Lecture 4
General characterization of mitochondrial pathology. Clinical symptoms. Diagnostics. Treatment.
Mitochondria are ubiquitous organelles that are intimately involved in many cellular processes, but whose principal task is to provide the energy necessary for normal cell functioning and maintenance. Disruption of this energy supply can have devastating consequences for the cell, organ, and individual. Over the last two decades, mutations in both mitochondrial DNA (mtDNA) and nuclear DNA have been identified as causative in a number of well-characterized clinical syndromes, although for mtDNA mutations in particular, this relationship between genotype and phenotype is ofteot straightforward. Despite this, a number of epidemiological studies have been undertaken to assess the prevalence of mtDNA mutations and these have highlighted the impact that mtDNA disease has on both the community and individual families. Although there has been considerable improvement in the diagnosis of mitochondrial disorders, disappointingly this has not been matched by developments toward effective treatment. Nevertheless, our understanding of mitochondrial biology is gathering pace and progress in this area will be crucial to devising future treatment strategies. In addition to mitochondrial disease, evidence for a central role of mitochondria in other processes, such as aging and neurodegeneration, is slowly accumulating, although their role in cancer remains controversial. In this chapter, we discuss these issues and offer our own views based on our cumulative experience of investigating and managing these diseases over the last 20 years.
Mitochondria are intracellular organelles that play a critical role in cellular metabolism. Mitochondria contain the electron transport chain, which transfers electrons to oxygen by means of a process called oxidative phosphorylation. This process releases energy for the production of adenosine triphosphate (ATP) by forming a pH and electrical gradient (called the chemiosmotic gradient) across the inner mitochondrial membrane. In addition to oxidative phosphorylation, the mitochondria fulfill a number of other functions, including the following:
Make ATP for cellular energy
Metabolize fats, carbohydrates, and amino acids
Interconvert carbohydrates, fats, and amino acids
Synthesize some proteins
Reproduce themselves (replicate)
Participate in apoptosis
Make free radicals
Of these functions apoptosis is particularly important in development and disease. However, human disease may result from impairment of any of these functions.
Mitochondria are inherited from the mother, but not from the father. In the process of egg formation, there is thought to be a “bottleneck” in mitochondrial number, such that the unfertilized egg may have as few as 1,000 mitochondria. This number increases 100-fold after the ovum is fertilized. The mitochondria contain their own DNA, mitochondrial or mtDNA, and during development there may be selective amplification of some of these mtDNA molecules, leading to increases or decreases in the presence of mutated mtDNAs.
The Importance of the Electron Transport Chain
The origins of mitochondria are unknown, but the likely explanation, called the endosymbiont hypothesis, holds that they arose as free-living bacteria that colonized proto-eukaryotic cells, thereby establishing a symbiotic relationship. Primitive eukaryotic cells with intracellular mitochondria capable of metabolizing oxygen would have had an advantage in an oxygen-rich environment. The electron transport chain produces far more energy for each molecule of glucose consumed than is produced by anaerobic respiration. The oxidative phosphorylation process conducted by the mitochondria produces thirty-eight molecules of ATP, compared to two molecules of ATP produced by anaerobic glycolysis. Oxidative phosphorylation allows the conversion of toxic oxygen to water, a protective biological advantage.
A disadvantage of oxidative phosphorylation, however, is the formation of reactive oxygen species, such as singlet oxygen and hydroxyl radicals, which damage such cellular components as lipids, proteins, and DNA. A normally functioning electron transport chain produces reactive oxygen species from about 2 percent of the electrons that it transports. In disease states and in aging, larger quantities of reactive oxygen species are generated, and this may be a significant factor in cellular deterioration as well as a major contributor to the aging process.
Mitochondrial Genes and Disease
Mitochondrial DNA encodes approximately 3 percent of mitochondrial proteins. The relative contribution of the mitochondrial and nuclear genomes in coding for electron transport chain subunits is detailed in Figure 1. Human mtDNA contains 16,569 nucleotide bases and encodes thirteen polypeptides of the electron transport chain, twenty-two transfer RNAs (tRNAs) and two ribosomal RNAs (rRNAs). In addition, mtDNA has a control region (termed the D-loop), which contains considerable genetic variation. The D-loop forms the basis of forensic medicine DNA identification and has been very useful in the molecular anthropological study of human origins.
In 1988 the first human disease associated with mtDNA deletions was reported. These patients suffered from muscle and brain diseases with ragged red fiber muscle disease (myopathy), with or without progressive neurological deterioration. Ragged red fibers are muscle fibers, that have a disorganized structure and an excess of abnormal mitochondria and that stain red when treated with a histochemical stain called modified Gomori trichrome. In 1988 Kearns-Sayre syndrome, which primarily affects the muscles, heart, and brain, was found to be due to mtDNA deletions or duplications. About the same time, the maternally inherited disorder Leber’s hereditary optic atrophy was traced to point mutations in mitochondrial DNA encoding subunits of complex I of the electron transport chain.
Mitochondrial diseases tend to affect multiple organ systems. The cells and organs most severely affected are those most heavily dependent on ATP, such as those listed in Table 1. Patients will frequently have multiple symptoms or signs, a circumstance that often causes confusion in diagnosis and treatment.
