A novel prion protein variant in a patient with semantic dementia

Prion diseases are a group of fatal neurodegenerative diseases that can be sporadic, inherited or acquired. Inherited prion diseases are caused by mutations in the prion protein gene, PRNP , usually single nucleotide substitutions or structural variants of an octapeptide repeat encoding region. Although the classical presentation of sporadic Creutzfeldt Jakob disease (CJD) is rapidly progressive ataxia, myoclonus and cognitive decline, the presentation of genetic cases is variable and decline can be much slower. Prion diseases can mimic many neurodegenerative diseases. Genetic dementias are pleiotropic, with similar clinical syndromes being caused by mutations in different genes; additionally, mutations in a single gene may cause diverse clinical phenotypes. Due to the diagnostic difficulties arising from this clinical and genetic heterogeneity, next-generation sequencing technologies including gene panels and exome sequencing are helpful in elucidating genetic causes of dementia.1 Here we report a novel variant in PRNP in a patient diagnosed with semantic dementia, a variant of frontotemporal dementia (FTD). Patients with semantic dementia develop progressive loss of semantic knowledge resulting in significant early language impairment, with subsequent wider cognitive impairment and behavioural problems. MRI appearances are characteristic with focal asymmetric anteroinferior temporal lobe atrophy. The predominant histopathological finding is accumulation of Tar DNA-binding protein 43 (TDP-43) deposits in the temporal and frontal lobes, although other pathologies, including Alzheimer’s disease, are occasionally observed.2 A Mendelian genetic aetiology is rarely documented. A woman in her seventh decade presented with a 1-year history of rapidly progressive language problems and behavioural change. She had particular difficulty naming objects and suffered from impaired comprehension, but had preserved recognition of faces and …