Unclassifiable tauopathy associated with an A152T variation in MAPT exon 7

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Mutations in the microtubule-associated tau (MAPT) gene are linked to frontotemporal dementia (FTD) and related parkinsonian syndromes.
• The specific role of variations in exon 7 of the MAPT gene in neurodegenerative diseases remains largely unexplored.

Observation:

• A 63-year-old male presented with progressive memory and speech disturbances, dementia, and myoclonus, with a similar history in his father.
• Neuropathological examination revealed significant neuronal loss in the frontal, temporal cortices, and substantia nigra.
• Distinct tau pathology characterized by 4R tau isoform, thread-like phospho-tau structures, and twisted ribbon filaments was observed, with a lack of typical astrocytic plaques.

Findings:

• A novel A152T variation in exon 7 of the MAPT gene was identified in the patient.
• The patient's disorder exhibited a unique neuropathological phenotype, differing from tauopathies caused by mutations affecting microtubule binding domains.
• The observed tau pathology primarily involved the 4R tau isoform.

Implications:

• The A152T MAPT variation may represent a novel pathogenic mutation contributing to familial frontotemporal dementia-like syndromes.
• This finding suggests that MAPT gene variations outside the canonical microtubule-binding regions can lead to distinct tau neuropathological phenotypes.
• Further research is warranted to elucidate the precise mechanism by which this MAPT variation contributes to neurodegeneration.