The cystathionine beta-synthase variant c.844_845ins68 protects against CNS demyelination in X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

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 _845 ins 68 (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 _845 ins 68 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 .