Mitochondrial disorders: Treatment

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 regulation and functions" and "Mitochondrial myopathies: Clinical features and diagnosis".)

SUPPORTIVE CARE AND MONITORING — The mainstay of 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 indicated [1,2]:

●Respiratory – Respiratory evaluation and management 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, family, and caregivers. 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 [3].

●Epilepsy – 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.

●Cardiac – Cardiac involvement occurs in up to 30 percent of patients with mitochondrial disease [4]. Therefore, assessment for cardiomyopathy and conduction defects is important.

●Ophthalmologic – 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 – Sensorineural hearing loss can be addressed with cochlear implants. Aminoglycosides should be avoided [6]. (See 'Potentially toxic agents' below.)

●Endocrine – Diabetes mellitus 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", section on 'Lactic acidosis'.)

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

●Neurodevelopmental assessment – Many mitochondrial disorders can lead to neuroregression, characterized by a loss of developmental and cognitive abilities [2]. Patients should have baseline cognitive, behavioral, and developmental evaluations, along with appropriate intervention, as well as repeated evaluations as needed to track their function.

●Liver and pancreas – Certain mitochondrial disorders are associated with an increased risk of liver dysfunction and failure [2]. Annual transaminase levels are recommended, with more thorough evaluation if transaminases are elevated or if the patient develops symptoms. Note that many medications used to treat epilepsy are metabolized by the liver and may be affected by liver dysfunction.

Screening for pancreatic insufficiency is warranted for patients with mitochondrial disorders and unexplained diarrhea, steatorrhea, or growth failure [2].

●Nutrition – For patients with dysphagia, diabetes, weight loss, or exocrine pancreas dysfunction, 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.

●Renal and adrenal – 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. Patients should be monitored for electrolyte balance including sodium, potassium, calcium, magnesium, and phosphate. Electrolyte abnormalities should trigger an evaluation of renal tubular and adrenal function [2].

Although adrenal failure is not common overall in mitochondrial disease, it does occur in Kearns-Sayre syndrome and can be life threatening.

●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, psychologic, 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 pathogenic variants in different tissues (see "Mitochondrial regulation and functions"). Parents of severely affected children and affected patients of reproductive age should be offered genetic counseling to help with reproductive planning.

NONSPECIFIC TREATMENTS — There is no proven effective therapy for the primary mitochondrial disorders. Nonspecific empiric treatments include antioxidants and cofactor supplements (see 'Antioxidant and cofactor supplements' below), exercise (see 'Exercise' below), and dietary therapies (see 'Ketogenic dietary therapy' below).

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 [9].

Antioxidant and cofactor supplements

Our approach

●Although not established as effective for mitochondrial disorders, our typical regimen for adults and adolescents is a multivitamin, coenzyme Q10 (CoQ10; 400 mg daily), creatine (10 g daily), L-carnitine (levocarnitine) supplementation (990 mg daily in three divided doses), folate (1 mg daily), and B complex vitamins (eg, vitamin B-100 complex, one tablet daily). We add vitamin D and vitamin B12 supplementation if measured to be deficient in the serum.

●For children, some experts advocate the following regimen: CoQ10 (10 to 20 mg/kg per day), L-carnitine supplementation (50 mg/kg per day), and vitamine B2 (riboflavin) 100 to 400 mg per day; other experts include thiamine (50 to 100 mg per day).

Rationale — Mitochondrial diseases in general result in an increase in oxidative stress and higher levels of reactive oxygen species [10]. This may cause damage to the cell membrane through lipid peroxidation.

Several 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 CoQ10 (antioxidant in its reduced form), idebenone (a synthetic analog of CoQ10), vitamin E, alpha-lipoic acid (or dihydrolipoate, its reduced form), and compounds with antioxidant activity (eg, L-carnitine, vitamin C) [11].

Succinate, riboflavin, thiamine, CoQ10, creatine monophosphate, and alpha-lipoic acid 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 [12].

Levels of carnitine, creatine, and folate are decreased in patients with mitochondrial disorders, although the exact mechanisms are unclear [13,14]. Given the relatively 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.

Specific supplements

●Alpha-lipoic acid – Alpha-lipoic acid is an antioxidant that is used in some mitochondrial disease "cocktails," but clinical data are sparse [15,16].

