doi:10.1093/brain/awv116
BRAIN 2015: 138; 1–3
| e386
LETTER TO THE EDITOR Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?
1 2 3 4 5 6
IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, France Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, France Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK 7 Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France 8 Sorbonne Universite´, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle e´pinie`re (ICM), F-75013 Paris, France 9 National Reference Centre on Rare Dementias, AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France 10 Department of Medical Genetics, Timone Hospital, Marseille Teaching Hospital, France 11 Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK Correspondence to: Prof. Ve´ronique Paquis-Flucklinger, IRCAN UMR CNRS 7284 / INSERM U1081 / UNS, School of Medicine, 28 av de Valombrose, 06107 Nice cedex 2, France E-mail: [email protected]
Sir, We and others have identified different CHCHD10 mutations responsible for mitochondrial DNA instability disorder, early-onset mitochondrial myopathy, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum and late-onset spinal motor neuropathy (SMAJ) (Bannwarth et al., 2014, 2015; Chaussenot et al., 2014; Johnson et al., 2014; Mu¨ller et al., 2014; AjroudDriss et al., 2015; Kurzwelly et al., 2015; Penttila¨ et al., 2015; Ronchi et al., 2015). The letter from Dobston-Stone et al., (2015) asks the question about the pathogenicity of the Pro34Ser variant that was previously identified by our group in two unrelated French patients with FTD-ALS
(Chaussenot et al., 2014) and by Ronchi et al. (2015) in one Italian patient with ALS. We read with interest this study reporting the screening of CHCHD10 in several Australian cohorts that leads to the identification of the Pro34Ser variant in (i) two unrelated patients with familial FTD; (ii) five individuals with early-onset dementia among a cohort of 132 patients whereas this variant was not found in another cohort of 145 Australian patients with FTD; and (iii) 9/807 aged individuals, three of whom only showed mild cognitive impairment (MCI). In this report, several observations raise the question about the deleterious effect of the Pro34Ser variant. First, Proband 2 with familial FTD had two sisters who developed
Advance Access publication May 7, 2015 ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
Sylvie Bannwarth,1,2 Samira Ait-El-Mkadem,1,2 Annabelle Chaussenot,1,2 Emmanuelle C. Genin,1 Sandra Lacas-Gervais,3 Konstantina Fragaki,1,2 Laetitia Berg-Alonso,1 Yusuke Kageyama,4 Vale´rie Serre,5 David Moore,6 Annie Verschueren,7 Ce´cile Rouzier,1,2 Isabelle Le Ber,8,9 Gae¨lle Auge´,1,2 Charlotte Cochaud,2 Franc¸oise Lespinasse,1 Karine N’Guyen,10 Anne de Septenville,8 Alexis Brice,8 Patrick Yu-Wai-Man,6,11 Hiromi Sesaki,4 Jean Pouget,7 Ve´ronique Paquis-Flucklinger,1,2
e386
| BRAIN 2015: 138; 1–3
the Ser59Leu mutation, demonstrating the pathogenicity of this variant that seems to predominate in Australian patients. Further studies will be necessary to clarify the intriguing hypothesis that this predominance could be due to a mutational founder effect.
Funding This work was made possible by grants to V.P-F from the Association Franc¸aise contre les Myopathies (AFM) and the Fondation pour la Recherche Me´dicale (FRM), to H.S from National Institutes of Health (GM089853) and to A.B by the program ‘Investissements d’avenir’ ANR-10IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’ (to I.L.B.) and the 7th framework program of the European Union (FP7, E12009DD, Neuromics). P.YWM is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK). P.YWM also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration.
References Ajroud-Driss S, Fecto F, Ajroud K, Lalani I, Calvo SE, Mootha VK, et al. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. Neurogenetics 2015; 16: 1–9. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, LacasGervais S, Fragaki K, et al. Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain 2015; pii: awv015. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, LacasGervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 2014; 137: 2329–45. Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, et al. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging 2014; 35: 2884.e1-4. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245–56. Dobson-Stone C, Hallupp M, Loy CT, Thompson EM, Haan E, Sue CM, et al. C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementiapatients. PLoS One 2013; 8: e56899. Dobstone-Stone C, South W, Shaw A, Hallupp M, Bartley L, McCann H, et al. Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis? Brain 2015; in press. Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, Restagno G, et al. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain 2014; 137: e311. Kurzwelly D, Kru¨ger S, Biskup S, Heneka MT. A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain 2015; pii: awv014.
