Understanding mitochondrial myopathies: a review

Pathology of mitochondrial myopathy

When either the Mitochondrial DNA (mtDNA) or Nuclear DNA (nDNA) is abnormal, the mitochondria cannot produce the energy needed by cells for their metabolism and diseases occur. We can think of this as a power failure within the body. The impact of such power failure within the body can range from mild to severe and even can lead to death. Genetic mutations in either mtDNA or nDNA coding for mitochondria are responsible for disease (Muscular Dystrophy Association (MDA), 2009c).

nDNA defects tend to be autosomal recessive and are transmitted in a Mendelian fashion where half of the genetic material of a fertilized egg derives from each parent. Since the egg has multiple mitochondria while sperm has virtually none, mutations of mitochondrial genes in mtDNA are transmitted through the maternal line, or they may be sporadic (Agamanolis, 2017). The number of mitochondria within cells varies depending on the energy needs of the cells. Cells which have more ATP requirements will have more mitochondria. As an example, muscle cells and heart muscle cells need more energy than the cells of the liver and have more mitochondria to generate more ATP. The heart muscle cells have about 5,000 mitochondria and each liver cell contains 1,000–2,000 mitochondria (Alberts et al., 2002). Cells are unevenly affected by abnormal mtDNA. This is because a cell may have some mitochondria containing normal (referred to as wild type) mtDNA while the other mitochondria within the same cell may contain mutant mtDNA.

Mitochondria segregate in a random way when cells divide and so the percentage of wild type and mutant mtDNA coexisting in any given cell is variable and this is known as heteroplasmy (Agamanolis, 2017). After several cell division cycles, a cell may contain mitochondria with a majority of mutant mtDNA and when the proportion of such mutant mtDNA in mitochondria exceed a threshold of 80–90%, cellular disease becomes manifested. Due to heteroplasmy, mitochondrial disease takes many forms and even family members may present differently with the disease.

Diseased muscle fibers containing groups of abnormal mitochondria look to be “Ragged Red Fibers” when the muscle is tinged with Gomori trichome stain. These red ragged fibers are specific to mitochondrial disorders but are present in only 1/3rd of these disorders (Agamanolis, 2017). A mitochondrial disease causing prominent muscular problems is referred to as a mitochondrial myopathy. Due to their high energy requirements, organs such as the brain and skeletal and cardiac muscles are disproportionately affected by mitochondrial dysfunction and are collectively referred to as mitochondrial encephalomyopathies.

Review methodology

Scholarly articles that were reviewed in this paper were searched in journal databases and subject-specific professional websites. The search terms that were used when searching for articles included mitochondrial myopathy, genetic mutations, and treatment. Inclusion criteria for selected articles required that articles be directly related to the topic on mitochondrial myopathy and be peer reviewed. Both qualitative and quantitative articles were reviewed. Qualitative articles provide insights into the problem by helping understand reasons, opinions, and motivations. Quantitative articles on the other hand use measurable data to formulate facts and discover patterns in research.

Causes

Mitochondrial diseases are caused by mutations in mtDNA or nDNA. These mutations can be inherited or spontaneously engendered, which alters the function of the proteins or RNA molecules that are usually a part of mitochondria (United Mitochondrial Disease Foundation, 2017a). Mitochondrial diseases such as Leigh Syndrome and Mitochondrial Neurogastrointestinal Encephalopathy Syndrome (MNGIE) that are caused by nDNA mutations and even mitochondrial DNA depletion syndrome (MDS) are autosomal recessive, requiring mutations in copies of a gene from both parents to induce disease (Muscular Dystrophy Association (MDA), 2009a). So, essentially the person must be homozygous recessive, i.e., have two copies of the recessive allele for manifestation of a mitochondrial disease. For example, more than one defect may cause Leigh’s Syndrome. Such defects include a pyruvate dehydrogenase (PDHC) deficiency, and respiratory chain enzyme defects—complexes I, II, IV, and V (Muscular Dystrophy Association (MDA), 2009a). The mode of inheritance can vary based on the type of defect. It may be X-linked dominant with the defect on the X chromosome and disease usually occurs in males only. It may also be autosomal recessive or maternal. Some cases may be spontaneous and these are not inherited.

mtDNA is inherited maternally. This is because only the mother’s egg cell contributes mitochondria to an embryo and the father’s sperm does not do so (Muscular Dystrophy Association (MDA), 2009a). It should however, be noted that not all mitochondrial mutations are inherited. Some of the mutations can occur during embryonic development in the womb (Muscular Dystrophy Association (MDA), 2009a).

