Materials for practical class 6

June 4, 2024
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PEDIGREE ANALYSIS AND TWIN STUDIES. CHROMOSOME DISEASES.

CYTOGENETIC METHOD IN DIAGNOSTICS OF CHROMOSOME DISEASES.

 

Pedigree analysis

 The pedigree patterns shown by such traits depend on two factors: (1) whether the gene responsible is on an autosome or on the X-chromosome and (2) whether it is dominant, that’s, expressed even when present on only one chromosome of a pair, or recessive, expressed only when present on both chromosomes. Thus there are only four basic patterns: autosomal (dominant and recessive), X-linked (dominant and recessive).

 

 

 

An individual pedigree is also determined by the chance distribution of genes from parents to children through the gametes. Especially with the small family size typical of most developed countries, the patient may be the only affected family member. Complications arising from lack of information, difficulties in diagnosis, genetic heterogeneity, variation in clinical expression and environmental effects may make a pedigree difficult to interpret.

Though some pedigrees show the pattern of transmission so clearly that it can hardly be misinterpreted, a single pedigree is usually not enough to establish the genetics of a disorder. Fortunately, by now clinical geneticists have made considerable progress in the description and cataloging of single-gene defects. If the diagnosis is clear, the pedigree can be examined to see if it is consistent with the expected pattern. If the diagnosis is not clear, the family history can sometimes lead to a very good guess of what it might be and the guess can be followed up specific diagnostic tests.

 At this point several terms with special connotations in genetics must be introduced and defined. The family member who first brings a family to the attention of an investigator is the proband (index case, propositus). Sibs (or siblings) are brothers and sisters of unspecified sex. The parent generation is designated the Pi, and the first generation offspring of two parents the F1, but these terms are used more frequently in experimental genetics with inbred lines of plants or animals than in human genetics.

 Family data can be summarized in a pedigree, which is merely a shorthand method of classifying the data for ready reference. Symbols used in drawing up a pedigree are shown in the figure. Variants of these symbols may be invented to demonstrate special situations. By convention, gene symbols are always in italics.

 The human gene nomenclature and symbols have recently been standardized in order to facilitate computerization. Most loci are now designated by capital letters or a combination of capital letters and Arabic numerals not more than four characters in length, with no superscripts or subscripts. An asterisk separates the gene symbol from the allele symbol, which is also capitalized. A genotype is conventionally shown with a slash between the symbols for a pair of alleles. In common usage the slash is often omitted, except when sets of linked genes, rather than single gene pairs, are discussed. Many traits are determined by genes at a single locus, in either homozygous or heterozygous state.

 

Autosomal dominant inheritance

 1. The trait appears in every generation, with no skipping. Although this statement is theoretically true, in clinic genetics there are apparent exceptions, when the proband is a new mutant or because of failure of variability of expression.

2. Any child of an affected person has a 50% risk of inheriting the trait. Because statistically each child is an “independent event”, in an individual family wide variation from the expected 1:1 ratio may be present.

3. Unaffected family members do not transmit the trait to their children. Failure of penetrance of the condition can lead to exceptions to this rule.

4. The occurrence and transmission of the trait are not influenced by sex; that’s, male and female are equally likely to have the trait and equally likely to transmit to children of either sex.

Autosomal recessive inheritance

1. The trait characteristically appears only in sibs, not in their parents, offspring or other relatives.

2. On the average, one fourth of the sibs of the proband are affected; in other words, the recurrence risk is one in four for each birth.

3. The parents of the affected child may be consanguineous.

4 Males and females are equally likely to he affected.

X-linked recessive inheritance

1.     The incidence of the traits is much higher in males than in females.

2.     The trait is passed from an affected man through all his daughters to, on the average, half his sons.

3.     The trait is never transmitted directly from father to son.

4.     The trait may be transmitted through a series of carrier females; if so, the affected males in kindred are related to one another through females.

5.     Carriers show variable expression of the trait.

 

X-linked dominant inheritance

1.     Affected males have no normal daughters and no affected sons.

2.     Affected heterozygous females transmit the condition to half their children of either sex. Affected homozygous females transmit it to all their children. Transmission by females follows the same pattern as an autosomal dominant. X-linked dominant inheritance can’t be distinguished from autosomal dominant inheritance by the progeny of affected females, but only by the progeny of affected males.

3.     Affected females are more common than affected males, but as they are almost always heterozygous they usually have milder (but variable) expression.

 Y-Linked inheritance: 1) a trait affects only males; 2) father passes a trait  to all sons.

 

 

 

Twin method

Twins have a special place in human genetics because of their usefulness for comparison of the effects of genes and environment. Diseases caused wholly or partly by genetic factors have a higher concordance rate in monozygotic than in dizygotic twins. Even if a condition does not show a simple genetic pattern, comparison of its incidence in monozygotic and dizygotic twin pairs can reveal that heredity is involved; moreover, if monozygotic twins are not fully concordant for a given condition, nongenetic factors must also play a part in its etiology. The importance of twin studies for comparison of the effects of “nature and nurture” was originally pointed out by Galton in 1875.

 There are two kinds of twins, monozygotic (MZ) and dizygotic (DZ), or, in common language, identical and fraternal. Monozygotic twins arise from a single fertilized ovum, the zygote, which divides into two embryos at an early developmental stage, that’s within the first 14 days after fertilization. Because the members of an MZ pair normally have identical genotypes, they are like-sexed and alike (concordant) in their genetic markers. They are less similar in traits readily influenced by environment; for example, they may be quite dissimilar in birth size, presumably because of differences in prenatal nutrition. Phenotypic differences between MZ co-twins may be produced by the same factors that cause differences between the right and left sides of an individual; for example, cleft lip may be bilateral or unilateral in an individual, and may be concordant or discordant in an MZ pair.

 Dizygotic twins result when two ova, shed in the same menstrual cycle, fertilized by two separate sperm. DZ twins are just as similar genetically as ordinary sib pairs, having, on the average, half their genes in common. Phenotypic distinctions between the members of a DZ pair reflect their genotypic dissimilarities as well as differences arising from nongenetic causes.

 There is a simple way of estimating how many of the twin births in a population are MZ and how many are DZ. MZ twins are always like-sexed, while approximately half of the DZ twin pairs are boy-girl sets. Therefore, the total number of DZ pairs is twice the number of unlike-sexed pairs, and the number of MZ pairs can be found by subtracting the number of unlike-sexed pairs from the total number of like-sexed pairs.

All twin pairs – 2 (unlike-sexed pairs) = Frequency

                   All twin pairs                       of MZ pairs

 For precision, a small correction is required because the sex ratio is not exactly 1:1, but the simple method described gives a close approximation. Among white North Americans, approximately 30%of all twins are MZ, 35% are like-sexed DZ and 35% are unlike-sexed DZ. In some black populations the proportion of DZ twins is considerably higher; in some Asian populations it is lower.

 Comparison of the ratio of like-sexed to unlike-sexed pairs in populations with varying frequencies of twin births has shown that the proportion of MZ births relative to all births is much the same everywhere, about 1 in 300 births, but that the proportion of DZ births varies with ethnic group maternal age and genotype.

 Traits

Concordance,%

MZ

DZ

Blood groups (ABO)

100

46

Colour of eyes

99.5

28

Finger and palm prints

92

40

Measles

98

94

 

Dermatoglyphic method

Dermatoglyphics are the patterns of the ridged skin of the digits, palms and soles. They are important in medical genetics chiefly because of their diagnostic usefulness in some dysmorphic syndromes, especially Down syndrome. They are also a useful aid in the determination of twin zygosity.

 

Dermatoglyphics (from ancient Greek derma = “skin”, glyph = “carving”) is the scientific study of fingerprints and can be traced back to 1892 when one of the most original biologists of his time Sir Francis Galton, a cousin of Charles Darwin, published his now classic work on fingerprints. The study was later termed Dermatoglyphics by Dr. Harold Cummins, the father of American fingerprint analysis, even though the process of fingerprint identification had already been in use for several hundred years.[1] All primates have ridged skin. It can also be found on the paws of certain mammals, and on the tails of some monkey species. In humans and animals, dermatoglyphs are present on fingers, palms, toes and soles. This helps shed light on a critical period ofembryogenesis, between four weeks and five months, when the architecture of the major organ systems is developing.

The word dermatoglyphics comes from two Greek words (derma, skin and glyphe, carve) and refers to the friction ridge formations which appear on the palms of the hands and soles of the feet. Characteristically, hair does not grow from this area. The ridging formations serve well to enhance contact, an area of multiple nerve endings (Dermal Papillae) and aids in the prevention of slippage. People of African ancestry display reduced skin pigmentation in the designated locations. All studies of the dermal ridge arrangements including genetics, anthropology and Egyptologyare classified under the term dermatoglyphics.

The word subdermatoglyphic is cited as one of the longest isograms in the English language.

In the early development of the hand and foot, the dermal patterns begin to form at about the 13th week of prenatal life and are essentially complete by the end of the fourth month. Because the patterns remain unchanged thereafter, any abnormalities of the patterns must have had their origin before or during this time span.

