Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased activity of complex I (NAD:ubiquinone oxidoreductase) is the most frequent biochemical finding associated with mutation at the base pair 3243 of the mitochondrial DNA. The mutation has been previously shown to lead to a defective translation. We hypothesized that due to an imperfect assembly of complex I subunits the substrate affinity of this enzyme may be lowered and this may be counteracted by increasing the mitochondrial NAD+NADH concentration. Therefore, we studied the effect and mechanism of action of nicotinamide treatment in a MELAS patient with the base pair 3243 mutation. Nicotinamide treatment was initiated after his first stroke-like episode. The blood NAD concentration (representing the intracellular concentration in erythrocytes) increased linearly being 24-fold at 6 weeks of treatment. Blood lactate and pyruvate concentration decreased by 50% within three days and 24 h urine lactate content within 2 weeks and we observed a clinical improvement together with a decrease in the lesion volume in magnetic resonance imaging within the first month. The cellular NAD increase upon nicotinamide administration was probably universal, because it occurred in a time and dose-dependent manner in cultured fibroblasts from both the patient and the controls. Alleviation of the lactate accumulation during the nicotinamide treatment suggests that an increase in the cellular NAD+NADH concentration leads to enhancement of the oxidation of reducing equivalents. However, the Km of complex I for NADH in skeletal muscle from the patient was similar to that of controls. This may indicate that physiologically mitochondrial complex I operates at non-saturating substrate concentration, and this may explain the effect of nicotinamide treatment.
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PMID:Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. 859 19

Eight carriers of the A3243G mutation of mitochondrial DNA without stroke-like episodes were monitored for up to 7 years in clinical and metabolic studies, by magnetic resonance imaging (MRI) and positron emission tomography (PET). None developed mitochondrial encephalopathy (MELAS), but 2 developed diabetes mellitus, 1 terminal kidney failure and 2 cardiomyopathy. One patient improved markedly under ubiquinone. Electroencephalography showed progressive slowing in 2 cases, but electrophysiological tests and MRI were otherwise noncontributary. PET showed widespread cortical and basal ganglion metabolic deficits in 6 cases. We conclude that internal medical complications are more common than MELAS in adult carriers of the mutation. PET findings, firstly reported in such patients, suggest that chronic subclinical encephalopathy is very frequent, and PET may play a role in monitoring in the future.
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PMID:Follow-up in carriers of the 'MELAS' mutation without strokes. 947 18

A thirty-two-year-old woman who had been diagnosed MELAS with 3243A > G mutation presented headache, nausea, decreased bilateral visual acuity, and topographical disturbance on January 1 in 2002. Although brain CT showed no fresh lesion, recurrence of stroke-like episode was considered. Immediately, she was treated with ubiquinone (210 mg/day, p.o.) and tocopherol nicotinate (300 mg/day, p.o.). She became confused on the fifth day. Diffusion weighted- and T2 weighted-MRI revealed appearance of hyperintense lesion at the right occipital lobe. We started edaravone infusion (30 mg, twice a day, div.) for two weeks with informed consent from her family. On 13th day her consciousness was improved. Edema and signal intensity of the lesion were decreased on MRI with minimal spread to the parietal lobe. She discharged on the 30th day with marked visual field loss, hemispatial neglect, and topographical amnesia. MRI after four months showed remarkable atrophy of the right occipital region. In our department, five stroke-like episodes including this case were treated with ubuiquinone and tocopherol nicotinate. This regimen was effective in prevention of progressive spread of lesions only in two episodes. Edaravone is radical scavenger used in acute cerebral infarction. Progressive spread into the neighboring regions is one of characteristics of MELAS, although its precise mechanisms are not well known. Oxidative stress induced by released free radicals through mitochondrial dysfunction might be one of factors and edaravone would make an effect through blockage of the free radicals. Edaravone could not rescue neurons in the initial lesion. Although more numbers of cases are needed to establish the effect of edaravone on MELAS, it could minimize the neurological deficits after stroke-like episode of MELAS.
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PMID:[A case of stroke-like episode of MELAS of which progressive spread would be prevented by edaravone]. 1602 65