Classification
Mitochondrial myopathies
Diabetes mellitus and deafness (DAD)
this combination at an early age can be due to mitochondrial disease
Diabetes mellitus and deafness can also be found together for other reasons
Leber’s hereditary optic neuropathy (LHON)
visual loss beginning in young adulthood
Wolff-Parkinson-White syndrome
multiple sclerosis-type disease
Leigh syndrome, subacute sclerosing encephalopathy
after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood
a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
progressive symptoms as described in the acronym
dementia
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
gastrointestinal pseudo-obstruction
neuropathy
One of the more common presentations of mitochondrial disease in infants and young children is Leigh’s disease, first described by the pathologist Dennis Leigh in 1951. This progressive disease primarily affects the brain, with episodic deterioration that is often triggered by mild viral illnesses. Other organ systems are often involved, and there is often high blood or brain lactic acid as a result of a failure in oxidative metabolism (lactic acid is formed from glucose in the absence of oxygen). Complex I and IV defects are autosomal recessive diseases, with the culprit genes residing on the nuclear chromosomes. Complex V mutations are mtDNA inherited, and another 25 percent of cases are X-linked, due to pyruvate dehydrogenase deficiency
One of the most common mtDNA diseases seen is due to a single point mutation at position 3,243, with an adenine to guanine mutation in a tRNA leucine gene. Patients with this mutation may have phenotypes ranging from asymptomatic (that is, having no visible effects) to diabetes mellitus (with or without deafness). It is estimated that 1 to 2 percent of all diabetics have the A3243G mutation as the cause, affecting 200,000 people in the United States alone. The most severe phenotype to occur from this mutation has been given the acronym MELAS, for mitochondrial encephalomyopathy, with lactic acidosis and stroke-like episodes. The variability of disease phenotype or heterogeneity of disease due to mtDNA mutations arises in part because of variations in the amount of mutated mtDNA within different tissues. This mixture of wild type and mutant DNA within a cell is called heteroplasmy. In many mtDNA diseases, heteroplasmy changes over time, so that there is an increase in mutant DNA in nondividing cells and tissues such as muscle, heart, and brain, with a decrease over time in rapidly dividing tissues such as bone marrow.
LEBER’S SYNDROME
(Leber Hereditary Optic Neuropathy ,Hereditary Optic Neuroretinopathy, LHON, Leber’s Disease, Leber’s Optic Atrophy, Leber’s Optic Neuropathy)
Clinical Diagnosis
Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are approximately four times more likely to be affected than females.
Acute phase
Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye an average of eight weeks later. In an estimated 25% of cases, visual loss is bilateral at onset.
The ocular fundus may have a characteristic appearance that includes disk swelling, edema of the peripapillary nerve fiber layer, retinal telangiectasia, and an increased vascular tortuosity. The changes may be subtle; approximately 20% of affected individuals show no fundal abnormalities.
Visual acuity is severely reduced, to counting fingers or worse in most cases, and visual field testing (Goldmann perimetry or a similar technique) shows an enlarging central or centrocecal scotoma.
Atrophic phase. After the acute phase, the optic discs become atrophic. Significant improvements in visual acuity are rare; in most individuals, vision remains severely impaired and within the legal requirement for blind registration.
Other findings. The pathologic hallmark of LHON is the selective degeneration of the retinal ganglion cell layer and optic nerve.
Although visual failure is the defining feature in this mitochondrial disorder, cardiac arrhythmias and neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in LHON as compared to controls . In addition, the association between all three primary LHON-causing mtDNA mutations and an MS-like illness among Caucasians, especially females, is well known .
Family history. Affected individuals are often aware of other affected family members, but up to 40% have no family history [Harding et al 1995]. These most likely represent cases where family history is difficult to trace, given that de novo mutation is rare in LHON
Electrophysiologic studies (pattern electroretinogram and visual evoked potentials) confirm optic nerve dysfunction and the absence of retinal disease.
Cranial imaging is necessary to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. In individuals presenting with LHON, MRI is ofteormal but may reveal a high signal within the optic nerves, the latter probably representing slight edema or gliosis in the atrophic phase.
Testing
Biochemical studies. Although the three primary LHON-causing mtDNA mutations all affect different respiratory chain complex I subunit genes, the mutations are not always associated with a respiratory chain abnormality that can be measured in vitro [Brown 1999]. The absence of a respiratory chain complex defect thus does not rule out the possibility of LHON.
In a small number of in vivo studies using phosphorus magnetic resonance spectroscopy, the most consistent defect of mitochondrial function was identified in individuals with the m.1778G>A mutation; it was not found among those with the m.3460G>A mutation (Table 1). A striking feature of all these biochemical studies is that none found a significant difference between affected and unaffected individuals with a disease-causing mutation. Balancing the current weight of evidence, LHON is associated with a respiratory chain defect that is more subtle than respiratory chain defects in other mitochondrial disorders and biochemical studies have been superseded by molecular genetic testing.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
If the ophthalmologic assessment (including an assessment of acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of Leber hereditary optic neuropathy (LHON), further evaluation of the anterior visual pathways and brain with contrast MRI and lumbar puncture are appropriate to exclude other potentially treatable optic neuropathies.
Acute phase. A wide range of non-genetic causes of bilateral visual failure must be excluded during the acute phase.
Atrophic phase. If an individual is only seen at this stage, it can be difficult to exclude other possible causes of optic atrophy, especially if there is no clear maternal family history. In these cases, neuroimaging of the anterior visual pathways is mandatory while awaiting the results of molecular genetic testing.
LHON must also be distinguished from other causes of sporadic and inherited optic neuropathies such as deafness-dystonia-optic neuropathy (DDON). This disorder is characterized by prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment seems constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:
Measurement of best corrected visual acuity
Assessment of visual fields with static or kinetic perimetry
Treatment of Manifestations
Currently, no available treatment improves the final visual outcome in LHON.
Management of affected individuals is supportive and includes provision of visual aids and registration with the relevant social services.
ECG may reveal a pre-excitation syndrome in both affected and unaffected LHON carriers; such a finding does not necessitate further intervention in the absence of cardiac symptoms.
Agents/Circumstances to Avoid
Individuals harboring established LHON-causing mtDNA mutations are advised to avoid smoking and to moderate alcohol intake.
Mode of Inheritance
Leber hereditary optic neuropathy (LHON) is caused by mutations in mtDNA and is transmitted by maternal inheritance.
Risk to Family Members
Parents of a proband
The father of a proband is not at risk of having the disease-causing mtDNA mutation.
The mother of a proband usually has the mtDNA mutation and may or may not have symptoms.
