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Neurology. 2013 Nov 19;81(21):1810-8. doi: 10.1212/01.wnl.0000436067.43384.0b. Epub 2013 Oct 23.

Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations.

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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.



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.


Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts.


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.


Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment.

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