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The aim of this study was to assess the methylation levels of specific DNA sequences from the nuclear and mitochondrial genomes in a population with ALS to elucidate their relationship with nutritional status and the evolution of the disease. Methods: Patients with ALS were evaluated between 2013 and 2021 (n = 66). They were categorized according to their nutritional status, using the Global Leadership Initiative on Malnutrition (GLIM) criteria, and disease progression, using the ALS Functional Rating (ALSFRS-R) Scale. DNA samples were extracted from leukocytes at the time of diagnosis for analysis of DNA methylation levels of markers of oxidative stress, mitochondrial function and global methylation (D-loop, GSTP1, and LINE-1). Results: According to the GLIM criteria, 29 (43.9%) patients had malnutrition (22.7%\u2014moderate; 21.2%\u2014severe), which was positively correlated with ALS disease progression (r = 0.414; p &lt; 0.01) and death (r = 0.687; p &lt; 0.01). Mortality occurred in 43.9% of the patients (median time to death, 18.7 (1.7\u201382.7) months). A significant association was observed between DNA methylation levels of the D-loop, GSTP1, and the CpG1 site of LINE-1 and malnutrition, disease progression at diagnosis, and death. The D-loop was the best predictor of malnutrition (AUC, 0.79; p &lt; 0.01), disease progression (AUC, 0.70; p &lt; 0.01), and mortality (AUC, 0.71; p &lt; 0.01). Conclusions: This study revealed, for the first time, the early detection of D-loop methylation levels as a potential biomarker of nutritional status in patients with ALS, which may be useful for personalized nutritional management aimed at counteracting disease progression.<\/jats:p>","DOI":"10.3390\/nu17081295","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T11:05:02Z","timestamp":1744110302000},"page":"1295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Blood DNA Methylation in Nuclear and Mitochondrial Sequences Links to Malnutrition and Poor Prognosis in ALS: A Longitudinal Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1268-7538","authenticated-orcid":false,"given":"Antia","family":"Fernandez-Pombo","sequence":"first","affiliation":[{"name":"Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"},{"name":"Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-8834","authenticated-orcid":false,"given":"Andrea G.","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"},{"name":"CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Canton-Blanco","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"},{"name":"CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain"},{"name":"Molecular Endocrinology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Garcia-Sobrino","sequence":"additional","affiliation":[{"name":"Department of Neurology, Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-4961","authenticated-orcid":false,"given":"David","family":"Herv\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Applied Statistics and Operational Research and Quality, Universitat Polit\u00e8cnica de Val\u00e8ncia, 46022 Valencia, Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3279-8091","authenticated-orcid":false,"given":"Miguel A.","family":"Mart\u00ednez-Olmos","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"},{"name":"CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain"},{"name":"Molecular Endocrinology Group, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8807-1310","authenticated-orcid":false,"given":"Julio","family":"Pardo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4392-0301","authenticated-orcid":false,"given":"Ana B.","family":"Crujeiras","sequence":"additional","affiliation":[{"name":"Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, A Coru\u00f1a, Spain"},{"name":"CIBER 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