| Research Abstract |
We report the morphological, biochemical, and molecular genetic findings in a four-generation family with clinically and pathologically defined Leigh syndrome (LS) having an A-to-G transition at the nucleotide position 3243 (A3242G) in the mitochondrial tRNALeu (UUR) gene. The symptoms were not restricted to the CNS and muscle : the most severe features being LS with cardiomyopathy (CM), other severe features being mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) or non-insulin dependent diabetes mellitus (NIDDM), and milder features being muscle weakness, easy fatiguability and short stature without life-threatening symptoms. A 3-yewr-old floppy infant was died at the age of 10 years by cardiac failure. A muscle biopsy had revealed ragged-red fibers (RRF), scattered cytochrome c oxidase (COX) negative fibers and strongly SDH reactive vessels (SSVs), pathologically, and complex I plus IV deficiency, biochemically. Mitochondrial DNA (mtDNA) analys
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is in various tissues-including skeletal muscle, liver, heart, kidney and brain-showed a high percentage (>90%) of this mutation. Single fiber PCR analysis of muscle revealed that the percentage of mutation in muscle fibers with RRF-COX nagative (95.6(]SY.+-。[)1.7, mean(]SY.+-。[)SD) was significantly higher than that in fibers with RRF-COX positive (91.6(]SY.+-。[)2.9), and that with the non-RRF-COX positive (89.2(]SY.+-。[)3.3). The above findings suggested that the LS phenotype was a final common outcome for severe defect in the oxidative phosphorylation (OXPHOS) genes. 2) We report a patient with Leigh disease Having an A3243G mutation in the mitochondrial tRNALeu (UUR) gene. RNA analysis in muscle had shown a consistent increase in the steady state levels of RNA 19, polycistronic RNA precursor containing sequence for 16S rRNA,tRNALeu (UUR) and ND1. The above findings suggested that abnormal RNA processing may play an important role in the pathogenesis of human disease having this mutation.
3) To investigate the prevalence of mitochondrial tRNALeu (UUR) gene mutation in diabetic children, we screened 115 diabetic patients in Japan, whose age at onset was under 15 years. Among 115 patients, 92 were diagnosed with insulin dependent diabetes mellitus (IDDM), 21 with non-insulin dependent diabetes mellitus (NIDDM), and 2 with abnormal glucose intolerance. All patients showed no sign of sensorineural hearing loss, no short stature, and no other symptom suggesting any mitochandrial disease. One IDDM patient was found to have an A to G substitution at position 3243 of mitochondrial tRNALeu (UUR) gene (A3243G), however this mutation did not demonstrate maternal inheritance in this family. In our study, the prevalence of the A3242G mutation among these diabetic children was 0.89%, suggesting that this mutation was a significant factor in the etiology of diabetes mellitus in children. Less
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