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Mitochondrial myopathies: Treatment

Mitochondrial myopathies: Treatment
Author:
Erin O'Ferrall, MD
Section Editors:
Jeremy M Shefner, MD, PhD
Sihoun Hahn, MD, PhD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Jul 2022. | This topic last updated: Dec 11, 2020.

INTRODUCTION — Mitochondrial diseases are present with a wide range of clinical phenotypes. The organ systems most reliant on aerobic metabolism are preferentially affected. Myopathy may be the sole or main sign, or merely an incidental finding associated with a multisystemic illness. Involvement of the nervous system in general (referred to as mitochondrial encephalomyopathy) is common. When skeletal muscle is affected, either alone or with central nervous system disease, the term mitochondrial myopathy is used. Although mitochondria are known to play a role in diverse cellular functions including redox balance, apoptosis, fatty acid oxidation, and calcium homeostasis, this review will focus on the treatment of mitochondrial diseases due to pathologic dysfunction of the mitochondrial respiratory chain.

The following groups illustrate the different ways mitochondrial myopathies can present clinically:

As chronic progressive external ophthalmoplegia (with or without mild proximal muscle weakness) or Kearns-Sayre syndrome

As an isolated myopathy with or without exercise intolerance and/or myalgia

As a severe myopathy or encephalomyopathy of infancy and childhood

As a predominantly multisystem disease (eg, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS])

A certain degree of overlap exists between all these entities. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Clinical features'.)

This topic will discuss symptomatic management of mitochondrial myopathies and review the evidence for exercise and pharmacologic agents, concentrating on those with more robust or more promising evidence. Finally, strategies for gene therapy will be introduced. Other aspects of mitochondrial myopathies are discussed separately. (See "Mitochondrial structure, function, and genetics" and "Mitochondrial myopathies: Clinical features and diagnosis".)

SYMPTOM MANAGEMENT — The mainstay of current treatment for patients with mitochondrial myopathies is supportive. Depending on the degree of impairment and the extent of neurologic involvement, the following evaluations and interventions may be required [1-3]:

Respiratory care – This is often a life-saving or life-sustaining measure in patients with chronic respiratory failure. A discussion of respiratory or sleep-related symptoms should occur regularly with the patient and family. Pulmonary function tests should be obtained at baseline and again as clinically indicated when symptoms appear. Interventions include noninvasive measures such as continuous positive air pressure (CPAP) and bilevel positive air pressure (BiPAP). Some patients may eventually require tracheostomy [4].

Control of seizures – Standard anticonvulsant therapy can be used to control seizures. An exception is that valproic acid and its derivatives should be avoided if possible because they inhibit the biosynthesis of carnitine, potentially leading to impaired mitochondrial beta-oxidation and fatty acid metabolism.

Cardiologic assessment for cardiomyopathy and conduction defects.

Ophthalmologic evaluation – Ptosis can be treated with frontalis muscle-eyelid suspension, levator palpebrae resection, eyelid crutches, or blepharoplasty. Cataracts are treated with intraocular lens replacement. Ophthalmoplegia usually does not require any specific intervention, but can be addressed by glasses with corrective prisms when accompanied by significant diplopia. Strabismus surgery is also an option if the degree of ophthalmoplegia is stable for at least six months on serial measurements [5].

Audiologic evaluation – Sensorineural hearing loss can be addressed with cochlear implants. Aminoglycosides should be avoided [6]. (See 'Drugs to avoid' below.)

Screening for diabetes mellitus – Diabetes can be managed with dietary modification, oral agents, or insulin as appropriate. However, metformin should be avoided because it has been associated with lactic acidosis. (See "Metformin poisoning".)

Multidisciplinary speech, physical, and occupational therapy – This can be helpful for patients with central nervous system deficits such as dysarthria, dysphagia, weakness, spasticity, and/or ataxia [7].

Cognitive evaluation and appropriate intervention.

Evaluation of liver and pancreatic function – Many medications used to treat epilepsy are metabolized by the liver and may be affected by liver dysfunction. Pancreatic enzymes (eg, pancrelipase) can be used to treat exocrine pancreas dysfunction.