In approximately 60% of cases, a history of visual loss affecting maternal relatives at a young age is present; up to 40% of individuals with LHON have no known family history of LHON. The explanation for these simplex cases may be that a detailed family history is not available or is unreliable, or that the proband has a de novo mtDNA mutation.
De novo mutations are assumed to be rare.
Sibs of a proband
The risk to sibs depends on the genetic status of the mother.
If the mother has the mtDNA mutation, all sibs are at risk of inheriting it.
Offspring of a proband
A male (affected or unaffected) with a primary LHON-causing mtDNA mutation cannot transmit the mutation to any of his offspring.
A female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring.
The presence of the mtDNA mutation does not predict the occurrence, age of onset, severity, or the rate of progression of this typically adult-onset disease. See Risk Factors for Visual Loss for information regarding the risk to individuals with a primary LHON-causing mtDNA mutation of being affected.
If an affected female has heteroplasmy, she may transmit a low level of mutant mtDNA to her offspring, conferring a low disease risk
Other family members. The risk to other family members depends on the genetic status of the proband’s mother. If the proband’s mother has a mtDNA mutation, her sibs and mother are also at risk.
Related Genetic Counseling Issues
Penetrance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary LHON-causing mtDNA mutations. Large studies have established accurate risks for the m.11778G>A and m.14484T>C mutations. Confirming the genetic status of an individual at risk for one of these mutations who is seeking counseling allows for an accurate estimation of the risks, based on established age- and gender-specific penetrance data (see Risk Factors for Visual Loss). Less data are available for the m.3460G>A mutation, and counseling for the other mutations requires cautious extrapolation.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for LHON is available using the same techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, or rate of progression in asymptomatic individuals. When testing at-risk individuals for LHON, an affected family member should be tested first to confirm the identification of the disease-causing mutation. The most important factors determining risk are gender and age. The presence of the mutation in leukocytes confers a lifetime risk (see Risk Factors for Visual Loss). For example, an 18-year-old male has a lifetime risk of approximately 50% for LHON after a positive test result. The risk declines with age but, because loss of sight can occur at any age, the risk never falls to zero. In large, multigenerational LHON pedigrees, these risks were known before the advent of molecular genetic testing. In smaller families it is important to confirm the genetic status because it is possible that the mutation is heteroplasmic in the affected individual or his mother, and it may not be present in every family member.
Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the “need to know.” Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual’s knowledge of LHON, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential.
Testing of at-risk individuals during childhood. Consensus holds that individuals younger than age 18 years at risk for adult-onset disorders for which no treatment exists should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Children who are symptomatic usually benefit from having a specific diagnosis established. (See also the National Society of Genetic Counselors resolution on genetic testing of children.)
Family planning. The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of developing LHON.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The mtDNA mutation in the mother must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Accurate interpretation of a positive prenatal test result is difficult for the following reasons:
Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues.
The presence of the mtDNA mutation does not predict the occurrence, age of onset, severity, or rate of progression of this typically adult-onset disease. See Risk Factors for Visual Loss for information regarding the risk to individuals with a primary LHON-causing mtDNA mutation of being affected.
MERRF syndrome
Disease characteristics.
The clinical diagnosis of MERRF (myoclonic epilepsy with ragged red fibers) is based on the following four “canonical” features:
Myoclonus
Generalized epilepsy
Ataxia
Ragged red fibers (RRF) in the muscle biopsy
Additional frequent manifestations include the following:
Sensorineural hearing loss
Myopathy
Peripheral neuropathy
Dementia
Short stature
Exercise intolerance
Optic atrophy
Less common clinical signs (seen in <50% of affected individuals) include the following:
Cardiomyopathy
Pigmentary retinopathy
Pyramidal signs
Ophthalmoparesis
Multiple lipomas
Diagnosis/testing.
The clinical diagnosis of MERRF is based on the following four “canonical” features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy. The mitochondrial DNA (mtDNA) gene MT-TK encoding tRNALys is the gene most commonly associated with MERRF. The most common mutation, present in over 80% of affected individuals with typical findings, is an A-to-G transition at nucleotide 8344 (m.8344A>G). Mutations are usually present in all tissues and are conveniently detected in mtDNA from blood leukocytes. However, the occurrence of “heteroplasmy” in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having few symptoms consistent with MERRF or in asymptomatic maternal relatives of an affected individual, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, urinary sediment, oral mucosa, hair follicles, or, most reliably, skeletal muscle.
Management.
Treatment of manifestations: conventional antiepileptic drugs (AEDs) for seizures; physical therapy to improve any impaired motor function; aerobic exercise; standard pharmacologic therapy for cardiac symptoms. Levetiracetam, clonazepam, zonisamide, and valproic acid (VPA) have been used to treat myoclonic epilepsy; however, VPA may cause secondary carnitine deficiency and should be avoided or used with L-carnitine supplementation. Other: Coenzyme Q10 (100 mg 3x/day) and L-carnitine (1000 mg 3x/day) are often used in hopes of improving mitochondrial function.
Genetic counseling.
MERRF is caused by mutations in mtDNA and is transmitted by maternal inheritance. The father of a proband is not at risk for having the disease-causing mtDNA mutation. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. A male with an mtDNA mutation cannot transmit the mutation to any of his offspring. A female with the mutation (whether affected or unaffected) transmits the mutation to all of her offspring. Prenatal diagnosis for MERRF is possible if an mtDNA mutation has been detected in the mother. However, because the mutational load in the mother’s tissues and in the fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues and because the mutational load in tissues sampled prenatally may shift in utero or after birth secondary to random mitotic segregation, prediction of the phenotype from prenatal studies is not possible.
MELAS Syndrome
Background
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a progressive neurodegenerative disorder. Patients may present sporadically or as members of maternal pedigrees with a wide variety of clinical presentations. The typical presentation of patients with MELAS syndrome includes features that comprise the name of the disorder, such as mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Other features, such as seizures, diabetes mellitus, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, and neuropsychiatric dysfunction are clearly part of the disorder.
