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Main text Tauopathies are neurodegenerative disorders characterized by hyperphosphorylated microtubule-associated protein tau (MAPT) forming protein aggregates. Over sixty dominantly inherited mutations in MAPT have been reported. These mutations cause frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) whose symptom onset and survival are highly heterogeneous [4]. We describe here the genetic, clinical, neuropathological and biochemical characterization of a case of de novo MAPTG335A mutation in a male patient. Symptoms of poor organisation skills, attention and concentration difficulties appeared when the proband was 14 years old. A few years later, he developed anxiety, panic attacks and time obsession. Firstly, he was considered to be suffering from a schizophrenic disorder. Since behavioral and phasic disturbances progressivly appeared, he was referred to a department of neurology at the age of 24. By this time, MRI showed a frontotemporal atrophy and SPECT demonstrated an hypofixation in the same regions. The clinical evolution was marked by a progressive decline in cognitive functions, particularly in speech output, semantic memory and in executive functions, an hyperorality, an emotional blunting and a buccofacial apraxia with swallowing disturbance necessiting an institutionalisation in an appropiate facility when he was 25. He never developed major extrapyramidal features, except a dystonia of upper left arm and a slight upper arms rigidity probably of iatrogenic origin (i.e. neuroleptic drugs). Sequencing of MAPT gene revealed a novel heterozygous mutation G335A due to G→C transition at the second base position in codon 335 in exon 12 (NM_ 005910.5: c.1004G > C p.Gly335Ala). The mutation was not found in his parents, thus strongly arguing for a de novo mutation. The proband died at 34, 20 years after the onset of symptoms. The proband’s brain was removed at autopsy, collected and stored in the brain bank of the LHNN (BB190052). One brain hemisphere was fixed in 10% buffered formalin. The other hemisphere was cut into coronal sections and kept at − 80 °C. A small piece of frontal cortex was fixed in 4% glutaraldehyde for transmission electron microscopy. The macroscopic examination showed a severe atrophy of the frontal and anterior temporal lobes (Fig. 1a) with a whole wet brain weight of 928 g. A marked dilatation of the frontal horn of the lateral ventricule was present (Fig. 1b). Neuropathological analysis was done on paraffin-embedded sections. In all regions examined, there were neurodegenerative changes consistent with a tauopathy (Table 1). Possible neuropathological

de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia