A Rare Genetic Mutation Reveals an Unexpected Path for Dementia

A fascinating case study of a 78-year-old patient has reshaped clinical perspectives on a specific genetic form of dementia. The patient presented with a six-year history of progressive memory decline and mild anomia—a difficulty in recalling names—which typically points towards Alzheimer's disease. However, his condition evolved to include motor clumsiness, gait disturbances, late-onset parkinsonism, and significant behavioural changes.

Advanced imaging proved crucial for the diagnosis. While brain scans showed atrophy in the temporal lobes and low metabolic activity, a negative amyloid PET scan ruled out Alzheimer’s, supporting a diagnosis of Frontotemporal Dementia (FTD). FTD represents a group of disorders caused by the degeneration of the frontal and temporal lobes, usually affecting personality and language rather than memory initially.

Genetic analysis uncovered a mutation in the SQSTM1 gene, consistent with the patient's history of Paget disease of bone. Post-mortem examination revealed a complex biological landscape: the brain contained an atypical distribution of TDP-43 protein, alongside tau and Lewy body pathology. This coexistence of different toxic proteins underscores the phenotypic heterogeneity—or observable physical variety—of SQSTM1 mutations.

This case is significant because it highlights an "amnestic" onset, where memory fails first, which is rare for FTD. It serves as a reminder to clinicians that prominent memory impairment can indeed signal this specific genetic anomaly, necessitating comprehensive genetic and neuropathological evaluation to ensure accurate diagnosis.