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
dementia, only one of whom carried the variant. As mentioned by the authors, it is possible that the Pro34Ser-negative patient is a phenocopy. No full clinical assessment was available for the two sisters but the phenotype of the Pro34Ser-negative patient seemed different with significant memory impairment and no frontal features. Secondly, one FTD patient from the early-onset dementia cohort also harboured the C9orf72 repeat expansion that is responsible for FTD and ALS (DeJesus-Hernandez et al., 2011; Renton et al., 2011). This patient had neuropathologically confirmed TARDBP (previously known as TDP-43) inclusions that are pathologic hallmark of both ALS and FTD (Neumann et al., 2006). We do not know yet whether TARDBP inclusions are observed in patients harbouring CHCHD10 mutations, and whether CHCHD10 protein may be found in neuronal inclusions. However, several studies suggest an oligogenic pathogenesis of ALS with the identification of patients harbouring both C9orf72 expansions and a mutation in another ALS and/or FTD associated gene (van Blitterswijk et al., 2012, 2013). Double mutation carriers generally have an early disease onset and the FTD patient carrying both C9orf72 expansion and Pro34Ser CHCHD10 variant developed the first symptoms at 43 years of age (Dobson-Stone et al., 2013). Although we can not exclude that the presence of both mutations might be coincidental, a more plausible explanation is that C9orf72 expansion and Pro34Ser CHCHD10 variant could have additive effects in disease expressivity and possibly in the early onset disorder. Lastly, the identification of the Pro34Ser variant in 9/807 aged individuals, six of whom were non-demented in their seventies and eighties is another argument against its deleterious effect. However, C9orf72 expansions that appear to account for 34% of familial ALS and 26% of familial FTD have also been identified in control individuals and several studies reported incomplete penetrance (van Blitterswijk et al., 2012). Regarding CHCHD10, Mu¨ller et al. (2014) also described incomplete penetrance in two German ALS families carrying the p.Arg15Leu mutation. In conclusion, we agree with Dobston-Stone and colleagues that ‘none of these observations in isolation would be sufficient evidence to discount the pathogenicity of the CHCHD10 Pro34Ser variant’. Only functional studies will determine the deleterious effect of Pro34Ser and other CHCHD10 variants. We identified the CHCHD10 Ser59Leu mutation in the original family with a late-onset phenotype including motor neuron disease, FTD, cerebellar ataxia and mitochondrial myopathy (Bannwarth et al., 2014). Patient fibroblasts presented with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Expression of the CHCHD10S59L mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. In a submitted manuscript, we show that the expression of the CHCHD10P34S mutant allele leads to the same alterations as those observed with
Letter to the Editor
Letter to the Editor Mu¨ller K, Andersen PM, Hu¨bers A, Marroquin N, Volk AE, Danzer KM, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain 2014; 137: e309. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130–33. Penttila¨ S, Jokela M, Bouquin H, Saukkonen AM, Toivanen J, Udd B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann Neurol 2015; 77: 163–72. Renton AE, Majounie E, Waite A, Simo´n-Sa´nchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72
BRAIN 2015: 138; 1–3
| e386
is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257–68. Ronchi D, Riboldi G, Del Bo R, Ticozzi N, Scarlato M, Galimberti D, et al. CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis. Brain 2015; pii: awu384. van Blitterswijk M, Baker MC, DeJesus-Hernandez M, Ghidoni R, Benussi L, Finger E, et al. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 2013; 81: 1332–41. van Blitterswijk M, van Es MA, Hennekam EA, Dooijes D, van Rheenen W, Medic J, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 2012; 21: 3776–84.
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
BRAIN 2015: 138; 1–3
| e386
LETTER TO THE EDITOR Reply: Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis?
