Objective:

Investigate the natural history and clinical variability of Gerstmann-Sträussler-Scheinker (GSS) syndrome caused by the p.P102L variant in the PRNP gene in various Brazilian families, identifying early signs of symptomatic disease conversion.

Background:

GSS syndrome is a rare genetic prion disease with a broad clinical presentation. The p.P102L variant (PRNP gene) has high penetrance and represents a good model for studying natural history and identifying early biomarkers of conversion to symptomatic disease.

Design/Methods:

We used clinical histories, medical charts, and genetic panels to identify over 30 individuals in various Brazilian states. Neurologic exams assessed symptoms, while the Addenbrooke's Cognitive-Examination-Revised evaluated cognition. Ancillary tests, conducted as needed, checked for hearing loss and neurophysiological issues. We've tracked these patients for over 60 months.

Results:

-The age of onset ranged between the second and fifth decades.
-Unsteadiness was the most frequently reported initial symptom, followed by lower limb paresthesia, spasticity, and hearing loss.
-Cognitive impairment manifested much later for the majority, as did agitation, aggressiveness, hallucinations, and behavioral abnormalities.
-Unlike in global cohorts, hearing loss was prevalent in this study (44%).
-MRI scans were mostly normal, with some showing mild cerebellar atrophy as the disease progressed.
-The average survival post-onset was 6.4 years, with aspiration pneumonia being the primary cause of death.

Conclusions:

When investigating patients with hereditary ataxia who don't exhibit the anticipation phenomenon, GSS should be suspected. Symptoms such as hearing loss, lower limb weakness, gait abnormalities, and an early Babinski sign further suggest GSS. Although dementia can manifest later in the disease's course, its absence should not exclude a GSS diagnosis. There is a pressing need for more studies to understand GSS's natural history, recognize early symptoms, and identify factors contributing to clinical variability. This knowledge is essential for designing timely interventions for pre-symptomatic patients in therapeutic clinical trials focused on prion disease treatments.