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

Am J Hum Genet. 1999 Jul;65(1):59-67. doi: 10.1086/302439.


Homocystinuria due to cystathionine beta-synthase (CBS) deficiency, inherited as an autosomal recessive trait, is the most prevalent inborn error of methionine metabolism. Its diverse clinical expression may include ectopia lentis, skeletal abnormalities, mental retardation, and premature arteriosclerosis and thrombosis. This variability is likely caused by considerable genetic heterogeneity. We investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Clinical symptoms and biochemical parameters were recorded at diagnosis and during long-term follow-up. 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 homocysteine levels than those seen in patients with other genotypes (n=17), but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P<.01). This intervention in Dutch patients significantly reduces the risk of cardiovascular disease and other sequelae of classical homocystinuria syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Betaine / pharmacology
  • Child
  • Child, Preschool
  • Cystathionine beta-Synthase / deficiency*
  • Cystathionine beta-Synthase / genetics*
  • Female
  • Fibroblasts / metabolism
  • Folic Acid / pharmacology
  • Genotype
  • Homocystinuria / complications*
  • Homocystinuria / genetics*
  • Homocystinuria / therapy
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Netherlands
  • Phenotype
  • Pyridoxine / pharmacology


  • Betaine
  • Folic Acid
  • Cystathionine beta-Synthase
  • Pyridoxine