Genetic counseling – As defined by the National Society of Genetic Counselors, genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease [8]. Inheritance of mitochondrial diseases may be maternal, autosomal dominant, autosomal recessive, or X-linked. Transmission can be complex due to several factors including heteroplasmy, denoting variable levels of mitochondrial mutations in different tissues (see "Mitochondrial structure, function, and genetics"). Parents of severely affected children, in particular, and affected patients of reproductive age should be offered genetic counseling to help with reproductive planning.

Nutritional support for patients with dysphagia, diabetes, weight loss, or exocrine pancreas dysfunction – In these cases, consultation with a nutritionist is indicated. A gastrostomy tube may be required if severe dysphagia is present. Specific diets may be used depending on both the nutritional status of the patient and the specific biochemical defect present.

Evaluation of renal and adrenal function – Renal function can be impaired due to proximal or distal renal tubule acidosis or as a complication of diabetes and may lead to significant electrolyte abnormalities. Although adrenal failure is not common overall in mitochondrial disease, it does occur in Kearns-Sayre syndrome and can be life-threatening.

EXERCISE — Exercise appears to be beneficial in mitochondrial disorders [9,10]. Aerobic exercise has been associated with increased peak work, oxidative capacity, and mitochondrial volume [11-14]. In addition, aerobic exercise can prevent muscle deconditioning and decrease exercise intolerance [15].

There is also some evidence that the response to resistance training exercise can alter the proportion of mutant and wild-type mitochondrial DNA (ie, gene shifting) in regenerated muscle fibers by activating wild-type satellite cells [13,16,17]. However, it is not clear whether this is a viable strategy to reduce the burden of mutant mitochondrial DNA in muscle and thereby improve muscle function.

Given these data, we suggest routine moderate level aerobic exercise (eg, walking, running, cycling, or swimming) combined with regular mild resistance strength training for patients with mitochondrial disorders who are able to participate in physical activity.

PHARMACOLOGIC THERAPY — There is no proven effective therapy for the primary mitochondrial disorders, although many agents are being evaluated in clinical trials [18,19]. Pharmacologic strategies that have been tested for these conditions include the use of respiratory chain cofactors, treatment with antioxidants, and agents that correct secondary biochemical deficits. Much of the evidence comes from single case reports and small open-label studies. A systematic review published in 2012 identified 12 randomized controlled trials that evaluated pharmacologic agents for mitochondrial diseases, but no clear evidence was found to support the use of any intervention [20].

Although not established as effective for mitochondrial disorders, our typical regimen for adults and adolescents is coenzyme Q10 (400 mg daily), creatine 10 g daily, and L-carnitine (990 mg daily in three divided doses). For children, some experts advocate the following regimen: coenzyme Q10 (10 to 20 mg/kg per day), L-carnitine (50 mg/kg per day), and riboflavin 100 to 400 mg a day; other experts include thiamine (50 to 100 mg per day).

Respiratory chain cofactors — Succinate, riboflavin, thiamine, and coenzyme Q10 participate as cofactors in the electron transport chain enzymes (figure 1). Supplementation is thought to enhance the activity of these enzymes when they are deficient [1].

Although evidence of possible modest benefit with coenzyme Q10 is sparse, we suggest it for patients with primary mitochondrial disorders, as discussed in the next section.

Vitamin B2 (riboflavin) replacement therapy (10 to 50 mg/kg day in children and up to 1500 mg/day in adults) was associated with stable or substantially improved function in case reports of patients with riboflavin transporter deficiency, and there were no observed adverse effects [21]. However, there is no evidence for its use in other mitochondrial diseases.

There is no evidence that supplementation with succinate or thiamine is useful in patients with mitochondrial disease.

Coenzyme Q10 — While treatment seems clearly indicated in primary or secondary coenzyme Q10 (CoQ10) deficiency (see 'Coenzyme Q10 deficiency' below), CoQ10 has also been used to treat mitochondrial disorders in which CoQ10 levels are not known or are not reduced. Coenzyme Q10 is both an antioxidant (as discussed in the next section) and an integral part of the mitochondrial respiratory chain, where it acts as an electron acceptor. It is uncertain which (if either) of these roles is beneficial when CoQ10 supplementation is used for patients with mitochondrial disorders. However, for patients with CoQ10 deficiency, benefit probably derives from its function as an electron carrier [1]. (See 'Coenzyme Q10 deficiency' below.)