1 2 3 4 5 6
IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France Joint Centre for Applied Electron Microscopy, Nice Sophia-Antipolis University, France Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, France Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK 7 Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France 8 Sorbonne Universite´, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle e´pinie`re (ICM), F-75013 Paris, France 9 National Reference Centre on Rare Dementias, AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France 10 Department of Medical Genetics, Timone Hospital, Marseille Teaching Hospital, France 11 Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK Correspondence to: Prof. Ve´ronique Paquis-Flucklinger, IRCAN UMR CNRS 7284 / INSERM U1081 / UNS, School of Medicine, 28 av de Valombrose, 06107 Nice cedex 2, France E-mail: [email protected]
Sir, We and others have identified different CHCHD10 mutations responsible for mitochondrial DNA instability disorder, early-onset mitochondrial myopathy, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum and late-onset spinal motor neuropathy (SMAJ) (Bannwarth et al., 2014, 2015; Chaussenot et al., 2014; Johnson et al., 2014; Mu¨ller et al., 2014; AjroudDriss et al., 2015; Kurzwelly et al., 2015; Penttila¨ et al., 2015; Ronchi et al., 2015). The letter from Dobston-Stone et al., (2015) asks the question about the pathogenicity of the Pro34Ser variant that was previously identified by our group in two unrelated French patients with FTD-ALS
(Chaussenot et al., 2014) and by Ronchi et al. (2015) in one Italian patient with ALS. We read with interest this study reporting the screening of CHCHD10 in several Australian cohorts that leads to the identification of the Pro34Ser variant in (i) two unrelated patients with familial FTD; (ii) five individuals with early-onset dementia among a cohort of 132 patients whereas this variant was not found in another cohort of 145 Australian patients with FTD; and (iii) 9/807 aged individuals, three of whom only showed mild cognitive impairment (MCI). In this report, several observations raise the question about the deleterious effect of the Pro34Ser variant. First, Proband 2 with familial FTD had two sisters who developed
Advance Access publication May 7, 2015 ß The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
Sylvie Bannwarth,1,2 Samira Ait-El-Mkadem,1,2 Annabelle Chaussenot,1,2 Emmanuelle C. Genin,1 Sandra Lacas-Gervais,3 Konstantina Fragaki,1,2 Laetitia Berg-Alonso,1 Yusuke Kageyama,4 Vale´rie Serre,5 David Moore,6 Annie Verschueren,7 Ce´cile Rouzier,1,2 Isabelle Le Ber,8,9 Gae¨lle Auge´,1,2 Charlotte Cochaud,2 Franc¸oise Lespinasse,1 Karine N’Guyen,10 Anne de Septenville,8 Alexis Brice,8 Patrick Yu-Wai-Man,6,11 Hiromi Sesaki,4 Jean Pouget,7 Ve´ronique Paquis-Flucklinger,1,2
e386
| BRAIN 2015: 138; 1–3
the Ser59Leu mutation, demonstrating the pathogenicity of this variant that seems to predominate in Australian patients. Further studies will be necessary to clarify the intriguing hypothesis that this predominance could be due to a mutational founder effect.
Funding This work was made possible by grants to V.P-F from the Association Franc¸aise contre les Myopathies (AFM) and the Fondation pour la Recherche Me´dicale (FRM), to H.S from National Institutes of Health (GM089853) and to A.B by the program ‘Investissements d’avenir’ ANR-10IAIHU-06, ‘The Programme Hospitalier de Recherche Clinique’ (to I.L.B.) and the 7th framework program of the European Union (FP7, E12009DD, Neuromics). P.YWM is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK). P.YWM also receives funding from Fight for Sight (UK) and the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration.
References Ajroud-Driss S, Fecto F, Ajroud K, Lalani I, Calvo SE, Mootha VK, et al. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy. Neurogenetics 2015; 16: 1–9. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, LacasGervais S, Fragaki K, et al. Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain 2015; pii: awv015. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, LacasGervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 2014; 137: 2329–45. Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, et al. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging 2014; 35: 2884.e1-4. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245–56. Dobson-Stone C, Hallupp M, Loy CT, Thompson EM, Haan E, Sue CM, et al. C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementiapatients. PLoS One 2013; 8: e56899. Dobstone-Stone C, South W, Shaw A, Hallupp M, Bartley L, McCann H, et al. Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis? Brain 2015; in press. Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, Restagno G, et al. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain 2014; 137: e311. Kurzwelly D, Kru¨ger S, Biskup S, Heneka MT. A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain 2015; pii: awv014.
