Nörodejeneratif Koşulları Olan Yetişkinlerde GALC Gen Çeşitlerinin Yüksek Yaygınlığı.

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Background and purposeGalactocerebrosidase (GALC) deficiency causes Krabbe disease, a severe lysosomal neurodegenerative condition. Emerging evidence suggests that heterozygous GALC variants may contribute to multiple sclerosis, attention-deficit hyperactivity disorder, and synucleinopathies. We aim to investigate the potential association between GALC heterozygous variants and neurodegenerative disorders, expanding on existing literature.MethodsWe 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.ResultsWe found GALC 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 GALC variants and/or the disease-associated polymorphism p.(Arg184Cys). One patient, compound heterozygous for a pathogenetic variant and the p.(Arg184Cys), exhibited reduced  GALC activity and a clinical course consistent with late-onset Krabbe disease. In another patient, we found the very rare synonymous variant p.(Leu238Leu) in the GALC gene. Two patients carrying known pathogenetic GALC variants were also heterozygous for other known pathogenetic variants in other LSD-associated genes, including HEXB (Sandhoff disease) and GUSB (mucopolysaccharidosis VI). 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.ConclusionsOur findings indicate a possible connection between the patients' neurodegenerative conditions and GALC defects, including disease-associated polymorphisms and silent variants. Additional genetic alterations affecting sphingolipid and glycosaminoglycan metabolism may act as contributing factors.

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