●Carnitine – L-carnitine 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 [12]. While we recommend measuring total and free carnitine levels on a regular basis, the suggested dose for adolescents and adults is L-carnitine supplementation 1000 mg daily in the morning. The suggested dose for children is 50 to 100 mg/kg per day, given in four divided doses [17]. Older patients on carnitine who are at high risk for or are known to have coronary artery disease should be monitored in consultation with cardiology, since some studies suggest a theoretical risk of progression due to the trimethylamine-N-oxide metabolite of carnitine [18,19]. However, other reports suggest that higher L-carnitine levels are associated with a lower risk of cardiovascular events [20].

●Coenzyme Q10 – Given the evidence of modest benefit in one trial and the lack of serious side effects, we suggest treatment with CoQ10 for most patients with mitochondrial disorders in which CoQ10 levels are not known or are not reduced. 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 'CoQ10 deficiency' below.)

CoQ10 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 [21]. 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 it 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 washout period and then placebo for one month, or placebo for one month followed by CoQ10 for three months [22]. CoQ10 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 [23].

It is unlikely there is a different response to CoQ10 between the reduced form (ubiquinol) and the oxidized form (ubiquinone), though CoQ10 bioavailability in humans is highly variable [24].

●Creatine – Given the evidence from at least one controlled trial of possible modest benefit, as well as 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 [25]. However, cramps can be a problem at such high doses. Therefore, we usually start creatine at 4.5 g daily given in three divided doses and titrate it up as tolerated, with a maximum total dose of 10 g per day. For infants and young children, creatine doses from 0.08 to 0.35 g/kg daily have been used [26].

However, the evidence for benefit is inconsistent. 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 [25]. 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) [27].

In another placebo-controlled crossover trial that analyzed results from 16 patients with various mitochondrial disorders, treatment with a combination of creatine, CoQ10, and alpha-lipoic acid resulted in a reduction of serum lactate and a reduction in the decline of peak ankle dorsiflexion strength [15]. However, there was no effect on pulmonary function or on peak handgrip or knee extension strength.

●Folate – Folate is part of a metabolic pathway that provides methyl groups in the biosynthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), hormones, and neurotransmitters. Folate deficiency can alter gene expression of mitochondrial DNA.

Cerebral folate deficiency is a condition in which 5-methyltetrahydrofolate levels are low in the cerebrospinal fluid while peripheral folate status is normal [28,29]. Cerebral folate deficiency has been associated with several mitochondrial disorders including Kearns-Sayre syndrome; the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP); Leigh syndrome; and mitochondrial encephalomyopathies [30]. 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 [31].

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 [28].

●Vitamin B2 – 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 [32]. However, there is no evidence for its use in other mitochondrial diseases.

Exercise — 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 can participate in physical activity.

Exercise appears to be beneficial in mitochondrial disorders [11,33]. Aerobic exercise has been associated with increased peak work, oxidative capacity, and mitochondrial volume [34-37]. In addition, aerobic exercise can prevent muscle deconditioning and decrease exercise intolerance [38].

There is also some evidence that the response to resistance training exercise can alter the proportion of mutant and wildtype mitochondrial DNA (ie, gene shifting) in regenerated muscle fibers by activating wildtype satellite cells [36,39,40]. 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.

Ketogenic dietary therapy — Ketogenic dietary therapy (KDT) is an option for patients with mitochondrial disorders, particularly for patients with drug-resistant epilepsy, which is a common manifestation of mitochondrial dysfunction, and for patients with pyruvate dehydrogenase deficiency [11]. However, KDT is contraindicated in patients with mitochondrial DNA deletion-related myopathy [41]. When employed, KDT should be administered in the context of a multidisciplinary team including a nutritionist and with careful monitoring of blood sugar, electrolytes, cholesterol, bone density, and symptoms suggesting renal colic or constipation. Growth should also be monitored in pediatric patients.

The classic ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that produces metabolic changes in plasma ketones, insulin, glucose, glucagon, and free fatty acids. Potential mechanisms of ketone body metabolism that may benefit patients with mitochondrial disorders include reduced levels of oxidative stress and increased levels of antioxidants and free radical scavengers [41-43].

