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mitochondrial myopathies

Saturday 4 February 2006

Approximately one-fifth of the proteins involved in mitochondrial oxidative phosphorylation are encoded by the mitochondrial genome (mtDNA); additionally, this circular genome encodes 22 mitochondrial-specific tRNAs and 2 rRNA species. The remainder of the mitochondrial enzyme complexes are encoded in the nuclear genome.

Mutations in both nuclear and mitochondrial genes cause the so-called mitochondrial myopathies. Diseases that involve the mtDNA show maternal inheritance, since only the oocyte contributes mitochondria to the embryo. There is a high mutation rate for mtDNA compared with nuclear DNA.

The mitochondrial diseases may present in young adulthood and manifest with proximal muscle weakness, sometimes with severe involvement of the muscles that move the eyes (external ophthalmoplegia). The weakness may be accompanied by other neurologic symptoms, lactic acidosis, and cardiomyopathy, so this group of disorders is sometimes classified as mitochondrial encephalomyopathies.


The most consistent pathologic finding in skeletal muscle is aggregates of abnormal mitochondria that are demonstrable only by special techniques.

These occur under the subsarcolemma in early stages; but with severe involvement, they may extend throughout the fiber. The abnormal mitochondria impart a blotchy red appearance to the muscle fiber on the modified Gomori trichrome stain.

Since they are also associated with distortion of the myofibrils, the muscle fiber contour becomes irregular on cross-section, and the descriptive term ragged red fibers has been applied to them.

The electron microscopic appearance is often distinctive: There are increased numbers of, and abnormalities in, the shape and size of mitochondria, some of which contain paracrystalline parking lot inclusions or alterations in the structure of cristae.

Cytochrome oxidase activity can be determined in muscle biopsy specimens using histochemistry, and cytochrome oxidase negative fibers may be present in a number of mitochondrial myopathies.

The relationship between clinical course in the mitochondrial disorders and the genetic alterations is not entirely clear; however, three general categories have been defined.

One set of mutations consists of point mutations in mtDNA. These disorders tend to show a maternal pattern of inheritance, and some examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber hereditary optic neuropathy (LHON), and mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS).

A second set of mutations involves genes encoded by nuclear DNA and shows autosomal-dominant or autosomal-recessive inheritance.

Some cases of subacute necrotizing encephalopathy (Leigh syndrome), exertional myoglobinuria, and infantile X-linked cardioskeletal myopathy (Barth syndrome) are due to mutations in nuclear DNA. The final subset of mitochondrial myopathies is caused by deletions or duplications of mtDNA.

Examples include chronic progressive external ophthalmoplegia, characterized by a myopathy with prominent weakness of external ocular movements.

Kearns-Sayre syndrome, another myopathy in this group, is also characterized by ophthalmoplegia but, in addition, includes pigmentary degeneration of the retina and complete heart block.


- Kearns-Sayre syndrome

  • characterized by ophthalmoplegia, pigmentary degeneration of the retina and complete heart block.

See also

- OXPHOS disorders
- oxydative phosphorylation (OXPHOS)