Gerstmann-Sträussler-Scheinker syndrome with unexpected concomitant GRN variant: case report

The objective is to report a patient with Gerstmann-Sträussler-Scheinker syndrome caused by a pathogenic PRNP P102L variant harboring an unexpected concomitant pathogenic GRN variant p.R110X and to discuss the potential contribution of combined genetic pathology to the clinical and neuroimaging phenotype confirmed by autopsy. Moreover, we discuss the potential role of TMEM106B as an important modifier of the protein TDP-43 neuropathology associated with the GRN mutation in this case. The patient underwent detailed clinical assessment, serial neuropsychological evaluation, brain MRI, cerebrospinal fluid analysis, whole-exome sequencing, and next generation sequencing. A postmortem neuropathologic examination was performed to confirm the diagnosis. The patient presented slowly progressive paresthesia, cerebellar ataxia, dysarthria, and later cognitive and behavioral changes. Genetic testing revealed a heterozygous PRNP P102L variant and an unpenetrated GRN p.R110X variant; a protective TMEM106B polymorphism associated with TDP-43 pathology was also identified. Neuroimaging demonstrated progressive cerebellar and parietal atrophy with asymmetric left frontal opercular and insular involvement. The clinical course was dominated by a cerebellar GSS phenotype. The patient died 4 years after symptom onset. Neuropathology confirmed GSS, nevertheless without detectable TDP-43-associated neuropathology. This case highlights the diagnostic complexity of rare neurodegenerative disorders and illustrates that pathogenic variants may not influence phenotypic expression. Comprehensive genetic testing should be considered in atypical cases, as certain genetic variants may contribute to phenotypic variability and represent potential modifiers of phenotypic expression.