Gerstmann-Sträussler-Scheinker syndrome

GSS is a fatal autosomal neurodegenerative prion disease dominated by cerebellar and cognitive features. Onset is typically around 51 years of age, with a rare pure-dementia variant reported around age 35. The cardinal presentation is a slowly progressive cerebellar syndrome with ataxia and gait disturbance (~72%), followed by cognitive decline (~80%); extrapyramidal signs (~36%), psychiatric symptoms (~21%), and myoclonus (~15%) occur with variable frequency. Pyramidal signs and sensory abnormalities are also recognised. Disease course is more protracted than in sporadic Creutzfeldt-Jakob disease, with typical disease duration of up to four years and, in rare cases, up to ten years. Mean survival from symptom onset has been reported at approximately 49 months.

The estimated prevalence is 1/10,000,000-1/100,000,000.

GSS is caused by heterozygous germline pathogenic variants in PRNP (20p13), the gene encoding the cellular prion protein. Pathogenic variants destabilise the cellular prion protein (PrPC) and enhance its propensity to misfold into the scrapie-like isoform (PrPSc), which acts as a conformational template, recruits native PrPC, and accumulates in the central nervous system. Neuropathologically, GSS is characterised by deposition of a C- and N-terminally truncated internal PrPSc fragment as amyloid plaques, predominantly in cerebral and cerebellar cortices, accompanied by tau pathology in the form of neurofibrillary tangles and dystrophic neurites around the PrP plaques. Although some PRNP pathogenic variants are associated with specific neuropathologic phenotypes, evidence also suggests that heterozygotes for the same variant in the same family may develop distinct clinicopathologic phenotypes.

GSS is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic PRNP variant.

The clinical diagnosis is suggested by a slowly progressive cerebellar syndrome with subsequent cognitive decline in an individual with a positive family history of a prion disease. Confirmation of the diagnosis rests on the identification of a heterozygous pathogenic variant in PRNP by molecular genetic testing.

Main differential diagnoses include:

• (sCJD): most common human prion disease and primary mimic, with clinically similar rapidly progressive dementia and ataxia but no pathogenic PRNP variant on molecular testing (sporadic prion disease, no causal gene)
• Hereditary ataxia / (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8): slowly progressive cerebellar ataxia with overlapping early phenotype but typically without rapid cognitive decline or PrP amyloid pathology; ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, CACNA1A
• Frontotemporal dementia (FTD): rapidly progressive dementia with behavioural and language features and uncommon cerebellar signs; C9orf72, GRN, MAPT

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the definitive aetiological classification of the disease.
• Identification of the underlying pathogenic variant is a prerequisite for individualised clinical management and supportive multidisciplinary care, decisions on which rest with the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, testing of at-risk relatives is technically possible and may inform reproductive and family planning following genetic counselling.

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