A neurologist who has seen a few patients with mitochondrial disease will be puzzled by a number of questions. If mitochondria are so important, why don’t mitochondrial diseases affect every tissue in the body, and if primary mitochondrial disorders are all genetically determined, why do they have such a varied clinical phenotype, even within the same family? Recent advances in our understanding of the molecular pathology of mitochondrial disease have provided us with some explanations and also raised new questions.
The clinical features of mitochondrial disease have been discussed widely elsewhere,27–29 and they will not be considered in detail here (an overview is given in table 2 and fig 4).
In general terms, tissues and organs that are heavily dependent upon oxidative phosphorylation bear the brunt of the pathology. This means that neurological features are common, but cardiac, endocrine, and ophthalmological features are often prominent. Other tissues are less dependent upon sustained oxidative phosphorylation so are less likely to be involved in mitochondrial disease, but there are some notable exceptions.
While this general rule is helpful, it can only be part of the explanation. Mitochondrial disease ultimately reflects a defect of oxidative phosphorylation within a cell, but the pattern of cellular involvement will determine the clinical features of the disease. On the one hand, there must be common mechanisms explaining why patients with mutations in nDNA and mtDNA can have a similar clinical phenotype (for example, clinically indistinguishable Leigh syndrome can be caused by mutations both in the nuclear COX assembly gene SURF1 and the mtDNA ATPase 6 gene30,31). On the other hand, there must be different mechanisms to explain why the same genetic defect can cause very different clinical phenotypes (for example, the A3243G mtDNA mutation in the tRNALeu(UUR) gene can present with classical MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), with CPEO, or with diabetes and deafness32–34). It is also puzzling that many mitochondrial disorders affect multiple organ systems, whereas others have a highly stereotyped and organ specific phenotype (such as Leber hereditary optic neuropathy and aminoglycoside induced deafness).35,36 Nuclear genetic mechanisms have been discussed in the preceding articles in this series, so in this article we will concentrate on mitochondrial genetic factors.
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