Objective: We describe a late-onset presentation of Gerstmann-Sträussler-Scheinker disease (GSS) with a novel mutation in the prion protein (PRNP) gene. We compare this case to two other cases seen at our institution.

Background: Genetic prion diseases are rare, fatal neurodegenerative disorders, typically associated with a combination of progressive ataxia and cognitive/neuropsychiatric symptoms. GSS typically presents in the 40s/50s, with relentlessly progressive symptoms. Late onset cases are rare. The P102L mutation in PRNP is the most common genetic cause.

Method: Records from the Ataxia Center at the Massachusetts General Hospital, Boston from 1990 to 2020 were reviewed, yielding 3 cases of GSS with genetic confirmation.

Results: At age 71, Case 1 developed slowly progressive gait and balance problems and dysarthria. On examination 4 years into her disease, she had a mild global cerebellar syndrome, with mild memory deficits, without other cognitive features. She has a dominant-appearing family history of several maternal relatives with late-onset balance problems, without cognitive decline. Brain MRI revealed moderate T2/FLAIR subcortical white matter lesions, without cerebellar/brainstem atrophy or diffusion-weighted abnormalities. Whole genome sequencing and confirmation by the National Prion Disease Surveillance laboratory revealed a heterozygous c.392G>A (p.G131E) pathogenic mutation and a c.395A>G resulting in p.129M/V polymorphism in the PRNP gene. Probability analyses considering family history, clinical phenotype, and similar point mutation previously reported (p.G131V) suggest p.G131E is a new pathogenic mutation. The other two GSS cases harbored the P102L mutation. Case 2 had a typical GSS presentation, whereas case 3 had GSS with areflexia and paresthesia phenotype. Histopathology was available for Case 3.

Conclusion: We describe a patient with p.G131E, representing a new mutation in the PRNP gene responsible for GSS, with a novel, late-onset, very slowly progressive phenotype mimicking a late-onset spinocerebellar ataxia and 2 other cases with the typical P102L mutation. Hereditary prion diseases are likely under-appreciated, particularly when there is late onset. Our findings expand the genetic and phenotypic spectrum of GSS and highlight the importance of genetic testing through exome and genome sequencing in ataxia patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gerstmann-straussler-scheinker-disease-presenting-as-a-late-onset-slowly-progressive-spinocerebellar-ataxia-expanding-the-phenotypic-spectrum-of-genetic-prion-disease/