title: Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America.
abstract: Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD. Twenty-one members over 6 generations composed the pedigree. An extensive neurologic and neurocognitive examination was performed on 2 symptomatic individuals and 3 nonsymptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these 5 individuals and whole-exome sequencing was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals, a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: (1) aggressive, symmetrical, and early-onset Parkinsonism; (2) late parkinsonism associated with FTD; and (3) progressive supranuclear palsy but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.
authors.affiliation: Department of Movement Disorders, Fundación INEBA, Buenos Aires, Argentina; Department of Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina.
authors.forename: Emilia M
authors.initials: EM
authors.lastname: Gatto
authors.affiliation: Department of Cognitive Neurology, Memory and Aging Center, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Investigator at CONICET the Argentine Research Council (CONICET), Cdad. Autónoma de Buenos Aires, Argentina; Universidad de la Costa (CUC), Barranquilla, Colombia.
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Allegri
authors.affiliation: Department of Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Da Prat
authors.affiliation: Department of Cognitive Neurology, Memory and Aging Center, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina.
authors.forename: Patricio
authors.initials: P
authors.lastname: Chrem Mendez
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hanna
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.affiliation: Department of Neuropathology, Laboratorio de Biología Molecular, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Investigator at CONICET the Argentine Research Council (CONICET), Cdad. Autónoma de Buenos Aires, Argentina.
authors.forename: Ezequiel I
authors.initials: EI
authors.lastname: Surace
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, Seattle, WA, USA.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, Seattle, WA, USA. Electronic address: nachofm@uw.edu.
authors.forename: Ignacio F
authors.initials: IF
authors.lastname: Mata
mesh_terms: D001118:Argentina; D001921:Brain / Q000000981:diagnostic imaging; D005091:Exons / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics; D057174:Frontotemporal Lobar Degeneration / Q000000981:diagnostic imaging / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020774:Pick Disease of the Brain; D049268:Positron-Emission Tomography; D013494:Supranuclear Palsy, Progressive / Q000235:genetics; D013577:Syndrome; D055815:Young Adult; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins
keywords: CBS; Cognition; FTD; MAPT; P301L