Coenzyme Q10 has been evaluated in small randomized controlled trials, with equivocal results.

A placebo-controlled blinded crossover design evaluated 30 patients with various mitochondrial encephalomyopathies, including 15 with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and 11 with chronic progressive external ophthalmoplegia [22]. Treatment with CoQ10 (1200 mg daily) for 60 days did not lead to improvement in clinical measures such as grip strength, activities of daily living, or quality of life but did increase oxygen uptake (VO2) after 15 minutes of exercise and attenuated the rise in lactate.

Another double-blind crossover trial evaluated eight patients with various mitochondrial encephalomyopathies, including three with MELAS, who took CoQ10 (160 mg/day) for three months followed by a one month wash out period and then placebo for one month, or placebo for one month followed by CoQ10 for three months [23]. Coenzyme Q10 treatment led to a statistically significant increase in a global scale of muscle strength and an increase in serum levels of CoQ10.

The earliest trial evaluated 17 patients with chronic progressive external ophthalmoplegia and was negative [24].

Given the evidence of modest benefit in one trial, and the lack of serious side effects, we suggest treatment with CoQ10 for patients with mitochondrial disorders. The suggested dose is 5 mg/kg per day for infants and children and 400 mg daily for adolescents and adults. Higher doses are suggested for patients who have mitochondrial disease with CoQ10 deficiency. (See 'Coenzyme Q10 deficiency' below.)

Antioxidants — Mitochondrial diseases in general result in an increase in oxidative stress and higher levels of reactive oxygen species [25]. This may cause damage to the cell membrane through lipid peroxidation.

A number of antioxidants have been used to treat patients with mitochondrial myopathies, with the rationale that scavenging reactive oxygen species would lead to clinical improvement. The list includes coenzyme Q10, idebenone, vitamin E, and dihydrolipoate. While some reports suggested partial improvement in clinical function and/or biochemical parameters in some patients [26,27], there is no convincing evidence that use of vitamin E or dihydrolipoate leads to a clinically meaningful benefit. The evidence for coenzyme Q10 and idebenone is discussed separately. (See 'Coenzyme Q10' above and 'Idebenone' below.)

Idebenone — Idebenone (a synthetic analogue of coenzyme Q10) was tested in a randomized, placebo-controlled, double-blind trial of 85 patients with Leber hereditary optic neuropathy (LHON) [28]. There was no benefit with idebenone by intention-to-treat analysis for the primary outcome (best recovery in visual acuity). However, there was a trend for improved vision, and a post hoc analysis suggested benefit for a subgroup of patients with discordant visual acuity between eyes at baseline. These data led to the approval of idebenone in 2015 by the European Medicines Agency for the treatment of visual impairment in adolescent and adult patients with LHON.

Correcting secondary biochemical deficits — Levels of carnitine, creatine, and folate are decreased in patients with mitochondrial disorders, although the exact mechanisms are unclear [29,30]. Given the relative harmless effect of their supplementation, they are often given as part of a "mitochondrial cocktail" to patients. However, there is no compelling evidence that supplementation of these agents produces a clinically important benefit. Nevertheless, we suggest treatment with creatine and L-carnitine for patients with mitochondrial disorders, as discussed in the next sections.

Creatine — Two small trials tested creatine for mitochondrial disorders, with conflicting results.

In a placebo-controlled crossover trial involving six patients (five with MELAS and one with a mitochondrial myopathy), treatment with creatine (10 g/day for two weeks followed by 4 g/day for one week) resulted in improvement in some variables, including a statistically significant 20 percent increase in hand grip strength [31]. However, there was no improvement in activities of daily living.

A second placebo-controlled crossover trial involving 16 patients with a mitochondrial disorder (including 13 with chronic progressive external ophthalmoplegia) found no significant benefit after four weeks with high dose creatine (20 g daily) [32].

