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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population

by
Rômulo Morais Azevedo
1,
Nayane Soares de Lima
1,
Rayana Pereira Dantas de Oliveira
1,
Leandro do Prado Assunção
1,
Dhiogo da Cruz Pereira Bento
1,
Angela Adamski da Silva Reis
1,2,* and
Rodrigo da Silva Santos
1,2,*
1
Núcleo de Pesquisas em Neurogenética (NeuroGene), Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiania 74690-900, Goiás, Brazil
2
Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiania 74690-900, Goiás, Brazil
*
Authors to whom correspondence should be addressed.
Sclerosis 2026, 4(2), 12; https://doi.org/10.3390/sclerosis4020012
Submission received: 17 March 2026 / Revised: 2 May 2026 / Accepted: 15 May 2026 / Published: 21 May 2026
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Abstract

Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is a rare, neurodegenerative disease with complex genetic and environmental determinants. The MTHFR C677T (rs1801133) variant, known for reducing enzymatic activity in the folate cycle, has been implicated in ALS risk, though findings remain inconsistent across diverse populations. Methods: A population-based case–control study was conducted in 248 age-matched individuals to investigate the MTHFR C677T (rs1801133) and ALS susceptibility. Molecular analysis was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Genetic associations were evaluated under multiple inheritance models, while survival analysis utilized the Kaplan–Meier method to assess the relationship between MTHFR genotypes and patient prognosis. Results: The C677T variant showed a significant association under the codominant and recessive models, suggesting involvement in ALS risk (OR = 4.63; p = 0.01 and OR = 3.92; p = 0.02), respectively. However, stratification by sex demonstrated an association predominantly in women (OR = 7.10, p = 0.02; OR = 5.87, p = 0.04). Additionally, Kaplan–Meier analysis revealed a numerically shorter mean survival time for the mutant genotype compared with wild-type and heterozygous carriers, without statistical significance. Conclusions: Notably, we identified a significant association between the MTHFR C677T (rs1801133) variant and ALS risk, particularly among women. These findings suggest that the mutant (T/T) genotype showed a stronger association, potentially reflecting postmenopausal hormonal influences on one-carbon metabolism and related susceptibility pathways.
Keywords: amyotrophic lateral sclerosis; MTHFR C677T; one-carbon metabolism; hyperhomocysteinemia; genetic association study; sex-specific effects amyotrophic lateral sclerosis; MTHFR C677T; one-carbon metabolism; hyperhomocysteinemia; genetic association study; sex-specific effects
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MDPI and ACS Style

Azevedo, R.M.; de Lima, N.S.; Oliveira, R.P.D.d.; Assunção, L.d.P.; Bento, D.d.C.P.; Reis, A.A.d.S.; Santos, R.d.S. Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population. Sclerosis 2026, 4, 12. https://doi.org/10.3390/sclerosis4020012

AMA Style

Azevedo RM, de Lima NS, Oliveira RPDd, Assunção LdP, Bento DdCP, Reis AAdS, Santos RdS. Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population. Sclerosis. 2026; 4(2):12. https://doi.org/10.3390/sclerosis4020012

Chicago/Turabian Style

Azevedo, Rômulo Morais, Nayane Soares de Lima, Rayana Pereira Dantas de Oliveira, Leandro do Prado Assunção, Dhiogo da Cruz Pereira Bento, Angela Adamski da Silva Reis, and Rodrigo da Silva Santos. 2026. "Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population" Sclerosis 4, no. 2: 12. https://doi.org/10.3390/sclerosis4020012

APA Style

Azevedo, R. M., de Lima, N. S., Oliveira, R. P. D. d., Assunção, L. d. P., Bento, D. d. C. P., Reis, A. A. d. S., & Santos, R. d. S. (2026). Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population. Sclerosis, 4(2), 12. https://doi.org/10.3390/sclerosis4020012

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