Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) due to microtubule‐associated protein tau (MAPT) p.P301L mutation, including a patient with globular glial tauopathy

Abstract

Aim The p.P301L mutation in microtubule-associated protein tau (MAPT) is a common cause of frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). We compare clinicopathologic features of five unrelated and three related (brother, sister and cousin) patients with FTDP-17 due to p.P301L mutation. Methods Genealogical, clinical, neuropathologic, and genetic data were reviewed from eight individuals. Results The series consisted of five men and three women with an average age of death of 58 years (52–65 years) and average disease duration of 9 years (3–14 years). The first symptoms were those of behavioral variant frontotemporal dementia in seven patients and semantic variant of primary progressive aphasia in one. Three patients were homozygous for the MAPT H1 haplotype; five had H1/H2 genotype. The apolipoprotein E genotype was ε3/ε3 in seven and ε3/ε4 in one. The average brain weight was 1015 grams (876 – 1188 grams). All had frontotemporal lobar or more diffuse cortical atrophy. Except for one patient, the hippocampus and parahippocampal gyrus had minimal atrophy, while there was atrophy of middle and inferior temporal gyri. Dentate fascia neuronal dispersion was identified in three patients, two of whom had epilepsy. In one patient there was extensive white matter tau involvement with Gallyas-positive globular glial inclusions typical of globular glial tauopathy (GGT). Conclusions This clinicopathologic study shows inter- and intra-familial clinicopathologic heterogeneity of FTDP-17 due to MAPT p.P301L mutation, including GGT in one patient.

Frontotemporal Dementia Caused by the P301L Mutation in<b> </b>the<b><i> MAPT</i></b> Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain

“…The clinical features of our patients are relatively homogeneous and consistent with the previously described phenotype [8,9,10,11,12,13]. The most frequent presentation in our series was behavior disturbances (54%).…”

“…There was a classic FLTD atrophy pattern with prominent neuronal loss, gliosis and superficial spongiosis in frontotemporal and parietal cortical regions, basal ganglia and substantia nigra with relative preservation of the hippocampus and occipital cortex. In contrast to Tacik et al [8], in our cases, the parahippocampal gyrus was severely affected. The underlying pTau pathology was relatively uniform and extensive and consisted of 4R isoforms with neuronal and glial involvement.…”

“…While Tacik et al [8] report that the P301L mutation is associated with clinical and pathologic heterogeneity based on the variability of the glial inclusions, in our series the neuropathological findings were relatively homogeneous. There was a classic FLTD atrophy pattern with prominent neuronal loss, gliosis and superficial spongiosis in frontotemporal and parietal cortical regions, basal ganglia and substantia nigra with relative preservation of the hippocampus and occipital cortex.…”

“…The postmortem detection of a moderate or severe loss of pigmented neurons of the substantia nigra pars compacta in all patients suggests that parkinsonism could have been clinically underestimated. Four patients developed secondary epilepsy in the latest stages of the disease according to previous reports showing that epilepsy is not uncommon in patients with MAPT mutations [8,20]. Four patients were clinically misdiagnosed as having Alzheimer disease.…”

“…These deposits consist of 3-repeat and/or 4-repeat (4R) classes of tau isoforms. Significant variability has been described concerning the clinical and pathological phenotype depending on the MAPT mutation and even among individuals carrying the same mutation [5,6,7,8,9,10,11,12,13]. …”