Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree

Dubeau, François; Stefano, Nicola De; Zifkin, Benjamin G.; Arnold, Douglas L.; Shoubridge, Eric A.

doi:10.1002/1531-8249(200002)47:2<179::aid-ana7>3.0.co;2-z

Cited by 98 publications

(58 citation statements)

References 27 publications

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“…11 -13 Interestingly, Dubeau et al commented that mutation levels in urinary epithelial cells were consistently higher than those observed in blood and buccal cells from four individuals with this mutation. 14 Here, we present data that show the level of 3243A4G mutation in urinary epithelium to be a useful indicator of the level observed in skeletal muscle, a finding which we believe has important implications for both clinical practice and diagnosis.…”

Section: Introductionmentioning

confidence: 67%

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

et al. 2004

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The 3243A4G mutation is one of the most frequently observed mutations of mitochondrial DNA (mtDNA), and is associated with numerous clinical presentations including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), progressive external ophthalmoplegia (PEO) and diabetes and deafness. The routine diagnosis of the 3243A4G mutation in blood is difficult as mutation levels are known to decrease in this tissue over time, while in some patients it may be absent. We have directly compared the levels of the 3243A4G mutation in skeletal muscle, blood and urinary epithelial cells in 18 patients and observed a striking correlation between the mutation load in postmitotic muscle and urinary epithelium, a mitotic tissue. These data strongly support the use of urinary epithelial cells as the tissue of choice in the noninvasive diagnosis of the 3243A4G mutation.

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Section: Introductionmentioning

confidence: 67%

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

et al. 2004

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“…The CSF or intra-cerebral lactate may not only be elevated in MCDs but also in CNS infections or CNS malignancies. Abnormal P-MRS was particularly reported in LHON 85,86 .…”

Section: Principally Two Techniques Are Available For Mrs Proton-mrmentioning

confidence: 99%

Central Nervous System Imaging in Mitochondrial Disorders

Finsterer

2009

Can. j. neurol. sci.

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Imaging of central-nervous-system (CNS) abnormalities is important in patients with mitochondrial disorders (MCDs) since the CNS is the organ second most frequently affected in MCDs and some of them are potentially treatable. Clinically relevant imaging techniques for visualization of CNS abnormalities in MCDs are computed tomography, magnetic resonance imaging, and MR-spectroscopy. The CNS abnormalities in MCDs visualized by imaging techniques include stroke-like lesions with cytotoxic or vasogenic edema, laminar cortical necrosis, basal ganglia necrosis, focal or diffuse white matter lesions, focal or diffuse atrophy, intra-cerebral calcifications, cysts, lacunas, hypometabolisation, lactacidosis, hemorrhages, cerebral hypo- or hyperperfusion, intra-cerebral artery stenoses, or moyamoya syndrome. The CNS lesions may proceed with or without clinical manifestations, why neuroimaging should be routinely carried out in all MCDs to assess the degree of CNS involvement. Some of these lesions may remain unchanged for years, some may show contiguous spread and progression, but some may even disappear, spontaneously or in response to medication. Dynamics of Stroke-like lesions may be positively influenced by L-arginine, dichloracetate, steroids, edavarone, or antiepileptics. Symptomatic treatment of CNS abnormalities in MCD patients may positively influence their outcome.

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“…Previously, we 5 and others [6][7][8][9][10] had reported elevated cerebral lactate levels in patients with MELAS and their mutation carrier relatives.…”

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confidence: 99%

Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers

et al. 2014

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Objective: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ( 1 H MRSI) and to assess their potential as prognostic biomarkers.Methods: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with 1 H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-L-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]).Results: Consistent with prior studies, the patients with MELAS had higher lactate (p , 0.001) and lower NAA levels (p 5 0.01) than HVs. Unexpectedly, converters showed higher NAA (p 5 0.042), tCho (p 5 0.004), and total creatine (p 5 0.002), in addition to higher lactate levels (p 5 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p 5 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. Conclusions:1 H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype. Neurology ® 2014;82:798-805 GLOSSARY CNS 5 Columbia Neurological Score; GNP 5 Global Neuropsychological; 1 H MRSI 5 proton magnetic resonance spectroscopic imaging; HV 5 healthy volunteer; MELAS 5 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetyl-L-aspartate; tCho 5 total choline; tCr 5 total creatine.

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Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree

Cited by 98 publications

References 27 publications

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

Central Nervous System Imaging in Mitochondrial Disorders

Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers

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