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J Neurol Neurosurg Psychiatry. 2018 Feb;89(2):162-168. doi: 10.1136/jnnp-2017-316820. Epub 2017 Sep 9.

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.

Author information

1
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
2
Center for Networked Biomedical Research into Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
3
ALS Unit, Department of Neurology, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain.
4
Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
5
Neuromuscular Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
6
ALS Unit, Department of Neurology, Hospital Universitario Gregorio Marañón, Madrid, Spain.
7
Department of Neuropathology and Tissue Bank, CIEN Foundation, Carlos III Institute of Health, Madrid, Spain.
8
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
9
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
10
ALS Unit, Department of Neurology, Hospital Clínico Universitario San Carlos, Madrid, Spain.
11
Neurological Tissue Bank of the Biobanc-Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
12
Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain.

Abstract

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.

PMID:
28889094
DOI:
10.1136/jnnp-2017-316820

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