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ESSENTIALS OF DIAGNOSIS

  • Hyperhomocysteinemia: more vascular disease but lowering homocysteine levels is not helpful.

  • Homocystinuria: Marfan-like habitus, ectopia lentis, mental retardation, thromboses.

  • Elevated homocysteine in the urine or plasma.

GENERAL CONSIDERATIONS

Patients with clinical and angiographic evidence of coronary artery disease and cerebrovascular and peripheral vascular diseases tend to have higher levels of plasma homocysteine than persons without these vascular diseases. Although this effect was initially thought to be due at least in part to heterozygotes for cystathionine beta-synthase deficiency (see below), there is little supporting evidence. Rather, an important 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—copy of an allele that causes thermolability of methylene tetrahydrofolate reductase predisposes people to elevated fasting homocysteine levels. 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 fortified with folic acid. However, therapy with B vitamins and folate lowers homocysteine levels significantly but does not reduce the risk of either venous thromboembolism or complications of coronary artery disease. The role of lowering homocysteine as primary prevention for cardiovascular disease has received modest direct support in clinical trials. Hyperhomocysteinemia occurs with end-stage chronic kidney disease. In the general population, elevated homocysteine correlates with cognitive impairment.

CLINICAL FINDINGS

A. Symptoms and Signs

Homocystinuria in its classic form is caused by cystathionine beta-synthase deficiency and exhibits autosomal recessive 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 syndrome, since patients may have a similar body habitus and ectopia lentis is almost always present. However, mental retardation is often present in homocystinuria, and the cardiovascular events are those of repeated venous and arterial thromboses whose precise cause remains obscure. Thus, the diagnosis should be suspected in patients in the second and third decades of life who have arterial or venous thromboses without other risk factors. Bone mineral density is reduced in untreated patients. 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 by newborn screening for hypermethioninemia; however, pyridoxine-responsive infants may not be detected. In addition, homozygotes for a common mutant allele, p.I278T, show marked clinical variability, with some unaffected as adults.

B. Laboratory Findings

Although many mutations have been identified in the cystathionine beta-synthase gene (CBS), amino acid analysis of plasma ...

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