Atypical Frontotemporal Dementia Associated With SQSTM1 Gene Mutation: A Clinicopathological Case

Abstract

A 78-year-old man presented with a six-year history of progressive memory decline, initially manifesting as recent memory impairment and mild anomia, which gradually evolved into motor clumsiness, gait disturbances, language difficulties, behavioral changes, and late-onset parkinsonism. He had been diagnosed with Paget disease of bone (PDB) at the age of 45. Brain MRI revealed asymmetric left anterior temporal atrophy, while [18F]-Fluorodeoxyglucose (FDG) PET demonstrated frontotemporal hypometabolism, predominantly on the left side, with marked involvement of both temporal poles and greater hypometabolism in the left temporal pole. A negative amyloid PET scan supported a diagnosis of frontotemporal dementia (FTD). Genetic analysis identified an SQSTM1 gene mutation (c.1210A>G; p.(Met404Val)). Post-mortem examination confirmed frontotemporal lobar degeneration with atypical TDP-43 protein distribution, alongside tau and Lewy body pathology. This case exemplifies an atypical presentation of FTD, characterized by amnestic onset with subsequent language and behavioral involvement, thereby broadening the recognized clinical spectrum of SQSTM1-associated FTD. The coexistence of parkinsonism and PDB, alongside mixed proteinopathies, underscores the phenotypic heterogeneity of SQSTM1 mutations. These findings emphasize the importance of considering prominent memory impairment, semantic deficits, and parkinsonism as potential manifestations in this genetic form and highlight the need for comprehensive clinical, genetic, and neuropathological evaluation to improve diagnosis and inform therapeutic strategies.