Mitochondrial disorders: prevalence, myths and advances

Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are renowned for their variability in clinical features and genetic causes. This makes it difficult to determine their true prevalence, but recent studies have documented a minimum birth prevalence of 13.1/100000 or 1/7634 for oxidative phosphorylation disorders with onset at any age. This clearly remains an underestimate but it indicates that oxidative phosphorylation disorders can be regarded as the most common group of inborn errors of metabolism. Pathogenic mutations causing human oxidative phosphorylation disorders have now been identified in more than 30 of the 37 mitochondrial DNA genes and in more than 30 nuclear genes. Most of the nuclear gene defects cause autosomal recessive diseases, but autosomal dominant and X-linked disorders also occur. It is likely that at least another 30, and perhaps over 100, nuclear-encoded oxidative phosphorylation disorders await identification. Oxidative phosphorylation genetics are complex and there appear to be a number of common misconceptions about mitochondrial DNA mutations that may impede optimal investigation and management of patients. In our experience, mitochondrial DNA mutations are not a negligible cause of OXPHOS disorders in children but account for 20-25% of cases. Similarly, a family history suggesting maternal inheritance is the exception rather than the norm for children with mitochondrial DNA mutations, many of whom have de novo mutations. Only some mitochondrial DNA mutations disappear from cultured cells, so deficient enzyme activity in fibroblasts does not imply the presence of a nuclear defect. Finally, it is still widely thought that there are very few reproductive options that can be offered to women at risk of transmitting a mitochondrial DNA mutation. While a cautious approach is needed, there is now a consensus that prenatal diagnosis should be offered to some women, particularly those at lower recurrence risk. Preimplantation genetic diagnosis can also be an option.