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
dementia, only one of whom carried the variant. As mentioned by the authors, it is possible that the Pro34Ser-negative patient is a phenocopy. No full clinical assessment was available for the two sisters but the phenotype of the Pro34Ser-negative patient seemed different with significant memory impairment and no frontal features. Secondly, one FTD patient from the early-onset dementia cohort also harboured the C9orf72 repeat expansion that is responsible for FTD and ALS (DeJesus-Hernandez et al., 2011; Renton et al., 2011). This patient had neuropathologically confirmed TARDBP (previously known as TDP-43) inclusions that are pathologic hallmark of both ALS and FTD (Neumann et al., 2006). We do not know yet whether TARDBP inclusions are observed in patients harbouring CHCHD10 mutations, and whether CHCHD10 protein may be found in neuronal inclusions. However, several studies suggest an oligogenic pathogenesis of ALS with the identification of patients harbouring both C9orf72 expansions and a mutation in another ALS and/or FTD associated gene (van Blitterswijk et al., 2012, 2013). Double mutation carriers generally have an early disease onset and the FTD patient carrying both C9orf72 expansion and Pro34Ser CHCHD10 variant developed the first symptoms at 43 years of age (Dobson-Stone et al., 2013). Although we can not exclude that the presence of both mutations might be coincidental, a more plausible explanation is that C9orf72 expansion and Pro34Ser CHCHD10 variant could have additive effects in disease expressivity and possibly in the early onset disorder. Lastly, the identification of the Pro34Ser variant in 9/807 aged individuals, six of whom were non-demented in their seventies and eighties is another argument against its deleterious effect. However, C9orf72 expansions that appear to account for 34% of familial ALS and 26% of familial FTD have also been identified in control individuals and several studies reported incomplete penetrance (van Blitterswijk et al., 2012). Regarding CHCHD10, Mu¨ller et al. (2014) also described incomplete penetrance in two German ALS families carrying the p.Arg15Leu mutation. In conclusion, we agree with Dobston-Stone and colleagues that ‘none of these observations in isolation would be sufficient evidence to discount the pathogenicity of the CHCHD10 Pro34Ser variant’. Only functional studies will determine the deleterious effect of Pro34Ser and other CHCHD10 variants. We identified the CHCHD10 Ser59Leu mutation in the original family with a late-onset phenotype including motor neuron disease, FTD, cerebellar ataxia and mitochondrial myopathy (Bannwarth et al., 2014). Patient fibroblasts presented with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Expression of the CHCHD10S59L mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. In a submitted manuscript, we show that the expression of the CHCHD10P34S mutant allele leads to the same alterations as those observed with
Letter to the Editor
Letter to the Editor Mu¨ller K, Andersen PM, Hu¨bers A, Marroquin N, Volk AE, Danzer KM, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain 2014; 137: e309. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130–33. Penttila¨ S, Jokela M, Bouquin H, Saukkonen AM, Toivanen J, Udd B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann Neurol 2015; 77: 163–72. Renton AE, Majounie E, Waite A, Simo´n-Sa´nchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72
BRAIN 2015: 138; 1–3
| e386
is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257–68. Ronchi D, Riboldi G, Del Bo R, Ticozzi N, Scarlato M, Galimberti D, et al. CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis. Brain 2015; pii: awu384. van Blitterswijk M, Baker MC, DeJesus-Hernandez M, Ghidoni R, Benussi L, Finger E, et al. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 2013; 81: 1332–41. van Blitterswijk M, van Es MA, Hennekam EA, Dooijes D, van Rheenen W, Medic J, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 2012; 21: 3776–84.
Downloaded from http://brain.oxfordjournals.org/ by guest on November 15, 2015