A 2020 systematic review identified 17 reports of 20 patients with genetically proven mitochondrial disease using KDT that met inclusion criteria [41]. KDT was associated with seizure control of refractory epilepsy in 7 of 8 cases (temporary in 4), improved muscular symptoms in 3 of 10, and reversal of the clinical phenotype in 4 of 20 cases. However, in five adults with mitochondrial DNA deletion-related myopathy, KDT was stopped due to the development of rhabdomyolysis. Three patients with POLG pathogenic variants and Alpers syndrome died while on KDT, but their death was not considered related to KDT.

In a prospective open-label study of pediatric patients with mitochondrial disease and epilepsy, KDT was associated with a ≥50 percent reduction in seizures at three months in 9 of 22 patients (41 percent) [44]. A similar proportion withdrew from the study due to inability to tolerate or comply with KDT.

Patients with epilepsy and complex I mitochondrial disorders may be particularly responsive to KDT [45]. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

POTENTIALLY TOXIC AGENTS

Drugs of concern — A number of medications should be avoided if possible, or used with caution when necessary, for patients with mitochondrial disorders [11,46]:

●Antiseizure medications:

•Valproic acid and its derivatives

•Carbamazepine

•Phenytoin

•Phenobarbital

•Topiramate

•Zonisamide

●Antibiotics:

•Aminoglycosides

•Antiretrovirals

•Chloramphenicol

•Clevudine

•Linezolid

●Dichloroacetate

●Metformin

●Statins

●Anesthetics:

•Isoflurane

•Propofol

Associated risks

●Valproate increases the risk of liver failure and seizures including status epilepticus, particularly in patients with pathogenic variants in POLG [46]. Weaker evidence suggests that carbamazepine, phenytoin, and phenobarbital may cause seizure aggravation [11]. Topiramate and zonisamide are partial carbonic anhydrase inhibitors that can cause metabolic acidosis in some patients [47].

●Mitochondria are susceptible to aminoglycosides and other antibiotics targeting the bacterial ribosome [46]. 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".)

●Chloramphenicol use is associated with a low risk of acute hepatitis, blood dyscrasia, and bone marrow suppression, so alternative agents are preferred for patients with systemic mitochondrial disorders affecting the liver or bone marrow, including mitochondrial DNA depletion syndromes and Pearson syndrome [46].

●Linezolid and metformin increase the risk of lactic acidosis [46]. This may be particularly important for patients with mitochondrial disorders who have undetected cardiomyopathy, a condition that probably increases the risk of lactic acidosis. (See "Metformin poisoning", section on 'Lactic acidosis'.)

●Antiretrovirals, clevudine, and statins increase the risk of myopathy, and patients with mitochondrial disorders may be particularly susceptible to myopathy associated with statin therapy [11,46,48]. (See "Statin muscle-related adverse events".)

●Isoflurane and propofol are potential mitochondrial toxins, and patients with mitochondrial disorders may be at increased risk of developing propofol infusion syndrome [48,49].

MANAGEMENT OF INDIVIDUAL DISORDERS

CoQ10 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. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Coenzyme Q10 deficiency'.)

●Treatment – We suggest 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 [50-53].

Although some patients with primary or secondary CoQ10 deficiency respond to CoQ10 replacement, it is not universally successful. In a 2022 systematic review that identified 89 patients with primary CoQ10 deficiency treated with oral CoQ10 supplementation, nonresponders made up 73 percent of the cases [53]. In the 27 percent with improvement, the response was only partial and frequently involved only a single symptom. CoQ10 supplementation was not associated with substantial adverse effects in patients with CoQ10 deficiency [53].

However, limited observational evidence suggests that high-dose oral CoQ10 treatment is associated with clinically meaningful improvement in muscle function in some patients [52,54-57]. Furthermore, CoQ10 treatment can be life-saving in infants with encephalomyopathy [12,50,51]. On the other hand, central nervous system manifestations may be only partially reversible or may continue to progress despite treatment [52,58,59]. Anecdotal evidence suggests that treatment prior to the onset of overt neurologic symptoms (age 12 months in the reported case) can prevent neurologic involvement [59].

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 brainstem on magnetic resonance imaging (MRI). It most often presents in infancy or early childhood, although late childhood and adult onset have been reported. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Leigh syndrome'.)

