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Sylvie Bannwarth, Samira Ait-El-Mkadem, Annabelle Chaussenot, Emmanuelle C. Genin, Sandra Lacas-Gervais, Konstantina Fragaki, Laetitia Berg-Alonso, Yusuke Kageyama, Valérie Serre, David Moore, Annie Verschueren, Cécile Rouzier, Isabelle Le Ber, Gaëlle Augé, Charlotte Cochaud, Françoise Lespinasse, Karine N’Guyen, Anne de Septenville, Alexis Brice, Patrick Yu-Wai-Man, Hiromi Sesaki, Jean Pouget, Véronique Paquis-Flucklinger, Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?, Brain, Volume 137, Issue 12, December 2014, Page e314, https://doi.org/10.1093/brain/awu300
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Sir,
In a Letter to the Editor submitted to Brain, van Rheenen and colleagues (2014) critically appraise the involvement of the CHCHD10 gene in familial amyotrophic lateral sclerosis (ALS). They also question the involvement of CHCHD10 in frontotemporal dementia (FTD)-ALS when they state that ‘the assumption that the novel variants indeed cause ALS/FTD in these families is derived from the fact that these variants are well conserved across different species’. The authors outline a number of methodological concerns in their letter and we welcome this opportunity to clarify some of the points that were raised. In our original article published in Brain, we described a novel heterozygous CHCHD10 mutation (c.176C > T; p.Ser59Leu) in a large French family with a late-onset phenotype including cognitive decline resembling FTD, motor neuron disease, cerebellar ataxia and mitochondrial myopathy with multiple mtDNA deletions (Bannwarth et al., 2014). We found the same pathogenic mutation in one family among a cohort of 21 families with pathologically proven FTD-ALS. These results provide solid evidence that CHCHD10 is a novel gene responsible for FTD-ALS and it is not correct to say that the pathogenicity of p.Ser59Leu variant is based on the conservation of the serine residue at position 59. Indeed, the segregation within the large French family is the major evidence for the pathogenicity of this mutation that was present in the eight patients tested and absent in two healthy individuals with normal neurological examination at 79 and 69 years of age, respectively (Bannwarth et al., 2014). Cristae alterations and fragmentation of the mitochondrial network found in HeLa cells overexpressing the CHCHD10S59L mutant are similar to those observed in patient fibroblasts and these results also provide strong arguments for the deleterious effect of the p.Ser59Leu variant (Bannwarth et al., 2014). Secondarily, we sequenced CHCHD10 in a cohort of 94 FTD-ALS patients and found a novel heterozygous missense variant (c.100C > T; p.Pro34Ser) in two unrelated individuals (Chaussenot et al., 2014). We fully agree that putative pathogenicity of this novel substitution in this second article, which van Rheenen and colleagues do not mention, was based on the conservation of the proline residue at position 34 and on the absence of this variant in public single-nucleotide polymorphism databases and in 200 ethnically and geographically matched control alleles (Chaussenot et al., 2014). To further elucidate the deleterious consequences of these reported CHCHD10 variants, we have performed a number of functional tests and the pathophysiological pathways that we have uncovered clearly indicate a biologically plausible link with neurodegeneration (unpublished data).
