Mitochondrial myopathy
Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate, 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 or environmental. 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. 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 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.The five most common are MELAS, MERF, KSS, CPEO, and MNGIE which are listed below:
- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome
- * Varying degrees of cognitive impairment and dementia
- * Lactic acidosis
- * Strokes
- * Transient ischemic attacks
- * Hearing loss
- * Weight loss
- Myoclonic epilepsy and ragged-red fibers
- * 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
- * External ophthalmoplegia
- * Cardiac conduction defects
- * Sensorineural hearing loss
- Chronic progressive external ophthalmoplegia
- * Progressive ophthalmoparesis
- * Symptomatic overlap with other mitochondrial myopathies
- Mitochondrial neurogastrointestinal encephalopathy
- * Muscle weakness and atrophy, more prominent distally
- * Hyporeflexic or areflexic
- * Ptosis and ophthalmoparesis common
- * Gastrointestinal dysmotility
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, 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, 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 gene, which causes mitochondrial DNA 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 appearing normal.Blood tests: lactate/pyruvate ratio may be elevated or normal, creatine kinase 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.
DNA tests: whole exome sequencing neuromuscular panels, or whole genome sequencing for more complex cases. 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, the most common pathogenic mutation is the intronic IVS5+382 G>C.
There are two groups of DNA that affect the mitochondria: mitochondrial genome 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, 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.
DNA testing is helpful for determining between the similar presenting, but different in bioenergetic system origin, metabolic myopathies. When DNA testing is inconclusive, a muscle biopsy is necessary.
Differential diagnosis
Diseases that mimic the symptoms of mitochondrial myopathy include electrolyte imbalance, myasthenia gravis, thyroid abnormalities, vitamin D deficiency, immune-mediated necrotizing myopathy, diabetes-related pseudohypoxia, and fatty acid metabolism disorders. Hypoxia due to ischemia can be found in a number of myopathies other than the inherited primary mitochondrial myopathies. 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.Secondary mitochondrial myopathy can be caused by biological aging, inflammatory myopathies, and chronic alcohol use disorder. It can also be due to certain drugs such statins, bupivacaine, antiepileptic drugs, and nucleoside reverse transcriptase inhibitors such as zidovudine and clevudine.
Some metabolic myopathies affect multiple bioenergetic pathways, for instance multiple acyl-CoA dehydrogenase deficiency (MADD), formerly known as glutaric acidemia type II. The ETF genes involved in MADD impairs beta-oxidation, impairs amino acid catabolism, 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, known as riboflavin-responsive MADD.
Riboflavin-responsive exercise intolerance, a fatty acid metabolism disorder involving the SLC25A32 gene, has symptoms similar to MADD, with muscle biopsy showing ragged red fibres and lipid deposits, small type II fibres, and impaired FAD-dependent mitochondrial respiratory chain.
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 and folate.
Pompe disease, another type of metabolic myopathy, has secondary mitochondrial dysfunction present in both the earlier onset forms 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. Three unrelated young boys, with a mutation in the DMD gene, exhibited a pseudometabolic presentation with symptoms of exercise intolerance manifesting as exercise-induced myalgia, muscle stiffness, myoglobinuria and rhabdomyolysis.
A few Limb–girdle muscular dystrophies are known to have secondary mitochondrial dysfunction, including: LGMDR1 calpain3-related, LGMDR2 dysferlin-related, LGMDR3 α-sarcoglycan-related, LGMDR5 γ-sarcoglycan-related, and LGMDR6 δ-sarcoglycan-related. As well as Myofibrillar myopathy 8 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.
Avoiding physically stressful situations that deplete glycogen reserves, such as fasting and endurance exercise, may help. A high-carb/low-fat/low-protein diet may help.