●Treatment – 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 [60-62].

In addition to biotin and thiamine, it is also reasonable to treat Leigh syndrome empirically with a combination of antioxidant and oxidative phosphorylation cofactors, including CoQ10, carnitine supplementation, vitamin B2 (riboflavin), alpha-lipoic acid, creatine monohydrate, and vitamin E [63].

LHON — Leber hereditary optic neuropathy (LHON) is a maternally inherited bilateral subacute optic neuropathy that typically produces severe and permanent visual loss, typically in young males but increasingly recognized in females [64]. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Leber hereditary optic neuropathy'.)

●Evaluation – Prior to treatment, patients with LHON should be referred to neuro-ophthalmology for clinical evaluation, management, and follow-up. Testing typically includes visual acuity, automated visual fields, and optical coherence tomography for analysis of the optic nerve head, retinal nerve fiber layer, and macular nerve fiber and ganglion cell layer [65].

●Treatment – There is no proven effective treatment for LHON. Idebenone (a synthetic analog of CoQ10) is approved in Europe for the treatment of visual impairment in adolescent and adult patients with LHON. Most of the data suggesting benefit are retrospective [65-67]. Idebenone was tested in a randomized, placebo-controlled, double-blind trial of 85 patients with LHON [68]. 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. Where available, a one- to three-year trial of idebenone may be considered for symptomatic patients in conjunction with regular neuro-ophthalmologic testing as described above.

Small studies have evaluated gene therapy for LHON, employing a viral vector to deliver a wildtype version of the defective gene. In an open-label study, five legally blind patients with LHON due to ND4 pathogenic variants in mitochondrial DNA were treated with an intravitreal injection of an adeno-associated virus (AAV) vector containing the wildtype ND4 gene [69]. 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. Subsequent studies of gene therapy for LHON using intravitreal injections of AAV vectors found that the treatment is safe and well tolerated [70-75]. Although most of these studies were underpowered for efficacy, several reported improved visual acuity.

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.

●Evaluation – For suspected acute stroke-like episodes, evaluation involves blood studies to include serum lactate, brain MRI, electroencephalography (EEG), and additional tests as appropriate for the evaluation of acute stroke and seizure (table 1) [76].

●Treatment – Stroke-like episodes in MELAS can be triggered by seizure, which causes energy depletion, neuronal injury, and breakdown of the blood-brain barrier, which in turn leads to vasogenic edema [77].

For patients with MELAS who have stroke-like episodes accompanied by seizure, a 2019 consensus statement recommends aggressive treatment with antiseizure medication using intravenous levetiracetam (20 to 40 mg/kg, maximum 4500 mg) as first choice [76]. Other options are phenytoin (15 to 20 mg/kg with cardiac monitoring), phenobarbitone (10 to 15 mg/kg with respiratory monitoring), or lacosamide (200 to 400 mg). The role of antiseizure medications is unclear for patients with no history of seizure-like events and no epileptiform activity on EEG. Some experts have also treated stroke-like episodes with urgent intravenous normal saline to maintain cerebral perfusion and with dextrose-containing fluids to provide an anabolic substrate [78,79].

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 [80-82]. However, evidence of efficacy is lacking. A systematic review of L-arginine treatment of stroke-like episodes in patients with mitochondrial disease identified 37 articles (zero randomized controlled trials, three nonrandomized open-label studies, one retrospective cohort study, and 33 case reports or case series) with a total of 91 patients [83]. There was no obvious clinical benefit of L-arginine treatment, and the overall quality of the evidence was rated as poor. However, there is no clear consensus on the use of arginine for MELAS [84].

Controlled trials would be needed to establish whether arginine and citrulline treatment are beneficial in MELAS patients.

●Mechanism – The mechanism of the stroke-like episodes that occur in MELAS is not well defined.

•One theory suggests that the stroke-like episodes result from ictal activity with neuronal hyperexcitability [76,85,86]. In support of this, stroke-like episodes in MELAS may be triggered by seizures, causing energy depletion, neuronal injury, and breakdown of the blood-brain barrier, which in turn leads to vasogenic edema [77]. Furthermore, observational data suggest that the clinical, radiologic, electroencephalographic, and neuropathologic findings associated with stroke-like episodes in MELAS are similar to those associated with epilepsy [87].