 The scientific classification of dermatoglyphics was originally proposed by Galton, who was the first to study dermal patterns in families and racial groups. The term dermatoglyphics was coined by Cummins, who noted that the dermal patterns in Down syndrome are characteristic and different from those of normal individuals. The first dermatoglyphics index for detection of Down syndrome was developed by Walker, who showed that 70% of Down patients could be distinguished from controls on the basis of the derma) patterns alone.

 Prints of the digits, palms and soles can be made by one of several standard methods. The dermatoglyphics of importance in medical genetics are fingerprints, palm prints and prints of the hallucal area of the sole. Rules for the formulation of the dermal patterns in these areas are described by Holt.

Pattern combinations and frequencies are more significant than pattern types alone as indicators of abnormal development. In Down syndrome, for example, there is no single dermal pattern that does not also occur in controls but the combination of a number of patterns, most of which are more common in Down syndrome that in normal persons, is highly specific.

 Fingerprints are classified, according to Galton’s system as whorls, loops or arches. The classification is made on the basis of the number of triradii: two in a whorl (W), one in a loop (L) and none in an arch (A). A triradius is a point from which three ridge systems course in three different directions, at angles of about 120°. Lops are subclassified as radial (R) or ulnar (U) depending on whether they open to the radial or ulnar side of the finger. The frequency of the different patterns varies greatly from finger to finger.

 The size of a finger pattern is expressed as the ridge count, that is, the number of ridges between the triradius and the pattern core. An arch has account of zero, since it has no triradius. The line of count for a loop and the two lines for a whole are shown in figure. The total ridge count (TRC) of the ten fingers is a useful dermatoglyphic, which has been shown to be inherited as a multifactorial trait.

 Palm patterns are defined chiefly by five triradii: four digital triradii, near the distal border of the palm, and an axial triradius, which is commonly near the base of the palm but sometimes displayed distally, especially in Down syndrome. Interdigital patterns (loops or whorls) may be formed by the recurving of ridges between the digital triradii. Hypothenar or thenar patterns may be present.

The position of the axial triradius is perhaps the single most important feature, because it is distally displaced in many abnormal conditions. Its location may be measured either as a fraction of the total length of the palm, or as the atd angle.

The flexion creases – the heart, head and life lines of palmistry – are not strictly speaking, dermal ridges, but they are formed at the same time, and may be determined in part by the same forces that affect ridge alignment. A simian crease in place of the usual two creases, on at least one hand, occurs in 1% or more of normal individuals. Simian creases are not unusual in abnormal individuals such as children with congenital malformations, even when the dermal patterns themselves are not obviously disturbed. In Down syndrome and other chromosomal disorders, single flexion creases are much more common than in controls.

The Sydney line is a variant type of palmar crease seen in about 10% iormal individuals, in which the proximal crease extends across the palm, like a simian crease, but a distal crease is also present. Various transitional types also occur.

 Sole (plantar) patterns have been studied less extensively than palm patterns, chiefly because soles are more difficult to print and to classify. Only in the hallucal area have distinctive patterns been described in clinical syndromes. The unusual tibial arch (At) pattern, which is found iearly 50% of all cases of Down syndrome and very rarely (0,3%) in controls, is the single most useful dermal pattern in Down syndrome.

A British Commissioner in India, Sir William Herschel, noticed the use of fingerprints as a form of signature amongst illiterate Indians and put this to good use to for his employees to authenticate their identity when collecting their wage packets. Successfully using this over a twenty year period clearly established the fact that fingerprints did not change their form over time and that therefore they could be used as a reliable form of personal identification.

Around the same time in Japan, a Scottish medical missionary by the name of Henry Faulds noticed the use of fingerprints as a form of signature on pieces of pottery and in 1880 he wrote a piece for ‘Nature Magazine’ suggesting that the individuality and uniqueness of fingerprints gave them a potential usefulness in criminal identification.

In Argentina, the Croatian Juan Vucetich had developed his own system of identification through the use of fingerprinting and by 1891 this was being successfully employed by the Argentinian authorities. Although it was first suggested to the Home Office in 1887, it wasn’t until 1901 that fingerprinting became an established procedure in criminological investigation in England. This came about largely through the efforts of Faulds and Herschel, in conjunction with Francis Galton.

Francis Galton

 

Francis Galton (1822-1911), the cousin of Sir Charles Darwin, was a scientist with a wide range of interests covering anthropology, geology, biology, heredity and eugenics, publishing some 240 written works, including some fifteen books. He conducted extensive research into the significance of skin ridge patterns not only to demonstrate their permanence and consequently their use as a means of identification, but also to demonstrate the hereditary significance of fingerprints and to show the biological variations of different fingerprint patterns amongst different racial groups. He collected vast numbers of fingerprints from all types of people, noting the variations of pattern types amongst different races and established the relative frequency

with which each pattern type occurred amongst different peoples. His classification of fingerprint patterns was considerably more simple than that proposed by Purkinje, delineating only three main types of pattern. He identified the triradius as being the significant indicator of a fingerprint pattern type and hence based his classification on the number of triradii to be found within each pattern.

For Galton there are therefore only three main types of pattern, the simple arch (with no triradius), the loop (with one triradius) and the whorl (with two triradii). Although he recognises the other main patterns that can be found in the hand, he subsumes them into this primary threefold classification. Consequently, tented arches become a type of loop whilst double loops become a type of whorl.  Whilst his system of classification may suffice for the purposes of criminal identification, it is clear that it leaves much to be desired in terms of discriminating the different psychological qualities associated with each type. Alas, it is this system of classification rather than that of Purkinje which has been adopted by both the police and dermatoglyphicists, and this must be borne in mind when considering fingerprint statistics from either of these sources

However, Galton is perhaps the single most influential figure in the whole study of the skin ridge patterns of the hands and many of his methods for analysing fingerprints have carried through into the work of later genetic dermatoglyphic researches. His interest in heredity focused on the possibility of raising the standards of physical and mental health amongst the population as a whole and he saw in the study of fingerprints a means to initiate investigations into human genetics with this aim in mind. To this end, in 1895 he established the Galton Laboratory for Eugenics (a term he himself coined in 1883), at the University of London, which was later to conduct extensive investigations into the genetic significance of the hand as well as investigating correlations between dermatoglyphic patterns and known chromosomal abnormalities. His two works ‘Fingerprints’ (1892) and ‘Fingerprint Directories’ (1895) are rightly considered as classics in the field of early dermatoglyphic research and stimulated the interest of all sorts of scientific investigators,such as anthropologists and zoologists as well as geneticists and criminologists.

 

The Genetics of Dermal Ridges

After Galton’s initial pioneering work, many further investigations were undertaken to develop this fledgling science of dermatoglyphics. Anthropologists concentrated on researching dermatoglyphic distributions of different peoples from around the world, and work was done on clarifying both the methodology and morphology of dermatoglyphic analysis. Meanwhile, the scientific world pioneered studies to investigate the embryogenesis of dermatoglyphic patterns and the first studies investigating the genetic significance of dermatoglyphic patterns were conducted. In America, HH Wilder inaugerated investigations into comparative dermatoglyphics, producing work on both the methodology and morphology of both palmar and plantar (feet) dermatoglyphics. H Poll and J Dankmeijer instigated research into dermatoglyphic distributions amongst different races and K Bonnevie investigated the embryology of dermatoglyphics as well as conducting studies on the genetic inheritance of dermatoglyphic patterns. The scientific investigation of the hand was beginning to prove without doubt that the hand was indeed a study worthy of the finest minds and could reveal not only vital genetic and medical information about an individual but also something of the psychological uniqueness of each person. With the discovery of the significance of dermatoglyphics, the study of the hand was truly beginning to come of age.

 

Fingerprints, Palms and Soles

From the mid 1930’s onwards, the hand was coming to be recognised as an important diagnostic aid in the diagnosis of congenital syndromes such as mongolism. LS Penrose had studied the hands of people with Down’s Syndrome and other conditions of congenital mental defect for many years and had discovered that the hand revealed particular malformations peculiar to these conditions. In 1931, he penned an article for The Lancet correlating the absence of the medial digital crease on the little finger with congenital mental retardation, research that proved to be but the start of a long and detailed investigation into the relevance of the hand in the clinical diagnosis of congenital conditions. However, the main breakthrough in establishing the significance of the dermatoglyphic analysis of the hand came with the publication of the results of the research of Harold Cummins and Charles Midlo in their seminal work ‘Fingerprints Palms and Soles’ in 1943.

Cummins and Midlo were professors of Microscopic Anatomy at Tulane University in the United States, and it was they who in fact coined the term ‘dermatoglyphics’ in 1926 (derma = skin, glyph = carving). The main thrust of their research was into Down’s Syndrome and the characteristic hand formations it produces. They showed that the hand contained significant dermatoglyphic configurations that would assist the identification of mongolism in the new-born child and thus they set the stage for much of the later dermatoglyphic research work. They also researched the embryo-genesis of skin ridge patterns and established that the fingerprint patterns actually develop in the womb and are fully formed by the fourth foetal month.

