The maternally inherited 8344 A>G mutation in the mitochondrial Lys tRNA is classically associated with the myoclonic epilepsy, ragged-red muscle fiber (MERRF) syndrome. Multiple lipomatosis (Madelung's disease) is occasionally described. Here we report a large kindred with a statistically significant clustering of very unusual clinical manifestations. We have studied a Greek family that includes seven symptomatic cases of 8344 A>G. Clinical features, glucose tolerance and heteroplasmy in fat, muscle and blood were analyzed. The patients, aged 34-76 at the time of assessment, all suffer from progressive proximal limb-girdle myopathy and extensive lipomatosis. Four of the seven have either impaired glucose tolerance or diabetes but none has had epilepsy, a cardinal feature of MERRF. Heteroplasmy was not higher in adipose tissue than that found in the literature. Compared to literature reports, the familial clustering of this unusual combination of manifestations (lipomatosis in all, epilepsy in none) is statistically significant. The clustering of unusual manifestations in this large kindred strongly suggests that much of the phenotypic variability of 8344 A>G is determined by mitochondrially encoded modifiers in cis.
© 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.