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
+Name (alternate names)Gene(s)Inheritance pattern (MT, AR, AD, X-Linked)OMIM # (GD: gene description, PS: phenotypic series)Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS) (Juvenile myopathy, encephalopathy, lactic acidosis and stroke)MT-TL1, MT-TQ, MT-TH, MT-TK, MT-TC, MT-TS1, MT-ND1, MT-ND5, MT-ND6, MT-TS2 MT540000Myoclonic epilepsy and ragged-red fibers (MERRF)MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, MT-TF MT545000Kearns–Sayre syndrome (KSS) (Ophthalmoplegia, pigmentary degeneration of retina, and cardiomyopathy; oculocraniosomatic syndrome; ophthalmoplegia-plus syndrome; mitochondrial cytopathy, ophthalmoplegia, progressive external, with ragged-red fibers; chronic progressive external ophthalmoplegia with myopathy; CPEO with myopathy; CPEO with ragged-red fibers)MT-TL1MT530000Chronic progressive external ophthalmoplegia (CPEO) (Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive/dominant)POLG, SLC25A4, RNASEH1, TWNK, TK2, POLG2, DGUOK, TOP3A, RRM2BAR/ADPS157640Mitochondrial DNA depletion syndrome (MNGIE type) (Mitochondrial neurogastrointestinal encephalopathy (MNGIE); myoneurogastrointestinal encephalopathy syndrome; polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudoobstruction; POLIP syndrome)TYMP, RRM2B, POLG, LIG3AR603041; 612075;
613662;
619780Mitochondrial DNA depletion syndrome (Alpers type, cardiomyopathic type, encephalomyopathic type, hepatocerebral type, and myopathic type) MGME1, SLC25A10, TK2, POLG, SLC25A21, SUCLA2, TWNK, TFAM, AGK, MRM2, SLC25A4, OPA1, SUCLG1AR/ADPS603041Mitochondrial myopathy, infantile, transient (MMIT) (Mitochondrial myopathy, infantile, transient, due to respiratory chain deficiency; COX deficiency myopathy, infantile, transient; respiratory chain deficiency, infantile, transient)MT-TEMT500009Mitochondrial myopathy, lethal, infantile (LIMM) (Lethal infantile mitochondrial myopathy)MT-TTMT551000Hereditary myopathy with lactic acidosis (HML) (Myopathy with exercise intolerance, Swedish type; myopathy with deficiency of succinate dehydrogenase and aconitase; myoglobinuria due to abnormal glycolysis; Larsson–Linderholm syndrome; Linderholm myopathy)ISCUAR/AD255125Mitochondrial myopathy with diabetes (Mitochondrial myopathy, lipid type)MT-TEMT500002Maternally inherited diabetes and deafness (MIDD) (Diabetes and deafness (DAD); Ballinger–Wallace syndrome; Noninsulin-dependent diabetes mellitus with deafness, maternally inherited)MT-TL1, MT-TE, MT-TKMT520000Myopathy, mitochondrial progressive, with congenital cataract and developmental delay (MPMCD) (Myopathy with cataract and combined respiratory chain deficiency; mitochondrial complex deficiency, combined)GFERAR613076Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) (Mitochondrial myopathy and sideroblastic anemia)PUS1, YARS2, MT-ATP6AR/MT600462 613561
GD: 516060Myopathy, isolated mitochondrial, autosomal dominant (IMMD)CHCHD10AD616209Myopathy, mitochondrial, and ataxia (MMYAT)MSTO1AR/AD617675Mitochondrial myopathy, episodic, with or without optic atrophy and reversible leukoencephalopathy (MEOAL)FDX2AR251900Mitochondrial myopathy with lactic acidosis (MMLA)PNPLA8AR251950Mitochondrial myopathy with a defect in mitochondrial-protein transportUnknownAR251945Myotonic dystrophy-like myopathy; Mitochondrial myopathyMT-TAMTGD: 590000Mitochondrial myopathy, isolatedMT-TDMTGD: 590015Myopathy, mitochondrialMT-TWMTGD: 590095Barth Syndrome (BTHS) (Cardioskeletal