Clinical phenotype of frontotemporal dementia associated with the Pro392Leu SQSTM1 mutation

Objective: To characterize the phenotypic spectrum of patients with frontotemporal dementia (FTD) carrying the P392L SQSTM1 mutation. Methods: We describe the clinical phenotype of three well-characterized probands carrying the P392L mutation, and review ten previously published FTD cases with the mutation. Results: All three cases were male with a presenile age of onset (52 or 64 years). Case 1 developed an amnestic-anomic syndrome followed by a behavioral variant of FTD (bvFTD). Case 2, with an autosomal dominant family history of dementia, developed a bvFTD associated with parkinsonism. Both cases had Paget's disease of the bone (PDB). Case 3 presented with a semantic aphasia and, years later, developed a hemilateral upper motor neuron disease (MND) (Mills syndrome). Among the ten previously reported cases (four from the same family), bvFTD was the cognitive phenotype in five, but semantic, nonfluent and logopenic aphasic variants, as well as a pure hippocampal amnestic syndrome were also documented. PDB was observed in six cases, two exhibited parkinsonism, and one MND. Neuroimaging findings showed a tendency toward asymmetric temporal/frontal atrophy, sometimes with periventricular white matter signal abnormalities. Only one third of the cases reported a family history of dementia. Conclusions: The P392L mutation exhibits a pleiotropic effect, giving rise to a broad phenotypic spectrum that includes PDB, FTD, amnestic syndrome, parkinsonism, and MND. Penetrance for the different phenotypes is variable and may be influenced by additional factors. The outlined features may encourage healthcare professionals to screen for this gene, even in cases without a clear family history.