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

Aims: 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 such changes („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 polymorphism c.844_845ins68 is supossed to influence the availability of activated methionine as well as of glutathione.

Methods: In this study, we analyzed the CBS c.844_845ins68 polymorphism in genomic DNA samples of 86 X-ALD patients.

Results: 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-sqare=10.531; p=0.001).

Conclusions: We conclude that the insertion allele of CBS c.844_845ins68 protected X-ALD patients from CNS demyelination in our study sample. The individual conditions in methionine metabolism may constitute a disease modifyer of X-ALD. Methionine metabolism can be modulated by vitamin and amino acid substitution. Our observation suggests that nutritional treatment strategies could alleviate the course of X-ALD.