title: Molecular and clinical characterisation of homocystinuria in two Austrian families with cystathionine beta-synthase deficiency.
abstract: The influence of the genotype on the phenotypic expression of homocystinuria due to cystathionine beta-synthase (CBS) deficiency is frequently unclear. We therefore investigated the genotype and the phenotype of CBS deficiency in two Austrian families also considering genetic polymorphisms with a putative association with vascular disease (MTHFR 677C-->T, MTHFR 1298A-->C, F5 1691G-->A, F2 20210G-->A) and response to therapy. We identified the CBS 833T-->C/1058C-->T and CBS 828ins104/1358del134 compound heterozygous genotype in our index patients. Both patients showed mental retardation and ectopia lentis. CBS 833T-->C/1058C-->T was associated with severe vascular complications, which was not the case for CBS 828ins104/1358del134. The patient with CBS 828ins104/1358del134 was negative for F5 1691G-->A, F2 20210G-->A, MTHFR 677C-->T, and MTHFR 1298A-->C, while the patient with CBS 833T-->C/1058C-->T was heterozygous for MTHFR 1298A-->C. A combination therapy including pyridoxine, folic acid, hydroxycobalamin, and betaine failed to lower total homocysteine plasma levels below 50 mumol/L in both patients. In summary, our study demonstrates that the CBS 833C/1058T-MTHFR 1298AC genotype can be related to severe vascular disease, while the CBS 828ins104/1358del134-MTHFR 1298AA genotype presents with a somewhat milder clinical phenotype. Both genotypes do not allow for normalisation of total homocysteine plasma levels following vitamin therapy.
authors.affiliation: Department of Laboratory Medicine, Division of Endocrinology and Metabolism, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna.
authors.forename: U
authors.initials: U
authors.lastname: Tröndle
authors.forename: G
authors.initials: G
authors.lastname: Sunder-Plassmann
authors.forename: H
authors.initials: H
authors.lastname: Burgmann
authors.forename: H
authors.initials: H
authors.lastname: Buchmayer
authors.forename: L
authors.initials: L
authors.lastname: Kramer
authors.forename: C
authors.initials: C
authors.lastname: Bieglmayer
authors.forename: W H
authors.initials: WH
authors.lastname: Hörl
authors.forename: M
authors.initials: M
authors.lastname: Födinger
mesh_terms: D000328:Adult; D001317:Austria; D001483:Base Sequence; D003541:Cystathionine beta-Synthase / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005838:Genotype; D006712:Homocystinuria / Q000097:blood / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012091:Repetitive Sequences, Nucleic Acid; D044465:White People
chemical_list: D004247:DNA; D003541:Cystathionine beta-Synthase