Strokelike episodes and mitochondrial myopathy characterize MELAS syndrome. Multisystemic organ involvement is seen, including the CNS, skeletal muscle, eye, cardiac muscle, and, more rarely, the GI and renal systems.
Approximately 80% of patients with the clinical characteristics of MELAS syndrome have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the transfer RNA (tRNA)Leu (UUR) gene at base pair (bp) 3243 (ie,
The pathogenesis of the strokelike episodes in MELAS syndrome has not been completely elucidated. These metabolic strokelike episodes may be nonvascular and due to transient oxidative phosphorylation (OXPHOS) dysfunction within the brain parenchyma. A mitochondrial angiopathy of small vessel is responsible for contrast enhancement of affected regions and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction in patients with MELAS syndrome may be due to both parenchymal and vascular OXPHOS defects. Increased production of free radicals in association with an OXPHOS defect leading to vasoconstriction may offset the effect of potent vasodilators (eg, nitric oxide).
The unusual strokelike episodes and higher morbidity observed in MELAS syndrome may be secondary to alterations iitric oxide homeostasis that cause microvascular damage. Nitric oxide can bind the cytochrome c oxidase–positive sites in the blood vessels present in the CNS, displacing heme-bound oxygen and resulting in decreased oxygen availability in the surrounding tissue and decreased free nitric oxide. Furthermore, coupling of the vascular mitochondrial dysfunction with cortical spreading depression might underlie the selective distribution of ischemic lesions in the posterior cortex in these subjects.
Mutations in this disorder affect mitochondrial tRNA function, leading to the disruption of the global process of intramitochondrial protein synthesis. Measurements of respiratory enzyme activities in intact mitochondria have revealed that more than one half of the patients with MELAS syndrome may have complex I or complex I + IV deficiency. A close relationship is apparent between MELAS and complex I deficiency. The decreased protein synthesis may ultimately lead to the observed decrease in respiratory chain activity by reduced translation of UUG-rich genes such as ND6 (component of complex I).
In addition, studies revealed that the
No estimates concerning the prevalence of the common MELAS mutation are available for the North American population; however, the syndrome has been observed to be less frequent in blacks.
International
The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population. If the assumption is made that all first-degree maternal relatives of a verified mutation carrier also harbor the mutation, prevalence increases to more than 16.3 per 100,000. This high prevalence suggests that mitochondrial disorders may constitute one of the largest diagnostic categories of neurogenetic diseases among adults. In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.
The progressive disorder has a high morbidity and mortality. The encephalomyopathy, associated with strokelike episodes followed by hemiplegia and hemianopia, is severe. Focal and general convulsions may occur in association with these episodes.
Other abnormalities that may be observed are ventricular dilatation, cortical atrophy, and basal ganglia calcification. Mental deterioration usually progresses after repeated episodic attacks. Psychiatric abnormalities and cognitive decline (eg, altered mental status, schizophrenia) may accompany the strokelike episodes. Bipolar disorder is another psychiatric abnormality observed in MELAS syndrome. Autism spectrum disorders (ASDs) with or without additional neurological features can be early presentations of the m.3243 A → G mutation. Myopathy may be debilitating. The encephalopathy may progress to dementia; eventually, the clinical course rapidly declines, leading to severe disability and premature death.
Another cause of high mortality is the less common feature of cardiac involvement, which can include hypertrophic cardiomyopathy, hypertension, and conduction abnormalities, such as atrioventricular blocks, long QT syndrome, or Wolff-Parkinson-White syndrome. Subjects with MELAS syndrome were found to have increased ascending aortic stiffness and enlarged aortic dimensions suggesting vascular remodeling. Aortic root dissection was found in one patient with MELAS syndrome.3 Some patients may develop Leigh syndrome (ie, subacute necrotizing encephalopathy). Patients may develop renal failure due to focal segmental glomerulosclerosis.
More rarely, these patients may exhibit severe GI dysmotility and endocrine dysfunction, including hypothyroidism and hyperthyroidism.
No predilection for a particular ethnic group is noted.
No sexual predilection is present.
In many patients with MELAS syndrome, presentation occurs with the first strokelike episode, usually when an individual is aged 4-15 years. Less often, onset of disease may occur in infancy with delayed developmental milestones and learning disability. One presentation of the disorder was reported in a 4-month-old infant.
Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance.
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome onset may occur early in infancy with a history of developmental delay and learning disabilities. Developmental delay, learning disability, or attention deficit disorder is primarily found in patients prior to the development of the first stroke. An encephalopathic picture that is progressive and leads to dementia may be present. Patients may be apathetic. The level of cognitive functioning worsens over time by Karnofsky score in fully symptomatic patients.
Failure to thrive may be the presenting feature in some patients with MELAS syndrome.
Strokelike episodes are the hallmark feature of this disorder. Initially, episodes may manifest with vomiting and headache that may last several days. These patients may also experience episodes of seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic.
Migraine or migrainelike headaches observed in these patients may also reflect the strokelike episodes. Pedigrees of patients with classic MELAS syndrome identify many members whose only manifestations are migraine headaches.
Patients may have visual complaints due to ophthalmoplegia, and they may experience blindness because of optic atrophy and difficulties with night vision due to pigmentary retinopathy.
Some patients may experience hearing loss, which may accompany diabetes. It may be observed in association with the classic disorder of MELAS syndrome.
Polydipsia and polyuria may be the presenting signs of diabetes; diabetes appears to be the most common manifestation of MELAS syndrome. Usually, type 2 diabetes is described in individuals with MELAS syndrome, although type 1 (formerly termed insulin-dependent diabetes) may also be observed. Guidelines for diagnosis and management of type 2 diabetes have been established.4
Palpitations and shortness of breath may be present in some patients with MELAS syndrome secondary to cardiac conduction abnormalities, such as Wolff-Parkinson-White syndrome. Patients may experience shortness of breath secondary to cardiomyopathy, which is usually of the hypertrophic type; however, dilated cardiomyopathy has also been described.