When it was later discovered that Down’s Syndrome was in fact caused by chromosomal abnormality, research was begun to see how far the hand could be used as a guide to diagnosing other chromosomal defects and dermatoglyphic analysis soon became referred to as ‘the poor man’s karyotype’. The researches of Cummins and Midlo had proved that the hand could be of particular significance in the study of diseases with a genetic origin and, given the expense involved in conducting analyses of the chromosomes themselves, dermatoglyphic analysis was now beginning to prove itself as an extremely useful tool for preliminary investigations into conditions with a suspected genetic basis.

 

Genetic and Chromosomal Research

It was reading Cummins and Midlo’s work that inspired LS Penrose to conduct his own dermatoglyphic investigations as a further aspect of his research into Down’s Syndrome and other congenital medical disorders. In 1945, he was appointed to the Galton Chair of Eugenics at London University. Although the post had existed for some fifty years up to this point, very little research had actually been done into the genetic significance of fingerprints. Penrose was about to change all of that. Whilst he held the post, he conducted extensive investigations into chromosomal disorders and their dermatoglyphic manifestations, considering not only the more common trisomies such as Down’s Syndrome, Edwards Syndrome and Patau’s Syndrome, but also initiating investigations into other more rare chromosomal disorders such as ‘Cri du Chat’ Syndrome, and the sex chromosome disorders, Turner’s Syndrome and Kleinefelter’s Syndrome.

 

Biochemical method

 

http://www.nature.com/nchembio/journal/v9/n4/images_article/nchembio.1199-F6.jpg

Many different proteins are synthesized in body cells. These proteins, which may be either enzymes or structural components, or even serve both functions, are responsible for all the developmental and metabolic processes of the organism. The fundamental relationship between genes and proteins is that the coding sequence of bases in the DNA of a given gene specifies the sequence of amino acids in the corresponding polypeptide chain. Alteration of the base sequence in the gene may result in the synthesis of a variant polypeptide with a correspondingly altered amino acid sequence. Proteins are composed of one or more polypeptide chains. Hence, a gene mutation may lead to the formation of a variant protein, which may have altered properties as a consequence of its changed structure.

The phenotypic changes produced by gene mutations are numerous, varied and frequently unexpected. If mutation results in an amino acid substitution in a so-called structural protein, such as hemoglobin, the phenotypic effect, if any will depend on how the alteration in amino acid sequence affects such properties of the hemoglobin molecule as its affinity for oxygen or its tendency to sickle. If the amino acid sequence of an enzyme polypeptide is altered, the enzyme synthesis by the mutant gene may have altered enzymatic activity. Most of the variant enzymes known have less activity than the normal forms; some are completely inactive. Rarely, a mutation may produce excessively high activity. Occasionally a mutation leads to synthesis of an unstable polypeptide chain that is rapidly destroyed in vivo, or to other types of change.

Not all variant proteins are clinically abnormal. On the contrary, many proteins exist in two or more relatively common, genetically distinct and structurally different “normal” forms. Such a situation is known as a polymorphism.

 

Radioactive probes

Hemophiliacs suffer from defective Factor VIII, which can be detected in fetuses 20 weeks old. A more accurate test, which can also be administered earlier during pregnancy, involves the use of a radioactive probe (36 nucleotide RNA fragment), which hybridizes restriction fragments. The gene for hemophilia is 186,000 base pairs, and has 26 exons separated by 25 introns. Mutations in the gene can be detected by RFLPs. This technology has also been used to detect the single base-pair difference betweeormal and mutated beta-chains, a screen for sickle-cell anemia. A DNA probe has been developed that hybridizes with the gene for dystrophin. The previous screening for Duchenne Muscular Dystrophy was a sex screen, with option to abort a male. The new technique allows differentiation between the healthy and diseased male fetus, so parents have more information with which to make an informed choice (if they chose). The hybridization only occurs if the normal dystrophin gene is present, no hybridization occurs in the DMD sufferer.

 

Cytogenetic method. Chromosome diseases

Human autosomal disorders

A common abnormality is caused by nondisjunction, the failure of replicated chromosomes to segregate during Anaphase II. A gamete lacking a chromosome cannot produce a viable embryo. Occasionally a gamete with n+1 chromosomes can produce a viable embryo.

In humans, nondisjunction is most often associated with the 21st chromosome (Figure 52), producing a disease known as Down’s syndrome (also referred to as trisomy 21). Sufferers of Down’s syndrome suffer mild to severe mental retardation, short stocky body type, large tongue leading to speech difficulties, and (in those who survive into middle-age), a propensity to develop Alzheimer’s Disease. Ninety-five percent of Down’s cases result from nondisjunction of chromosome 21. Occasional cases result from a translocation in the chromosomes of one parent. A translocation occurs when one chromosome (or a fragment) is transferred to a non-homologous chromosome (15+21). A child has 46 chromosomes in all, but the karyotype is effectively trisomic for chromosome 21. The phenotypic consequences are indistinguishable from those of standard trisomy 21. The incidence of Down’s Syndrome increases with age of the mother, although 25% of the cases result from an extra chromosome from the father.

About one person of Down syndrome patients are mosaics, usually 46/47 mosaics (that’s, with a mixture of 46- and 47-chromosome cells). It is likely that most mosaic Down patients derive from trisomy 21 zygotes. Such patients have relatively mild stigmata and are less retarded than the typical trisomics. Low-grade mosaicism in germinal tissues of a parent is a postulated cause of Down syndrome.

The older name of mongolism, now falling into disuse, refers to the somewhat Oriental cast of countenance produced by the characteristic epicanthal folds, which give the eyes a slanting appearance.

Down syndrome can usually be diagnosed at birth or shortly thereafter by its phenotypic features. Hypotonia is often the first abnormality noticed. Mental retardation is present to intelligence quotient usually being in the 25-50 range when a child is old enough to be tested. There is a 15-fold increase in the risk of leukemia. The head is brachycephalic, with a flat occiput. The eyes have epicanthal folds and the iris shows speckles around the margin. The nose has a low bridge. The tongue usually protrudes and is furrowed, lacking a central fissure. The hands are short and broad, usually with a simian crease and clinodactyly of the fifth finger. There may be a single crease on the fifth finger. The dermal patterns are characteristic. On the feet, there is often a white gap between the first and second toes and a furrow extending proximally along the plantar surface. In about half the patients the hallucal dermal pattern is an arch tibial, which is rare iormal persons. About one-third of the patients have congenital malformations of the heart. Radiologically, the acetabular and iliac angles are decreased. The stature is below average. Often the diagnosis presents no particular difficulty, but karyotyping is nevertheless indicated for confirmation and for determine whether the child has the typical 47,XX or XY, +21 karyotype (95% of cases), a translocation (4%) or mosaicism (1%).

The syndrome caused by trisomy 18 (47,XX or XY, +18) was first described by Edwards and colleagues. Its incidence is about 1 in 8000 newborns. Probably 95% of trisomy 18 fetuses abort spontaneously. Postnatal survival is also poor. Among those who are liveborn, the mean survival is only 2 months, though a few survive for 15 years or more. About 80% of the patients are female, perhaps because of preferential survival. Maternal age is advanced. Usually the cause is nondisjunction. About 10% of cases are mosaics; these display milder manifestations, survive longer and are born to mothers of normal age distribution.

Mental retardation and failure to thrive are always present. Hypertonia is a typical finding. The head has a prominent occiput, and the jaw recedes. The ears are low-set and malformed. The sternum is short. The fists clench in a characteristic way, the second and fifth digits overlapping the third and fourth. The feet are rocker-bottom, with prominent calcanei. The dermal patterns are very distinctive, with simian creases on the palms and simple arch patterns on most or all digits. The nails are usually hypoplastic. Severe congenital malformations of the heart are present in almost all cases.

The syndrome caused by trisomy 13 (47,XX or XY, +13) was first identified by Patau and associates. Trisomy 13 is a severe disorder, lethal in about half the liveborn infants within the first month. It is very rare or unknown in first-trimester abortions and is not often seen in prenatal diagnosis even though the mean maternal age is advanced.

About 20% of the cases are caused by translocation. Even when one parent is a translocation carrier, the empirical risk of the same defect in a subsequent child seems to be below 2%.

The phenotype of trisomy 13 includes severe central nervous system malformations such as archinencephaly and holoprosencephaly. Growth retardation and severe mental retardation are present. The forehead is sloping, there is ocular hypertelorism, and there may be microphthalmia, iris coloboma or even absence of the eyes. The ears are malformed. Cleft lip and cleft palate are often present. The hands ad feet may show postaxial polydactyly and the hands clench with the second and fifth fingers overlapping the third and fourth. The feet are rocker-bottom. The dermal patterns are unusual, with simian creases on the palms, distal axial triradii and distinctive hallucal patterns. Internally there are usually congenital heart defects of specific types and urogenital defects including cryptorchidism in males, bicornuate uterus and hypoplastic ovaries in females and polycystic kidneys.

