Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations
| العنوان: | Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations |
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| المؤلفون: | Nathalie Streichenberger, Odile Dubourg, Christophe Vial, Damien Sternberg, Christophe Vandier, Anne-Laure Bedat-Millet, Karine Auré, Anne Lombès, Emmanuel Fournier, Claude Jardel, Frédéric Bouillaud, Valerie Drouin-Garraud, Helene Gervais-Bernard, Philippe Petiot, Bertrand Fontaine, Lucie Clarysse, Pascal Laforêt |
| المصدر: | Neurology. 81:1810-1818 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Adult, Male, Mitochondrial DNA, Oxidative phosphorylation, Biology, medicine.disease_cause, MELAS syndrome, DNA, Mitochondrial, Paralyses, Familial Periodic, MELAS Syndrome, medicine, Humans, Cells, Cultured, Sequence Deletion, Genetics, Mutation, Periodic paralysis, Fibroblasts, Mitochondrial Proton-Translocating ATPases, medicine.disease, Molecular biology, Pedigree, Acetazolamide, Phenotype, Lactic acidosis, MT-ATP6, biology.protein, Anticonvulsants, Female, Neurology (clinical), Oxidative stress |
| الوصف: | 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. |
| تدمد: | 1526-632X 0028-3878 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a50eca35318d69dad0a3260a59534f59Test https://doi.org/10.1212/01.wnl.0000436067.43384.0bTest |
| رقم الانضمام: | edsair.doi.dedup.....a50eca35318d69dad0a3260a59534f59 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1526632X 00283878 |
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