Considering that mitochondrial dysfunction may originate from mutations in more than 1,000 genes, the type of mutation may vary greatly. Scarpelli et al. (2018) report two mtDNA mutations in mitochondrial myopathy patients. Specifically, the paper identifies the m.8305C>T mutation in the MTTK gene and the MTTM gene m.4440G>A mutation (Scarpelli et al., 2018). The authors conclude that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults. Another recent paper by Bartsakoulia et al. (2018) identifies mutations in MIEF2 gene that results in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.

There are too many variants of mitochondrial myopathies; as such it must be stated that analysis of each specific type is beyond the scope of this paper. For example, some diseases such as Myoclonic Epilepsy and Ragged-Red Fiber (MERRF) are caused by point mutations in the mitochondrial DNA, while Pearson Syndrome is usually sporadically inherited and is caused by large deletions of mtDNA. Such deletions can range from 1,000 to 10,000 DNA building blocks (nucleotides). The mtDNA deletions involved in Pearson marrow-pancreas syndrome impair oxidative phosphorylation and decrease the energy available to cells.

Genes within the mitochondria normally code for proteins that work inside the mitochondria. Proteins within each mitochondrion manufacture ATP in an assembly line fashion. They consume fuel molecules in the form of sugar and fat, in the presence of oxygen to manufacture ATP (Muscular Dystrophy Association (MDA), 2018a). Within the mitochondrial matrix, the Krebs cycle, or the citric acid cycle, generates the high-energy electron carriers NADH and FADH₂. These are generated through the oxidation of acetyl CoA to CO₂ coupled with the reduction of NAD+ and FAD. Five protein complexes referred to as complexes I, II, III, IV and V are embedded in a tightly folded membrane called the inner mitochondrial membrane. During oxidative phosphorylation, the protein complexes carry out chemical reactions that drive the production of ATP. An unequal electrical charge is created on either side of the inner mitochondrial membrane through a step-by-step transfer of electrons (released from NADH and FADH₂) coupled with movement of protons into the intermembrane space which creates an electrochemical gradient across the inner membrane. Complexes I through IV, which constitute the electron transport chain, move the electrons down the assembly line. Complex V which actually makes the ATP is called ATP synthase (Muscular Dystrophy Association (MDA), 2018a). Protons flow back into the matrix down their concentration gradient through ATP synthase resulting in the synthesis of ATP.

Defects in one or more these complexes typically cause mitochondrial disease (Muscular Dystrophy Association (MDA), 2018a). Muscle and nerve cells have high energy requirements which need ATP generated by mitochondria and hence, are very sensitive to mitochondrial defects. Besides not being able to produce ATP, mitochondrial defects can lead to an excess formation of harmful oxygen radicals within cells (Muscular Dystrophy Association (MDA), 2018a).

Risk factors

Risks of inheriting mitochondrial disease vary based on whether the mutations are in nDNA or mtDNA. For an autosomal recessive disorder it takes two mutated genes in nDNA to cause illness (Muscular Dystrophy Association (MDA), 2009a). A person with one gene mutation for an illness that requires two mutations to produce the illness is said to be a carrier (Muscular Dystrophy Association (MDA), 2018a). Assuming both parents are carriers for an autosomal recessive disorder, the likelihood of a child inheriting this disorder is 25 percent with each conception (Muscular Dystrophy Association (MDA), 2018a).

With respect to mitochondrial disorders caused by mutations in mtDNA the offspring of heteroplasmic mothers with mitochondrial DNA mutations are at risk of developing the same disorder. The mother’s egg cells contain both normal (wild type) and mutant mitochondria. Some egg cells may have just a few mutant mitochondria and so an offspring from one of these cells is likely to be healthy but an egg cell with more mutant mitochondria is likely to cause the disease in the offspring (Muscular Dystrophy Association (MDA), 2009a). The severity of the offspring’s disorder is dependent on how many normal versus mutant mitochondria the offspring inherits. Therefore, the risk of inheriting disease through mtDNA is variable. Finally, mitochondrial disease can also occur with no family history in a sporadic manner (Muscular Dystrophy Association (MDA), 2009a). Special care must be taken during pregnancy as this disorder can also occur at the embryonic stage. Another risk factor is a family history of the disease.

A person with a mitochondrial disease is at special risk immediately following an illness including colds, flu, and infections which can cause degradation in the person’s overall health condition and possibly even lead to death. Any illness needs prompt medical treatment.

Symptoms

Muscle weakness, muscle atrophy, and exercise intolerance which refer to exhaustion caused by physical exertion are some of the main symptoms of mitochondrial myopathy (Muscular Dystrophy Association (MDA), 2018b). These symptoms can vary even within the same family. Often times, weakness begins with the muscles of the eyes and the eyelids. This leads to progressive external ophthalmoplegia (PEO) or the progressive paralysis of eye movements, and ptosis which can be one of the first symptoms of this disease (Muscular Dystrophy Association (MDA), 2018b). Some of these symptoms may not be apparent till the patient is older.

