Clinical Characterization of a Kindred With a Novel 12-Octapeptide Repeat Insertion in the Prion Protein Gene

Abstract

ObjectiveTo report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene, PRNP.DesignClinical description of a kindred.SettingMayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota).SubjectsTwo pathologically confirmed cases and their relatives.Main Outcome MeasuresClinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses, and neuropathologic features.ResultsThe proband was a woman with clinical and neuroimaging features of atypical frontotemporal dementia and ataxia. Generalized tonic-clonic seizures developed later in the disease course, and electroencephalography revealed spike and wave discharges but no periodic sharp-wave complexes. Her affected sister and father also exhibited frontotemporal dementia–like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in the disease course. Genetic analyses in the proband identified a novel defect in PRNP, with 1 mutated allele carrying a 288–base pair insertion consisting of 12 octapeptide repeats. Neuropathologic examination of the proband and her sister revealed prion protein–positive plaques and widespread tau-positive tangles.ConclusionsThis kindred has a unique combination of clinical and neuropathologic features associated with the largest base pair insertion identified to date in PRNP and underscores the need to consider familial prion disease in the differential diagnosis of a familial frontotemporal dementia–like syndrome.

Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

“…The most recently described mutation in this subgroup was an insertion of 12 OPRI causing a FTD-like disorder. 3 To further clarify genotype-phenotype associations for IPD with extra OPRI as well as rate of disease progression additional thorough phenotype characterizations using validated tools such as the recently published scale for prion diseases, 38 functional imaging studies, EEG and biochemical analysis of neurodegenerative markers in the CSF and plasma would be needed. We therefore encourage other researchers and clinicians to report cases of IPDs with extra OPRI.…”

“…Insertions of 4 to 12 OPRI, also known as base pair insertions (BPIs), lead to heterogeneous phenotypes. [1][2][3][4] These phenotypes include progressive and varying degrees of early-onset cognitive decline/dementia; movement disorders, e.g., parkinsonism, chorea; ataxia; pyramidal symptoms; aphasia; seizures; and psychiatric symptoms/behavioral disturbances. The rarity of PRNP mutations with extra OPRI has limited understanding of genotype-phenotype correlations and the polymorphisms modulating disease expression.…”

Pathogenic Mechanisms of the Prion Protein Gene Mutations: A Review and Speculative Hypotheses for Pathogenic Potential of the Pro39Leu Mutation in the Associated FTD-Like Phenotype

“…from IPD, such as Alzheimer's disease and Frontotemporal dementia [31][32][33][34][35][36]39]. This confirms that the search for mutations in the PRNP gene should be considered in these phenotypic manifestations, especially after exclusion of causative mutations in FTD or AD genes.…”

“…In some cases, the clinical picture is not specific and is confined to psychiatric features [24,30]. Moreover, PRNP gene mutations were found to be associated with clinical pictures resembling other neurodegenerative diseases, such as Frontotemporal dementia [31][32][33][34][35][36], Cerebral amyloid angiopathy (CAA) [37], familial neuropsychiatric illness [38], familial Alzheimer's disease [39] and Huntington's disease [24].…”

“…In contrast, a relationship between a certain PRNP gene mutation (genotype) and a specific neuropathological phenotype has been proven: Atypical clinical phenotypes with mutations in the PRNP gene (such as FTD-like phenotypes) for which neuropathological data were available, have shown the presence of prion disease [31,33,36].…”