Deletion of part of the short arm of chromosome 5 results in a syndrome, which has beeamed cri du chat (46.XX or XY, 5p–) because of the resemblance of the cry of an affected newborn to the mewing of a cat. The facial appearance is distinctive, with microcephaly, hypertelorism, antimongoloid slant of the palpebral fissures, epicanthus, low-set ears and micrognathia. The dermal patterns of the palms, fingers and soles are also characteristic, with simian creases, a high total ridge count and a high frequency of thenar patterns.

Most cases are sporadic, but 10 to 15% are the offspring of translocation carriers. Families with translocations involving 5p show that deletion of a chromosome segment can be much more harmful than duplication of the same segment.

 Mitochondrial inheritance. Mitochondria, which are cytoplasmic organelles involved in cellular respiration, have their own chromosome, which contains 16,569 DNA base pairs arranged in a circular molecule. This DNA encodes 13 proteins that are subunits of complexes in the electron transport and oxidative phosphorylation processes. Mitochondrial DNA encodes 22 transfer RNAs and two ribosomal RNAs. Because a sperm cell contributes no mitochondria to the egg cell during fertilization, mitochondrial DNA is inherited exclusively through females to their offspring. A typical cell contains hundreds of mitochondria in its cytoplasm. Sometimes a specific mutation is seen in only some of the mitochondria, a condition known as heteroplasmy. Variations in heteroplasmy can result in substantial variation in the severity of expression of mitochondrial diseases. Disease example: Leber hereditary optic neuropathy. This form of hereditary blindness is caused by mutations in protein-coding mitochondrial DNA. Typically, a rapid, irreversible loss of vision in the central visual field begins in the third decade of life. The case of vision loss is optic nerve death. Heteroplasmy is relatively uncommon for this mitochondrial disease, so affected individuals tend to have similar levels of expression.

Mitochondrial DNA (mtDNA) is not transmitted through nuclear DNA (nDNA). In humans, as in most multicellular organisms, mitochondrial DNA is inherited only from the mother’s ovum. There are theories, however, that paternal mtDNA transmission in humanscan occur in certain circumstances.

Mitochondrial inheritance is therefore non-Mendelian, as Mendelian inheritance presumes that half the genetic material of a fertilized egg (zygote) derives from each parent.

Eighty percent of mitochondrial DNA codes for functional mitochondrial proteins, and therefore most mitochondrial DNA mutations lead to functional problems, which may be manifested as muscle disorders (myopathies).

Because they provide 30 molecules of ATP per glucose molecule in contrast to the 2 ATP molecules produced by glycolysis, mitochondria are essential to all higher organisms for sustaining life. The mitochondrial diseases are genetic disorders carried in mitochondrial DNA, or nuclear DNA coding for mitochondrial components. Slight problems with any one of the numerous enzymes used by the mitochondria can be devastating to the cell, and in turn, to the organism.

Because mitochondrial diseases (diseases due to malfunction of mitochondria) can be inherited both maternally and through chromosomal inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic mutations that occur in the nuclear DNA can occur in any of the chromosomes (depending on the species). Mutations inherited through the chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows normal Mendelian laws, despite the fact that the phenotype of the disease may be masked.

Because of the complex ways in which mitochondrial and nuclear DNA “communicate” and interact, even seemingly simple inheritance is hard to diagnose. A mutation in chromosomal DNA may change a protein that regulates (increases or decreases) the production of another certain protein in the mitochondria or the cytoplasm; this may lead to slight, if any, noticeable symptoms. On the other hand, some devastating mtDNA mutations are easy to diagnose because of their widespread damage to muscular, neural, and/or hepatic tissues (among other high-energy and metabolism-dependent tissues) and because they are present in the mother and all the offspring.

Mitochondrial genome mutations are passed on 100% of the time from mother to all her offspring. The number of affected mtDNA molecules inherited by a specific offspring can vary greatly because

·         the mitochondria within the fertilized oocyte is what the new life will have to begin with (in terms of mtDNA),

·         the number of affected mitochondria varies from cell (in this case, the fertilized oocyte) to cell depending both on the number it inherited from its mother cell and environmental factors which may favor mutant or wildtype mitochondrial DNA,

·         the number of mtDNA molecules in the mitochondria varies from around two to ten.

It is possible, even in twin births, for one baby to receive more than half mutant mtDNA molecules while the other twin may receive only a tiny fraction of mutant mtDNA molecules with respect to wildtype (depending on how the twins divide from each other and how many mutant mitochondria happen to be on each side of the division). In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but paternal mitochondria are actively decomposed.

Mitochondrial DNA Polymerase (Pol gamma, encoded by the POLG gene) is used in the copying of mtDNA during replication. Because the two (heavy and light) strands on the circular mtDNA molecule have different origins of replication, it replicates in a D-loop mode. One strand begins to replicate first, displacing the other strand. This continues until replication reaches the origin of replication on the other strand, at which point the other strand begins replicating in the opposite direction. This results in two new mtDNA molecules. Each mitochondrion has several copies of the mtDNA molecule and the number of mtDNA molecules is a limiting factor in mitochondrial fission. After the mitochondrion has enough mtDNA, membrane area, and membrane proteins, it can undergo fission (very similar to that which bacteria use) to become two mitochondria. Evidence suggests that mitochondria can also undergo fusion and exchange (in a form ofcrossover) genetic material among each other. Mitochondria sometimes form large matrices in which fusion, fission, and protein exchanges are constantly occurring. mtDNA shared among mitochondria (despite the fact that they can undergo fusion).

 

The sex chromosomes and their disorders

The Y Chromosome

The short arm of the human Y chromosome is thought to be the segment chiefly responsible for male sex differentiation. Deletions of Yp lead to a female phenotype, streak gonads and absence of H-Y antigen. The long arm of the Y, in contrast, can show considerable variability in length without any phenotypic consequences, apparently because its distal portion is composed of highly repetitive DNA sequences. This part of Yq fluoresces so brilliantly with quinacrine staining that it can be seen even in interphase cells. About 10 percent of males have a fluorescent segment of Yq that is longer or shorter thaormal; the difference is inherited.

The maleness factor or factors on the Y chromosome appear to be localized to a segment of Yp very close to the centromere. A few studies have also indicated the presence of one or more male factors on Yq, also near the centromere. Several patients who lacked the paracentromeric part of Yp were phenotypic females with varying degrees of Turner syndrome, whereas other patients with a dicentric Y that contained a duplicated paracentromeric segment of Yp were males with testes.

The presence of an extra Y chromosome is quite a common observation, occurring in about 1 of every 1000 male births. Numerous different structural rearrangements of the Y have been reported, including deletions, dicentrics, duplications, inversions, isochromosomes, rings, satellited Y-chromosomes or translocations involving either the X or an autosome. Mosaicism may be present, the second line having a normal XY karyotype or sometimes a single X. Since there are so many types of structural alteration, the phenotypic consequences are also variable. There may be normal differentiation and fertility or varying degrees of abnormal testicular development and ambiguity of the external genitalia.

 

The X Chromosome

Sex chromatin

It has been known since 1921 that male and female cells differ in their sex chromosome complement, but it was not until 1949 that a sex difference in interphase cells was detected. In mat year Barr and Bertram noted that a mass of chromatin in the nuclei of some nerve cells in cats was frequently present in females but not in males. This mass is now known as the sex chromatin or Barr body (Figure 53). Cells (or people) are said to be chromatin-positive if sex chromatin is present and chromatin-negative if it is absent.

 

Barr and his students later found sex chromatin in the cells of most of the tissues of females of many species of mammals including humans. The Barr body can be seen in many cell types, but is most conveniently examined in the epithelium of the buccal mucosa. A buccal smear is made simply by scraping a few cells from the inside of the cheek, smearing them on a slide and staining. The slide is then examined microscopically to determine the percentage of cells that show Barr bodies. At one time buccal smears were widely used in diagnosis of disorders of sexual development; today they have been replaced by complete karyotyping.

Sex chromatin is present if there are two or more X chromosomes, and the number of Barr bodies is always one less than the number of X’s.

The Barr body represents one of the two X chromosomes of female cells, which remains condensed and genetically inactive throughout interphase and is late-replicating. This is true only on somatic cells. In the germ line of the female both X’s remain active; in the germ line of the male the single X is inactive.

 

Klinefelter syndrome

The condition 47,XXY is named after Harry Klinefelter, who described it in 1942. Because the phenotype is male but Barr bodies are present, Klinefelter syndrome was a prime candidate for chromosome analysis; its XXY chromosome complement was found shortly after human chromosome studies became possible.

A boy with Klinefelter syndrome is not recognizable before puberty unless his chromosomes are analyzed for some unrelated reason, such as participation in a newborn survey. After puberty, the chief characteristics are small testes and hyalinization of the seminiferous tubules. Usually the secondary sexual characteristics are poorly developed and gynecomastia may appear; many patients are tall and eunuchoid. The patients are almost always sterile, and sterility may be the presenting complaint.

About 15 percent of Klinefelter males are mosaics, with two or more distinct cell lines. The most common mosaic form is XY/XXY, and in these patients it is noteworthy that though the buccal smear may be chromatin-positive, testicular development and mental status may not be abnormal.

