Homocystinuria

Key Features

• Caused by cystathionine β-synthase deficiency, which results in extreme elevations of plasma and urinary homocysteine levels

• Autosomal recessive inheritance with a prevalence of 1 per 100,000

Clinical Findings

• Similar to Marfan syndrome in body habitus

• Ectopia lentis almost always present

• Mental impairment often present

• Cardiovascular events caused by repeated arterial or venous thromboses

• Bone mineral density is reduced in untreated patients

• Life expectancy is reduced, especially in untreated and pyridoxine-unresponsive patients

• Elevated blood homocysteine increases the risk of Alzheimer dementia in the elderly

• Myocardial infarction, stroke, and pulmonary embolism are most common causes of death

Diagnosis

• Diagnosis suspected in patients in the second and third decades of life who have repeated arterial or venous thromboses and no other risk factors

• DNA analysis can detect mutations in the cystathionine β-synthase gene

• Amino acid analysis of plasma is most appropriate diagnostic test: elevated plasma methionine and homocysteine levels

Treatment

• In ~50% of cases, β-synthase deficiency improves biochemically and clinically with pharmacologic doses of pyridoxine (50–500 mg orally daily) and folate (5–10 mg orally daily)

• Treatment from infancy can prevent neurologic impairment and the other clinical problems

• Pyridoxine nonresponders must be treated with dietary reduction in methionine and supplementation of cysteine

• Vitamin betaine useful in reducing plasma methionine levels

• Anticoagulation for patients with documented venous thrombosis

• Prophylactic use of warfarin or antiplatelet agents not recommended