Acute onset of GI manifestations (eg, acute onset of abdominal pain) may reflect pancreatitis, ischemic colitis, and intestinal obstruction.
Numbness, tingling sensation, and pain in the extremities can be manifestations of peripheral neuropathy.
Psychiatric disorders (eg, depression, bipolar disorder) have been associated with the m.3243 A → G mutation. Dementia has been another clinical manifestation. Moreover, autism spectrum disorders (ASD) have been associated with the
Patients may develop features of hypothyroidism and hyperthyroidism
Some patients may develop apnea and an ataxic gait in association with neuroradiologic features of MELAS syndrome.
Oliguria can be associated with MELAS syndrome and may indicate the onset of nephrotic syndrome.
Patients with MELAS syndrome may have functional vascular involvement. Aortic root dissection has been reported in one patient with MELAS syndrome.
Patients with MELAS syndrome may exhibit hypertension.
Myopathy presents with hypotonia and weakness. Proximal muscles tend to be more involved than distal muscles. Musculature is thin, and patients may present with a myopathic face.
Strokelike episodes may present with convulsions, visual abnormalities, numbness, hemiplegia, and aphasia. Episodes may be followed by transient hemiplegia or hemianopia, which lasts a few hours to several weeks.
Additional features oeurologic examination may include ataxia, tremor, myoclonus, dystonia, visual disturbances, and cortical blindness. Some patients may present with ophthalmoplegia and ptosis.
On ophthalmologic examination, patients have presented with pigmentary retinopathy.
Sensorineural deafness has been reported as part of the disorder in approximately 25% of patients with MELAS syndrome.
Cardiomyopathy with signs of congestive heart failure (CHF) may also be observed upon physical examination.
Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS syndrome.
Short stature may be the first manifestation of MELAS syndrome in many patients.
MELAS syndrome has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNALeu (UUR) gene. The most common mutation, found in 80% of individuals with MELAS syndrome, is an A → G transition at nucleotide (nt)
These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS syndrome reflects variable segregation in the ovum. Mutations in tRNALys may be expected to have an important effect on translation and protein synthesis in mitochondria. The MELAS disorder–associated human mitochondrial tRNALeu (UUR) mutation causes aminoacylation deficiency and a concomitant defect in translation initiation.
Abnormal calcium homeostasis resulting ieuronal injury has been suggested as another mechanism contributing to the CNS involvement observed in MELAS syndrome.
Patients with MELAS syndrome have been found to have a marked decrease in the activity of complex I. The major effects observed secondary to nt 3243 and nt 3271 mutations have been a reduction in protein synthesis and the activity of complex I. These effects have been demonstrated through studying cybrids in which human cell lines without mtDNA are fused with exogenous mitochondria containing 0-100% of the common m.3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.
Other Problems to Be Considered
Sensorineural hearing loss
Peripheral neuropathy
Rhabdomyolysis
Intestinal pseudoobstruction
Myoclonic epilepsy and ragged red fiber disease
Neurodegeneration, ataxia, and retinitis pigmentosa
Primary mtDNA depletion syndrome
Disorders of pyruvate metabolism
Serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid
Lactic acidosis is an important feature of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome.
Pathophysiologic classification of lactic acidosis.
In general, lactic acidosis does not lead to systemic metabolic acidosis, and it may be absent in patients with impressive CNS involvement.
In some individuals with MELAS syndrome, lactic acid levels may be normal in blood but elevated in CSF.
In respiratory chain defects, the ratio between lactate and pyruvate is high.
Serum creatine kinase levels
The levels of serum creatine kinase are mildly to moderately increased in some patients with MELAS syndrome.
Levels tend to increase during and immediately after episodes.
Respiratory chain enzyme activities in skeletal muscle
If a muscle biopsy is performed to pursue a diagnostic evaluation, then test respiratory chain enzyme activities.
Patients with MELAS syndrome have been found to have marked deficiency in complex I activity of the respiratory chain.
Some patients with the disorder have a combined deficiency of complex I and complex IV.
Mitochondrial DNA mutation analysis on blood, skeletal muscle, hair follicles, buccal mucosa, and urinary sediment
Individuals with more severe clinical manifestations of MELAS syndrome generally have greater than 80% mutant mtDNA in stable tissues such as muscle.
In rapidly dividing cells, such as the components of the hematopoietic lineages, the m.3243 A → G mutation may segregate to extremely low levels, making genetic diagnosis from blood difficult. The percentage of the mutation decreases progressively in DNA isolated from blood. The mutant load isolated from blood is neither useful for prognosis nor for functional assessment.
Urinary sediment, followed by skin fibroblasts and buccal mucosa, are the accessible tissues of choice because they are easy to access and the mutation load is higher than that found in blood.
If the diagnosis is still suspected after normal mtDNA mutation analysis results in these tissues, a skeletal muscle biopsy is required to confirm or rule out the presence of the mutation.
CT scan or MRI of the brain following a strokelike episode reveals a lucency that is consistent with infarction.
Later, cerebral atrophy and calcifications may be observed on brain imaging studies.
Patients with MELAS syndrome who have a presentation similar to Leigh syndrome may have calcifications in the basal ganglia.
Positron emission tomography (PET) studies
PET studies may reveal a reduced cerebral metabolic rate for oxygen.
Increased cerebral blood flow in cortical regions may be observed.
PET may demonstrate preservation of the cerebral metabolic rate for glucose.
Single-photon emission CT studies
Single-photon emission computed tomography (SPECT) studies can ascertain strokes in individuals with MELAS syndrome using a tracer, N -isopropyl-p-[123-I]-iodoamphetamine.
The tracer accumulates in the parietooccipital region, and it can delineate the extent of the lesion. SPECT studies are used to monitor the evolution of the disease.
Proton magnetic resonance spectroscopy (1 H-MRS): This is used to identify metabolic abnormalities, including the lactate-to-creatine ratio in either muscle or brain and the decreased CNS N -acetylaspartate–to–creatine ratio in regions of stroke. With this technique, elevated regions of lactate have been detected while serum levels are normal.
