Clinical spectrum and diagnosis of mitochondrial disorders

Respiratory chain deficiencies have long been regarded as neuromuscular diseases mostly originating from mutations in the mitochondrial DNA. Actually, oxidative phosphorylation, i.e., adenosine triphosphate (ATP) synthesis-coupled electron transfer from substrate to oxygen through the respiratory chain, does not only occur in the neuromuscular system. For this reason, a respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, owing to the dual genetic origin of respiratory chain enzymes (nuclear DNA and mitochondrial DNA). In recent years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in both childhood and adulthood. Diagnosis of a respiratory chain deficiency is difficult initially when only one symptom is present, and easier when additional, seemingly unrelated, symptoms are observed. The clinical heterogeneity is echoed by the genetic heterogeneity illustrated by the increasing number of nuclear genes that have been shown to be involved in these diseases. In the absence of clear-cut genotype-phenotype correlations and in front of the large number of possibly involved genes, biochemical analyses are still the cornerstone of the diagnosis of this condition.