High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands

Abstract

Classical homocystinuria is the most commonly inherited disorder of sulfur metabolism, caused by the genetic alterations in human cystathionine beta-synthase (CBS) gene. In this study, we present comprehensive clinical findings and the genetic basis of homocystinuria in a cohort of Turkish patients. Excluding some CBS mutations, detailed genotype-phenotype correlation for different CBS mutations has not been established in literature. We aimed to make clinical subgroups according to main clinical symptoms and discussed these data together with mutational analysis results from our patients. Totally, 16 different mutations were identified; twelve of which had already been reported, and four are novel (p.N93Y, p.L251P, p.D281V and c.829-2A>T). The probands were classified into three major groups according to the clinical symptoms caused by these mutations. A psychomotor delay was the most common diagnostic symptom (n=12, 46.2% neurological presentation), followed by thromboembolic events (n=6, 23.1% vascular presentation) and lens ectopia, myopia or marfanoid features (n=5, 19.2% connective tissue presentation). Pyridoxine responsiveness was 7.7%; however, with partial responsive probands, the ratio was 53.9%. In addition, five thrombophilic nucleotide changes including MTHFR c.677 C>T and c.1298 A>C, Factor V c.1691 G>A, Factor II c.20210 G>A, and SERPINE1 4G/5G were investigated to assess their contributions to the clinical spectrum. We suggest that the effect of these polymorphisms on clinical phenotype of CBS is not very clear since the distribution of thrombophilic polymorphisms does not differ among specific groups. This study provides molecular findings of 26 Turkish probands with homocystinuria and discusses the clinical presentations and putative effects of the CBS mutations.

Keywords: AT; AdoMet; CBS; CVST; Cystathionine beta-synthase; DVT; F; Genotype–phenotype correlation; Hcy; Homocystinuria; KS; LE; LTS; M; MA; MF; MR; MTHFR; MTR; MTRR; MVP; Mutation analysis; NB; NBS; ND; OP; PCR; PD; PLP; PolyPhen2; RSS; RT-PCR; RTS; RVT; Ri; S-adenosyl-l-methionine; SERPINE1; SIFT; SSS; cerebral venous sinus thrombosis; cystathionine beta-synthase; dHPLC; deep vein thrombosis; denaturating high-performance liquid chromatography; female; homocysteine; individual information content; kyphoscoliosis; left transverse sinus; lens ectopia; malar rash; male; marfanoid features; megaloblastic anemia; methionine synthase; methionine synthase reductase; methylenetetrahydrofolate reductase; mitral valve prolapse; newborn; newborn screening; not determined; osteopenia; polymerase chain reaction; polymorphism phenotyping v2; psychomotor delay; pyridoxal 5′-phosphate; real-time polymerase chain reaction; renal vein thrombosis; right atrial thrombosis; right sigmoid sinus; right transverse sinus; serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1; sorting intolerant from tolerant; superior sagittal sinus.