title: Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia.
abstract: A discrepancy has been identified between numbers of expected and identified patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency. Patients homozygous for the frequent c.833T>C (p.I278T) are most often responsive to vitamin B6, and can present with a total-homocysteine (tHcy) <100 μM on a normal diet. In Denmark, patients with tHcy <100 μM are not routinely sequenced for CBS(2) mutations. This study investigated the prevalence of CBS mutations and the common methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism in patients with tHcy ≥ 50 μM and the association with clinical manifestations. We studied a cohort of patients with intermediate and severe hyperhomocysteinemia (tHcy ≥ 50 μM) determined between 1996 and 2011. Among the 413 eligible patients, 184 (45%) patients agreed to participate in the present follow-up study. A MTHFR(3)c.677TT genotype was found in 49% of the patients. Eight patients were found to have mutations in CBS(2). Of those, two were homozygous for c.833T>C (p.I278T), and four were compound heterozygous for c.833T>C. One c.833T>C (p.I278T) compound heterozygote was identified by lowering the threshold for sequencing from tHcy at 100 μM to 50 μM. The most prominent clinical presentation among patients with a CBS(2) mutation was thrombosis presenting at a median age of 25 years. In case of arterial or venous thrombosis without any explanation in individuals below 40 years, tHcy should be part of the thrombophilia screening. When tHcy is between 50 and 100 μM genotyping for the MTHFR(3) c.677TT is relevant, and when tHcy >100 μM CBS should be genotyped.
authors.affiliation: Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry Aarhus University Hospital, Denmark.
authors.forename: Jannie Tanderup
authors.initials: JT
authors.lastname: Sørensen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Gaustadnes
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.affiliation: Laboratory of Molecular Biology, National Institute of Mental Health, NIH, Bethesda, USA.
authors.forename: S Harvey
authors.initials: SH
authors.lastname: Mudd
authors.affiliation: Centre for Haemophilia and Thrombosis, Department of Clinical Biochemistry Aarhus University Hospital, Denmark. Electronic address: am.hvas@dadlnet.dk.
authors.forename: Anne-Mette
authors.initials: AM
authors.lastname: Hvas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D015519:Bone Density; D003541:Cystathionine beta-Synthase / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D006712:Homocystinuria / Q000209:etiology / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D013923:Thromboembolism / Q000209:etiology; D055815:Young Adult
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003541:Cystathionine beta-Synthase
keywords: Cystathionine beta-synthase deficiency; Homocystinuria; Hyperhomocysteinemia; Methylenetetrahydrofolate reductase; Thrombosis