Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease.

To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. A total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27-30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. This study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.

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Declaration of competing interest None declared.