The Molecular Basis of Cystathionine β-Synthase Deficiency in Dutch Patients with Homocystinuria: Effect of CBS Genotype on Biochemical and Clinical Phenotype and on Response to Treatment

Abstract

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.

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

“…1). In fact, these four mutations are particularly prevalent in certain populations Kluijtmans et al, 1999;Janosik et al, 2001; and this study]. G307S is prevalent in Ireland (71%), I278T in the Netherlands (55%), T191M in the Iberian Peninsula (50%), and IVS11-2A>C in Germany (20%) and in the former Czechoslovakia (19%).…”

Emerging Risk Factors for Atherosclerotic Vascular Disease

“…87 This risk can be substantially ameliorated by the provision of high-dose B vitamins, which partially lower homocysteine levels back toward the normal range. 90,91 It has been postulated that mild to moderate elevations of homocysteine in the general population predispose to atherosclerosis in a manner akin to the classic risk factors. This is important because of the availability of an inexpensive, safe, and effective therapy for lowering homocysteine (B vitamins).…”

Genetics of hyperhomocysteinaemia in cardiovascular disease

“…More than 100 mutations in the CBS gene have been described in CBSde¢cient patients, and most of them have been found to decrease CBS enzyme activity signi¢cantly. 45 The two most frequent mutations are 833T!C (I278T), which accounts for about one-quarter of all homocystinuric alleles and is the most common cause of homocystinuria in the Netherlands, 46 and 919G!A (G307S), which is the leading cause of homocystinuria in Ireland. 47 Reduced MS activity due to inborn errors of methylcobalamin transport or synthesis have been described as causing severe hyperhomocysteinaemia, but such cases are very rare.…”