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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.

The female heterozygotes may also exhibit mental retardation. The responsible gene (FMR-1) has been cloned, and it includes the sequence that causes the fragile X mutation. Normal individuals have an average of about 30 repeats. Alleles with more than about 50 repeats, including those identified in a normal family.

Individuals with no significant phenotypic abnormalities, but who are at high risk for having an affected offspring, have triple repeats ranging between 50 and 200. Such individuals are said to have a premutation, because it has a high probability of expanding to a full mutation in the next generation. Individuals with more that 200 CGG repeats are affected with the fragile X syndrome. The passage from premutation to full mutation status occurs only with transmission.

Expanded CGG repeats appear to cause abnormal methylation of the FMR-1 gene, which, in turn, causes a reduction in gene transcription, resulting in disease. Molecular testing for clinical diagnosis, cartier detection, and prenatal diagnosis of the fragile X syndrome is available and is proving more reliable than cytogenetic testing. Results from chorionic villus sampling should be interpreted with caution because the methylation status of the FMR-1 gene is rarely established in chorionic villi at the time of sampling. Chorionic villus sampling, although a standard technique for prenatal diagnosis, may lead to a situation where follow-up amniocentesis is necessary.

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.

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, male pattern baldness, male infertility (hypogonadism), and other associated endocrinopathies. The age of onset and severity of the disease show extreme variation, both within and between families. The rare congenital form of myotonic dystrophy is associated with profound newborn hypotonia and mental retardation.

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.