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Over 30 mutations within the prion protein gene (PRNP) are associated with familial prion disease. We sequenced the coding segment of PRNP in a patient with clinical features of prion disease and a positive family history.

Case Report: A 43 year-old African American female presented with one-year of progressive cognitive decline, behavioral change, intermittent vertigo, and gait ataxia. On exam, she exhibited inappropriate laughter, aphasia without dysarthria, orientation only to self, and limited ability to follow simple commands.  Hypertonia and hyperreflexia were present throughout, with non-sustained ankle clonus. Gait was wide-based with severe truncal ataxia.  EEG showed background slowing consistent with moderate encephalopathy, but no periodic sharp wave complexes. Brain MRI revealed intense restricted diffusion within the basal ganglia and thalami along with subtle cortical ribboning within the frontal, parietal, temporal, and occipital regions.  CSF was non-inflammatory with a total tau of 3026 pg/ml, and “inconclusive” 14-3-3 protein and RT-QuIC assay, due to interference from blood contamination. The patient died 2 years after symptoms onset. The family refused autopsy. The patient’s older sister and mother had similar presentations in their late 30s and early 40s, leading to death in roughly 4 years. Genetic testing revealed a single nucleotide change (c.391G>A), resulting in an arginine (R) substitution of glycine (G) at residue 131, paired with valine (V) coding at the polymorphic codon 129 (129V). The normal allele encoded methionine at 129 (129M) along with a single octapeptide repeat deletion, a previously reported polymorphism.

Despite inconclusive RTQuIC and 14-3-3 results, the clinical presentation, MRI findings, and elevated CSF tau protein are highly consistent with prion disease, likely the Creutzfeldt-Jakob Disease subtype, although without pathology this cannot be confirmed. The presence of a non-conservative PRNP-G131R mutation in the proband and the familial occurrence of disease suggest this mutation is causal.