MITOCHONDRIAL DIABETES-MELLITUS - PREVALENCE AND CLINICAL CHARACTERIZATION OF DIABETES DUE TO MITOCHONDRIAL TRNA(LEU(UUR)) GENE MUTATION INJAPANESE PATIENTS

Mutations in the mitochondrial gene were recently identified in a larg e pedigree of diabetes mellitus and deafness. As the mitochondrial gen e is maternally inherited, Japanese diabetic patients whose mothers we re also diabetic were screened, using peripheral leucocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a t RNA(Leu(UUR)) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients who were screened. Diabetes co-segr egated with the mutation, except in one young subject, and was materna lly inherited. The apparent onset of disease occurred between 11 and 6 8 years of age. Some of the affected members developed hearing impairm ent and congestive heart failure due to cardiomyopathy, though general ly long after the onset of diabetes, and these patients had therefore not been diagnosed as having a specific form of diabetes. The duration of sulphonylurea treatment was not more than 8 years in these pedigre es and affected members were prone to progression to insulin-requiring diabetes. Thus, these patients were secondary sulphonylurea failures. Longterm follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. Some were in itially diagnosed as having IDDM based on an apparent acute onset in y outh and the clinical severity of their diabetes. Others were regarded as having MODY with an aggressive course. The mitochondrial gene muta tion or diabetes is not transmitted to all offspring of the affected m others. In conclusion, a mitochondrial tRNA(Leu(UUR)) gene mutation ac counts for slightly more than 1% of diabetic patients with maternally inherited disease and manifests a wide range of diabetic phenotypes, f rom the NIDDM phenotype to IDDM in Japanese.