| Research Abstract |
MELAS(mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes)is characterized by stroke before 20 years old, mitochondrial angiopathy demonstrating degenerative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles have been reported in many MELAS patients. However, the primary cause of the young MELAS strokelike episodes, either mitochondreial cytopathy or angiopathy, or both is still controversial. Since abnormal mitochondria generates superoxide anion, we hypothesized that vascular complications in MELAS may be associated with endothelial dysfunction caused by oxidative stress. Nine patients were clinically, muscle pathologically or genetically diagnosed as MELAS.Six patients have an A3243G mutation, one patient has a T3271C mutation in the mitochondrial tRNALeu(UUR)gene, and two patients have not been found their genetic abnormality. In this study, we examined flow-mediated vasodilatation, as a
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non-invasive measure of endothelial function, and effect of an antioxidant, vitamin C in patient with MELAS.We analyzed the correlationship between the amount of point mutation in the endothelial cell and the endothelial function by single-cell PCR analysis. We also studied the pharmacological effect on the clinical course, and biochemical parameters after administration of L-arginine to a patient in the acute phase of stroke on three separated occasions, and on the functional aspects of the cerebral hemodynamics using single photon emission computed tomography(SPECT). Flow-mediated vasodilatation was significantly less(10% of the age-matched controls)in MELAS patients. Endothelium dependent vasodilatation included by glyceryl trinitrate was also impaired. Vitamin C administration significantly restored flow-mediated dilatation and gryceryl trinitrate-included vasodilatation to near-normal levels in MELAS but did not affect them in controls. After the administration of L-arginine, all the symptoms of the patient suggesting the strokelike episode were clinically improved. On SPECT using ECD, the intracranial hemodynamics were also improved in the ischemic area(in the left temporal lobe), but unchanged in the brain stem(thalamus). There are clear inverse correlationships between the amount of point mutation and the capacity of endothelial dependent-vasodilatation in the endothelial cells. Our data demonstrated that angiopathy seen in MELAS involved abnormality in the capacity of vasodilatation in the endothelial system, which may play an important role in causing strokelike episodes in this disorder. Less
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