High phenotypic variability in Gerstmann-Sträussler-Scheinker disease.

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare, autosomal dominant genetic prion disease.
• The p.Pro102Leu mutation in the PRNP gene is the most common cause of GSS.
• Clinical presentation of GSS is highly variable, posing diagnostic challenges.

Purpose of the Study:

• To characterize the clinical, molecular, and neuropathological features of GSS in two Brazilian kindreds.
• To investigate the influence of PRNP codon 129 polymorphism and apoE genotype on GSS phenotype variability.
• To understand the genetic basis of disease heterogeneity in GSS.

Main Methods:

• Clinical data collection: patient history, age at onset, disease duration, and phenotypic presentation.
• Molecular analysis: PRNP sequencing and analysis of codon 129 polymorphism and apoE genotype.
• Neuropathological examination: assessment of brain tissue for prion protein deposits (PrPSc) and characteristic plaques.

Main Results:

• Seven individuals from two unrelated Brazilian kindreds carrying the p.Pro102Leu mutation were studied.
• Significant variability in age at onset, disease duration, and clinical phenotypes (dementia vs. ataxia) was observed.
• Codon 129 heterozygosis was associated with earlier disease onset, but did not fully explain clinical variability; apoE genotype showed no association.
• Neuropathology confirmed GSS hallmarks, including plaques and PrPSc immunopositivity.

Conclusions:

• The p.Pro102Leu mutation in GSS exhibits marked clinical heterogeneity, even within families.
• PRNP codon 129 heterozygosis may influence GSS onset but does not account for the full spectrum of clinical variability.
• Further research is needed to elucidate other genetic or environmental factors contributing to GSS phenotype diversity.