Magnetic resonance spectroscopy in patients with MELAS

Möller, Harald E.; Kurlemann, Gerhard; Pützler, Manfred; Wiedermann, Dirk; Hilbich, Thorsten; Fiedler, Barbara

doi:10.1016/j.jns.2004.11.014

Cited by 60 publications

(44 citation statements)

References 39 publications

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“…This metabolic fragility is also seen in OXPHOS disorders affecting other tissues. For example, brain magnetic resonance imaging studies in patients with OXPHOS disorders indicated a decline in phosphorylation potential, implying a similar low energy reserve (30) to that seen in Ndufs6 gt/gt mouse hearts. These observations emphasize that prevention or minimizing the impact of metabolic stresses is a key approach to maintaining the stability of patients with OXPHOS disorders.…”

Section: Discussionmentioning

confidence: 91%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6 gt/gt mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6 gt/gt mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6 gt/gt mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6 gt/gt hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6 gt/gt mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6 gt/gt isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches. mouse model | mitochondrial diseases M itochondria generate the majority of energy required for cellular function and survival. Defects in mitochondrial oxidative phosphorylation (OXPHOS) cause a wide range of diseases, collectively affecting ∼1/5,000 births (1). OXPHOS dysfunction was first identified in neuromuscular disorders but symptoms can potentially affect any organ, with any age of onset and any mode of inheritance (2). The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3, 4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5, 6). As identified by Cochrane review, "there is currently no clear evidence supporting the use of any intervention in OXPHOS disorders" (7). Thus, there is an urgent need for suitable animal models to study pathogenic mechanisms and novel therapeutic approaches. Such models can also shed light on the wide range of common, complex diseases to which mitochondrial dysfunction contributes (8).Despite the high prevalence of OXPHOS disorders, relatively few genetic models have been...

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Section: Discussionmentioning

confidence: 91%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Similar but less prominent alterations can be found in the grey matter 67 . The most frequent finding on MRS in MCD with CNS involvement is an increased lactate peak 15,18,33,65,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] , which may precede the SLLs 15 . High levels of intra-ventricular lactate are usually associated with severe neurologic impairment 6 .…”

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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“…To our knowledge, MRS findings in the brain of patients with mitochondrial disorders have been reported only in individual cases or small series, and most studies were carried out in areas of the brain that appeared abnormal on magnetic resonance imaging (MRI) as part of the clinical investigation of the patient. [7][8][9][10][11][12][13][14][15] The most consistent findings have been higher lactate levels and lower N-acetyl-aspartate levels, although lower creatine and glutamate levels, and altered levels of choline have also been reported. [7][8][9][10][11][12][13][14][15] In this study, we measured metabolites in vivo in patients with mitochondrial disorders compared with age-and sexmatched healthy controls using standardized voxel placement in 3 brain regions commonly implicated in neuropsychiatric disorders: the caudate nucleus, anterior cingulate cortex and hippocampus.…”

Section: Cmaj Openmentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14][15] The most consistent findings have been higher lactate levels and lower N-acetyl-aspartate levels, although lower creatine and glutamate levels, and altered levels of choline have also been reported. [7][8][9][10][11][12][13][14][15] In this study, we measured metabolites in vivo in patients with mitochondrial disorders compared with age-and sexmatched healthy controls using standardized voxel placement in 3 brain regions commonly implicated in neuropsychiatric disorders: the caudate nucleus, anterior cingulate cortex and hippocampus. [16][17][18][19] Our primary hypothesis was that patients with mitochondrial disorders would have reduced levels of markers of mitochondrial dysfunction (N-acetyl-aspartate and creatine) compared with healthy controls in the 3 candidate brain regions.…”

Section: Cmaj Openmentioning

confidence: 99%

“…However, we examined multiple metabolites in several regions of interest using standardized voxel placement and partial volume correction, and found reduced N-acetyl-aspartate levels in the caudate nucleus. [7][8][9]22 Despite its abundance in the brain and decades of research, the function of N-acetyl-aspartate remains unclear. Proposed functions have included providing a source of acetate for myelin lipid synthesis, and acting as an organic osmolyte.…”

Section: Comparison With Other Studiesmentioning

confidence: 99%

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