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High Prevalence of Impaired Glucose Homeostasis and Myopathy in Asymptomatic and Oligosymptomatic 3243A>G Mitochondrial DNA Mutation-Positive Subjects

Department of Endocrinology (A.L.F., P.H.A.), Ribe County Hospital, DK-6700 Esbjerg, Denmark; Department of Endocrinology (A.L.F.), Odense University Hospital, DK-5000 Odense, Denmark; Neuromuscular Research Unit, Department of Neurology (T.D.J., J.V.), and Department of Clinical Genetics (M.S.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; The Danish Twin Registry (K.O.K.), Epidemiology, Institute of Public Health, University of Southern Denmark, DK-5230 Odense, Denmark; and Research Laboratory (O.S., P.L.P.), Department of Endocrinology M, Aarhus University Hospital, DK-8200 Aarhus, Denmark

Address all correspondence and requests for reprints to: Anja Lisbeth Frederiksen, Department of Endocrinology, Ribe County Hospital, Esbjerg, Finsensgade 35, DK-6700 Esbjerg, Denmark. E-mail: anja.frederiksen{at}ouh.regionsyddanmark.dk.

Introduction: The point mutation of 3243A>G mtDNA is the most frequent cause of mitochondrial diabetes, often presenting as the syndrome maternally inherited diabetes and deafness (MIDD). The mutation may also cause myopathy, ataxia, strokes, ophthalmoplegia, epilepsy, and cardiomyopathy in various combinations. Consequently, it is difficult to predict the "phenotypic risk profile" of 3243A>G mutation-positive subjects. The 3243A>G mutation coexists in cells with wild-type mtDNA, a phenomenon called heteroplasmy. The marked variability in mutation loads in different tissues is the main explanation for the different phenotypes associated with this mutation.

Aim: The aim of the study was to screen asymptomatic and oligosymptomatic 3243A>G mtDNA carriers for diabetes and myopathy.

Methods: The study is a case-control study. Nineteen adult 3243A>G carriers presumed to be normoglycemic and matched healthy controls were subjected to an oral glucose tolerance test. Twenty-six adult 3243A>G carriers with unknown myopathy status and 17 healthy controls had a maximal cycle test and a muscle biopsy performed. The mutation loads were quantified in blood and muscle biopsies and correlated to the clinical manifestations of the mutation.

Results: In the presumed normoglycemic 3243A>G-positive subjects, one subject had overt diabetes, and 10 subjects had impaired glucose tolerance. Sixteen of the 26 subjects with unknown oxidative capacity fulfilled criteria for myopathy. The mutation load in blood and muscle correlated with the age for diagnosis of impaired glucose homeostasis and hearing impairment ( = –0.71 to –0.78; P < 0.0001).

Conclusion: The findings suggest that 3243A>G mutation carriers should be screened for diabetes and myopathy.