EXTRA-PANCREATIC MANIFESTATIONS IN DIABETES SECONDARY TO MITOCHONDRIAL-DNA POINT MUTATION WITHIN THE TRNA(LEU(UUR)) GENE

OBJECTIVE-A point mutation in the mitochondrial genome has been identi fied as a cause of diabetes and deafness. We report two pedigrees with an A-to-G transition at nucleotide 3243 of mtDNA within the tRNA(Leu( UUR)) gene and focus our investigations on other localizations of the anomaly, particularly muscle and retina. RESEARCH DESIGN AND METHODS-M uscular localization has been studied in probands by invasive and noni nvasive methods, including muscle biopsy (evaluation of the proportion of mutated mtDNA in comparison to blood cells, measurement of respira tory chain complex activities and histological and histochemical aspec ts) and P-31-nuclear magnetic resonance (NMR) spectroscopy. Ophthalmic and angiographic examination of retina, electroretinography, and visu al evoked potentials were performed in five subjects. RESULTS-This mut ation, previously described in patients with mitochondrial myopathy, e ncephalopathy, lactic acidosis, and stroke-like episodes (MELAS), was expressed more abundantly in muscle than in nucleated blood cells. Thi s low expression in blood cells could hamper the diagnosis for some pa tients. In addition, despite poor clinical expression, muscle was foun d to be highly affected. Ragged red fibers and dystrophic mitochondria were observed in muscle biopsy. Histochemical assays showed decreased activity of respiratory chain complexes, and P-31-NMR in vivo data fu rther confirmed the defect of muscle oxidative processes. Exercise-ind uced lactate production was increased. Finally, in both families, an a typical ''salt and pepper'' pigmentary retinopathy was observed withou t consequences on visual acuity. CONCLUSIONS-In diabetes secondary to 3243 mtDNA mutation, infraclinical muscular and ocular lesions are fre quent. These two locations of the disease, which are easily investigat ed by simple methods, can help in the diagnosis of this new type of di abetes.