The novel p.K317N mutation in MAPT gene with clinicopathological phenotype of globular glial tauopathy (P2.161)

OBJECTIVE: Globular glial tauopathy (GGT) is a rare 4-repeat tauopathy pathologically defined by widespread globular glial inclusions (GGIs). GGIs include Gallyas-positive globular oligodendroglial incusions and Gallyas-negative globular astrocytic inclusions. BACKGROUND: 30 cases with GGTs identified so far were sporadic. DESIGN/METHODS: Six patients with GGT identified in our brain bank were screened for mutations in the microtubule-associated protein tau gene (MAPT) gene using Sanger sequencing. Genealogical, clinical, neuropathological, and genetic data were collected. Functional studies included microtubule assembly, tau filament formation and Western blot. RESULTS: There were 4 males. Mean age of death was 72.7 years (55-83 years). Mean disease duration was 7.2 years (5-14 years). Mean age of onset was 65.5 years (50-77 years), and early symptoms included frontotemporal dementia (n=4), corticobasal syndrome (n=1) and short-term memory decline (n=1). Average brain weight was 1166.7 grams (1000-1260 grams). All brains demonstrated lobar atrophy of frontotemporal distribution. Three patients had a positive family history of dementia; the novel p.K317N mutation was identified in one of them. All patients were homozygous for the H1 MAPT haplotype. Recombinant K317N tau showed a reduced ability to promote microtubule polymerization by turbidity but no significant effect on the kinetics of tau filament aggregation when assessed using electron microscopy. CONCLUSIONS: While often sporadic, GGT can be caused by the novel MAPT p.K317N mutation. Sequencing of MAPT should be considered in patients with GGT and a positive family history of frontal lobe symptoms, motor neuron disease and/or extrapyramidal features. In patients who did not have MAPT mutations, other genetic factors may play a role in the pathogenesis of GGT. Study Supported by: NIH/NINDS P50 NS072187 and R01 NS078086, the NIH/NINDSP50 NS072187, the Michael J. Fox Foundation for Parkinson’s Research, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch and the Max Kade Foundation. Disclosure: Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism u0026 Related Disorders and the European Journal of Neurology. Dr. Tacik has nothing to disclose. Dr. DeTure has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Sanchez Contreras has nothing to disclose. Dr. Wojtas has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Walton has nothing to disclose. Dr. Carlomango has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Strongosky has nothing to disclose. Dr. Kouri has nothing to disclose. Dr. Murray has nothing to disclose. Dr. Josephs has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Ross has nothing to disclose. Dr. Dickson has nothing to disclose.