Clinical phenotype associated with A118V mutation of PRPN gene

Creutzfeldt-Jakob disease (CJD) is the most common human prion disease, with genetic forms linked to PRNP gene mutations accounting for 10-15% of cases. We present a case of probable genetic prion disease associated with a novel PRNP mutation.

A previously healthy 60-year-old woman developed gait ataxia and micrographia. Six months later, she experienced severe anxiety, emotional lability, and visual hallucinations. Brain magnetic resonance imaging (MRI) showed cortical ribboning in the frontal-insular regions. Her condition progressed to walking dependence and cerebellar dysarthria. She died 15 months after symptom onset. CSF analysis revealed elevated total-Tau (1933 pg/mL; reference < 450 pg/mL). RT-QuIC assay using full-length recombinant PrP was negative. Genetic testing revealed a Met/Val polymorphism at codon 129 and a novel heterozygous A118V mutation in the PRNP gene. A second RT-QuIC using truncated PrP confirmed abnormal prion seeds, supporting a probable diagnosis of prion disease.

The compound heterozygous A118V and M129V PRNP variant had not previously been associated with prion disease. Family history was unobtainable, as relatives declined testing. The patient's presentation-cerebellar and psychiatric symptoms-resembled Gerstmann-Sträussler-Scheinker syndrome, though a definitive diagnosis was not possible without neuropathology. MRI and RT-QuIC findings supported prion disease. The positive result with truncated PrP highlights its diagnostic value, offering improved sensitivity. This case underscores the phenotypic diversity of PRNP mutations and the importance of molecular testing, especially when family history or neuropathology is unavailable. PRNP gene analysis should be considered in patients with rapidly progressive motor and cognitive symptoms suggestive of prion disease.