Mitochondrial myopathy is a collective term for diseases related to defective mitochondria in cells, which are energy factories found inside almost all the cells in the body. Mitochondrial diseases that cause prominent muscular problems are called mitochondrial myopathies (myo means muscle and pathos means disease), while mitochondrial diseases that causes both prominent muscular and neurological problems are called mitochondrial encephalomyopathies (encephalo refers to the brain). In patients with mitochondrial myopathy, mitochondria are not able to undergo normal oxygen consumption and energy production due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA that affect the mitochondrial machinery of cells.
The most common types of mitochondrial myopathy are:
• Kearns-Sayre syndrome (KSS)
• Leigh’s syndrome and maternally inherited Leigh’s syndrome (MILS)
• Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
• Myoclonus epilepsy with ragged red fibers (MERRF)
• Neuropathy, ataxia and retinitis pigmentosa (NARP)
• Pearson syndrome
• Chronic progressive external ophthalmoplegia (CPEO)
• Myogastrointestinal encephalomyopathy (MNGIE)
Mitochondrial diseases are caused by genetic mutations. Genes provide the instructions for making proteins, and the genes involved in mitochondrial disease normally make proteins that work inside mitochondria. Producing energy within the mitochondria is a complex, multistep process which involves about 100 different proteins. If there is a problem with any one of these proteins, the energy “production line” breaks down and consequently the cells cannot function normally. A cell filled with defective mitochondria becomes deprived of ATP and can accumulate a backlog of unused fuel molecules and destructive forms of oxygen called free radicals or reactive oxygen species. In such cases, excess fuel molecules are used to make ATP by inefficient means, which can generate potentially harmful byproducts such as lactic acid. (This also occurs when a cell has an inadequate oxygen supply, which can happen to muscle cells during strenuous exercise.) The buildup of lactic acid in the blood—called lactic acidosis—is associated with muscle fatigue, and might damage muscle and nerve tissue. . The combined effects of energy deprivation and toxin accumulation in these cells can lead to many muscular and neurological symptoms.
Some types of mitochondrial myopathy are inherited, while some are sporadic (the mutation only occurs in the affected person; it was not inherited and will not be passed onto children). These disorders are caused by a defect in either a mitochondrial gene or a gene in the cell nucleus that affects the functioning of the mitochondria.
Mitochondrial myopathies affect people in different ways. The most common problem is a combination of mild weakness of the arms and legs together with droopy eyelids (ptosis) and difficulty in moving the eyes (ophthalmoplegia). Others only have weakness of the arms and legs, which gets worse after exertion. This may be associated with nausea and headache. If the illness is severe, muscle weakness may be obvious in small babies, and they may have difficulties with swallowing and feeding. Less commonly, some of these conditions affect the brain. This can lead to epilepsy (fits) and progressive loss of memory. Not all individuals with brain involvement (called encephalopathy) get worse, but some will. The light-sensitive membrane at the back of the eye (the retina) is often affected (abnormal pigment accumulates) and hearing difficulties are common. In addition the heart may be affected requiring the insertion of a pacemaker – an electrical device that helps the heart to beat properly.
Diagnosis begins with a physician taking the patient’s personal medical history, and then proceeds with physical and neurological exams. The physical exam typically includes tests of strength and endurance, such as an exercise test, which can involve activities like repeatedly making a fist, or climbing up and down a small flight of stairs. The neurological exam can include tests of reflexes, vision, speech and basic cognitive (thinking) skills. This is followed with more specialized tests including muscle biopsy. When treated with a dye that stains mitochondria red, muscles affected by mitochondrial disease often show ragged red fibers — muscle cells (fibers) that have excessive mitochondria. Other stains can detect the absence of essential mitochondrial enzymes in the muscle. Muscle phosphorus magnetic resonance spectroscopy (MRS) may be done to measure levels of phosphocreatine and ATP (compounds that are often depleted in muscles affected by mitochondrial disease). Routine CT, MRI, EEG, EKG and blood tests may also be involved. A genetic test can determine whether someone has a genetic mutation that causes mitochondrial disease.
Treatment of MM concentrates on the management of disease complications. There is no curative therapy yet for any of the mitochondrial myopathies. However, supportive treatment is available which can modify some of the symptoms and this can be quite helpful for many patients including hearing aids, medication, surgery, specialized glasses, assistive devices, speech therapy, diet modification and respiratory support. Several agents (mostly nutritional supplements) have been investigated with double-blind, placebo-controlled studies. These include carnitine, creatine, CoQ10, cysteine, dichloroacetate, dimethylglycine and the combination of creatine, CoQ10, and lipoic acid. None has demonstrated efficacy in clinical disease end-points but some patients report minor improvement in symptoms.