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

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Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) is an umbrella term for hereditary tauopathies caused by mutations in the microtubule‐associated protein tau gene (MAPT) at chromosome 17q21.3 1. Of 16 MAPT exons, alternative splicing of exon 10 results in two functionally distinct isoforms that have either three or four 31‐amino acid repeats depending on whether exon 10 is excluded (3R tau) or included (4R tau) 2. To date more than 50 mutations in exons 1, 9–13 and introns 9 and 10 have been reported in about 200 families (see 3. The p.P301L mutation in exon 10 is one of the most common 3. The pathogenetic effect of this mutation includes reduced ability of mutated 4R tau to bind to microtubules and promote microtubule assembly 4, as well as enhanced in vitro heparin‐induced assembly into pathological tau filaments 5.
FTDP‐17 follows a pattern of autosomal dominant inheritance with clinical, biochemical and neuropathologic heterogeneity 3. The phenotypes overlap with phenotypes of sporadic primary tauopathies, including progressive supranuclear palsy 6, Pick's disease (PiD) 7, corticobasal degeneration (CBD) 8 and globular glial tauopathy (GGT) 9.
GGT is a newly recognized 4R tauopathy with extensive white matter tau pathology and characteristic glial inclusions, including Gallyas‐positive globular oligodendroglial inclusions (GOI) and globular astrocytic inclusions (GAI). The latter are usually Gallyas‐negative or at most show only weak staining with Gallyas silver method 10. A proposed classification of GGT includes three clinicopathologic subtypes: subtype I with frontotemporal distribution of tau pathology and clinical features of frontotemporal dementia (‘FTD‐type’); subtype II with pyramidal features from motor cortex involvement and corticospinal tract degeneration [‘motor neuron disease (MND)‐type’]; and subtype III with a combination of FTD and MND (‘FTD & MND‐type’) 10.
Here, we compare and contrast clinicopathologic features of five unrelated and three related patients with FTDP‐17 due to p.P301L mutation, including one patient with a GGT phenotype.

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