title: The cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy.
abstract: The clinical course of X-linked adrenoleukodystrophy (X-ALD) is of unexplained heterogeneity. Major X-ALD phenotypes are the progressive childhood cerebral form (CCALD) with early confluent cerebral demyelination and the adult-onset adrenomyeloneuropathy (AMN). Adult AMN may present with demyelinated foci of the CNS (adrenoleukomyeloneuropathy, ALMN) or without ("pure" AMN). Activated methionine is essential for CNS myelination, and methionine metabolism is important for glutathione synthesis, which may influence neurodegeneration. Cystathionine beta-synthase (CBS) is a key enzyme of methionine metabolism. The CBS variant c.844_845ins68 (p.-) may influence the availability of activated methionine as well as of glutathione. In this study, we analyzed this variant in genomic DNA samples of 86 X-ALD patients. We observed the allele carrying the insertion in 12 of 49 patients without CNS demyelination ("pure" AMN), but in none of the 37 patients with CNS demyelination (CCALD or ALMN; chi(2)=10.531; p=0.001). We conclude that the insertion allele of CBS c.844_845ins68 protected X-ALD patients against CNS demyelination in our study sample. These data suggest that the individual conditions in methionine metabolism may be a disease modifier of X-ALD. Since methionine metabolism can easily be influenced by vitamin and amino acid substitution, this observation could be a basis of novel treatment strategies in this yet untreatable disease. (c) 2006 Wiley-Liss, Inc.
authors.affiliation: University Hospital Bonn, Department of Neurology, Bonn, Germany. Michael.Linnebank@ukb.uni-bonn.de
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
authors.forename: Alexander
authors.initials: A
authors.lastname: Semmler
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: Marianne L T
authors.initials: ML
authors.lastname: van der Sterre
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.forename: Klaus
authors.initials: K
authors.lastname: Fliessbach
authors.forename: Piotr
authors.initials: P
authors.lastname: Sokolowski
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Köhler
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
mesh_terms: D000326:Adrenoleukodystrophy / Q000201:enzymology / Q000235:genetics*; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D003711:Demyelinating Diseases / Q000201:enzymology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional / Q000235:genetics*; D010641:Phenotype
chemical_list: D003541:Cystathionine beta-Synthase