Clinical phenotypic variability in an Italian family bearing the IVS6+ 5_8delGTGA mutation in PGRN gene

Background Frontotemporal dementia (FTD) is a complex presenile disorder characterized by behavioural changes and executive functions, expression of fronto-temporal degeneration. Hereditary FTD accounts for 20-30% of cases and, in the past decade, mutations in the microtubule associated protein tau (MAPT)gene were identified as a main genetic causes of familial FTD. In 2006, mutations in the gene encoding progranulin (PGRN) were reported, to account for a wide part of the familial FTD cases. Clinically, an high phenotypic variability within and among the kindreds is reported in the familial FTD associated with PGRN mutations and occasionally the memory deficits are the first symptoms, resembling Alzheimer's disease (AD). We report an Italian family with dementia associated with a PGRN mutation characterized by a deletion of 4 base pairs inside the intron 6 of the gene, leading to haploin sufficiency In our kindred, all three affected patients carried the mutation, but presented very different clinical phenotypes, evoking FTD, AD and rapidly-progressive dementia mimicking prion disease. Methods Informations on the members of the first, second and third generations were obtained conducting interviews with relatives, while for the three patients studied, the clinical evidence of dementia symptoms and their characterization was documented directly with sequential neurological examinations, cognitive assessments and neuroimaging. Blood sample collection and DNA extraction from peripheral blood lymphocytes for genetic analysis were performed after written informed consent of the patients. Results In our pedigree, the PGRN mutated patients are affected by dementia with three different clinical pictures: FTD, AD and rapidly progressive dementia mimicking prion disease. Neuropsychological examinations supported these diagnoses, documenting generalized deficits of cortical functions in AD patient and deficits in executive functions and in language in FTD patient. Regarding neuroimaging, in the same two cases MRI results do not correspond to the clinical diagnosis. Conclusions These findings confirms the marked heterogeneity of the clinico-radiological features in patients with PGNR mutations and underline the need of considering mutations of this gene as causes of familial dementing diseases with atypical or uncommon features or discrepancies between the clinical and the neuroimaging findings.