Maternal age is advanced in the XX Y syndrome, and about 60 percent of the group owe their origin to either meiotic or postzygotic nondisjunction of the maternal X chromosome(s); that is, they are XmXmY. The remaining 40 percent are XmXpY, indicating nondisjunction of the X and Y in the first meiotic division of spermatogenesis.

Follow-up study of 90 XXY boys, the majority 8 to 14 years of age, has indicated that school problems are frequent, and that verbal IQ tends to be lower thaormal. The boys are increasingly taller thaormal, from 5 years of age on. The legs are proportionately long. Weight is also above normal but less so than height, so that the boys tend to be tall and thin. Head circumference is significantly small at birth and continues small. Bone age is below the mean in childhood but catches up almost to the mean by 12 years of age. The boys tend to be normal in performance IQ but less so in verbal IQ. They have a rather high incidence of educational problems. They may be less aggressive and active and more susceptible to social stress than their peers.

There are several variants of Klinefelter syndrome: XXYY, XXXY, XXXXY and others. As a rule the additional X’s cause a correspondingly more abnormal phenotype, with a greater degree of dysmorphism, more defective sexual development and more severe mental retardation.

 

Turner syndrome (X monosomy)

 The syndrome of sexual infantilism, short stature, webbing of the neck and cubitus valgus (reduced carrying angle at the elbow) is originally described in 1938 by Turner. The phenotype is female though the patients are (usually) chromatin-negative. The discrepancy suggested a chromosome abnormality, and this was confirmed by Ford and colleagues 11959), who demonstrated the 45,X karyotype.

 Other features of the phenotype include the low hairline at the nape of the neck, characteristic facial appearance, unusual dermatoglyphics with high total ridge count, wide dies with broadly spaced nipples, coarctation of the aorta and, especially iewborns, lymphedema of the feet, which together with neck webbing should alert the physician to the need for chromosome studies. The external genitalia are juvenile, and the internal sexual organs are female although the ovary is often only a streak of connective tissue; however, the streak, may be arranged in the manner of ovarian stroma and ovarian follicles may be present in fetal life, though usually not postnatally. Axillary and pubic hair are usually present but sparse. Primary amenorrhea is usual, though not invariable.

 The high incidence of the 45,X karyotype in spontaneous first-trimester abortions was noted earlier. It is curious that 45,X is so severe a defect prenatally, yet relatively benign after birth. Probably the chief explanation is the high proportion of mosaicism among the survivors.

 Only about 60 percent of patients with the Turner syndrome have monosomy X. The remainder has a variety of karyotypes with a structural alteration of the X or mosaicism involving one or more cell lines with abnormal number or structure. The most frequent of these is 46, X, i (Xq), that is, an isochromosome for the long arm of the X. Deletions of part of Xp or Xq and ring-X chromosomes are not uncommon. Ion-mosaics deletions of Xp are associated with short stature, whereas deletions of Xq are unlikely to be associated with short stature, but in general are associated with the presence of streak gonads and consequent infertility.

 Mosaicism accounts for about 40 percent of all cases. About 15 percent are X/XX or XXXX, and 10 percent or more are XX/X, I (Xq). As usual with mosaicism, the phenotype in such patients varies depending on the time of the postzygotic accident and the proportion of abnormal cell lines in different tissues. X/XY mosaicism also leads to variable phenotypic changes.

 Unlike other sex chromosome aneuploids, children with Turner syndrome can often be identified at birth or before puberty by their characteristic phenotypic features. Their intelligence is normal or only slightly reduced as compared with their sibs. Many patients with Turner syndrome have defective spatial perception. As they grow up, their short stature, failure to develop secondary sexual characteristics, and infertility may create psychological problems. Therapy is not totally effective, but most patients with Turner syndrome are given anabolic steroids when 10 to 14 years of age to increase their height, and receive estrogen replacement therapy at an appropriate age to permit the development of secondary sexual characteristics, with cycling to allow menstruation.

XYY syndrome

Males with a second Y chromosome have aroused great interest since they were found to be frequent among males in a maximum security prison. About 3 percent of males in prisons ad mental hospitals are XYY, and among the group over 6 feet tall the proportion is much higher, over 20 percent. Since iewborn surveys the incidence is about 1 in 1000 births, most XYY males must be indistinguishable from XY males on the basis of behavior or physical appearance.

The origin of the XYY karyotype is paternal nondisjunction at the second meiotic division, which produces YY sperm. The less common XXYY and XXXYY variants, which share the features of the XYY and Klinefelter syndromes, probably also originate in the father, by a sequence of nondisjunctional events.

The relationship between XYY and aggressive, psychopathic or criminal behavior has aroused great public interest. XYY males are perhaps six times as likely to be imprisoned as XY males. Parents whose child is found, prenatally or postnatally, to be XYY are often extremely concerned about the implications, and some physicians question the advisability of disclosing such information.

   

 

The 59 XYY boys 5 to 13 years of age who have been followed from birth are tall, but on average not as tall as XXY boys, and are not heavy for their height. Their head circumference is normal. They appear to be generally normal intellectually but seem to have a high incidence of educational difficulties. Excess temper tantrums, higher levels of activity and a more negative mood are mentioned by their parents.

 

XXX syndrome

Triple X syndrome (also known as triplo-Xtrisomy XXXX syndrome47,XXX aneuploidy) is a form of chromosomal variation characterized by the presence of an extra X chromosome in each cell of a human female. The condition occurs only in females. Females with triple X syndrome have three X chromosomes instead of two. The karyotype reads 47,XXX. A mosaic form also occurs where only a percentage of the body cells contain XXX while the remainder carry XX. The extent to which an individual is affected by the condition will depend upon the proportion of XXX to XX throughout. Triple X results during division of a parent’s reproductive cells and occurs about once in every 1,000 female births. Unlike most other chromosomal conditions (such as Down syndrome), there is usually no distinguishable difference to the naked eye between women with triple X and the rest of the female population.

 Trisomy X and the rare tetra-X and penta-X karyotypes are the counterparts in the female of Klinefelter syndrome in the male. Triple X females are not phenotypically abnormal. Some are first identified in infertility clinics, others in institutions for the mentally retarded, but probably many remain undiagnosed. Some have borne children, virtually all of whom have normal karyotypes.

 Follow-up of 54 XXX girls aged 2 to 16 years shows that most are tall with increased height velocity beginning at 4 to 8 years of age. They tend to be underweight for their height and to be long-legged. They have reduced bone age in early childhood but not later, and significantly reduced head circumference from birth onward. Deficiencies in speech development and verbal IQ are common, school achievement is significantly below normal and the children are thought to have greater than average difficulty in interpersonal relationships.

 The presence of four X chromosomes often leads to retardation in both physical and mental development, and XXXXX usually causes severe developmental retardation with multiple physical defects.

Symptoms

Because the vast majority of Triple X females are never diagnosed, it may be very difficult to make generalizations about the effects of this syndrome. The samples that were studied were small and may be nonrepresentative or biased.

Because of the lyonization, inactivation, and formation of a Barr body in all female cells, only one X chromosome is active at any time. Thus, Triple X syndrome most often has only mild effects, or has no unusual effects at all. Symptoms may include tall stature; small head (microcephaly); vertical skinfolds that may cover the inner corners of the eyes (epicanthal folds); delayed development of certain motor skills, speech and language; learning disabilities, such as dyslexia; or weak muscle tone. The symptoms vary from person to person, with some women being more affected than others. There are seldom any observable physical anomalies in Triple X females, other than being taller than average.

Females with Triple X syndrome are at increased risk of delayed language development, EEG abnormalities, motor-coordination problems and auditory-processing disorders, and scoliosis. They tend to show accelerated growth until puberty. Premature ovarian failure seems to be more prevalent in these women, but most Triple X females seem to have normal fertility. They are more likely to struggle with personality and psychological problems, and low self-esteem, but these respond well to treatment. Triple X females are at increased risk of poor academic results at school, and some may need special education. Sometimes, they may suffer from anxiety and be very shy, and this may affect their relations with school peers. They seem to feel much better after leaving school. They benefit very much from a stable home environment. 

 

XX MALES 

Phenotypic males with an XX karyotype, who may have a frequency of about 1 in 15,000 male births, have created much interest because they appear to contradict the rule that a Y chromosome is essential to differentiation of the primitive gonad into a testis. One of the hypotheses developed to account for XX males has been that they may simply be XX/XXY mosaics in whom the Y-containing cell line has not been identified. An argument in favor of this interpretation is that XX males typically resemble males with the Klinefelter syndrome, except that they are usually not so tall and seem to have normal intelligence. A second possible explanation is that an interchange between Xp and Yp during paternal meiosis results in XX males in whom the paternal X chromosome carries translocated male-determining Y chromosomal material.

Many genes code for the production of proteins. Some of these proteins function as enzymes. Therefore, if the gene that codes for a particular enzyme is missing or defective, the reaction catalyzed by the enzyme will not occur. Such a condition is called an inborn error of metabolism.

