CONGENITAL ENCEPHALOMYOPATHY AND ADULT-ONSET MYOPATHY AND DIABETES-MELLITUS - DIFFERENT PHENOTYPIC ASSOCIATIONS OF A NEW HETEROPLASMIC MTDNA TRANSFER-RNA GLUTAMIC-ACID MUTATION

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardat ion and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adul t-onset diabetes mellitus alone, Ragged-red and cytochrome c oxidase ( COX)-negative fibers were present in muscle biopsies. Biochemical stud ies of muscle mitochondria showed reduced complex I and TV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matri lineal relatives analyzed. Primary myoblast, but not fibroblast, cultu res containing high proportions of mutant mtDNA exhibited impaired mit ochondrial translation. These observations indicate that mtDNA tRNA po int mutations should be considered in the differential diagnosis of co ngenital myopathy. In addition they illustrate the diversity of phenot ypes associated with this mutation in the same family and further high light the association between mtDNA mutations and diabetes mellitus.