MAPT S305I mutation: implications for argyrophilic grain disease

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Familial frontotemporal dementia (FTLD) linked to MAPT gene mutations typically presents with tau pathology.
• While many MAPT mutations mimic sporadic tauopathies, none have been documented to resemble argyrophilic grain disease (AgD).

Observation:

• A patient with a novel S305I MAPT mutation exhibited behavioral changes and cognitive decline.
• Neuropathological examination revealed a unique phenotype with tau-positive structures, including argyrophilic grains, but lacked classical markers like neurofibrillary tangles.
• The observed tau pathology closely mimicked that of sporadic AgD.

Findings:

• The S305I MAPT mutation significantly increased 4R-tau isoforms due to altered exon 10 splicing.
• The tau inclusions consisted solely of 4R-tau isoforms and straight filaments.
• Neuronal loss was prominent in the medial temporal cortex, hippocampus, and amygdala.

Implications:

• This case broadens the phenotypic spectrum of FTLD caused by MAPT mutations.
• The findings suggest that sporadic AgD may represent a distinct disease entity with shared neuropathological features.
• Understanding MAPT mutation effects on tau isoform ratios is crucial for diagnosing and characterizing FTLD subtypes.