Genes also code for proteins that have other important functions. For example, some proteins make up part of the structure of cells. Other proteins act as carrier molecules that transport substances across cell membranes. A defect in a gene that codes for these kinds of proteins can have medical effects as serious as those caused by missing or defective enzymes.

There are about 4000 known genetic-based disorders in humans. When people plan to have children, information about the inheritance of genetic disorders is sometimes needed. This lesson will familiarize you with a few well-known disorders.

 

Disorders Caused by Gene Mutations

 Sickle-Cell Disease Sickle-cell disease is a disorder that occurs most often among people of tropical African descent. It is the result of a point mutation in the gene that codes for the protein hemoglobin. Hemoglobin in the red blood cells carries oxygen from the lungs to all the other cells of the body.

 Normal red blood cells are circular but slightly uneven. In sickle-cell disease, the red blood cells are curved, or sickle-shaped. This shape is caused by a single base substitution in the gene for hemoglobin. In the normal gene, a particular base triplet codes for the amino acid glutamic acid. In the sickle-cell gene, this triplet codes for valine. The sequence of amino acids determines the shape of a protein molecule. The substitution of valine for glutamic acid changes the shape of the hemoglobin molecule. As a result, the shape of the blood cell is also changed.

 The base substitution has many serious effects. Sickled cells are fragile and break apart easily. The body cannot produce new cells as fast as the defective ones break. This condition results in anemia, or a shortage of red blood cells. The sickled cells also clog small blood vessels, restricting blood flow. Reduced blood flow damages tissues and organs and causes severe pain in the affected areas.

 People with sickle-cell disease are also very prone to infection, which can be life-threatening. It is important to realize, however, that the severity of a particular genetic disease can vary greatly from person to person. One child with sickle-cell disease may be ill only once or twice a year, while another may be hospitalized very frequently. It has recently been found that when affected children are identified at birth, they can be treated with antibiotics for several years to prevent infection. In addition, they can be given special vaccinations. These types of treatments have enabled some affected children to live well into adulthood, which was not likely just a few years ago.

 In people who are heterozygous for the sickle-cell allele, some of the hemoglobin is normal and some is abnormal. These people are said to have sickle-cell trait. They are generally healthy, but have a higher risk of heart attacks during very strenuous exercise. In malaria-infested areas, such as tropical Africa, it is an advantage to be heterozygous. Having sickle-cell trait lowers an individual’s chances of developing malaria because the tiny organism that causes malaria cannot reproduce in the sickled cells. Because of African ancestry, one out of ten children born to black families in North America is heterozygous for the sickle-cell gene. If a husband and wife both have the sickle-cell trait, they have a 25-percent chance of producing a child with sickle-cell disease. Arabic people are also at higher risk for sickle-cell disease.

 Cystic Fibrosis Cystic fibrosis is the most common genetic disorder among North American Caucasians. One in twenty white Americans is a carrier. In cystic fibrosis, thick mucus builds up in the lungs, allowing the growth of bacteria that cause severe respiratory infections. The disorder also causes a digestive enzyme deficiency, which prevents food from being digested and absorbed properly. This disorder leads to malnutrition.

Cystic fibrosis is now thought to be caused by a genetic defect that affects certain molecules in the plasma membrane of cells. Recall that some molecules help to regulate the movement of substances across membranes. In cystic fibrosis, this defect in regulation causes water to be excreted too quickly from the cells. The resulting imbalance causes mucus to accumulate.

Many exciting developments have recently taken place in understanding cystic fibrosis. The gene has been located, which means that people can be screened for the presence of the gene. Once the gene’s function is identified, treatment may be possible. At present, antibiotics and respiratory therapy enable half of those with the disorder to reach age 21.

Huntington Disease Huntington disease is a lethal disorder caused by a dominant gene. Each child of a person with Huntington disease has a 50-percent chance of inheriting the dominant gene and developing the disease. It affects 1 in 25 000 people.

Although the gene for Huntington disease is present at birth, the symptoms of the disease do not appear until about age 40. These symptoms include loss of muscle coordination that makes a person’s movements dancelike and uncontrollable. Mental deterioration can cause personality changes. A new test can tell members of a family with a history of Huntington disease whether or not they have inherited the disease-causing gene.

 

Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).

Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person’s thirties or forties. Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington disease develop involuntary jerking or twitching movements known as chorea. As the disease progresses, these movements become more pronounced. Affected individuals may have trouble walking, speaking, and swallowing. People with this disorder also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with the adult-onset form of Huntington disease usually live about 15 to 20 years after signs and symptoms begin.

A less common form of Huntington disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. Additional signs of the juvenile form include slow movements, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance declines as thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50 percent of children with this condition. Juvenile Huntington disease tends to progress more quickly than the adult-onset form; affected individuals usually live 10 to 15 years after signs and symptoms appear.

Huntington disease affects an estimated 3 to 7 per 100,000 people of European ancestry. The disorder appears to be less common in some other populations, including people of Japanese, Chinese, and African descent.

Mutations in the HTT gene cause Huntington disease. The HTT gene provides instructions for making a protein called huntingtin. Although the function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain.

The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder.

An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate ieurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person usually inherits the altered gene from one affected parent. In rare cases, an individual with Huntington disease does not have a parent with the disorder.

As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats.

Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington disease, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington disease (36 repeats or more).

 

Hemophilia Gene mutations occur on sex chromosomes as well as on autosomes. Mutations on sex chromosomes give rise to sex-linked disorders. One well-known sex-linked disorder in humans is hemophilia, the inability of blood to clot. In most hemophilia victims, the body is not able to manufacture a certain protein needed for forming a blood clot. Hemophilia causes uncontrollable internal bleeding into the kidneys, brain, and other organs. Until recently, victims of hemophilia died at an early age. Now hemophilia can be treated with injections of clotting factor produced by recombinant DNA technology.

Hemophilia is caused by a recessive allele located on the X chromosome. Therefore, a maeeds only one recessive allele to express the trait. A woman must have two recessive alleles.

A woman who is a carrier of hemophilia has a 50-percent chance of passing the recessive allele on to each of her children.

The most famous carrier of hemophilia was Queen Victoria. She unknowingly passed the gene on to one of her sons and two of her daughters. To see how the gene for hemophilia was inherited in the royal families of Europe during the nineteenth century.

A pedigree is a diagram that shows how a trait is inherited in a family. Notice in the pedigree that circles represent females and squares represent males. The filled-in spaces represent people who have the trait or disorder being followed. Half-filled spaces represent carriers, and unfilled spaces represent people who do not have the trait. A horizontal line between a circle and a square represents marriage. The children of a given marriage are shown with vertical lines. Can you explain why all the carriers in this pedigree are female?

 Duchenne Muscular Dystrophy Another important sex-linked condition is Duchenne muscular dystrophy. This disorder causes deterioration of the muscles and then death by early adulthood. Males with muscular dystrophy do not live long enough to reproduce. Therefore, they never transmit the recessive allele to offspring.

Scientists recently located the gene responsible for Duchenne muscular dystrophy at a particular spot on the X chromosome and determined its DNA sequence. The protein it codes for is named dystrophin. Although dystrophin is normally present in only small amounts in muscles, its absence is devastating to muscle function, as seen in sufferers of Duchenne’s muscular dystrophy. Now that the nature of the protein abnormality is known, a treatment is more likely to be developed.

 

There are 4 main types of the genetic disorders:

1.  Abnormalities (Aneuploidy) of autosomes: Down syndrome, Patau syndrome, Edwards syndrome.

2.  Abnormalities (Aneuploidy) of sex chromosomes: Turner syndrome, the triplo-X syndrome, Klinefelter’s syndrome, the XYY syndrome.

3.  Abnormalities (chromosome aberrations) of autosomes: the cri-du-chat syndrome (5p-syndrome).

4.   Gene disorders (metabolic disorders or molecular pathology): phenylketonuria, albinism, sickle-cell anaemia, Tay-Sach’s disease, haemophilia, red-green colour blindness.

Nondisjunction. A common cause of changes in chromosome number.

 

1. Down Syndrome. The karyotype formula is 47, XX, 21+ or 47, XY, 21+. The frequency of births is 1/700.

Phenotypic effects of trisomy 21. Down syndrome is characterized by a small skull, round face and a long protruding tongue, short, flat-bridge nose, a mongolian type of eyelid fold (epicanthal fold), short neck, short phalanges (fingers), flat hands, unusual finger and palm prints (dermal rings), indcluding transverse palm crease, triradius near center (angle atd is equal to 80 degree). The patients with Down syndrome have mental retardation, little intelligence, abnormalities of heart.

 

   

 

Etiology of Down syndrome. The cause of Down syndrome is that during anaphase of meiosis chromosomes of 21 pair didn’t disjoin and move to opposite poles of the cell. As result gametes (eggs or sperm cells) have 22 chromosomes (-21th) or 24 chromosomes (+21th). Wheormal gamete with 23 chromosomes fuses with gamete with 24 (+21th) chromosomes, the resulting zygote will be 47,+21 chromosomes and will develop into a Down syndrome (trisomy 21).

