Homocystinuria due to cystathionine beta-synthase deficiency

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency, also known as classical homocystinuria, is an inherited metabolic disorder caused by mutations in the CBS gene located on chromosome 21q22.3. CBS is a key enzyme in the transsulfuration pathway that converts homocysteine to cystathionine. When this enzyme is deficient, homocysteine and methionine accumulate in the blood and urine, leading to toxic effects on multiple organ systems. The disease primarily affects the eyes, skeletal system, vascular system, and central nervous system. Key clinical features include ectopia lentis (dislocation of the eye lens, typically downward), myopia, skeletal abnormalities resembling Marfan syndrome (tall stature, long limbs, scoliosis, osteoporosis, and pectus deformities), thromboembolic events (a major cause of morbidity and mortality), and intellectual disability of variable severity. Thromboembolism can affect both arteries and veins and may occur at any age, including childhood. Symptoms typically become apparent in childhood, though the age of onset and severity vary considerably, particularly between pyridoxine-responsive and non-responsive forms. Treatment depends on whether the patient is responsive to pyridoxine (vitamin B6). Approximately half of patients show some degree of biochemical response to pharmacological doses of pyridoxine, and these individuals generally have a milder clinical course. For pyridoxine-responsive patients, high-dose vitamin B6 supplementation is the cornerstone of therapy. For non-responsive patients, treatment involves a methionine-restricted diet supplemented with cystine, along with betaine (trimethylglycine), which provides an alternative pathway for homocysteine remethylation. Folate and vitamin B12 supplementation are also commonly used. Early detection through newborn screening and prompt initiation of treatment can significantly improve outcomes and prevent or delay complications. Anticoagulation or antiplatelet therapy may be considered for thromboembolic risk management.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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