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

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

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.

MeSH terms

  • Acetazolamide / therapeutic use
  • Adult
  • Anticonvulsants / therapeutic use
  • Cells, Cultured / metabolism
  • DNA, Mitochondrial / genetics*
  • Female
  • Fibroblasts / metabolism
  • Humans
  • MELAS Syndrome / complications
  • MELAS Syndrome / genetics*
  • Male
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Paralyses, Familial Periodic / drug therapy
  • Paralyses, Familial Periodic / etiology
  • Paralyses, Familial Periodic / genetics*
  • Pedigree
  • Phenotype
  • Sequence Deletion / genetics

Substances

  • Anticonvulsants
  • DNA, Mitochondrial
  • MT-ATP6 protein, human
  • ATP synthase 8, human
  • Mitochondrial Proton-Translocating ATPases
  • Acetazolamide