Two novel tau mutations associated to a Frontotemporal Dementia Sporadic case: a clinical and neuropathological study

Objective: To present a case of clinico-pathological frontotemporal dementia (FTD) associated with two novel intronic MAPT gene mutations. Methods: An early-onset FTD case was diagnosed through standardized assessment. We sequenced the MAPT, PRGN genes on the genomic DNA of a patient and her relatives. Brain sections were studies with standard stains and immunohistochemistry (anti-B protein, anti-phospho tau (AT8), anti ubiquitin, anti-3R (RD3) and anti-4R tau (RD4) antibodies). Sarcosyl-insoluble Tau was studied by mmunoblot. Results: A 46 year-old patient presented with behavioural changes evolving into a complete FTD dementia. Death occurred at 57. Two novel MAPT gene mutations,the IVS10+4A>C in intron 10 and IVS9-15T>C in intron 9, were identified, transmitted by her mother and her father, respectively. Both parents were phenotypically normal. The genomic study is reported to this meeting by Losso et al. The severely atrophic brain weighted 650 gr, with relative sparing of Rolandic and calcarine regions. Histopathology evidenced nearly exceptional loss in frontotemporal cortex associated with protoplasmic gliosis and relative sparing of primary motor and sensory cortices; area 17 was normal. The putamen was nearly normal, the pallidum and thalamus were severely affected. The cerebellum and brain stem were globally spared, with the exception od substantia nigra and griseum centrale mesencephali showing severe neuronal loss. AT-8 labelled abundant, rounded, star-like and coiled inclusions in neurons, astrocytes and oligodendroglia, respectively. Inclusions were mainly of 3R tau, no amyloid was found. Sarkosyl-insoluble tau was labelled with BR134 at 64 and 60 kDa; dephosphorilation produced two major bands, aligning with 3R0N and 3R1N isoforms of recombinant tau. Conclusion: Our findings are remarkable due to profound and diffuse atrophy with nearly complete cortical neuronal loss, sparing only the projection areas. We hypothesize that the expression of this condition depended on double heterozygocy for two MAPT mutations, which, when present alone, did non affect the phenotype.