Mitochondrial Myopathies

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate ( ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

Primary mitochondrial myopathies are inherited, while secondary mitochondrial myopathies may be inherited (e.g. Duchenne's muscular dystrophy) or environmental (e.g. alcoholic myopathy). When it is an inherited primary disease, it is one of the metabolic myopathies.

On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers on Gomori trichrome staining. The ragged-red appearance is due to a buildup of abnormal mitochondria underneath the plasma membrane. These ragged-red fibres may contain normal or abnormally increased accumulations of glycogen and neutral lipids, with histochemical staining showing abnormal respiratory chain involvement, such as decreased succinate dehydrogenase or cytochrome c oxidase. Inheritance was believed to be maternal ( non-Mendelian extranuclear). It is now known that certain nuclear DNA deletions can also cause mitochondrial myopathy such as the OPA1 gene deletion.

Signs and symptoms

Proximal muscle weakness, exercise intolerance, lactic acidosis, high serum lactate/pyruvate ratio, normal to elevated serum CK, dyspnea, exaggerated cardiorespiratory response to exercise are common symptoms. It may be isolated to the muscle (pure myopathy) or may be systemic including not only myopathy, but also eye abnormalities, peripheral neuropathy, and neurological abnormalities. Muscle biopsy typically shows ragged-red fibres, histochemical staining shows abnormality of respiratory chain or decreased cytochrome c oxidase (COX).

The five most common are MELAS, MERF, KSS, CPEO, and MNGIE which are listed below:
* Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)
** Varying degrees of cognitive impairment and dementia
** Lactic acidosis
** Strokes
** Transient ischemic attacks
** Hearing loss
** Weight loss
* Myoclonic epilepsy and ragged-red fibers (MERRF)
** Progressive myoclonic epilepsy
** Clumps of diseased mitochondria accumulate in muscle fibers and appear as "ragged-red fibers" when muscle is stained with modified Gömöri trichrome stain
** Short stature
* Kearns–Sayre syndrome (KSS)
** External ophthalmoplegia
** Cardiac conduction defects
** Sensorineural hearing loss
* Chronic progressive external ophthalmoplegia (CPEO)
** Progressive ophthalmoparesis
** Symptomatic overlap with other mitochondrial myopathies
* Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
** Muscle weakness and atrophy, more prominent distally
** Hyporeflexic or areflexic
** Ptosis and ophthalmoparesis common
** Gastrointestinal dysmotility (such as bloating, stomach cramps, diarrhea)

Cause

Mitochondrial myopathy literally means mitochondrial muscle disease, muscle disease caused by mitochondrial dysfunction. The mitochondrion is the primary producer of energy in nearly all cells throughout the body. The exception is mature erythrocytes (red blood cells), so that they do not use up the oxygen that they carry. In the eye, the lens and outer segment of the retina contain almost no mitochondria. Muscle cells have many mitochondria, particularly type I muscle fibres, and if the mitochondria have problems by which they do not produce enough energy for the cell to function, problems occur.

The cause may be genetic, with many having mitochondrial inheritance (involving the mitochondrial DNA which is only passed on from the mother), although nuclear DNA mutations with Mendelian inheritance that are either autosomal dominant, recessive, or X-linked recessive also exist. A nuclear DNA example is a mutation within the POLG (polymerase gamma) gene, which causes mitochondrial DNA (mtDNA) to become damaged and lose function.

Disease list

Diagnosis

Muscle biopsy: usually ragged red fibres in Gömöri trichrome stain, normal or excessive glycogen or lipid accumulation within these ragged red fibres, histochemical staining showing impairment of respiratory chain such as COX-negative fibres. Some mitochondrial myopathies are limited to disease expression only in skeletal muscle, with fibroblasts (from skin biopsy) appearing normal.

Blood tests: lactate/pyruvate ratio may be elevated or normal, creatine kinase (CK) may be elevated or normal. Electrolyte panel, anion gap, glucose, vitamin D, TSH, anti-HMGCR and AChR autoantibodies to rule-out pseudometabolic myopathies.

Exercise stress test: exaggerated cardiorespiratory response to exercise (inappropriate rapid heart rate response to exercise with breathlessness nowiki/>tachycardia and Shortness of breath">dyspnea