myopathy with neutropenia and abnormal mitochondria; 3-methylglutaconic aciduria, type II; MGCA2; MGA, type II; MGA2)TAFAZZINX-Linked302060Coenzyme Q10 deficiency, primary (COQ10D) (CoQ10 deficiency, primary; ubiquinone deficiency; Coenzyme Q deficiency; CoQ deficiency)COQ2, PDSS1, PDSS2, COQ8A, COQ9, COQ4, COQ7, COQ5ARPS607426Mitochondrial complex I deficiency, nuclear type (MC1DN) (NADH:Q(1) oxidoreductase deficiency; NADH-coenzyme Q reductase deficiency; mitochondrial NADH dehydrogenase component of complex I, deficiency of)NDUFS2, NDUFB3, NDUFS1, NDUFA10, NDUFAF3, TIMMDC1, ACAD9, NDUFS6, NDUFS4, NDUFAF2, NDUFA2, NDUFAF4, DNAJC30, NDUFAF6, NDUFB9, NDUFA8, NDUFB8, NDUFS3, NDUFV1, NDUFS8, NDUFC2, TMEM126B, FOXRED1, NDUFA9, NDUFA12, NUBPL, NDUFAF1, MTFMT, NDUFB10, NDUFAF8, NDUFV2, NDUFS7, NDUFA11, NDUFB7, NDUFA13, NDUFAF5, NDUFA6, NDUFB11, NDUFA1AR/XL/XLRPS252010Mitochondrial complex II deficiency, nuclear type (MC2DN) (Succinate CoQ reductase deficiency; succinate dehydrogenase deficiency)SDHA, SDHAF1, SDHD, SDHBARPS252011cytochrome b of complex III (MTCYB); Exercise intolerance; multisystem disorder; cardiomyopathy, infantile histiocytoid; exercise intolerance, cardiomyopathy, and septooptic dysplasia; parkinsonism/MELAS overlap syndrome MT-CYBMTGD: 516020Mitochondrial complex III deficiency, nuclear type (MC3DN)BCS1L, TTC19, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, UQCC3, UQCRFS1ARPS124000Mitochondrial complex IV deficiency, nuclear type (MC4DN) (mitochondrial complex IV deficiency; cytochrome c oxidase deficiency; COX deficiency)SURF1, SCO2, COX10, SCO1, LRPPRC, COX15, COX6B1, TACO1, COX14, COX20, PET100, COA6, COA3, COX8A, COX4I1, APOPT1, COX6A2, PET117, COX5A, COXFA4, COX16, COX11ARPS220110Mitochondrial complex V (ATP synthase) deficiency, nuclear type (MC5DN)ATPAF2, TMEM70, ATP5F1E, ATP5F1A, ATP5F1D, ATP5MD, ATP5POAR/ADPS604273Muscular dystrophy, limb-girdle, type 1H (As of 2017 was excluded from LGMD for showing histochemical evidence of being a mitochondrial myopathy, but not yet assigned new nomenclature)Chromosome 3 (3p23-p25), unknown geneAD613530
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 [tachycardia and dyspnea]).
DNA tests: whole exome sequencing (WES) neuromuscular panels (that only test exons), or whole genome sequencing (WGS) for more complex cases (that test exons, introns, and mitochondrial DNA). Introns were initially thought to be "junk DNA," however, some introns regulate the expression of exons. 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).
There are two groups of DNA that affect the mitochondria: mitochondrial genome (mtDNA) and nuclear DNA. For mitochondrial myopathies that involve a single mtDNA deletion, it would only be found on muscle-derived mtDNA, making a biopsy of affected muscle necessary for DNA analysis rather than saliva or blood. Even among siblings with the same inherited mutation, different muscle groups were affected, with unaffected tissues having near normal levels of mtDNA.
EMG: may be normal, myopathic, or rarely neurogenic.
The symptoms of exercise intolerance, abnormal muscle fatigue, myalgia (muscle pain), arrhythmia, possible fixed proximal muscle weakness, lipid deposits, possible episodes of rhabdomyolysis, with symptoms becoming evident or worsening while fasting, during a fever, during low-intensity aerobic activity or after prolonged activity–all these overlap with the symptoms of another metabolic myopathy, that of fatty acid metabolism disorders.