Clinical Utility of Testing

Patients with homocystinuria are at markedly increased risk for both atherosclerotic arterial occlusive disease and VTE. About 25% of patients with homocystinuria develop a thrombotic vascular occlusive event by age 16 years, and about 50% develop such an event by age 29 years.30 Of these, about half are arterial occlusive events (e.g., stroke, myocardial infarction, or peripheral artery thrombosis), and the remainder are VTE. The event rate is significantly reduced by vitamin therapy in B6-responsive patients.29

Homocystinuric patients generally have plasma homo-cyst(e)ine levels of 100 to 300 pmol/L. Multiple case-control studies have found that milder hyperhomocysteinemia (e.g., 15 to 100 pmol/L) is a risk factor for both arterial occlusive disease and VTE, with odds ratios of about 2.2 to 3.0.29 However, there is concern that these studies may have been confounded because plasma homocysteine levels may be elevated after thrombotic vascular events. Indeed, although fewer in number, prospective studies have provided conflicting results. Thus, hyperhomocysteinemia appears to be a weak risk factor for thrombotic arterial occlusive disease,while the risk for VTE remains uncertain. Heterozygotes for the MTHFR 677C^T mutation are not at risk for hyperhomocysteinemia, thrombotic arterial occlu-

sive disease, or VTE. While homozygotes are at increased risk for hyperhomocysteinemia, homozygosity for the MTHFR 677C^T mutation in the absence of hyperhomo-cysteinemia is not an independent risk factor for either arterial or venous thrombosis. There are no studies showing that reduction in plasma homocysteine levels by therapy with vitamins B6 or B12 or folic acid reduces the risk for arterial or venous thrombosis. Testing for hyperhomo-cysteinemia is recommended for patients with documented atherosclerotic arterial occlusive disease (e.g., coronary artery, cerebrovascular, or peripheral vascular), while testing patients with VTE remains controversial. Genotyp-ing for the MTHFR 677C^T mutation may provide insight into the etiology of hyperhomocyst(e)inemia but does not influence therapy or warrant family counseling.

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