Echocardiography: This is useful to evaluate for hypertrophic and dilated cardiomyopathy and aortic root dimensions; however, cardiomyopathy is not a common feature in individuals with MELAS syndrome.
EEG findings are usually abnormal.
Epileptiform spike discharges are usually present.
ECG
ECG is used to look for conduction abnormalities with ventricular arrhythmias.
ECG can identify presymptomatic cardiac involvement, preexcitation syndromes, and cardiac conduction block.
Consider performing a muscle biopsy if MELAS syndrome is suspected and if the mtDNA mutation analysis in blood and other accessible tissues provides unremarkable results.
In rapidly dividing cell lines, the mutations may segregate to low levels, making genetic diagnosis from blood difficult.
In muscle biopsies stained with hematoxylin and eosin, variation is observed in type 1 and type 2 fiber sizes, representing myopathic changes.
Ragged red fibers are the hallmark of MELAS syndrome. The ragged red fibers stain brilliant red with occasional cytoplasmic bodies with trichrome stain. Ragged red fibers usually stain positive with cytochrome oxydase stain.
Staining with periodic acid-Schiff, nicotinamide adenine dinucleotide (NADH) dehydrogenase tetrazolium reductase, or for succinic dehydrogenase demonstrates increased subsarcolemmal activity. This mitochondrial proliferation has also been observed in blood vessels and is determined using a stain for succinate dehydrogenase.
Electron microscopy demonstrates an increase iumber and size of mitochondria, some with paracrystalline bodies.
Evaluation for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome may be performed on an outpatient basis if the patient is stable.
Evaluation may consist of determining levels of serum lactate and serum pyruvate, mtDNA mutation studies on blood, and brain imaging studies (eg, head CT scan, brain MRI, brain1 H-MRS).
Muscle biopsy for mitochondrial enzymes and DNA mutation analysis can be performed as an elective procedure for which the patient is admitted to the hospital.
In incidents of acute decompensation, perform inpatient studies in the acute phase and following stabilization of the patient.
Various supportive measures are available, although no controlled trial has proven efficacy. Long-term benefits of dietary manipulations are unknown. Improvements in some patients may be related to improved nutritional status and hydration.
Treatment with coenzyme CoQ10 has been helpful in some patients with MELAS syndrome. No adverse effects have been reported from its administration.
Menadione (vitamin K-3), phylloquinone (vitamin K-1), and ascorbate have been used to donate electrons to cytochrome c.
Idebenone has also been used to treat this condition, and improvements in clinical and metabolic abnormalities have been reported.
Riboflavin has been reported to improve the function of a patient with complex I deficiency and the m.3250 T→C mutation.
Nicotinamide has been used because complex I accepts electrons from nicotinamide adenine dinucleotide (NADH) and ultimately transfers electrons to CoQ10.
Dichloroacetate is another compound used with these agents since levels of lactate are lowered in plasma and cerebrospinal fluid (CSF); patients reportedly may respond in a favorable manner. Sensory neuropathy may result after extended use of this drug.
Sodium succinate has been used, and a patient with MELAS syndrome reportedly had fewer strokelike episodes with its use; however, sodium succinate is not the standard of care. Further investigation is necessary.
Creatine monohydrate has also been used, and an increase in muscle strength in high-intensity anaerobic and aerobic activities has been reported.
The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impaired vasodilation in intracerebral arteries owing to nitric oxide depletion.
Neurologist (to evaluate patient for strokelike episodes)
Cardiologist (for evaluation of cardiomyopathy, arrhythmias and hypertension)
Nephrologist (to evaluate for the onset of nephrotic syndrome)
Ophthalmologist (to evaluate for pigmentary retinopathy)
Endocrinologist (to evaluate for endocrine dysfunctions such as diabetes mellitus, hypothyroidism, hyperthyroidism and hypoparathyroidism)
Psychiatrist (to evaluate for affective disorders)
Neuropsychologist (to evaluate for autism spectrum disorder [ASD])
The effect of dietary manipulation is not completely known, and the efficacy of dietary supplements is unproven.
Dicarboxylic aciduria and secondary impairment of long-chain fatty acid oxidation (LCFAO) may occur in mitochondrial disorders.
Improvement observed in many patients is probably related to improved nutrition.
In patients with mitochondrial myopathies, moderate treadmill training may result in improvement of aerobic capacity and a drop in resting lactate and postexercise lactate levels.
Concentric exercise training may also play an important role because after a short period of concentric exercise training a remarkable increase reportedly occurs in the ratio of wild type–to–mutant mtDNAs and in the proportion of muscle fibers with normal respiratory chain activity.
For individuals with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome and for those with other oxidative phosphorylation (OXPHOS) disorders, metabolic therapies are administered to increase the production of adenosine triphosphate (ATP) and to slow or arrest the deterioration of this condition and other mitochondrial encephalomyopathies. Metabolic therapies used for the management of MELAS syndrome include carnitine, CoQ10, phylloquinone, menadione, ascorbate (ie, ascorbic acid), riboflavin, nicotinamide, creatine monohydrate, idebenone, succinate, and dichloroacetate. However, assessment of the efficacy of these compounds is far from complete, and efficacy is believed to be limited to individual cases.
Treatment with CoQ10 has been helpful in some patients with MELAS syndrome. No adverse effects have been reported from its administration. Menadione (vitamin K-3), phylloquinone (vitamin K-1), and ascorbate have been used to donate electrons to cytochrome c. Idebenone has also been used to treat this condition, and improvements in clinical and metabolic abnormalities have been reported. Riboflavin has been reported to improve the function of a patient with complex I deficiency and the m.3250 T→C mutation. Nicotinamide has been used because complex I accepts electrons from nicotinamide adenine dinucleotide (NADH) and ultimately transfers electrons to Q10. Dichloroacetate is another compound used with these agents, because levels of lactate are lowered in plasma and cerebrospinal fluid (CSF). Patients reportedly may respond in a favorable manner.
