Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

Oriol Dols-Icardo, Alberto García-Redondo, Ricardo Rojas-García, Daniel Borrego-Hernández, Ignacio Illán-Gala, José Luís Muñoz-Blanco, Alberto Rábano, Laura Cervera-Carles, Alexandra Juárez-Rufián, Nino Spataro, Noemí De Luna, Lucía Galán, Elena Cortes-Vicente, Juan Fortea, Rafael Blesa, Oriol Grau-Rivera, Alberto Lleó, Jesús Esteban-Pérez, Ellen Gelpi, Jordi Clarimón

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    26 Citations (Scopus)

    Abstract

    © 2018 Article author(s) (or their employer(s) unless otherwise stated in the text of the article). All rights reserved. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. Objectives The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. Methods From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. Results We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. Conclusion Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.
    Original languageEnglish
    Pages (from-to)162-168
    JournalJournal of Neurology, Neurosurgery and Psychiatry
    Volume89
    Issue number2
    DOIs
    Publication statusPublished - 1 Feb 2018

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