In another placebo-controlled crossover trial that analyzed results from 16 patients with various mitochondrial disorders, treatment with a combination of creatine, coenzyme Q10, and lipoic acid resulted in a reduction of serum lactate and a reduction in the decline of peak ankle dorsiflexion strength [33]. However, there was no effect on pulmonary function, or on peak handgrip or knee extension strength.

Given the evidence from at least one controlled trial of possible modest benefit, and its relative lack of side effects, we suggest creatine to most of our patients with mitochondrial encephalomyopathies.

The optimal creatine dose is uncertain. For adolescents and adults, one trial used 10 g daily for the first two weeks, followed by 4 g daily for maintenance [31]. However, cramps can be a problem at such high doses. For that reason, we usually start creatine at 4.5 g daily given in three divided doses, and titrate it up as tolerated, with a maximum total daily dose of 10 g. For infants and young children, creatine doses from 0.08 to 0.35 g/kg daily have been used [34].

Carnitine — L-carnitine (levocarnitine) has not been studied in controlled trials in the context of primary mitochondrial respiratory chain disorders. However, carnitine supplementation can be almost curative in carnitine transporter deficiency, also called primary systemic carnitine deficiency, which typically presents in childhood with dilated cardiomyopathy. (See "Specific fatty acid oxidation disorders", section on 'Carnitine transporter deficiency'.)

We suggest treatment with L-carnitine because it is generally safe and may help to correct an underlying deficiency of free carnitine [1]. The suggested dose for adolescents and adults is L-carnitine 1000 mg daily in the morning. The suggested dose for children is 100 to 200 mg/kg daily in four divided doses [35].

Folate — Folate is part of a metabolic pathway that provides methyl groups in the biosynthesis of DNA, RNA, hormones, and neurotransmitters. Folate deficiency can alter gene expression of mitochondrial DNA.

Cerebral folate deficiency is a condition where 5-methytetrehydrofolate levels are low in the cerebrospinal fluid while peripheral folate status is normal [36,37]. Cerebral folate deficiency has been associated with several mitochondrial disorders including patients with Kearns-Sayre syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), Leigh syndrome, and mitochondrial encephalopathies [38]. Cerebral folate deficiency is not limited to mitochondrial disease and occurs with other disorders including an autoimmune form with folate-receptor blocking antibodies, Rett syndrome, and Aicardi-Goutières Syndrome [39].

Some authors suggest high dose folinic acid supplementation (from 0.5 to 8 mg/kg per day) for mitochondrial disease although this is based only on reports of improvement in a small number of cases [36].

Select mitochondrial disorders — Coenzyme Q10 deficiency is responsive to high-dose coenzyme Q10 therapy. Small preliminary studies have evaluated continuous peritoneal dialysis, allogeneic hematopoietic stem cell transplantation, and enzyme replacement therapy for mitochondrial neurogastrointestinal encephalopathy (MNGIE), and l-arginine treatment for the syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), but efficacy has not been established. The evidence is presented in the sections that follow.

Coenzyme Q10 deficiency — Primary coenzyme Q10 (CoQ10) deficiency occurs in patients with disorders of CoQ10 biosynthesis, while secondary CoQ10 deficiency arises when a disorder of the mitochondrial respiratory chain reduces CoQ10 levels. The five main phenotypes of CoQ10 deficiency are cerebellar ataxia, severe infantile multisystem disease, nephropathy, isolated myopathy, and encephalomyopathy. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Coenzyme Q10 deficiency'.)

Although many patients with primary or secondary CoQ10 deficiency respond to CoQ10 replacement, it is not universally successful. However, observational evidence suggests that high-dose oral CoQ10 treatment is associated with clinically meaningful improvement in muscle function in some patients [40-44]. Furthermore, CoQ10 treatment can be life-saving in infants with encephalomyopathy [1,45,46]. On the other hand, central nervous system manifestations may be only partially reversible or may continue to progress despite treatment [44,47,48]. Anecdotal evidence suggests that treatment prior to the onset of overt neurologic symptoms (age 12 months in the reported case) can prevent neurologic involvement [48].

In a retrospective series of 76 patients with CoQ10 deficiency treated with CoQ10 supplementation, the following observations were made [44]:

Ataxia (n = 54) improved in 25 patients, although this patient group tended to require higher doses

Encephalomyopathy (n = 4) – encephalopathy improved in 1 patient; myopathy improved in all 4 patients

Isolated myopathy (n = 8) improved in 6

Infantile multisystem disease (n = 4) – some but not all symptoms improved in 2 patients

Isolated nephropathy (n = 4) – proteinuria reduced in 3 patients

We recommend high-dose oral CoQ10 treatment for patients with CoQ10 deficiency. Suggested CoQ10 dosing is 5 to 30 mg/kg daily (in three divided doses) for infants and children, 300 to 1500 mg daily for adolescents, and up to 2400 mg daily for adults [44-46].

Leigh syndrome — Leigh syndrome (subacute necrotizing encephalomyelopathy) is characterized by progressive neurodegeneration, external ophthalmoplegia, seizures, lactic acidosis, and symmetric lesions in the basal ganglia or brain stem on MRI. It most often presents in infancy or early childhood, although late childhood and adult onset has been reported. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Leigh syndrome'.)

There is no proven treatment for Leigh syndrome. However, patients with suspected Leigh syndrome should be treated with biotin (10 mg/kg) and thiamine (20 mg/kg) daily, since biotin-thiamine-responsive basal ganglia disease (BTBGD) is a treatable condition that mimics Leigh syndrome [49-51]. In addition to biotin and thiamine, it is reasonable to treat Leigh syndrome empirically with a combination of antioxidant and oxidative phosphorylation cofactors, including coenzyme Q10, carnitine, and riboflavin as first-tier supplements. Alpha lipoic acid, creatine monohydrate, and vitamin E can be added as second-tier supplements [52].

MNGIE — Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a multisystem mitochondrial disorder caused by mutations of the nuclear TYMP gene that encodes thymidine phosphorylase. Absence of thymidine phosphorylase leads to toxic substrate (thymidine) accumulation in the plasma and imbalance in the nucleotide pool, causing dysfunctional mitochondrial DNA replication. Mitochondrial DNA point mutations, multiple deletions, and/or depletion have been observed. In patients with residual thymidine phosphorylase activity of <10 percent, life expectancy is limited to the fourth decade. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MNGIE'.)

Hemodialysis [53] and platelet infusions [54] can temporarily reduce the circulating toxic levels of thymidine but do not offer a long-term solution. In a few case reports, treatment with continuous peritoneal dialysis for up to three years was associated with substantial improvement in the debilitating gastrointestinal, autonomic, and neurologic manifestations of MNGIE [55-57].

Disease-modifying approaches for MNGIE are investigational:

Allogeneic hematopoietic stem cell transplantation (HSCT) can restore thymidine phosphorylase activity and correct biochemical abnormalities, but mortality is high [58,59]. In a retrospective series of 24 patients with MNGIE who were treated with allogenic HSCT and followed for a median of approximately four years, 9 patients (38 percent) remained alive [59]. Among survivors, improvements in clinical manifestations of MNGIE (eg, gastrointestinal symptoms and peripheral neuropathy) were observed, but only after two years.

In a case report, repeated cycles of enzyme replacement therapy over more than two years with carrier erythrocyte-encapsulated thymidine phosphorylase was associated with biochemical and clinical improvements [60].

Liver is a source of thymidine phosphorylase [61] and orthotopic liver transplant has been proposed a treatment for MNGIE [62].

Further study is needed to determine whether these approaches are beneficial.

MELAS — The syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'), but no specific disease-modifying therapy is available.

The stroke-like episodes that occur in MELAS are thought to result from both a mitochondrial cytopathy and a mitochondrial angiopathy [63]. The mitochondrial cytopathy results from energy failure due to defective mitochondrial energy production in brain tissue. The mitochondrial angiopathy is a result of abnormal mitochondria in the endothelial and smooth muscles cells of the cerebral arterioles and capillaries, which causes impairment of vasodilation.