Mitochondrial myopathies often cause weakness with other facial and neck muscles. This can cause speech to become slurred and more importantly, swallowing can become difficult or even impossible which can lead to aspiration into the lungs (Muscular Dystrophy Association (MDA), 2018b). People with mitochondrial myopathies experience increasing weakness in arms and/or legs and may eventually be unable to walk and/or use their arms (Muscular Dystrophy Association (MDA), 2018b). Another life-threatening symptom is weakness in the muscles that support breathing and consequently needing ventilator support to breathe (Muscular Dystrophy Association (MDA), 2018b).

Symptoms of mitochondrial encephalomyopathy include the above symptoms of mitochondrial myopathy in addition to hearing impairment, and migraine-like headaches and seizures often accompanied by stroke-like episodes (Muscular Dystrophy Association (MDA), 2018b). Vision can also be affected due to optic atrophy (shrinkage of the optic nerve) or retinopathy which affects the retinal cells at the back of the eye (Muscular Dystrophy Association (MDA), 2018b). Ataxia (difficulty with coordination and balance) can also occur, leading to falls (Muscular Dystrophy Association (MDA), 2018b).

Mitochondrial disease can also cause cardiac problems including conduction block (problem with rhythmic heart beats) and damage to cardiac muscle, kidney disease, gastrointestinal disorders, and/or diabetes (Muscular Dystrophy Association (MDA), 2018b).

There are specific pediatric concerns. Muscle weakness and/or brain abnormalities in children can lead to developmental delays (Muscular Dystrophy Association (MDA), 2018b). They may take longer to sit, crawl and walk (Muscular Dystrophy Association (MDA), 2018b). They may also have speech difficulties and other learning disabilities (Muscular Dystrophy Association (MDA), 2018b). So called “red flags” for mitochondrial disease in children include short stature, neurosensory hearing loss, ophthalmoplegia, ptosis, neuropathy or nerve disease, diabetes, hypertrophic cardiomyopathy or enlarged cardiac muscle, and renal tubular acidosis (Koenig, 2008).

Pharmaceutical treatments

More recent and not fully proven treatments seek to fix or bypass defective mitochondria. These treatments are not strictly drugs but rather supplements based on three natural occurring substances involved in ATP generation in cells (Muscular Dystrophy Association (MDA), 2009b). As such, they do not have the major side effects of pharmaceutical drugs though they can cause some side effects described below. These supplements are not efficacious in all people, though some people are helped by them.

The first substance, creatine, is a reserve for ATP and forms a compound called creatine phosphate (Muscular Dystrophy Association (MDA), 2009b). Creatine releases phosphate when a cell’s mitochondria cannot meet the cell’s demand for ATP. This is how the initial burst of ATP needed for demanding muscle activity is generated. However, this type of energy burst is short-lived. The standard dosage for adults is 10 grams/day, split into two doses. The pediatric dosage is 0.1 gram/kg per day, split into two doses (Parikh et al., 2009). The main side effect is gastrointestinal upset in some cases (Parikh et al., 2009).

Another substance, carnitine, helps improve the efficacy of ATP production by helping pull in specific fuel molecules such as fatty acids into mitochondria (Muscular Dystrophy Association (MDA), 2009b). Fatty acids are used as an energy substrate in all tissues except the brain. Carnitine is known as L-Carnitine supplement over-the-counter. The standard oral dose in children is 20–100 mg/kg/day split into two or three doses. The usual adult dose is 330–990 mg/dose twice or thrice per day, depending on clinical response (Parikh et al., 2009). One side effect is body odor caused by bacterial breakdown of carnitine. This can be treated by dose reduction. Gastrointestinal upset is another side effect (Parikh et al., 2009).

Lastly, coenzyme Q10, or coQ10, is a treatment target. It is a component of the electron transport chain that uses oxygen to create ATP (Muscular Dystrophy Association (MDA), 2009b). In some cases mitochondrial diseases are due to by coQ10 deficiency. In such cases supplementation with coQ10 may be of help. Recently CoQ10 is available in the form of ubiquinol with better absorption by the body. Standard dose of ubiquinol is 2 to 8 mg/kg per day twice a day with food (Parikh et al., 2009). Coenzyme Q10 is usually not prescribed for children. The main side effect is wakefulness (Parikh et al., 2009).

Creatine, L-carnitine and coQ10 supplements have been combined into a “mito cocktail” for treating mitochondrial disease. Although they do not work in many cases, they do provide modest benefits to some patients. The clinical ability to achieve optimal dosing of medications is limited and the long-term benefits of treatment are unknown at this time.