 

 Down syndrome (DS) or Down’s syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy ofchromosome 21. Down syndrome is the most common chromosome abnormality in humans. The CDC estimates that about one of every 691 babies born in the United States each year is born with Down syndrome.[3] It is typically associated with physical growth delays, a particular set of facial characteristics and a severe degree of intellectual disability. The average full-scale IQ of young adults with Down syndrome is around 50 (70 and below is defined as the cut-off for intellectual disability), whereas healthy young adult controls have an average IQ of 100. Many children with Down syndrome are educated in regular school classes while others require specialised educational facilities. Some children graduate from high school, and, in the US, there are increasing opportunities for participating in post-secondary education. Education and proper care has been shown to improve quality of life significantly. Many adults with Down syndrome are able to work at paid employment in the community, while others require a more sheltered work environment.

Down syndrome is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier by Jean Etienne Dominique Esquirol in 1838 and Edouard Seguin in 1844. Down syndrome was identified as a chromosome 21trisomy by Dr. Jérôme Lejeune in 1959. Down syndrome can be identified in a newborn by direct observation or in a fetus by prenatal screening. Pregnancies with this diagnosis are often terminated.

Signs and symptoms

The signs and symptoms of Down syndrome are characterized by the neotenization of the brain and body. Down syndrome is characterized by decelerated maturation (neoteny), incomplete morphogenesis (vestigia) and atavisms. Individuals with Down syndrome may have some or all of the following physical characteristics: microgenia (abnormally small chin), oblique eye fissures on the inner corner of the eyes, 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) ormacroglossia, “face is flat and broad”, a short neck, white spots on the iris known as Brushfield spots, excessive joint laxity includingatlanto-axial instability, excessive space between large toe and second toe, a single flexion furrow of the fifth finger, a higher number of ulnar loopdermatoglyphs and short fingers.

Growth parameters such as height, weight, and head circumference are smaller in children with DS than with typical individuals of the same age. Adults with DS tend to have short stature and bowed legs – the average height for men is 5 feet 1 inch (154 cm) and for women is 4 feet 9 inches (144 cm).  Individuals with DS are also at increased risk for obesity as they age.

Characteristics

Percentage

Characteristics

Percentage

stunted growth

100%

flattened nose

60%

mental retardation

99.8%

small teeth

60%

atypical fingerprints

90%

clinodactyly

52%

separation of the abdominal muscles

80%

umbilical hernia

51%

flexible ligaments

80%

short neck

50%

hypotonia

80%

shortened hands

50%

brachycephaly

75%

congenital heart disease

45%

smaller genitalia

75%

single transverse palmar crease

45%

eyelid crease

75%

macroglossia (larger tongue)

43%

shortened extremities

70%

epicanthic fold

42%

oval palate

69%

strabismus

40%

low-set and rounded ear

60%

Brushfield spots (iris)

35%

 

Individuals with Down syndrome have a higher risk for many conditions. The medical consequences of the extra genetic material in Down syndrome are highly variable, may affect the function of any organ system or bodily process, and can contribute to a shorter life expectancy for people with Down syndrome. Following improvements to medical care, particularly with heart problems, the life expectancy among persons with Down syndrome has increased from 12 years in 1912, to 60 years. In March 2012 the Guinness Book of Recordswebsite listed Joyce Greenman, now 87, of London, who was born on March 14, 1925, as the oldest living person with Down syndrome, (recorded correct and checked as of 29 April 2008). The causes of death have also changed, with chronic neurodegenerative diseases becoming more common as the population ages. Most people with Down syndrome who live into their 40s and 50s begin to suffer from dementia like Alzheimer’s disease.

The American Academy of Pediatrics, among other health organizations, has issued a series of recommendations for screening individuals with Down syndrome for particular diseases.[24]

 

Neurological effects

Most individuals with Down syndrome have intellectual disability in the mild (IQ 50–70) to moderate (IQ 35–50) range, with individuals having Mosaic Down syndrome typically 10–30 points higher. The methodology of the IQ tests has been criticised for not taking into account accompanying physical disabilities, such as hearing and vision impairment, that would slow performance.

Language skills show a difference between understanding speech and expressing speech, and commonly individuals with Down syndrome have a speech delay.[28] Fine motor skills are delayed[29] and often lag behind gross motor skills and can interfere with cognitive development. Effects of the condition 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 four. 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.

Children and adults with DS are at increased risk for developing epilepsy and also Alzheimer’s disease.

 

Congenital heart disease

The incidence of congenital heart disease in newborn babies with Down syndrome is up to 50%. An atrioventricular septal defect also known as endocardial cushion defect is the most common form with up to 40% of patients affected. This is closely followed by ventricular septal defect that affects approximately 35% of patients.

 

Cancer

Although the general incidence of cancer amongst individuals with Down syndrome is the same as in the general population, there are greatly reduced incidences of many common malignancies except leukemia and testicular cancer. People with Down syndrome also have a much lower risk of hardening of the arteries and diabetic retinopathy.

Hematologic malignancies such as leukemia are more common in children with DS. In particular, acute lymphoblastic leukemia is at least 10 times more common in DS and themegakaryoblastic form of acute myelogenous leukemia is at least 50 times more common in DS. Transient leukemia is a form of leukemia that is rare in individuals without DS but affects up to 20 percent of newborns with DS. This form of leukemia is typically benign and resolves on its own over several months, though it can lead to other serious illnesses.[38] In contrast to hematologic malignancies, solid tumor malignancies are less common in DS, possibly due to increased numbers of tumor suppressor genes contained in the extra genetic material.

 

Thyroid disorders

Individuals with DS are at increased risk for dysfunction of the thyroid gland, an organ that helps control metabolism. Low thyroid (hypothyroidism) is most common, occurring in almost a third of those with DS. This can be due to absence of the thyroid at birth (congenital hypothyroidism) or due to attack on the thyroid by the immune system.

 

Gastrointestinal

Down syndrome increases the risk of Hirschsprung’s disease, in which the nerve cells that control the function of parts of the colon are not present. This results in severe constipation. Other congenital anomalies occurring more frequently in DS include duodenal atresia, annular pancreas, and imperforate anus. Gastroesophageal reflux disease and celiac disease are also more common among people with DS.

 

Infertility

Males with Down syndrome usually cannot father children, while females demonstrate significantly lower rates of conception relative to unaffected individuals. Women with DS are less fertile and often have difficulties with miscarriage, premature birth, and difficult labor. Without preimplantation genetic diagnosis, approximately half of the offspring of someone with Down syndrome also have the syndrome themselves. Men with DS are almost uniformly infertile, exhibiting defects in spermatogenesis. There have been only three recorded instances of males with Down syndrome fathering children.

 

Brushfield spots, visible in the irises of a baby with Down Syndrome

 

Eye disorders are more common in people with DS. Almost half have strabismus, in which the two eyes do not move in tandem.Refractive errors requiring glasses or contacts are also common. Cataracts (opacity of the lens), keratoconus (thin, cone-shaped corneas), and glaucoma (increased eye pressures) are also more common in DS.[47] Brushfield spots (small white or grayish/brown spots on the periphery of the iris) may be present.

 

Hearing disorders

In general, hearing impairment and otological problems are found in 38-78% of children with Down syndrome compared to 2.5% of normal children. However, attentive diagnosis and aggressive treatment of chronic ear disease (e.g. otitis media, also known as glue-ear) in children with Down syndrome can bring approximately 98% of the children up to normal hearing levels.

The elevated occurrence of hearing loss in individuals with Down syndrome is not surprising. Every component in the auditory system is potentially adversely affected by Down syndrome.

Otitis media with effusion is the most common cause of hearing loss in Down children; the infections start at birth and continue throughout the children’s lives. The ear infections are mainly associated with Eustachian tube dysfunction due to alterations in the skull base. However, excessive accumulation of wax can also cause obstruction of the outer ear canal as it is oftearrowed in children with Down syndrome. Middle ear problems account for 83% of hearing loss in children with Down syndrome. The degree of hearing loss varies but even a mild degree can have major consequences for speech perception, language acquisition, development and academic achievement if not detected in time and corrected.

Early intervention to treat the hearing loss and adapted education are useful to facilitate the development of children with Down syndrome, especially during the preschool period. For adults, social independence depends largely on the ability to complete tasks without assistance, the willingness to separate emotionally from parents and access to personal recreational activities. Given this background it is always important to rule out hearing loss as a contributing factor in social and mental deterioration.

Genetics

Down syndrome disorders are based on having too many copies of the genes located on chromosome 21. In general, this leads to an overexpression of the genes. Understanding the genes involved may help to target medical treatment to individuals with Down syndrome. It is estimated that chromosome 21 contains 200 to 250 genes. Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome.

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.[58] In 1–2% of the observed Down syndromes. Some of the cells in the body are normal and other cells have trisomy 21, this is called mosaic Down syndrome (46,XX/47,XX,+21).

 

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,der(14;21)(q10;q10)]. A person with such a translocation is phenotypically normal. During reproduction, normal disjunctionsleading 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 asfamilial 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.

