Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis

Sir,

The letter to the editor from Johnson and colleagues provides new information confirming that mitochondrondrial dysfunction could be an important player contributing to the aetiology of amyotrophic lateral sclerosis (ALS) through the involvement of the CHCHD10 gene. We first identified four patients harbouring a mutation in this gene among a total population of 116 individuals presenting with ALS-frontotemporal dementia (FTD) (Bannwarth et al., 2014; Chaussenot et al., 2014). Then, whole exome sequencing in 102 German and 26 Nordic patients with pure ALS led to the identification of three families in which a CHCHD10 mutation segregates with the disease (Müeller et al., 2014). In their study, Johnson and colleagues showed that CHCHD10 is responsible for five novel cases among a cohort of 85 patients with familial ALS. All these data confirm the clinical, molecular and mechanistic continuum between FTD and ALS and raise the intriguing prospect of an underlying mitochondrial basis for this group of disorders.

Regarding CHCHD10 mutations, we agree with Johnson and colleagues that their identification by exome sequencing is difficult due to their location in a GC-rich region responsible for a low coverage. Genome sequencing can be an alternative approach but CHCHD10 sequencing using the Sanger method must be systematically performed when exome sequencing is not conclusive. Each CHCHD10 mutation that we identified in ALS-FTD patients was found twice. The p.Ser59Leu mutation is located in the hydrophobic N-terminal α helix of CHCHD10 while the p.Pro34Ser is located in the non-structured N-terminal region (Bannwarth et al., 2014; Chaussenot et al., 2014). The deleterious variants found in patients with pure ALS are different but also recurrent. The p.Arg15Leu mutation was identified in five of eight cases and all patients reported by Johnson and colleagues, who carried this variant, shared a 6.2 Mb haplotype across the gene. Only the Gly66Val mutation was found once until now. The p.Arg15Leu is located in the non-structured N-terminal region whereas the p.Gly66Val variant is located in the N-terminal α helix.

In conclusion, CHCHD10 mutations located in the non-structured N-terminal region or in the α helix are responsible for both ALS and ALS-FTD phenotypes. No deleterious variant has been found in the CHCH domain near the C-terminal region. The large majority of CHCHD10 mutations that were identified are recurrent, including the p.Arg15Leu variant that was found in five of eight cases with pure ALS. Further studies in larger cohorts are needed, but initial results involving French, German, Finnish, North American, Israeli, Italian and Canadian populations suggest that the frequency of CHCHD10 mutations must be between 3 and 5% in the ALS and ALS-FTD clinical spectrum (Bannwarth et al., 2014; Chaussenot et al., 2014; Müeller et al., 2014).

Funding

This work was made possible by grants to V.P.-F. from the Association Française contre les Myopathies (AFM) and the Fondation pour la Recherche Médicale (FRM), to H.S. from National Institutes of Health (GM089853) and to A.B. by the program ‘Investissements d’avenir’ ANR-10-IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’ (to I.L.B.) and the 7th framework program of the European Union (FP7, E12009DD, Neuromics). P.Y.-W.-M. is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK).