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This X-linked condition accounts for more cases of mental retardation in males than any condition except Down’s syndrome; about one in 4000 to 6000 males is affected; the condition also affects intellectual function in females about 50% less frequently than in males. The first marker for this condition was a small gap, or fragile site, evident near the tip of the long arm of the X chromosome. Subsequently, the condition was found to be due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1. All individuals have some CGG repeats in this location, but as the number increases beyond 52, the chances of further expansion during spermatogenesis or oogenesis increase. Being born with one FMR1 allele with 200 or more repeats results in mental retardation in most men and in about 60% of women. The more repeats, the greater the likelihood that further expansion will occur during gametogenesis; this results in anticipation, in which the disorder can worsen from one generation to the next. Affected (heterozygous) women show no physical signs other than early menopause, but they may have learning difficulties or frank retardation. Affected males show macroorchidism (enlarged testes) after puberty, large ears and a prominent jaw, a high-pitched voice, and mental retardation. Some show evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse.

Men who are not retarded but carry an increased number of CGG repeats in the FMR1 locus (premutation carriers) are at increased risk for developing intention tremor, ataxia, or both. Likewise, women who are premutation carriers (55–200 CGG repeats) are at increased risk for premature ovarian failure and mild cognitive or behavioral abnormalities. Male and female premutation carriers are at risk for developing tremor and ataxia beyond middle age. Because of the relatively high prevalence of premutation carriers in the general population, older people in whom any of these problems develop should undergo testing of the FMR1 locus.

DNA diagnosis for the number of repeats has supplanted cytogenetic analysis for both clinical and prenatal diagnosis. This should be done on any male or female who has unexplained mental retardation.

Hagerman PJ et al: The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004;74:805. [PMID: 15052536]

Hatton DD et al: Problem behavior in boys with fragile X syndrome. Am J Med Genet 2002;108:105. [PMID: 11857559]

Jacquemont S et al: Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460. [PMID: 14747503]

Kenneson A et al: The female and the fragile X reviewed. Semin Reprod Med 2001;19:159. [PMID: 11480913]

Sutherland GR et al: Fragile X syndrome and other causes of X-linked mental handicap. In: Emery and Rimoin’s Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2006.

Terracciano A et al: Fragile X syndrome. Am J Med Genet C Semin Med Genet 2005;137:32. [PMID: 16010677]

In humans, the normal diploid number of chromosomes is 46, consisting of 22 pairs of autosomal chromosomes (numbered 1–22 in decreasing size) and one pair of sex chromosomes (XX in females and XY in males). The genome is estimated to contain between 30,000 and 40,000 genes. Even the smallest autosome contains between 200 and 300 genes. Not surprisingly, duplications or deletions of chromosomes, or even small chromosome segments, have profound consequences on normal gene expression, leading to severe developmental and physiologic abnormalities.
Deviations in number or structure of the 46 human chromosomes are astonishingly common, despite severe deleterious consequences. Chromosomal disorders occur in an estimated 10–25% of all pregnancies. They are the leading cause of fetal loss and, among pregnancies surviving to term, the leading known cause of birth defects and mental retardation.
In recent years, the practice of cytogenetics has shifted from conventional cytogenetic methodology to a union of cytogenetic and molecular techniques. Formerly the province of research laboratories, fluorescence in situ hybridization (FISH) and related molecular cytogenetic technologies have been incorporated into everyday practice in clinical laboratories. As a result, there is an increased appreciation of the importance of “subtle” constitutional cytogenetic abnormalities, such as microdeletions and imprinting disorders, as well as previously recognized translocations and disorders of chromosome number.

Boys with an extra X chromosome are normal in appearance before puberty; thereafter, they have disproportionately long legs and arms, a female escutcheon, gynecomastia, and small testes. Infertility is due to azoospermia; the seminiferous tubules are hyalinized. The diagnosis is often not made until a couple is evaluated for inability to conceive. Mental retardation is somewhat more common than in the general population. Many men with Klinefelter syndrome have learning problems. However, their intelligence usually tests within the broad range of normal. As adults, detailed psychometric testing may reveal a deficiency in executive skills. The risk of breast cancer is much higher in men with Klinefelter syndrome than in 46,XY men, as is the risk of diabetes mellitus.

