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Failure to confirm influence of Methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease

DOI: 10.1186/1477-5751-4-12

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There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof.Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients.Huntington disease (HD) is caused by expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the 5'-translated region of the IT15 gene on chromosome 4, which encode the protein huntingtin [1]. The expansions result in the formation of elongated proteins with a variety of new properties. The extent of the expansion is inversely correlated with the age of onset (AO). Nevertheless, large part of the variance in AO remains unexplained [2]. The pathogenesis of HD has been implicated to relate to different aspects of the homocysteine metabolism: Cystathionine [beta]-synthase (CBS) appears to bind specifically to huntingtin (htt) [3]. CBS deficiency is associated with homocystinuria, which affects various physiological systems, including the central nervous system. Homocysteine, one of the substrates of CBS accumulates in homocystinuria and is metabolized to homocysteate and homocysteine sulphinate, both components of which are amino acids with significant excitotoxic potential. In this context homocysteine was suggested to influence the pathogenesis of HD. Two common polymorphisms have been described in the MTHFR gene, both single nucleotide substitutions resulting in amino acid changes (C677T → Ala222Val and A1298C → Glu429Ala) [4,5]. Whereas C677T unequivocally affects enzyme function and has been associated with increased plasma homocysteine concentrations and an altered balance of folate metabolites [4], the functional relevance in vivo of the A1298C allele is less well defined. A1298C affects enzyme function in vitro to a lesser degree, and individuals carrying the variation have frequently normal homocysteine and plasma folate concentrations [6,7]. It is unclear whether the substitution affects folate me


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