{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:50:45Z","timestamp":1790725845583,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Galactocerebrosidase (GALC) deficiency causes Krabbe disease, a severe lysosomal neurodegenerative condition. Emerging evidence suggests that heterozygous <jats:italic>GALC<\/jats:italic> variants may contribute to multiple sclerosis, attention\u2010deficit hyperactivity disorder, and synucleinopathies. We aim to investigate the potential association between <jats:italic>GALC<\/jats:italic> heterozygous variants and neurodegenerative disorders, expanding on existing literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened 110 adults with symptoms shared by lysosomal storage disorders (LSDs) and common neurodegenerative diseases, such as Parkinson's disease, Lewy body dementia, and ataxias of different etiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found <jats:italic>GALC<\/jats:italic> heterozygosity in this group to be notably enriched, approximately 1 in 28, compared to 1 in 150 in the general population. This led to a focus on 11 individuals with pathogenetic <jats:italic>GALC<\/jats:italic> variants and\/or the disease\u2010associated polymorphism p.(Arg184Cys). One patient, compound heterozygous for a pathogenetic variant and the p.(Arg184Cys), exhibited reduced\u00a0 GALC activity and a clinical course consistent with late\u2010onset Krabbe disease. In another patient, we found the very rare synonymous variant p.(Leu238Leu) in the <jats:italic>GALC<\/jats:italic> gene. Two patients carrying known pathogenetic <jats:italic>GALC<\/jats:italic> variants were also heterozygous for other known pathogenetic variants in other LSD\u2010associated genes, including <jats:italic>HEXB<\/jats:italic> (Sandhoff disease) and <jats:italic>GUSB<\/jats:italic> (mucopolysaccharidosis VI).<\/jats:p><jats:p>All the 11 patients in the selected cohort exhibited symptoms similar to atypical Parkinson's disease and a high frequency of leukoencephalopathy, inflammatory disorders, and cancer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings indicate a possible connection between the patients' neurodegenerative conditions and <jats:italic>GALC<\/jats:italic> defects, including disease\u2010associated polymorphisms and silent variants. Additional genetic alterations affecting sphingolipid and glycosaminoglycan metabolism may act as contributing factors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.70206","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T12:38:23Z","timestamp":1747744703000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["High Prevalence of <i>GALC<\/i> Gene Variants in Adults With Neurodegenerative Conditions"],"prefix":"10.1111","volume":"32","author":[{"given":"Federica","family":"Feo","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Pharmacology and Child Health University of Florence  Florence Italy"},{"name":"Neuroscience and Medical Genetics Department Meyer Children's Hospital IRCCS  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Tramacere","sequence":"additional","affiliation":[{"name":"USL Toscana Centro, 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