Nerve Conduction Abnormalities in Patients With MELAS and the A3243G Mutation

Kaufmann, Petra; Pascual, Juan M.; Anziska, Yaacov; Gooch, Clifton L.; Engelstad, Kristin; Jhung, Sarah; DiMauro, Salvatore; Vivo, Darryl C. De

doi:10.1001/archneur.63.5.746

Cited by 49 publications

(43 citation statements)

References 14 publications

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“…One study found that almost all patients with MELAS had clinical findings suggestive of neuropathy, with confirmation on nerve conduction studies in 77%. 7 The OCT and ERG results confirmed that our patient has dysfunction of the left optic nerve with normal retinal function. OCT measures the thickness of the retinal nerve fiber layer to quantify the extent of axonal loss.…”

Section: Sectionsupporting

confidence: 80%

Clinical Reasoning: A 62-year-old woman with deafness, unilateral visual loss, and episodes of numbness

Callaghan

Prasad²,

Galetta³

2009

Neurology

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Section: Sectionsupporting

confidence: 80%

Clinical Reasoning: A 62-year-old woman with deafness, unilateral visual loss, and episodes of numbness

Callaghan

Prasad²,

Galetta³

2009

Neurology

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Section: Discussionmentioning

confidence: 99%

“…Axonal peripheral neuropathies are a well-recognized complication of primary mitochondrial DNA (mtDNA) mutations; however, the neuropathy is rarely the presenting or predominant clinical manifestation of the disease. [1][2][3][4][5][6][7][8] In contrast, mutations in the nuclearencoded mitochondrial genes MFN2 9 and GDAP1, 10 which encode outer mitochondrial membrane proteins, usually present with isolated peripheral neuropathy and are now recognized to be important causes of both the axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease.One of the major unresolved challenges in neuromuscular diseases, such as CMT type 2 (CMT2) and distal hereditary motor neuropathy (dHMN), is the determination of the genetic cause of inherited axonal neuropathy. We investigated an extended family in whom the index case presented with a pure motor neuropathy in childhood evolving into motor-predominant Author affiliations and funding information are provided at the end of the article.…”

mentioning

confidence: 99%

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease

Pitceathly¹,

Murphy²,

Cottenie³

et al. 2012

Neurology

104

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Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185TϾC in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). Methods:A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185TϾC on complex V structure and function.Results: Three further probands with CMT2 harbored the m.9185TϾC mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185TϾC levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. Conclusions:We have shown that m.9185TϾC in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy. Neurology ® 2012;79:1145-1154 GLOSSARY BN-PAGE ϭ blue-native polyacrylamide gel electrophoresis; CMT ϭ Charcot-Marie-Tooth; CMT2 ϭ Charcot-Marie-Tooth type 2; dHMN ϭ distal hereditary motor neuropathy; LS ϭ Leigh syndrome; mtDNA ϭ mitochondrial DNA; NARP ϭ neurogenic muscle weakness, ataxia, and retinitis pigmentosa; NCS ϭ nerve conduction studies; OXPHOS ϭ oxidative phosphorylation; UMN ϭ upper motor neuron.Mitochondrial ATP generation by oxidative phosphorylation (OXPHOS) underpins key molecular processes that are essential for normal central and peripheral nervous system axonal function. Axonal peripheral neuropathies are a well-recognized complication of primary mitochondrial DNA (mtDNA) mutations; however, the neuropathy is rarely the presenting or predominant clinical manifestation of the disease. [1][2][3][4][5][6][7][8] In contrast, mutations in the nuclearencoded mitochondrial genes MFN2 9 and GDAP1, 10 which encode outer mitochondrial membrane proteins, usually present with isolated peripheral neuropathy and are now recognized to be important causes of both the axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease.One of the major unresolved challenges in neuromuscular diseases, such as CMT type 2 (CMT2) and distal heredit...

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“…This trial was terminated by the Data Safety and Monitoring Board because of evidence of excessive and frequently disabling peripheral neuropathy. Nerve conduction decreased in 68 % of the DCA-treated group within 6 months, and most patients (13/15) were taken off DCA [11]. There was no difference in GATE scores between the DCA and placebo groups at 3, 6, or 12 months, and no difference in MRS, CSF, or blood lactate in those who completed 24 months.…”

Section: Introductionmentioning

confidence: 90%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

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Nerve Conduction Abnormalities in Patients With MELAS and the A3243G Mutation

Cited by 49 publications

References 14 publications

Clinical Reasoning: A 62-year-old woman with deafness, unilateral visual loss, and episodes of numbness

Clinical Reasoning: A 62-year-old woman with deafness, unilateral visual loss, and episodes of numbness

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

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