Reproduction in Down’s syndrome should be possible. Meiotic studies in Down syndrome have not been possible in males, but ones have been possible in females with

 

2. Trisomy 13 (Patau syndrome). The karyotype formula is 47, XX, 13+ or 47, XY, 13+. The frequency of births is 1/15.000 .

Patau syndrome /ˈpæt/ is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. This can occur either because each cell contains a full extra copy of chromosome 13 (a disorder known as trisomy 13or trisomy D), or because each cell contains an extra partial copy of the chromosome (i.e., Robertsonian translocation) or because of mosaic Patau syndrome. Full trisomy 13 is caused by nondisjunction of chromosomes during meiosis (the mosaic form is caused by nondisjunction during mitosis). The extra genetic material from chromosome 13 disrupts the normal course of development, causing multiple and complex organ defects. Like allnondisjunction conditions (such as Down syndrome and Edwards syndrome), the risk of this syndrome in the offspring increases with maternal age at pregnancy, with about 31 years being the average.[1] Patau syndrome affects somewhere between 1 in 10,000 and 1 in 21,700 live births.

Patau’s syndrome is most often the result of trisomy 13, meaning each cell in the body has three copies of chromosome 13 instead of the usual two. A small percentage of cases occur when only some of the body’s cells have an extra copy; such cases are called mosaic Patau.

Patau syndrome can also occur when part of chromosome 13 becomes attached to another chromosome (translocated) before or at conception in aRobertsonian translocation. Affected people have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 13 and often the physical signs of the syndrome differ from the typical Patau syndrome.

Most cases of Patau syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each of the body’s cells. Mosaic Patau syndrome is also not inherited. It occurs as a random error during cell division early in fetal development.

Patau syndrome due to a translocation can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of Patau syndrome, people who carry this type of balanced translocation are at an increased risk of having children with the condition.

 

Diagnosis

Diagnosis is usually based on clinical findings, although fetal chromosome testing will show trisomy 13. While many of the physical findings are similar to Edward’s syndrome there are a few unique traits, such as polydactyly. However, unlike Edward’s syndrome and Down syndrome, the quad screen does not provide a reliable means of screening for this disorder. This is due to the variability of the results seen in fetuses with Patau. Unless one of the parents is a carrier of a translocation the chances of a couple having another trisomy 13 affected child is less than 1% (less than that of Down syndrome).

History

Trisomy 13 was first observed by Thomas Bartholin in 1657, but the chromosomal nature of the disease was ascertained by Dr. Klaus Patau in 1960. 

The disease is named in his honor.

In England and Wales during 2008–09 there were 172 diagnoses of Patau’s syndrome (trisomy 13), with 91% of diagnoses made prenatally. There were 111 elective abortions, 14 stillbirth/miscarriage/fetal deaths, 30 outcomes unknown, and 17 live births. Approximately 4% of Patau’s syndrome with unknown outcomes are likely to result in a live birth, therefore the total number of live births is estimated to be 18. The small percentage of babies with the full Patau’s syndrome who survive birth and early infancy may live to adulthood, and children with mosaic or partial forms of this trisomy may have a completely different and much more hopeful prognosis.

Treatment

Medical management of children with Trisomy 13 is planned on a case-by-case basis and depends on the individual circumstances of the patient. Treatment of Patau syndrome focuses on the particular physical problems with which each child is born. Many infants have difficulty surviving the first few days or weeks due to severe neurological problems or complex heart defects. Surgery may be necessary to repair heart defects or cleft lip and cleft palate. Physical, occupational, and speech therapy will help individuals with Patau syndrome reach their full developmental potential. Surviving children are described as happy and parents report that they enrich their lives.

Prognosis

More than 80% of children with Patau syndrome die within the first year of life.

 3. Trisomy 18 (Edwards syndrome). The karyotype formula is 47, XX, 18+ or 47, XY, 18+. The frequency of births is 1/5.000 .

        Edwards syndrome (also known as Trisomy 18 [T18]) is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. This genetic condition almost always results from nondisjunction during meiosis. It is named after John Hilton Edwards, who first described the syndrome in 1960. It is the second most common autosomal trisomy, after Down syndrome, that carries to term.

Edwards syndrome occurs in around one in 6,000 live births and around 80 percent of those affected are female. The majority of fetuses with the syndrome die before birth. The incidence increases as the mother’s age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.

Signs and symptoms

Children 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 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; choroid plexus cysts; underdeveloped thumbs and or nails, absent radius, webbing of the second and third toes; clubfoot or Rocker bottom feet; and in males,undescended testicles.

Clenched hand and overlapping fingers: index finger overlaps third finger and fifth finger overlaps fourth finger, characteristically seen in Trisomy 18.

 

In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18. Sometimes excess amniotic fluid or polyhydramnios is exhibited.

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 in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations but is more prevalent in female offspring.

A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by 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 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 individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.Prognosis

In 2008/2009, there were 495 diagnoses of Edwards syndrome (trisomy 18) in England and Wales, 92% of which were made prenatally. There were 339 abortions, 49 stillbirths/miscarriages/fetal deaths, 72 unknown outcomes, and 35 live births. Because approximately 3% of cases with unknown outcomes are likely to result in a live birth, the total number of live births is estimated to be 37 (2008/09 data are provisional). Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period. Half of infants with this condition do not survive beyond the first week of life.  The median lifespan is 5–15 days. About 8% of infants survive longer than 1 year, One percent of children live to age 10, typically in less severe cases of the mosaic Edwards syndrome. Parents with surviving children who take part in support groups report that these children enriched their family and their couple irrespective of the length of their lives.

Epidemiology

Edwards syndrome occurs in approximately 1 in 6,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive the prenatal period. Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with Edwards syndrome increases with a woman’s age. The average maternal age for conceiving a child with this disorder is 32½.

 

4.  The cri-du-chat syndrome. The karyotype formula is 46, XX, 5p- or 46, XY, 5p-. Such patients have a small head, low-set malformed ears, abnormalities of the heart and visceral, are mentally retarded. Abnormal development of the glottis and larynx results in the most characteristic symptom – the infant’s cry resembles that of a cat.

 

 

 Cri du chat syndrome, also known as chromosome 5p deletion syndrome, 5p minus syndrome or Lejeune’s syndrome, is a rare genetic disorder due to a missing part of chromosome 5. Its name is a French term (cat-cry or call of the cat) referring to the characteristic cat-like cry of affected children. It was first described by Jérôme Lejeune in 1963. The condition affects an estimated 1 in 50,000 live births, strikes all ethnicities, and is more common in females by a 4:3 ratio.

 

Signs and symptoms

The syndrome gets its name from the characteristic cry of affected infants, which is similar to that of a meowing kitten, due to problems with the larynx and nervous system. About 1/3 of children lose the cry by age 2. Other symptoms of cri du chat syndrome may include:

·        feeding problems because of difficulty swallowing and sucking;

·        low birth weight and poor growth;

·        severe cognitive, speech, and motor delays;

·        behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements;

·        unusual facial features which may change over time;

·        excessive drooling;

·        constipation;

·        small head and jaw;

·        wide eyes;

·        skin tags in front of eyes.

Other common findings include hypotonia, microcephaly, growth retardation, a round face with full cheeks, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, flat nasal bridge, down-turned mouth, micrognathia, low-set ears, short fingers, single palmar creases, and cardiac defects (e.g., ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot). People with Cri du chat are fertile and can reproduce.

Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, intestinal malrotation, megacolon, inguinal hernia, dislocated hips,cryptorchidism, hypospadias, rare renal malformations (e.g., horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus,syndactyly of the second and third fingers and toes, oligosyndactyly, and hyperextensible joints. The syndrome may also include various dermatoglyphics, including transverse flexion creases, distal axial triradius, increased whorls and arches on digits, and a single palmar crease.

Late childhood and adolescence findings include significant intellectual disability, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis.

Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females except for a report of a bicornuate uterus. In males, testes are often small, but spermatogenesis is thought to be normal.

 

Genetics

Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5, also called “5p monosomy“. Approximately 90% of cases result from a sporadic, or randomly occurring, de novo deletion. The remaining 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. These individuals may have more severe disease than those with isolated monosomy of 5p.

Most cases involve total loss of the most distant 10-20% of the material on the short arm. Fewer than 10% of cases have other rare cytogenetic aberrations (e.g., interstitial deletions,mosaicisms, rings and de novo translocations). The deleted chromosome 5 is paternal in origin in about 80% of de novo cases. Loss of a small region in band 5p15.2 (cri du chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition’s etiology. Two genes in these regions, Semaphorine F (SEMA5A) and delta catenin (CTNND2), are potentially involved in cerebral development. The deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 may contribute to the phenotypic changes in cri du chat syndrome as well.

Diagnosis and management 

Diagnosis is based on the distinctive cry and accompanying physical problems. Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome. Prenatally the deletion of the cri du chat related region in the p arm of chromosome 5 can be detected from amniotic fluid or chorionic villi samples with BACs-on-Beads technology.G-banded karyotype of a carrier is also useful.[3] Children may be treated by speech, sound, and occupational therapists. Cardiac abnormalities often require surgical correction.

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