edoc

Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C<T and a MTHFR gene mutation

Rummel, T. and Suormala, T. and Häberle, J. and Koch, H. G. and Berning, C. and Perrett, D. and Fowler, B.. (2007) Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C<T and a MTHFR gene mutation. Journal of inherited metabolic disease, Vol. 30, no. 3. p. 401.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/dok/A5253374

Downloads: Statistics Overview

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the regulation of plasma homocysteine levels. MTHFR deficiency, an autosomal recessive disorder, results in homocystinuria and hypomethioninaemia and presents with highly variable symptoms affecting many organs but predominantly the central nervous system. The common polymorphism of the MTHFR gene, c.677C<T, a known risk factor for elevated plasma homocysteine levels, occurs frequently in the caucasian population. In this study we investigated three subjects with moderate hyperhomocysteinaemia (total plasma homocysteine 72 micromol/L in case 1 and 90 micromol/L in case 3, total non-protein-bound homocysteine 144-186 micromol/L in case 2) but different clinical presentation with no symptoms in case 1, muscle weakness at 17 years of age in case 2, and syncopes and cerebral convulsions at 18 years of age in case 3. Each subject was compound heterozygous for the c.677C<T polymorphism and a novel mutation of the MTHFR gene (case 1: c.883G<A [p.D291N]; case 2: c.1552_c.1553delGA [p.E514fsX536]; case 3: c.616C<T [p.P202S]). Moderately decreased fibroblast MTHFR activity was associated with severely reduced affinity for NADPH and increased sensitivity to inhibition by S-adenosylmethionine (AdoMet) in case 2, and with mild FAD responsiveness in case 3. In case 1, fibroblast MTHFR activity was normal but the sensitivity to inhibition by AdoMet was slightly reduced. This study indicates that the sequence alteration c.677C<T combined with severe MTHFR mutations in compound heterozygous state may lead to moderate biochemical and clinical abnormalities exceeding those attributed to the c.677TT genotype and might require in addition to folate substitution further therapy to normalize homocysteine levels.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
UniBasel Contributors:Fowler, Brian
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Kluwer
ISSN:0141-8955
Note:Publication type according to Uni Basel Research Database: Journal article
Related URLs:
Identification Number:
Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:39

Repository Staff Only: item control page