Frontotemporal Dementia Sporadic Case associating two novel Tau mutations. Part one: clinico-pathological study

Objective: To present a clinico-pathological case of 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, PGRN genes on the genomic DNA of a patient and her relatives. Brain sections were studied with standard stains and immunohistochemistry. Sarcosyl-insoluble Tau was studied by immunoblot. Results: A 46 year-old patient presented with behaviour changes evolving into complete dementia. Two novel MAPt gene intronic mutations (IVS10+4A>C and IVS9-15T>C) were identified, transmitted by her mother and her father, respectively both phenotypically normal. The severely atrophic brain weighted 650g, with relative sparing of Rolandic and calcarine regions. Histopathology evidenced exceptional neuronal loss in frontotemporal cortex with protoplasmic gliosis and relative sparing of primary motor and sensory cortices; area 17 was normal. Putamen was nearly normal, pallidum and thalamus were severely affected. Cerebellum and brain stem were globally spared, with the exception of substantia nigra and griseum centrale mesencephali showing severe neuronal loss. AT-8 labelled abundant, rounded, star-like and coiled inclusions in neurones, astrocytes and oligodendrocytes, respectively. Inclusions were mainly of 3R Tau, no amyloid was found. Sarkosyl-insoluble Tau was labelled with BR134 at 64 and 60 kDa; dephosphorylation produced two major bands, aligning with 3R0N and 3R1N recombinant Tau isoforms. Conclusion: We suggest that the compound heterozygosity identified in the patient could be responsible for the clinical and neuropathological expression of the disease. This result illustrates that so-called “sporadic” cases of dementia may have a genetic cause.