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Click here to view next page of this article Gene TherapyChromosome Disorders The normal diploid human chromosome number is 46, occurring as 23 homologous pairs. Twenty-two pairs, called autosomes, are alike in males and females genetic diseases, gene therapy. The two sex chromosomes, the remaining pair, differ in males and females. The normal male chromosomal complement is designated 46,XY. Whether associated with duplication or deficiency of genetic information, chromosomal syndromes are usually characterized by multiple anomalies. Deleterious effects are consistently associated with chromosomal abnormalities. Trisomy 21 (Down syndrome) is the most common autosomal abnormality, occurring in 1 per 800 liveborn infants; other autosomal trisomies, such as trisomy 18 and trisomy 13, are well recognized, although less common. Each of these trisomies shows an increased incidence with advancing maternal age. Monosomy almost always causes early intrauterine death. Although monosomy for the X chromosome causes early abortion in most cases, it may result in a viable fetus with Turner's syndrome. The most common chromosomal abnormalities in the general population are the balanced structural rearrangements (translocations). The translocations are reciprocal in that two chromosomes are involved in a mutual exchange. Mendelian Disorders A mutation at a single genetic locus, on either an auto-some or a sex chromosome, results in a mendelian disorder. Such a disorder may be manifested in a dominant or recessive manner. An autosomal recessive disorder is one that is expressed only when each parent possesses one copy of the gene in question (the heterozygous state) and the affected child inherits a pair of the genes (the homozygous state). An autosomal dominant trait is one that is manifest in the individual who has only a single copy of the gene (the heterozygous state). It is transmitted from generation to generation. Because males (XY) and females (XX) differ in the number of X chromosomes they possess, the inheritance pattern of mutations carried on the X chromosome differs from that carried on autosomes. A trait controlled by a gene on the X chromosome is expressed in all males with the allele. Affected males are said to be hemizygous. Females are affected if they are homozygous or if most of their X chromosomes with the normal allele are inactivated. In X-linked inheritance, there is no male-to-male transmission; all daughters of an affected male receive the mutant gene and are carriers. Half of the sons and daughters of a heterozygous female receive the mutant gene. In general, X-linked recessive traits are not clinically expressed in the heterozygous female, whereas X-linked dominant traits are expressed. Important X-linked disorders include hemophilia A and B, Duchenne-type muscular dystrophy, and glucose-6-phosphate dehydrogenase deficiency. Uniparental Disomy and Imprinting Uniparental disomy is a newly identified mode of inheritance in which both chromosomes of a pair have been inherited from one parent. Uniparental disomy may be uniparental isodisomy if the two chromosomes in a pair are completely identical or uniparental heterodisomy if both chromosomes in a pair come from one parent. Multifactorial Disorders It is thought that multifactorial disorders result from a combination of the effects of two or more deleterious genes and environmental influences, which are often unidentified. Certain characteristics suggest that a trait is inherited in a multifactorial fashion.
The multifactorial disorders include many fairy common disorders, such as neural tube defects, congenital heart disease, cleft lip with or without cleft palate, and pyloric stenosis. Triple Repeat Mutations Recently, a newly identified class of human mutation, consisting of an amplification of unstable contiguous trinucleotide repeat sequences, has been shown to be the genetic cause of several common diseases, including fragile X syndrome, spinal and bulbar muscular atrophy (Kennedy's disease), myotonic dystrophy, and Huntington's. Fragile X Syndrome The fragile X syndrome is the most common inherited form of mental retardation. In addition to moderate to severe mental retardation, affected males have facial dysmorphic features, macroorchidism, and a folate-sensitive fragile site on the X chromosome, at band Xq27.3. The female heterozygotes may also exhibit mental retardation. The responsible gene (FMR-1) has been cloned, and it includes the repeated CGG (cytosine-guanine-guanine) sequence that causes the fragile X mutation. Normal individuals have 2-50 CGG repeats at this locus, with an average of about 30 repeats. Alleles with more than about 50 repeats, including those identified in a normal family. Kennedy's Disease Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked recessive disorder characterized by motor neuron degeneration that starts in adulthood and leads to progressive muscular weakness of the upper and lower extremities and late onset of mild androgen insensitivity. Affected males have reduced fertility and gynecomastia. Myotonic Dystrophy Myotonic dystrophy is the most common form of adult muscular dystrophy, with a prevalence of 2-14 per 100,000 individuals. This autosomal dominant condition is manifested by myotonia, cardiac arrhythmias, cataracts. Huntington's Disease Huntington's disease is an autosomal dominant disorder that affects about 1 per 100,000 individuals. This progressive neurodegenerative disorder is characterized by motor disturbances, cognitive loss, and psychiatric manifestations. Affected individuals develop a distinctive choreic movement disorder that has an insidious onset in the fourth to fifth decade of life and gradually worsens over a period of 10-20 years until death. A juvenile form of Huntington's disease exists, with a preponderance of paternal transmission of the disease. Gonadal Dysgenesis The term gonadal dysgenesis applies to persons who have streak gonads rather than ovaries. Gonadal dysgenesis is usually associated with monosomy for the X chromosome (45,X) or structural abnormalities of the sex chromosomes. Rarely, those with apparently normal female (46,XX) or male (46,XY) chromosomal complements have gonadal dysgenesis. Affected individuals lack germ cells and show hypogonadism at puberty. The most common chromosomal abnormality associated with gonadal dysgenesis is 45,X; however, the proportion of 45,X persons in a given sample depends on the method by which they have been identified. Androgen Insensitivity Syndromes In complete androgen insensitivity (complete testicular feminization), 46,XY individuals have bilateral testes, female external genitalia, blindly ending vaginas, and no müllerian derivatives. Affected individuals undergo breast development and feminization at puberty. Despite pubertal feminization, some individuals with androgen insensitivity show clitoral enlargement and labioscrotal fusion. Complete Androgen Insensitivity In complete androgen insensitivity, antimüllerian hormone is synthesized as in the normal testis. The body responds normally to antimüllerian hormone--the reason no uterus is present. Affected individuals undergo breast development, but areolae are often pale and underdeveloped. Pubertal feminization occurs; however, pubic hair and axillary hair are usually sparse. Incomplete Androgen Insensitivity At puberty, certain 46,XY individuals feminize (show breast development) despite having external genitalia that are characterized by phallic enlargement and partial labioscrotal fusion. Such individuals are said to have incomplete androgen insensitivity. Both incomplete and complete androgen insensitivity have the following features: bilateral testes with similar histologic findings. DNA Diagnostic Technologies Exciting new developments have occurred in DNA-based diagnostic technologies. Whereas detection of deficient or altered gene products (proteins) is not always possible, the ability to analyze directly the underlying genetic lesion. Direct Mutation Analysis When the molecular basis of a disease is known, precise tests can be designed to detect the underlying mutation, be it a deletion, insertion, or single-base pair change. The number of common mendelian diseases in which the molecular genetics are sufficiently understood to allow this sort of diagnosis is now large and rapidly expanding. Today, most of the direct tests rely on the ability to amplify quickly and efficiently a specific region of DNA by using the polymerase chain reaction. The polymerase chain reaction greatly facilitates cloning of individual genes from a patient sample. It allows amplification of a defined DNA segment, even from a single cell, by 105107 copies in about 3 hours. First, two short synthetic single-stranded oligonucleotide primers (18-30 bases long) flanking the region. Fluorescence In Situ Hybridization Fluorescence in situ hybridization is a new diagnostic approach that merges molecular genetics and cytogenetics. |