Karine Auré1, Odile Dubourg, Claude Jardel, Lucie Clarysse, Damien Sternberg, Emmanuel Fournier, Pascal Laforêt, Nathalie Streichenberger, Philippe Petiot, Hélène Gervais-Bernard, Christophe Vial, Anne-Laure Bedat-Millet, Valérie Drouin-Garraud, Frédéric Bouillaud, Christophe Vandier, Bertrand Fontaine, Anne Lombès. 1. From Inserm Institut Cochin U1016 (K.A., C.J., F.B., A.L.), Paris; AP/HP (K.A.), Hôpital Ambroise Paré, Service d'explorations fonctionnelles, Boulogne-Billancourt; Université Versailles-Saint-Quentin en Yvelines (K.A.); AP-HP (O.D.), CHU Pitié-Salpêtrière, Service de Neuropathologie, Paris; AP-HP (C.J., D.S.), CHU Pitié-Salpêtrière, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, Paris; Inserm U1069 (L.C., C.V.), Tours; Université François Rabelais (L.C., C.V.), Tours; UPMC (D.S., E.F., B.F.), Inserm UMR975, CNRS 7225, Institut Cerveau Moelle, Paris; AP-HP (E.F., P.L.), Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GH Pitié-Salpêtrière, Paris; AP-HP (E.F., B.F.), Centre de Référence des Canalopathies Musculaires, Hôpital Pitié-Salpêtrière, Paris; Hospices Civils de Lyon (N.S.), Centre de Pathologie Est, Bron; Université Claude Bernard Lyon1-CNRS UMR5292-INSERM U1028 (N.S.); Centre de référence Maladies Neuromusculaires Rares (P.P., H.G.-B., C.V.), Rhône-Alpes; Hospices Civils de Lyon (P.P.), Hôpital de la Croix-Rousse, explorations fonctionnelles neurologiques, Lyon; Hospices Civils de Lyon (H.G.-B., C.V.), Hôpital Pierre Wertheimer, service d'électromyographie et pathologies neuromusculaires, Bron; CHU de Rouen (A.-L.B.-M.), Service de neurologie, Rouen; CHU de Rouen (V.D.-G.), Service de génétique, Rouen; CNRS UMR 8104 (F.B., A.L.), Paris; and Université Paris-Descartes-Paris 5 (F.B., A.L.), Paris, France.
Abstract
OBJECTIVE: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide. METHODS: Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts. RESULTS: Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations. The MT-ATP6 m.9185T>C p.Leu220Pro mutation, previously associated with Leigh syndrome, was present in all family members, while the MT-TL1 m.3271T>C mutation, a known cause of MELAS syndrome, was observed in the sole patient with MELAS presentation. Significant defect of complexes V and I as well as oxidative stress were observed in both primary fibroblasts and cybrid cells with 100% m.9185T>C mutation. Permanent plasma membrane depolarization and altered permeability to K(+) in fibroblasts provided a link with the paralysis episodes. Screening of 9 patients, based on their clinical phenotype, identified 4 patients with similar deleterious MT-ATP6 mutations (twice m.9185T>C and once m.9176T>C or m.8893T>C). A fifth patient presented with an original potentially deleterious MT-ATP8 mutation (m.8403T>C). All mutations were associated with almost-normal complex V activity but significant oxidative stress and permanent plasma membrane depolarization. CONCLUSION: Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment.
OBJECTIVE: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide. METHODS: Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts. RESULTS: Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations. The MT-ATP6 m.9185T>C p.Leu220Pro mutation, previously associated with Leigh syndrome, was present in all family members, while the MT-TL1 m.3271T>C mutation, a known cause of MELAS syndrome, was observed in the sole patient with MELAS presentation. Significant defect of complexes V and I as well as oxidative stress were observed in both primary fibroblasts and cybrid cells with 100% m.9185T>C mutation. Permanent plasma membrane depolarization and altered permeability to K(+) in fibroblasts provided a link with the paralysis episodes. Screening of 9 patients, based on their clinical phenotype, identified 4 patients with similar deleterious MT-ATP6 mutations (twice m.9185T>C and once m.9176T>C or m.8893T>C). A fifth patient presented with an original potentially deleterious MT-ATP8 mutation (m.8403T>C). All mutations were associated with almost-normal complex V activity but significant oxidative stress and permanent plasma membrane depolarization. CONCLUSION: Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment.
Authors: Rebecca D Ganetzky; Claudia Stendel; Elizabeth M McCormick; Zarazuela Zolkipli-Cunningham; Amy C Goldstein; Thomas Klopstock; Marni J Falk Journal: Hum Mutat Date: 2019-03-04 Impact factor: 4.878
Authors: Laura Kytövuori; Joonas Lipponen; Harri Rusanen; Tuomas Komulainen; Mika H Martikainen; Kari Majamaa Journal: J Neurol Date: 2016-08-08 Impact factor: 4.849
Authors: Emma Matthews; Christoph Neuwirth; Fatima Jaffer; Renata S Scalco; Doreen Fialho; Matt Parton; Dipa Raja Rayan; Karen Suetterlin; Richa Sud; Roland Spiegel; Rachel Mein; Henry Houlden; Andrew Schaefer; Estelle Healy; Jacqueline Palace; Ros Quinlivan; Susan Treves; Janice L Holton; Heinz Jungbluth; Michael G Hanna Journal: Neurology Date: 2018-01-03 Impact factor: 9.910