The molecular basis of cystathionine beta-synthase deficiency in dutch patients with homocystinuria: Effect of CBS genotype on biochemical and clinical phenotype and on response to treatment

Homocystinuria due to cystathionine P-synthase (CBS) deficiency, inherited as an autosomal recessive trait, is the most prevalent inborn error of meth ionine metabolism. Its diverse clinical expression may include ectopia lent is, skeletal abnormalities, mental retardation, and premature arteriosclero sis and thrombosis. This variability is likely caused by considerable genet ic heterogeneity. We investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility o f a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Clinical sympt oms and biochemical parameters were recorded at diagnosis and during long-t erm followup. Of 10 different mutations detected in the CBS gene, 833T-->C (I278T) was predominant, present in 23 (55%) of 42 independent alleles. At diagnosis, homozygotes for this mutation (n = 12) tended to have higher hom ocysteine levels than those seen in patients with other genotypes (n = 17), but similar clinical manifestations. During follow-up, I278T homozygotes r esponded more efficiently to homocysteine-lowering treatment. After 378 pat ient-years of treatment, only 2 vascular events were recorded; without trea tment, at least 30 would have been expected (P < .01). This intervention in Dutch patients significantly reduces the risk of cardiovascular disease an d other sequelae of classical homocystinuria syndrome.