One‑carbon metabolism factor MTHFR variant is associated with saccade latency in Spinocerebellar Ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder due to a CAG-repeat expansion. This work is intended to identify modifiers of the clinical phenotype in SCA2, following up on recent genome-wide association analyses that demonstrated the prominent role of DNA-damage repair and met...

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Published in:Journal of the neurological sciences 2020-02, Vol.409, p.116586-116586, Article 116586
Main Authors: Almaguer-Mederos, Luis E., Jorge-Sainz, Yasnay, Almaguer-Gotay, Dennis, Aguilera-Rodríguez, Raúl, Rodríguez-Labrada, Roberto, Velázquez-Pérez, Luis, González-Zaldívar, Yanetza, Cuello-Almarales, Dany, Vázquez-Mojena, Yaimé, Canales-Ochoa, Nalia, Aguiar-Santiago, Jorge, Auburger, Georg, MacLeod, Patrick
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Language:English
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Summary:Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder due to a CAG-repeat expansion. This work is intended to identify modifiers of the clinical phenotype in SCA2, following up on recent genome-wide association analyses that demonstrated the prominent role of DNA-damage repair and methylation for the severity and progression of polyglutamine diseases. In particular, we assessed the impact of MTHFR as rate-limiting enzyme in DNA methylation pathways, which modulates cerebellar neurotransmission and motor neuron atrophy. A sample of 166 Cuban SCA2 patients and of 130 healthy subjects from the same geographical and ethnic background was selected. The ATXN2 CAG repeat length was determined by PCR followed by polyacrylamide gel electrophoresis. Two amino acid substitutions known to decrease the enzyme activity of MTHFR, encoded by C677T and A1298C polymorphisms, were assessed by PCR/RFLP. No significant differences were observed for C677T or A1298C alleles or genotype frequencies between cases and controls, confirming that disease risk in SCA2 does not depend on MTHFR activity. However, MTHFR A1298C genotypes showed a significant association with saccade latency. \MTHFR A1298C polymorphism is associated with saccade latency in SCA2 patients, but not with disease risk, age at onset or maximal saccade velocity. These results provide evidence that folate-mediated one‑carbon metabolism might be important in the physiopathology of SCA2. [Display omitted] •SCA2 shows strong variability in the clinical phenotype suggesting that genetic factors might modulate disease severity.•A study was conducted in Cuban SCA2 population to examine the effects of MTHFR polymorphisms on disease severity.•MTHFR A1298C polymorphism is strongly associated with saccade latency in SCA2 patients.
ISSN:0022-510X
1878-5883
DOI:10.1016/j.jns.2019.116586