Phenotypical variability in an Argentinian family, with history of frontotemporal lobar degeneration, caused by a mutation in the microtubule-associated protein tau 

Emilia M. Gatto a,b; Ricardo F. Allegri c,i,j; Gustavo Da Prat b; Patricio Chrem Méndez c David S. Hanna d,e; Michael O. Dorschner d,e; Ezequiel I. Surace f i; Ignacio F. Mata g,h 

a Departamento de trastornos del movimiento, Fundación INEBA, Buenos Aires, Argentina. b Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina. c Centro de la memoria y el envejecimiento, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina. d Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA. e Department of Pathology, University of Washington, Seattle, USA f Laboratorio de Biología Molecular, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina g Veterans Affairs Puget Sound Health Care System, Seattle, USA h Department of Neurology University of Washington, Seattle, WA USA i Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina j Universidad de la Costa (CUC), Colombia

OBJECTIVES:

To describe the first Argentinian family of Basque ancestry, with MAPT gene (p.P301L) mutation and intrafamilial phenotypical variability (Corticobasal Syndrome and Fronto Temporal Dementia).

BACKGROUND:

BackgroundbvFTD is a genetic disorder related with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Gene mutations involving the microtubule-associated protein tau, progranulin and C9orf72 are related

METHODS

The pedigree consists of 26 family members over 6 generations presenting with a history of autosomal dominant bvFTD (previously mentioned as Pick disease). Two different phenotypes were identified among affected members in the living generation, CBS in the proband and FTD in one of his siblings. We performed neurological examination, neuropsychological tests and neuroimaging in 5 individuals. A whole-exome sequencing (WES) was conducted in 5 individuals (Proband, 3 brothers and a cousin). A Sanger sequence was performed to identify candidate variants in all 5 siblings to assess segregation.

RESULTS:

We identify a mutation in the exon 10 of the MAPT gene (p.P301L; rs63751273) in the proband and one affected brother, which was absent in the other three syblings analyzed. This mutation has often been assigned as the cause of FTD, particularly in French populations, but rarely of CBS. The proband and her affected brother presented a CBS and FTD phenotype respectively. This is the first report in Argentina and South America.

CONCLUSIONS:

Our findings contribute to support the wide distribution of this mutation and the high phenotypic variability presented among families, and also within families, carrying the MAPT-p.P301L mutation. This observation emphasize the concept that other environmental or genetic factors could modify the phenotype.

http://www.pascongress2017.org/MDS-PAS-2017-Files/PDFs/PASmiami-FP-v9.pdf