Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, Genin EC, Serre V, Augé G, French research network on FTD and FTD-ALS, Brice A, Pouget J, Paquis-Flucklinger V. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging. 2014 Dec;35(12):2884.e1-4. Epub 2014 Jul 24 PubMed.
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I consider the latest results from Johnson and colleagues, along with the earlier reports of the French and German teams (Bannwarth et al., 2014; Chaussenot et al., 2014; Muller et al., 2014), as pretty compelling evidence for CHCHD10’s role as a disease gene of familial ALS and ALS-FTD. Analysis of the CHCHD10 gene in additional, well-phenotyped familial ALS and ALS-FTD cases should provide further insight into the relative frequency of disease-causing CHCHD10 mutations in this spectrum of neurodegenerative disorders.
The affected members of the initial family that led to the discovery of disease-causing CHCHD10 mutations had a complex clinical picture that seemed to go beyond an ALS-FTD phenotype. However, the more recent studies by the U.S. and German teams identified CHCHD10 mutations in cases with a confirmed ALS diagnosis, suggesting that CHCHD10 should indeed be added to the growing list of ALS disease genes. Deep phenotyping of additional patients with CHCHD10-linked disease is warranted to provide a better understanding of the clinical presentation of this genetic subgroup.
Previous research has implicated mitochondrial dysfunction in ALS mostly through the analysis of model systems of mutant SOD1-linked ALS and, more recently, mutant VCP-linked ALS. The discovery of ALS-causing CHCHD10 mutations provides an exciting new entry point for exploring mitochondrial dysfunction in ALS.
I expect other ALS genes to turn up. Next-generation sequencing efforts in familial ALS have mostly focused on whole-exome sequencing, which remains an incredibly powerful and efficient tool for identifying disease-causing mutations. It has already led to the discovery of a number of new ALS genes. Some groups have begun moving toward whole-genome sequencing. For sporadic ALS, whole-genome sequencing is underway by Project MinE, an initiative launched in 2013 and enabled by crowd-funding. The initiative aims to sequence at least 15,000 whole genomes of ALS patients and has already reached over 10 percent of this goal. One significant advantage of whole-genome sequencing is that it captures non-protein-coding and other intergenic regions of the genome that are missed by whole-exome sequencing. These intergenic regions may contain critical regulatory sequences that are relevant for disease. Whole-genome sequencing also has an increased capacity for covering GC-rich stretches of protein-coding sequences. As the cost of whole-genome sequencing continues to fall, it will likely gain increasing traction.
References:
Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore D, Verschueren A, Rouzier C, Le Ber I, Augé G, Cochaud C, Lespinasse F, N'Guyen K, de Septenville A, Brice A, Yu-Wai-Man P, Sesaki H, Pouget J, Paquis-Flucklinger V. Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain. 2014 Sep 26; PubMed.
Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, Genin EC, Serre V, Augé G, French research network on FTD and FTD-ALS, Brice A, Pouget J, Paquis-Flucklinger V. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging. 2014 Dec;35(12):2884.e1-4. Epub 2014 Jul 24 PubMed.
Müller K, Andersen PM, Hübers A, Marroquin N, Volk AE, Danzer KM, Meitinger T, Ludolph AC, Strom TM, Weishaupt JH. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014 Dec;137(Pt 12):e309. Epub 2014 Aug 11 PubMed.
View all comments by Amelie K. GubitzDuke University
Replication by these two other groups (Mueller et al. 2014; Johnson et al. 2014) definitely strengthens the original claim that CHCHD10 is an ALS gene (Bannwarth et al., 2014). Also, while there is still less optimal phenotypic description of the cases in these two new papers, they do appear more like ALS than did the cases in the original paper. The ALS is still atypical because of the reported slow progression rate, but it is within the range of what we see in our clinics.
References:
Müller K, Andersen PM, Hübers A, Marroquin N, Volk AE, Danzer KM, Meitinger T, Ludolph AC, Strom TM, Weishaupt JH. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014 Dec;137(Pt 12):e309. Epub 2014 Aug 11 PubMed.
Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, Restagno G, Drory VE, Chiò A, Rogaeva E, Traynor BJ. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain. 2014 Dec;137(Pt 12):e311. Epub 2014 Sep 26 PubMed.
Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore DG, Verschueren A, Rouzier C, Le Ber I, Augé G, Cochaud C, Lespinasse F, N'Guyen K, de Septenville A, Brice A, Yu-Wai-Man P, Sesaki H, Pouget J, Paquis-Flucklinger V. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014 Aug;137(Pt 8):2329-45. Epub 2014 Jun 16 PubMed.
View all comments by Richard BedlackTo date, both the association of CHCHD10 with FTD-ALS and the identification of recurrent variants in ALS families from different geographical origins are solid observations that substantiate a causal genetic link between CHCHD10 mutations and the development of ALS, at least in a subset of patients. Elucidating the cellular pathways disrupted by the expression of CHCHD10 mutant alleles will be crucial in clarifying the role of mitochondrial dysfunction, not only in ALS, but also more broadly in other more complex neurodegenerative disorders.
View all comments by Samira SaadiMake a Comment
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