About this condition
Homocystinuria
Classical homocystinuria is an autosomal recessive disorder of methionine metabolism caused by deficiency of cystathionine β-synthase (CBS, chromosome 21q22.3). CBS catalyzes the condensation of homocysteine with serine to form cystathionine — the first step of the transsulfuration pathway. CBS deficiency causes accumulation of homocysteine and methionine in blood and tissues. Homocystinuria affects approximately 1 in 200,000-300,000 births worldwide, with higher prevalence in Ireland (~1 in 65,000) and Qatar (~1 in 1,800). Pyridoxine (vitamin B6) is a cofactor for CBS, and approximately 50% of patients have B6-responsive forms that retain partial CBS activity.
Untreated homocystinuria produces a recognizable clinical syndrome: ectopia lentis (lens dislocation — characteristically downward, distinguishing it from Marfan syndrome where lenses dislocate upward), Marfanoid skeletal features (tall stature, long limbs, pectus deformity, scoliosis), thromboembolism (the leading cause of mortality — elevated homocysteine promotes endothelial damage and coagulation activation), and intellectual disability (variable, ranging from normal intelligence to severe impairment). The thromboembolic risk is lifelong: stroke, pulmonary embolism, and deep vein thrombosis cause significant morbidity and mortality, particularly during surgery, pregnancy, or immobilization.
Treatment depends fundamentally on B6 responsiveness. B6-responsive patients (approximately 50%) are treated with high-dose pyridoxine (100-500mg/day), which enhances residual CBS activity and normalizes or near-normalizes plasma homocysteine levels — these patients have substantially better outcomes including preserved intellect, reduced thromboembolic risk, and often no need for dietary methionine restriction. B6-non-responsive patients require lifelong methionine-restricted diet, betaine supplementation (which provides an alternative route for homocysteine remethylation), folate, and B12. The distinction between responsive and non-responsive forms is the critical management decision and is determined by the specific CBS genotype.
Lens dislocation in homocystinuria is typically downward (inferonasal), while in Marfan syndrome it is upward (superotemporal). Any patient with lens dislocation should have plasma homocysteine measured — this single lab test distinguishes the two conditions.
- Gene locus
- CBS (21q22.3)
