Clinical Heterogeneity Associated with the Mitochondrial DNA C3303T Point Mutation |[diams]| 734
1998
Dysfunction of mitochondria can affect all tissues and organs, especially those that depend heavily upon oxidative metabolism as the main energy source. In particular, evidence is accumulating that adequate mitochondrial function is critical to normal cardiac metabolism and that mutations in mitochondrial DNA (mtDNA) can result in severe cardiac disease. Cardiac involvement is frequent in mitochondrial disorders and, in some cases, biochemical studies have shown defects of the respiratory chain complexes and molecular studies have identified mtDNA mutations. In 1994, we reported a C3303T mutation in the mitochondrial tRNA Leu(UUR) gene in a family with cardiopathy and myopathy (Silvestri et al; Hum Mut 3:37). Although the mutation satisfied many of the generally accepted criteria for pathogenicity, its causative role remained uncertain because it had been described in a single family. Here we report four new unrelated families with the C3303T mutation who presented with clinical phenotypes ranging from isolated cardiopathy to isolated myopathy to a combination of cardiopathy and myopathy. Case 1 is an infant from an American Caucasian family who died with cardiomyopathy, with the mother and siblings asymptomatic at this time. Case 2 is a 1 year-old boy from an American family of Irish descent with cardiopathy; again, mother and an older sister are asymptomatic. Case 3 is a 4 year-old boy from an Australian family with myopathy. Cases 4-7 are members of a Chilean family where a 10 year-old girl and her maternal grandmother presented with cardiopathy and myopathy while her mother and her maternal uncle have isolated myopathy. Our findings confirm the pathogenicity of the C3303T mutation, suggest that it is not rare and is present in individuals from various ethnic backgrounds, and that it can have a heterogeneous clinical presentation. However, the pathogenic mechanism(s) by which this mutation causes disease remain to be elucidated. It is important to consider the C3303T mutation in the differential diagnosis of familial cardiomyopathies, especially when there is evidence of maternal inheritance.
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