Parkinson hastalığının ötesinde: GBA1 ilişkili bozuklukların nörodejeneratif spektrumunu genişletmek

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Abstract Heterozygous variants in the GBA1 gene represent the most significant genetic risk factor for Parkinson’s disease (PD). Among a larger cohort of 110 individuals with atypical parkinsonism and multisystem phenotypes, we identified nine patients carrying monoallelic pathogenic GBA1 variants. Clinical and biochemical phenotyping revealed marked heterogeneity, and a high prevalence of non-motor comorbidities. Exome sequencing of the entire cohort highlighted substantial GBA1 allelic complexity, with four patients carrying multiple variants in cis . Additional likely pathogenic variants were identified in five patients. These variants were heterogeneously distributed, with each individual carrying unique mutations in one or two genes associated with neurodegeneration or epilepsy. These findings suggest that a synergistic genetic architecture may drive these complex phenotypes. Our results expand the GBA1 -related phenotypic spectrum beyond classical PD and underscore the necessity of recognizing genetic complexity to improve diagnostic accuracy, disease stratification, and the development of targeted therapies in neurodegenerative conditions.

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