SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes

Abstract

X-linked adrenoleukodystrophy (XALD), a neurological disorder caused by mutations in the peroxisomal membrane protein gene ABCD1, presents as a rapidly progressing, inflammatory cerebral demyelination (cerebral cases) or a slowly progressing, distal axonopathy (non-cerebral cases). Specific ABCD1 defects do not explain this significant phenotypic variation. Patients have increased plasma and tissue very long chain fatty acid levels and increased cellular oxidative stress and oxidative damage. Superoxide dismutase 2 (SOD2), at candidate modifier locus 6q25.3, detoxifies superoxide radicals protecting against oxidative stress and damage. We tested an SOD2 variant C47T (Ala16Val) associated with reduced enzymatic activity as a potential modifier gene of cerebral demyelinating disease by comparing 117 cerebral XALD cases with 105 non-cerebral XALD cases. The hypoactive valine allele of the variant was associated with cerebral disease under a dominant model in the full data set (p = 0.04; ORT* = 1.90, 95% CI 1.01-3.56) and the non-childhood cerebral disease subset (p = 0.03; ORT* = 2.47, 95% CI 1.08-5.61). Three tag SNPs were genotyped to test for additional SNP or haplotype associations. A common haplotype, GTAC, which included the SOD2 valine allele, was associated with cerebral disease in the full data set (p = 0.03; OR = 1.75, 95% CI 1.11-2.75) and the non-childhood cerebral disease subset (p = 0.008; OR = 2.20, 95% CI 1.27-3.83). There was no association between childhood cerebral XALD and the C47T variant or the GTAC haplotype. Thus, reduced SOD2 activity may contribute to the development of cerebral demyelination in adolescent and adult XALD patients.

Natural history of a cohort of ABCD1 variant female carriers

“…Although this has been essentially noticed in previous cross‐sectional studies, neither statistical associations nor annual progression rate were calculated until now . Initially, the skewing X‐inactivation and other genetic factors, such as polymorphisms in genes involved in methionine metabolism or superoxide dismutase 2 variants , have been considered to contribute to clinical manifestations in female carriers. More recently, instead, it is being accepted that neurological involvement may finally affect most (if not all) of them and progress with age in severity, independently from the ABCD1 variant .…”

X-linked Adrenoleukodystrophy

“…Interestingly, a methyl B12 treatment in a 13-year-old X-ALD patient with non-24-h sleep-wake syndrome showed clinical improvements [354]. Another positive association has been found for a gene involved in oxidative stress homeostasis (SOD2) [355] while investigations on TNFa [338], MOG [356] and CD1 [306,357,358] concluded the absence of significant correlation. A minor reduction of its expression was observed in AMN brains.…”

Novel <b><i>ABCD1</i></b> Gene Mutation in Adrenomyeloneuropathy with Hypoplasia and Agenesis of the Corpus Callosum

“…Hypoplasia and agenesis of the CC are usually not observed in isolation but in conjunction with other neurological deficits. Thus, the ABCD1 and other modified genes also collectively regulate the development of commissures or structures in the brain and spinal cord [26,27]. Unfortunately, due to the absence of neuropsychological evaluations in details, the exact clinical significance of hypoplasia and agenesis of the CC noted in this study is not clear and thus needs further investigation.…”