Treatment with testosterone after puberty is advisable but will not restore fertility. However, men with Klinefelter syndrome have had mature sperm aspirated from their testes and injected into oocytes, resulting in fertilization. After the blastocysts were implanted into the uterus of a partner, “natural” children resulted. However, men with Klinefelter syndrome do have an increased risk for aneuploidy in sperm, and chromosome analysis of a blastocyst before implantation should be considered.

Homocystinuria in its classic form is caused by cystathionine -synthase deficiency and exhibits an autosomal recessive pattern of inheritance. This results in extreme elevations of plasma and urinary homocystine levels, a basis for diagnosis of this disorder. Homocystinuria is similar in certain superficial aspects to Marfan’s syndrome, since patients may show a similar body habitus and ectopia lentis is almost always present. However, mental retardation is often present, and the cardiovascular events are those of repeated venous and arterial thromboses whose precise cause remains obscure. Life expectancy is reduced, especially in untreated and pyridoxine-unresponsive patients; myocardial infarction, stroke, and pulmonary embolism are the most common causes of death. This condition is diagnosed in some states by newborn screening for hypermethioninemia; however, pyridoxine-responsive infants may not be detected. The diagnosis should be suspected in patients in the second and third decades of life who show evidence of arterial or venous thromboses and have no other risk factors. Although many mutations have been identified in the cystathionine -synthase gene, amino acid analysis of plasma remains the most appropriate diagnostic test. Patients should be studied after they have been off folate or pyridoxine supplementation for at least 1 week. The plasma should be separated promptly from the fresh venous blood specimen.

About 50% of patients have a form of cystathionine -synthase deficiency that improves biochemically and clinically through pharmacologic doses of pyridoxine and folate. For these patients, treatment from infancy can prevent retardation and the other clinical problems. Patients who are pyridoxine nonresponders must be treated with a dietary reduction in methionine and supplementation of cysteine, also from infancy. The vitamin betaine is also useful in reducing plasma methionine levels by facilitating a metabolic pathway that bypasses the defective enzyme. Patients who have suffered venous thrombosis receive anticoagulation therapy, but there are no studies to support prophylactic use of warfarin or antiplatelet agents.

Over the past 5 years, considerable evidence has accumulated to support the 20-year-old observation that patients with clinical and angiographic evidence of coronary artery disease tend to have higher levels of plasma homocysteine than controls without coronary artery disease. The relationship has been extended to cerebrovascular and peripheral vascular diseases. Although this effect was initially thought to be due at least in part to heterozygotes for cystathionine -synthase deficiency (see above), there is little evidence for this. Rather, the major factor leading to hyperhomocysteinemia is folate deficiency. Pyridoxine (vitamin B6) and vitamin B12 are also important in the metabolism of methionine, and deficiency of any of these vitamins can lead to accumulation of homocysteine. A number of genes influence utilization of these vitamins and can predispose to deficiency. For example, having one—and especially two—copies of an allele that causes thermolability of methylene tetrahydrofolate reductase predisposes patients to elevated fasting homocysteine levels. However, both nutritional and most genetic deficiencies of these vitamins can be corrected by dietary supplementation of folic acid and, if serum levels are low, vitamins B6 and B12. In the United States, cereal grains are now fortified with folic acid. Studies are ongoing to determine the long-term utility of routine vitamin supplementation in people at risk for arterial occlusive disease, but many workers in this field recommend, at a minimum, taking 1 mg of folic acid per day. Because patients with end-stage renal disease tend to have marked hyperhomocysteinemia and low serum folate, 5 mg of folic acid per day seems warranted.

Relatively few laboratories currently provide highly reliable assays for homocysteine. Processing of the specimen is crucial to obtain accurate results. The plasma must be separated within 30 minutes; otherwise, blood cells release the amino acid and the measurement will then be artificially elevated.