Familial Thrombophilia Associated With Homozygosity for the Cystathionine β-Synthase 833T→C Mutation

Abstract

Abstract-Severe hyperhomocysteinemia due to cystathionine ␤-synthase (CBS) deficiency is a strong risk factor for premature cardiovascular disease. Among untreated patients, Ϸ50% have suffered a thromboembolic event by 30 years of age. We report on 3 sisters with severe hyperhomocysteinemia due to homozygosity for the CBS 833T3 C mutation. These patients, who displayed no other known thrombophilic predisposition, had suffered single or multiple venous thrombosis before CBS deficiency was diagnosed relatively late in life. In this family, homozygosity for the 833T3 C mutation was associated with a mild phenotype with respect to other sequelae of CBS deficiency. Consequently, our results indicate that most cases with this genotype may remain undiagnosed. Investigated family members heterozygous for the 833T3 C mutation displayed normal total homocysteine in plasma (tHcy) levels, even when they were homozygous for the methylenetetrahydrofolate reductase 677C3 T polymorphism. The prevalence of homozygosity for the 833T3 C mutation has previously been estimated at no less than 1:20 500 in our population. Because a reduction of the severely elevated levels of tHcy in CBS deficiency reduces cardiovascular risk and because homozygosity for the 833T3 C mutation is more prevalent than previously thought, our results emphasize the importance of measuring tHcy routinely in thrombophilia screening. Key Words: venous thrombosis Ⅲ severe hyperhomocysteinemia Ⅲ cystathionine ␤-synthase deficiency Ⅲ family history Ⅲ mutation analysis A n elevated plasma level of homocysteine is an independent risk factor for arterial as well as venous thrombosis. 1,2 Mild or moderate hyperhomocysteinemia (an increased level of total homocysteine in plasma [tHcy] up to 30 mol/L and 30 to 100 mol/L, respectively) may result from a relative deficiency of folic acid, vitamin B 12 , or vitamin B 6 3 or from homozygosity for a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene (677C3 T). 4 Severe hyperhomocysteinemia (tHcy Ͼ100 mol/L) is most often caused by cystathionine ␤-synthase (CBS, EC 4.2.1.22) deficiency. 5 This autosomal recessive disease is the most common inborn error of sulfur amino acid metabolism, with an estimated incidence of Ϸ1:200 000 worldwide, ranging from 1:20 500 to 1:1 000 000 in different populations. 6,7 The clinical manifestations include premature atherosclerosis and early thromboembolism, ectopia lentis, mental retardation, other neuropsychiatric manifestations, and skeletal abnormalities, including osteoporosis. Vascular complications constitute the major cause of death. 5 Overall, 50% of patients with untreated CBS deficiency have suffered a thromboembolic event by 30 years of age. 8 Vascular occlusion can occur in any vessel at any age, with the majority of such occurrences involving peripheral veins (51%) and complicated by pulmonary embolism in one fourth of those cases. 5 Because most countries do not systematically screen newborns for homocystinuria, the majority of cases of CBS deficiency ...

The molecular basis of cystathionine ?-synthase deficiency in Australian patients: Genotype-phenotype correlations and response to treatment

“…The haplotypes of the alleles carrying these mutations were determined with respect to two common polymorphisms in the coding region. The haplotypes of the 833T/C alleles (I278T) were in agreement with previously reported data on Danish patients [Gaustadnes et al, 2000], whereas the haplotypes of the 919G/A alleles have not been published previously. Knowledge of these haplotypes may be helpful in the elucidation of the genetic origin of CBS deficiency in patients in whom a genetic analysis has not been performed so far.…”

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

“…It was shown previously that homozygosity and compound heterozygosity for the c.833T>C mutation is almost always associated with pyridoxine responsiveness (Kraus et al, 1999), and that pyridoxine responders exhibit milder phenotype with a later onset of disease and later age of diagnosis (Mudd et al, 1985). Detection of numerous adult homocystinuric patients with a mild phenotype and pyridoxine responsiveness was reported recently after total plasma homocysteine determination became easily available (Cruysberg et al, 1996;Gaustadnes et al, 2000a;Gaustadnes et al, 2000b). The milder phenotype and late age of diagnosis in patients carrying the c.833T>C allele was apparent also in our study; of the three patients who fell outside the birth cohort used for incidence calculations, two were diagnosed in adulthood and both were homozygous for the c.833T>C allele.…”

Novel Genomic Loci Influencing Plasma Homocysteine Levels

“…8 We found nominal evidence of linkage on chromosome 1p36 between the markers D1S468 and D1S1597 (Figure 1), the genomic region that harbors the MTHFR locus (LODϭ0.91, Pϭ0.0204). The classic disorder, homocystinuria, results from a mutation in cystathionine ␤-synthase (CBS; MIM 236200), 34 an enzyme in the trans-sulfuration pathway that catalyzes the conversion of homocysteine to cystathionine 35 ( Figure 3). We did not find a linkage signal on chromosome 21q22 in the region of the CBS gene.…”