The cystathionine beta‐synthase variant c.844_845ins68 protects against CNS demyelination in X‐linked adrenoleukodystrophy
2006
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
methionineis essential for CNS myelination, and
methionine metabolismis 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
methionineas 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 metabolismmay be a disease modifier of X-ALD. Since
methionine metabolismcan 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
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