Homocystinuria

Homocystinuria encompasses three biochemically distinct disorders of homocysteine metabolism, the most common being cystathionine beta-synthase (CBS) deficiency, an autosomal recessive enzymatic defect. CBS deficiency impairs the conversion of homocysteine to cystathionine in the transsulfuration pathway, resulting in severe elevation of homocysteine in plasma and urine. Elevated homocysteine causes endothelial damage, increased thrombotic risk, lens dislocation (often the presenting sign), and neurological complications including developmental delay and psychiatric manifestations. The typical presentation includes lens ectopia (usually inferior), myopia and astigmatism, tall stature with marfanoid features, arachnodactyly, and skeletal abnormalities. Without treatment, progressive intellectual disability, seizures, and thromboembolic events cause severe morbidity and mortality. Approximately 50% of patients with CBS deficiency respond to vitamin B6 (pyridoxine) supplementation, which can normalize homocysteine levels. All patients benefit from dietary protein restriction and supplementation with vitamins B6, B12, and folate.