Clinical phenotype associated with A118V mutation of PRPN gene

Area of Science:

• Neurology
• Genetics
• Molecular Biology

Background:

• Creutzfeldt-Jakob disease (CJD) is the most common human prion disease.
• Genetic forms of CJD, linked to PRNP gene mutations, represent 10-15% of cases.
• A novel PRNP mutation is presented in a case of probable genetic prion disease.

Purpose of the Study:

• To report a case of probable genetic prion disease associated with a novel PRNP mutation.
• To highlight the diagnostic utility of RT-QuIC assays with truncated PrP.
• To emphasize the importance of molecular testing in diagnosing prion diseases.

Main Methods:

• Clinical presentation of a 60-year-old woman with ataxia, micrographia, anxiety, and hallucinations.
• Brain MRI showing cortical ribboning.
• CSF analysis revealing elevated Tau.
• RT-QuIC assays (full-length and truncated PrP) and PRNP gene sequencing.
• Identification of a novel heterozygous A118V mutation and M129V polymorphism.

Main Results:

• The patient presented with cerebellar and psychiatric symptoms, progressing over 15 months.
• RT-QuIC with full-length PrP was negative, but positive with truncated PrP.
• Genetic testing revealed a compound heterozygous PRNP variant (A118V and M129V).
• The novel A118V mutation was not previously associated with prion disease.

Conclusions:

• The patient's presentation mimicked Gerstmann-Sträussler-Scheinker syndrome.
• MRI and RT-QuIC findings supported a diagnosis of prion disease.
• The positive RT-QuIC result with truncated PrP demonstrates its enhanced diagnostic sensitivity.
• This case underscores the phenotypic variability of PRNP mutations and the critical role of genetic analysis in diagnosing prion diseases, especially without family history or neuropathology.