Both L-arginine and citrulline are precursors to nitric oxide, which mediates vasodilation. In addition, L-arginine may also have a positive effect on aerobic capacity and muscle metabolism [64]. Arginine supplementation has been used as a strategy to treat patients with MELAS, both as an infusion in the acute phase of the stroke-like episodes, and as an oral daily therapy [65,66].

In an open-label pilot study, L-arginine infusion (0.5 g/kg) or placebo was given in an approximately 2:1 ratio during the acute phase of 34 stroke-like episodes [65]. L-arginine was associated with a statistically significant short-term (24 hours) improvement in clinical symptoms. In the same study, oral L-arginine (4 to 24 g daily) was given to six patients with MELAS for 18 months, with a reduction in the frequency and severity of stroke symptoms compared with baseline [65]. Based upon limited data, some experts suggest urgent treatment of stroke-like episodes with a loading dose of intravenous arginine hydrochloride 0.5 g/kg, followed by a continuous infusion of 0.5 g/kg per day for the next three to five days, along with urgent intravenous normal saline to maintain cerebral perfusion and dextrose-containing fluids to provide an anabolic substrate [67,68]. Beyond the acute period, the same experts suggest prophylaxis with oral arginine 0.15 to 0.3 g/kg per day given in three divided doses.

One small case-control study found that the mean serum level of arginine was significantly lower in patients with MELAS than in healthy controls [65]. Another report found that compared with normal controls, children with MELAS had reductions in nitric oxide production, arginine flux, plasma arginine concentration, and citrulline flux [66]. Both arginine and citrulline supplementation were associated with increased nitric oxide production; the increase was greater with citrulline, suggesting that citrulline should be studied for the treatment of MELAS.

However, controlled trials are needed to establish whether arginine and citrulline treatment are beneficial in MELAS patients.

Stroke-like episodes in MELAS are often triggered by seizure, which causes energy depletion, neuronal injury, and breakdown of the blood-brain-barrier, which in turn leads to vasogenic edema [69]. Therefore, treatment of stroke-like episodes with anticonvulsants and high-dose glucocorticoids such as dexamethasone may be beneficial. However, this management approach remains speculative.

Thymidine kinase 2 deficiency — Pathogenic variants in the nuclear thymidine kinase 2 gene (TK2) cause depletion and multiple deletions of mitochondrial DNA, resulting in a progressive mitochondrial myopathy that usually begins in childhood. In an open-label study of 16 patients with thymidine kinase 2 deficiency, treatment with deoxynucleoside monophosphates and deoxynucleoside was associated with improved outcomes [70]; survival and motor function were better than expected (compared with historical control patients) for five patients with severe early-onset disease, and clinical measures stabilized or improved for 11 childhood- and adult-onset patients. Treatment was generally well-tolerated; adverse effects included dose-dependent diarrhea (not leading to withdrawal of treatment) in 8 patients, and reversible increase in liver enzymes in 2 of 12 patients treated with deoxynucleoside. Further studies are needed to establish benefit.

Drugs to avoid — Certain drugs may interfere with respiratory chain function, including valproic acid and its derivatives, carbamazepine, phenytoin, phenobarbital, and topiramate. barbiturates, tetracyclines, and chloramphenicol [10]. These medications generally should be avoided for patients with primary mitochondrial disorders.

In addition, aminoglycosides should be avoided in patients with multisystem mitochondrial disorders because such patients are at increased risk of hearing loss. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

Metformin should also be avoided because its major toxicity is lactic acidosis. This may be particularly important for patients with mitochondrial disorders who have undetected cardiomyopathy, a condition that probably increases the risk of metformin-induced lactic acidosis. (See "Metformin poisoning".)

GENE THERAPY — Given the lack of effective pharmacologic agents for mitochondrial disorders, research into genetic strategies is ongoing. However, no strategy has been found to be conclusively effective. Therapeutic modification of the mitochondrial genome presents challenges beyond those seen in disorders of nuclear DNA [71]. In particular, heteroplasmy and the presence of multiple genomes in even single cells have complicated current research. (See "Mitochondrial structure, function, and genetics".)

