A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement
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 Nguyen,Anne de Septenville,Alexis Brice,Patrick Yu-Wai-Man,Hiromi Sesaki,Jean Pouget,Véronique Paquis-Flucklinger +22 more
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TLDR
A large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy is reported, showing that mitochondrial disease may be at the origin of some of these phenotypes.Abstract:
Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.read more
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ALS: Recent Developments from Genetics Studies
TL;DR: It is interesting to note that as the number of ALS genes grows, many of the proteins they encode are in shared intracellular processes.
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TL;DR: iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadicALS.
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Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain
Oriol Dols-Icardo,Irene Nebot,Ana Gorostidi,Sara Ortega-Cubero,Isabel Hernández,Ricard Rojas-García,Alberto García-Redondo,Mònica Povedano,Albert Lladó,Victoria Alvarez,Pascual Sánchez-Juan,Julio Pardo,Ivonne Jericó,Juan F. Vázquez-Costa,Teresa Sevilla,Fernando Cardona,Begoña Indakoechea,Fermin Moreno,Roberto Fernández-Torrón,Laia Muñoz-Llahuna,Sonia Moreno-Grau,Maitée Rosende-Roca,Álvaro Vela,José Luis Muñoz-Blanco,Onofre Combarros,Eliecer Coto,Daniel Alcolea,Juan Fortea,Alberto Lleó,Raquel Sánchez-Valle,Jesús Esteban-Pérez,Agustín Ruiz,Pau Pastor,Pau Pastor,Adolfo López de Munain,Jordi Pérez-Tur,Jordi Clarimón +36 more
TL;DR: A study identified a mutation in the CHCHD10 gene as a cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in a large pedigree with mixed phenotypes encompassing ALS, FTD, cerebellar ataxia and mitochondrial myopathy.
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Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians
TL;DR: Suggestions for genetic counseling and genetic testing for ALS in this new environment are provided, particularly in the era of emerging gene-based therapies.
Journal ArticleDOI
Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders
Kotaro Ogaki,Shunsuke Koga,Michael G. Heckman,Fabienne C. Fiesel,Maya Ando,Catherine Labbé,Oswaldo Lorenzo-Betancor,Elisabeth L. Moussaud-Lamodière,Alexandra I. Soto-Ortolaza,Ronald L. Walton,Audrey Strongosky,Ryan J. Uitti,Allan McCarthy,Timothy Lynch,Joanna Siuda,Grzegorz Opala,Monika Rudzińska,Anna Krygowska-Wajs,Maria Barcikowska,Krzysztof Czyzewski,Andreas Puschmann,Kenya Nishioka,Manabu Funayama,Nobutaka Hattori,Joseph E. Parisi,Ronald C. Petersen,Neill R. Graff-Radford,Bradley F. Boeve,Wolfdieter Springer,Zbigniew K. Wszolek,Dennis W. Dickson,Owen A. Ross +31 more
TL;DR: Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHd2 to other genetic forms of parkinsonism with mitochondrial dysfunction.
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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
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TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.
Stephan Züchner,Stephan Züchner,Irina V. Mersiyanova,Maria Muglia,Nisrine Bissar-Tadmouri,Nisrine Bissar-Tadmouri,Julie M. Rochelle,Elena L. Dadali,Mario Zappia,Eva Nelis,Alessandra Patitucci,Jan Senderek,Yesim Parman,Oleg V. Evgrafov,Peter De Jonghe,Yuji Takahashi,Shoij Tsuji,Margaret A. Pericak-Vance,Aldo Quattrone,Esra Battologlu,Alexander V. Polyakov,Vincent Timmerman,J. Michael Schröder,Jeffery M. Vance +23 more
TL;DR: It is concluded that the primary gene mutated in CMT2A is MFN2, and seven large pedigrees affected with Charcot-Marie-Tooth neuropathy type 2A are concluded.
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