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Background Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment.

IMPORTANCE: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. OBJECTIVE: To characterize the longitudinal clinical features, neuropsychological findings, MRI findings, and FGD-PET scan imaging findings in a subsequent generation of a family with a large 12-octapeptide repeat insertion in the PRNP gene. DESIGN: Clinical, neuropsychological, and neuroimaging characterization of a kindred. SETTING: Mayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota). PARTICIPANTS: Four mutation carriers and two non-carriers in the third generation of a kindred with a large octapeptide repeat insertion in the PRNP gene. RESULTS: Three of the four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Processing speed and executive function were abnormal before the identified onset. CONCLUSIONS AND RELEVANCE: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.