Experimental approaches to gene therapy include the following:

Delivery of a wild-type version of the defective gene using a viral vector. In a United States-based open-label study, five legally blind patients with Leber hereditary optic neuropathy (LHON) due to ND4 gene mutations in mitochondrial DNA were treated with an intravitreal injection of an adeno-associated virus vector containing the wild-type ND4 gene [72]. No serious safety issues were identified during 90 to 180 days of follow-up. Two of the five participants experienced an improvement in vision in the first 90 days. In a similar Chinese study, nine patients with LHON were treated, and were without complications over nine months of follow-up [73]. Controversy exists as to whether ND4 protein expression is truly increased inside the mitochondria. Further studies are needed.

Increasing the ratio of wild-type DNA to mutant DNA (ie, to manipulate the level of heteroplasmy), a method known as "gene shifting" [71,74]. Evidence that exercise can alter the ratio of wild-type DNA to mutant DNA in muscle is presented above. (See 'Exercise' above.)

Replacing the mutated mitochondrial DNA of the oocyte with a healthy mitochondrial genome from a donated oocyte. This can be accomplished by removing the cytoplasmic contents (including the abnormal mitochondria) from the mother's fertilized oocytes, transferring the nuclear content of these oocytes to a normal "enucleated" oocyte from a donor female prior to implantation [75-77]. The offspring would have all the nuclear genetic components of the parents but mitochondrial DNA from a donor female.

Using mitochondrial-targeted nucleases (termed zinc finger nuclease and transcription activator-like effector nucleases) to selectively eliminate or correct mutated mtDNA [78,79]. In addition, germline genome editing using CRISPR/Cas9 system has been proposed to correct pathologic mutations in the nuclear genome [78].

All of these techniques are experimental and most have been attempted only in animal models. Pre-implantation manipulation of embryos is controversial for ethical reasons and is not available in many areas.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mitochondrial disorders".)

SUMMARY AND RECOMMENDATIONS

The mainstay of current treatment for patients with mitochondrial disease remains supportive. Issues that may require evaluation and intervention include respiratory failure, seizures, cardiomyopathy and conduction defects, ophthalmoplegia, ptosis, cataracts, hearing loss, diabetes mellitus, neurologic deficits (including dysarthria, dysphagia, weakness, spasticity, and/or ataxia), and cognitive impairment. (See 'Symptom management' above.)

For patients with mitochondrial disorders who are able to participate in physical activity, we suggest routine, moderate level aerobic exercise and regular mild resistance training (Grade 2C). Options for aerobic exercise include walking, running, cycling, or swimming. (See 'Exercise' above.)

There is no proven pharmacologic therapy for the primary mitochondrial disorders. (See 'Pharmacologic therapy' above.)

For most patients with mitochondrial disorders, we suggest combination treatment with coenzyme Q10, creatine, and L-carnitine (Grade 2C). Our typical regimen for adults and adolescents is coenzyme Q10 400 mg daily, creatine 4 to 10 g daily in three divided doses, and L-carnitine 990 mg daily in three divided doses. (See 'Coenzyme Q10' above and 'Creatine' above and 'Carnitine' above.)

For patients with coenzyme Q10 deficiency, we recommend high-dose oral coenzyme Q10 treatment (Grade 1B). (See 'Coenzyme Q10 deficiency' above.)

For patients with mitochondrial neurogastrointestinal encephalopathy (MNGIE), case reports suggest that continuous peritoneal dialysis is a viable treatment option. (See 'MNGIE' above.)

For patients with the syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) who have acute stroke-like symptoms, we suggest urgent treatment with a loading dose of intravenous arginine hydrochloride 0.5 g/kg, followed by a continuous infusion of 0.5 g/kg per day for three to five days, along with intravenous normal saline and dextrose-containing fluids (Grade 2C). Beyond the acute period, we suggest oral arginine 0.15 to 0.3 g/kg per day given in three divided doses (Grade 2C). (See 'MELAS' above.)

Patients with primary mitochondrial disorders should avoid certain drugs if possible, including valproic acid and its derivatives, barbiturates, tetracyclines, chloramphenicol, aminoglycosides, and metformin. (See 'Drugs to avoid' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Angela Genge, MD, and Rami Massie, MD, who contributed to an earlier version of this topic review.

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Topic 5149 Version 25.0

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