ISBN 978-1-4020-6713-6
5. Mitochondrial DNA, Mitochondria, Disease and Stem Cells (Stem Cell Biology and Regenerative Medicine) Editor Justin C. St. John. Published by Humana Press, 2012 p.199. ISBN: 978-162-703-100-4.
6. Genetic Counseling Practice: Advanced Concepts and Skills. Bonnie S. LeRoy, Patricia M. Veach, Dianne M. Bartels. Published by Wiley-Blackwell, 2010, p. 415. ISBN: 978-047-018-355-7
7. A Guide to Genetic Counseling 2 edition; Wendy R. Uhlmann, Jane L. Schuette, Beverly Yashar. Published by Wiley-Blackwell, 2010, p. 644. ISBN: 978-047-017-965-9
