Mitochondrial myopathy

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==

showing ragged red fibres in a mitochondrial myopathy. Gömöi trichrome stain. 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. Electrolyte panel, anion gap, glucose, vitamin D, TSH, anti-HMGCR and AChR autoantibodies to rule-out pseudometabolic myopathies. For example, in the mitochondrial myopathy of hereditary myopathy with lactic acidosis (HML), the most common pathogenic mutation is the intronic IVS5+382 G>C (rs767000507). EMG: may be normal, myopathic, or rarely neurogenic. These include axonal Charcot–Marie–Tooth disease types 2CC & 2EE, congenital myasthenic syndrome types 12 & 14, congenital myopathy types 10B & 22A, and MYH7-related myopathies such as Laing distal myopathy and myosin storage myopathy. inflammatory myopathies, Some metabolic myopathies affect multiple bioenergetic pathways, for instance multiple acyl-CoA dehydrogenase deficiency (MADD), formerly known as glutaric acidemia type II (GA-II). The ETF genes involved in MADD impairs beta-oxidation (fatty acid metabolism), impairs amino acid catabolism (protein metabolism), and simultaneously impairs the respiratory chain by not transferring electrons from reduced FAD+/FADH2. The impaired protein metabolism leads to a buildup of glutaric acid and other acids. Fatty acid metabolism is further impaired as carnitine is used to detoxify the buildup of glutaric acid, causing secondary carnitine deficiency. Although MADD affects multiple bioenergetic pathways, it is classified as a fatty acid metabolism disorder as that is the bioenergetic pathway that is affected the most by the deficiency. However, it is important to note as a differential diagnosis as not only do the symptoms overlap with mitochondrial myopathies, but also muscle biopsies of some individuals with MADD show COX-negative fibres, respiratory chain impairment, and deficiency of coenzyme Q10. Some forms of MADD respond well to riboflavin (vitamin B2), known as riboflavin-responsive MADD (RR-MADD). Myopathies involving abnormal autophagy, including abnormal mitophagy, may present with secondary impaired fatty acid metabolism and/or mitochondrial defects in skeletal muscles, may have wide phenotypic variability, and may affect multiple other organs. For instance, EPG5-related Vici syndrome and TANGO2-related disease. TANGO2-related disease is at least partially responsive to B vitamin supplementations of panthotenic acid (B5) and folate (B9). Pompe disease (glycogen storage disease type II), another type of metabolic myopathy, has secondary mitochondrial dysfunction present in both the earlier onset forms (infantile and juvenile) and the late-onset form in adults. Myopathies involving the DMD gene, such as Duchenne and Becker muscular dystrophy, have secondary mitochondrial dysfunction impairing oxidative phosphorylation. The mechanisms leading to this mitochondrial dysfunction are many and it has yet to be elucidated which mitochondrial changes are directly due to the disease and which are compensatory. A few Limb–girdle muscular dystrophies are known to have secondary mitochondrial dysfunction, including: LGMDR1 calpain3-related (formerly LGMD 2A), LGMDR2 dysferlin-related (LGMD 2B), LGMDR3 α-sarcoglycan-related (LGMD 2D), LGMDR5 γ-sarcoglycan-related (LGMD 2C), and LGMDR6 δ-sarcoglycan-related (LGMD 2F). As well as Myofibrillar myopathy 8 (MFM8) PYROXD1-related, which has an adult-onset, slowly progressive, Limb–girdle phenotype. MICU1-related myopathy with extrapyramidal signs has disrupted calcium uptake causing secondary mitochondrial dysfunction. It has variable myopathic features as well as eye and neurological symptoms. ==Treatment==

Although no cure currently exists, there is hope in treatment for this class of hereditary diseases as trials continue. Aerobic training may improve oxidative capacity by the skeletal muscles becoming aerobically conditioned. Deoxynucleoside monophosphates and deoxynucleotide taken orally, may help in TK2 deficiency (Mitochondrial DNA depletion syndrome 2 myopathic type). Avoiding physically stressful situations that deplete glycogen reserves, such as fasting and endurance exercise (which rely predominantly on oxidative phosphorylation), may help. A high-carb/low-fat/low-protein diet may help. == See also ==