A patient with MELAS syndrome reportedly had fewer strokelike episodes with the use of sodium succinate; however, sodium succinate is not the standard of care, and further investigation is necessary. An increase in muscle strength in high-intensity anaerobic and aerobic activities has been reported with the administration of creatine monohydrate.
Arginine administration during the acute and interictal periods of the strokelike episodes of the MELAS syndrome may represent a potential new therapy to reduce brain damage due to mitochondrial dysfunction, and is one of the most promising therapies to date. Based on the hypothesis that the strokelike episodes in MELAS syndrome are triggered by impaired vasodilation in the intracerebral arteries due to decreased levels of circulating NO, elevation of arginine and NO levels may ameliorate this effect. In addition, L-arginine may modulate excitation by neurotransmitters at nerve endings and such effects might contribute to alleviation of strokelike symptoms in MELAS syndrome. Patients with MELAS may have less chance of having strokelike episodes by improving their endothelial function with oral supplementation of L-arginine.
Background
In 1979, Pearson et al described a previously unrecognized, often fatal disorder of infants with transfusion-dependent sideroblastic anemia, vacuolization of hematopoietic precursors, and exocrine pancreatic insufficiency. The large deletions of the mitochondrial genome that cause the disorder were discovered a decade later.
Pearson syndrome is currently recognized as a rare, multisystemic, mitochondrial cytopathy. Its features are refractory sideroblastic anemia, pancytopenia, defective oxidative phosphorylation, exocrine pancreatic insufficiency, and variable hepatic, renal, and endocrine failure. Death often occurs in infancy or early childhood due to infection or metabolic crisis. Patients may recover from the refractory anemia. Older survivors have Kearns-Sayre syndrome (KSS), which is a mitochondropathy characterized by progressive external ophthalmoplegia and weakness of skeletal muscle.
Pathophysiology
Mitochondropathies
The mitochondropathies comprise several diverse, overlapping syndromes caused by mutations of mitochondrial DNA. Pearson syndrome is a specific clinical subset of these syndromes that in which involvement of the bone marrow and exocrine pancreas is prominent. The pathogenesis of Pearson syndrome is complex and not well understood. Deletions of certain components of the electron transport chain, encoded by mitochondrial DNA, cause a defect in cellular oxidative metabolism. Certain transfer RNAs (tRNAs) may also be deleted, and their deletion impairs the translation of messenger RNAs (mRNAs) to proteins. Abnormal metabolism of iron, evidenced by sideroblastosis and hemosiderosis, may also be a key feature (see Image 3). These defects cause cellular injury in target tissues.
Other mitochondropathies, such as KSS and the mitochondrial myopathies, have deletions of mitochondrial DNA that may be similar or identical to those detected in Pearson syndrome. How similar abnormalities of mitochondrial DNA cause such diverse disorders is not well understood. The distinct phenotypes are probably the result of differences in the amount and in the tissue-specific distribution of abnormal mitochondrial DNA, the evolution of this distribution over time, and the effects of tissue-specific nuclear modifier genes.
Defining features of Pearson syndrome
The first defining feature of Pearson syndrome is marrow failure. Macrocytic sideroblastic anemia occurs with the characteristic vacuolation of hematopoietic precursors (see Images 1-2). The anemia is refractory, and patients may be transfusion dependent. Neutropenia and thrombocytopenia may also be present.
The second defining feature of Pearson syndrome is dysfunction of the exocrine pancreas due to fibrosis and acinar atrophy. The result is malabsorption and chronic diarrhea.
Another cardinal feature of Pearson syndrome is persistent or intermittent lactic acidemia, which is caused by a defect in oxidative phosphorylation.
Other organ systems are affected in various ways. Hepatic involvement may cause increases in transaminase, bilirubin, and lipid levels, as well as in steatosis. Some patients develop hepatic failure. Renal involvement is common and manifests as a tubulopathy, such as Fanconi syndrome. Endocrinologic disturbances, such as growth hormone deficiency, hypothyroidism, and hypoparathyroidism, are relatively uncommon. The endocrine pancreas usually remains functional; however, a few patients develop diabetes mellitus. Splenic atrophy and impaired cardiac function have also been reported.
Failure to thrive is common. Several factors are likely contributory. Such factors include a defect in cellular metabolic energy, malabsorption due to exocrine pancreatic failure, hepatic and renal insufficiency, and, perhaps, concomitant endocrinologic abnormalities.
Frequency
Pearson syndrome is rare. Approximately 60 cases have been reported worldwide.
Mortality/Morbidity
Pearson syndrome is often fatal in infancy or early childhood. The usual causes of death are bacterial sepsis due to neutropenia, metabolic crisis, and hepatic failure.
Race
All races can be affected.
Sex
Pearson syndrome has no sex predilection.
Age
Pearson syndrome is a progressive disease, and its features change with age. Neonates may be well at birth, but some neonates with Pearson syndrome have low birth weight, pallor, and anemia. Hydrops fetalis has also been reported. Anemic newborns may need transfusion.
During infancy and early childhood, failure to thrive, chronic diarrhea, and progressive hepatomegaly often occur in individuals with Pearson syndrome. These conditions are punctuated by episodic crises characterized by somnolence, vomiting, electrolytic abnormalities, lactic acidosis, and hepatic insufficiency. The lactic acidosis may become persistent with time. Typical causes of death in infants and young children with Pearson syndrome are metabolic crisis, hepatic failure, and overwhelming sepsis due to neutropenia.
Some patients survive infancy and early childhood and spontaneously recover from the hematologic dysfunction. Case reports document a shift in the phenotype of these individuals to a predominantly myopathic or encephalopathic condition. For example, some patients who survive early childhood may develop KSS or Leigh syndrome, whereas others may be neurologically healthy.
Clinical
History
· Although the history is nonspecific, the astute clinician recognizes the need for further evaluation.
· Parents and/or caregivers may notice that the infant has been pale since birth, perhaps increasingly so; this finding indicates refractory anemia.
· Chronic diarrhea and fatty stools may be reported and indicate pancreatic exocrine deficiency.
· Inquire about previous illnesses or hospitalizations. Episodes of anorexia, vomiting, fever, and lethargy can occur. Associated dehydration, electrolytic abnormalities, lactic acidosis, and hepatic dysfunction may occur.
· Inquire about weight and obtain a growth chart. The birth weight may have been low, and the infant may fail to gain weight.
· A dietary history is important because deficiencies of copper, riboflavin, and phenylalanine may cause anemia with vacuolization of hematopoietic precursors, similar to changes observed in Pearson syndrome.
· Obtain a history of exposure to drugs. Certain drugs can damage the bone marrow. For example, chloramphenicol can cause sideroblastic changes and vacuolization of hematopoietic precursors, similar to its effects in individuals with Pearson syndrome.
· Obtain a family history.
o Some anemias and syndromes of bone marrow failure, such as X-linked sideroblastic anemia and Diamond-Blackfan anemia, affect families. A good family history can alert the clinician to these possible diagnoses.
o Although mitochondropathies can be inherited maternally, Pearson syndrome appears to be sporadic.
Physical
· No pathognomonic physical characteristics are observed.
· Anemia causes pallor.
· The patient’s weight may be low for his or her age, and some patients are cachectic.
· Hepatomegaly, often progressive, occurs in patients with hepatic involvement.
· Patchy erythema and photosensitivity are also reported.
· Examine the patient for anomalies associated with other syndromes of bone marrow failure that present in the neonate or infant. For example, anomalies of the radii and thumb suggest Fanconi anemia, Diamond-Blackfan anemia, or the thrombocytopenia-absent radii syndrome.
Causes
Several types of abnormalities of mitochondrial DNA cause Pearson syndrome.
Other Problems to Be Considered
Shwachman-Diamond syndrome is the combination of pancreatic exocrine insufficiency and neutropenia. Epiphyseal and metaphyseal dysostosis also occur in Shwachman-Diamond syndrome. Patients with Pearson syndrome may be neutropenic, but severe anemia is most characteristic.
Hereditary sideroblastic anemia lacks the characteristic vacuolization of marrow precursors, and no concomitant pancreatic insufficiency occurs. Sideroblastic anemia may respond to pyridoxine or pyridoxal phosphate.
Copper deficiency can be differentiated from Pearson syndrome on the basis of a low serum copper concentration and improvement with supplemental administration of copper.
Fanconi anemia is a congenital bone marrow failure syndrome that can be distinguished from Pearson syndrome by performing physical examination, by examining the bone marrow, and by testing for chromosomal fragility. Individuals with Fanconi anemia may have short stature, hyperpigmentation, anomalies of the thumb and radius, and other congenital abnormalities. No vacuolization of hematopoietic precursors occurs in Fanconi anemia, and chromosomes from patients with Fanconi anemia develop breaks when incubated with diepoxybutane. The cytopenias of Fanconi anemia often improve with androgen therapy.
Diamond-Blackfan anemia is congenital pure red cell aplasia characterized by isolated, severe, macrocytic anemia and often bony abnormalities of the thumbs and radii. Serum adenosine deaminase levels are usually increased in Diamond-Blackfan anemia, and no pancreatic insufficiency is observed. Many cases of Diamond-Blackfan anemia respond to glucocorticoid therapy.
Workup
Laboratory Studies
· CBC count determination with differential and reticulocyte count
o Patients with Pearson syndrome have macrocytic anemia.
o The reticulocyte count is inappropriately low.
o Some patients also have neutropenia, thrombocytopenia, or both.
· Test of pancreatic exocrine function
o Document evidence of pancreatic exocrine dysfunction.
o Various direct and indirect tests are available, including the following:
§ Measurement of secretory capacity induced by exogenous hormones, a test meal, or a duodenal stimulant
§ Stool microscopy and analysis of fecal fat and nitrogen
§ Measurement of serum pancreatic isoamylase, trypsinogen, and lipase concentrations
· Measurement of serum lactic acid
o Patients may have lactic acidemia, though it may be intermittent.
o The ratio of lactate to pyruvate may be increased.
· Urinalysis
o Complex organic aciduria, including 3-methylglutaconic aciduria, is reported.
o Some patients have proximal renal tubular dysfunction that causes urinary wasting of amino acids, glucose, bicarbonate, phosphate, citrate, and urate.
· Hepatic study
o Hepatic transaminase values may be increased in patients with hepatic involvement.
o Bilirubin levels may be increased, and albumin concentrations and coagulation values (eg, prothrombin time) may reflect a defect in synthetic function.
· Endocrinologic study: Some patients have hypothyroid, hypoparathyroid, and a deficiency in growth hormone.
· Analysis of mitochondrial DNA
o The causative deletions of mitochondrial DNA can be demonstrated with molecular genetic analysis. Because of heteroplasmy, not all tissues contain abundant amounts of mutant mitochondrial DNA.
o Bone marrow cells are appropriate for sampling. Peripheral blood cells are also appropriate for mitochondrial DNA analysis. However, because of heteroplasmy, mutant DNA may not always be found. If Pearson syndrome is suspected despite normal findings in other tissues, analysis of bone marrow is prudent.
Imaging Studies
· No specific imaging studies are needed to diagnose Pearson syndrome.
· MRI of the brain may be performed to further investigate a phenotypic shift to a predominantly encephalopathic or myopathic condition, which may occur in older individuals with Pearson syndrome.
Procedures
Bone marrow aspiration and biopsy are necessary to obtain bone marrow for histologic analysis. Characteristic histologic findings of Pearson syndrome can be observed, and other causes of pancytopenia can be excluded.
References
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
9. http://intranet.tdmu.edu.ua/data/kafedra/internal/index.php?&path=pediatria2/classes_stud
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 (
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