•The vascular theory proposes that the stroke-like episodes result from both a mitochondrial cytopathy and a mitochondrial angiopathy [88]. 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 muscle cells of the cerebral arterioles and capillaries, which causes impairment of vasodilation and perfusion [89,90]. Some studies have suggested that stroke-like episodes are linked to deficiency of nitric oxide, which mediates vasodilation, or to low plasma levels of L-arginine or citrulline, which are precursors to nitric oxide [80,89,91]. However, convincing evidence of hypoperfusion or ischemia during stroke-like episodes is lacking, and the brain lesions accompanying the stroke-like episodes do not conform to vascular territories [76].

MNGIE — Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare multisystem mitochondrial disorder caused by pathogenic variants 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. 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'.)

●Treatment – Evidence for efficacy of treatments for MNGIE is limited.

•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 [92-94]. Hemodialysis [95] and platelet infusions [96] can temporarily reduce the circulating toxic levels of thymidine but do not offer a long-term solution.

•Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential disease-modifying treatments for MNGIE [11,97,98]. HSCT can restore thymidine phosphorylase activity and correct biochemical abnormalities, but mortality is high [97,99]. In a retrospective series of 24 patients with MNGIE who were treated with allogenic HSCT and followed for a median of approximately four years, only nine patients (38 percent) remained alive [97]. Among survivors, improvements in clinical manifestations of MNGIE (eg, gastrointestinal symptoms and peripheral neuropathy) were observed, but only after two years.

•Enzyme replacement therapy with carrier erythrocyte-encapsulated thymidine phosphorylase, given in repeated cycles over more than two years, was associated with biochemical and clinical improvements in a case report [100].

•Orthotopic liver transplantation has been proposed as a treatment for MNGIE [101,102], as the liver is a source of thymidine phosphorylase [103].

Since evidence is sparse, treatment recommendations for MNGIE are based on expert opinion [104,105] and are individualized according to patient context. In younger patients who are early in the disease course, orthotopic liver transplantation may be considered. Peritoneal dialysis or enzyme replacement therapy (if available) can be used as a bridge to liver transplantation or offered to patients who are not eligible for liver transplantation. Further study is needed to determine if the benefits of HSCT outweigh the risks. Autologous HSCT with genetically modified stem cells may be an option in the future [104].

TK2 deficiency — Pathogenic variants in the nuclear thymidine kinase 2 (TK2) gene cause depletion and multiple deletions of mitochondrial DNA, resulting in a progressive mitochondrial myopathy that usually begins in childhood.

●Treatment – Oral deoxynucleoside supplementation is a potential therapy for TK2 [46,106]. In an open-label study of 16 patients with TK2 deficiency, treatment with deoxynucleoside monophosphates and deoxynucleoside was associated with improved outcomes; 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 [107]. 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.

GENETIC 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 [108]. In particular, heteroplasmy and the presence of multiple genomes in even single cells have complicated research in this field. (See "Mitochondrial regulation and functions".)

Experimental approaches to gene therapy include the following:

●Delivery of a wildtype version of the defective gene using a viral vector for Leber hereditary optic neuropathy (LHON). (See 'LHON' above.)

●Increasing the ratio of wildtype DNA to mutant DNA (ie, to manipulate the level of heteroplasmy), a method known as "gene shifting" [108,109]. Evidence that exercise can alter the ratio of wildtype 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 [110-112]. 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 mitochondrial DNA [113,114]. In addition, germline genome editing using CRISPR/Cas9 system has been proposed to correct pathologic mutations in the nuclear genome [113].

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

●Supportive care – There is no proven pharmacologic therapy for the primary mitochondrial disorders. The mainstay of 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 'Supportive care and monitoring' above.)

●Supplements – For most patients with mitochondrial disorders, we suggest treatment with a combination of antioxidant and cofactor supplements (Grade 2C). However, these supplements are not established as effective for mitochondrial disorders. Our typical regimen for adults and adolescents is multivitamin, coenzyme Q10 (CoQ10; 400 mg daily), creatine (10 g daily), L-carnitine (levocarnitine) supplementation (990 mg daily in three divided doses), folate (1 mg daily), and B complex vitamins (eg, vitamin B-100 complex, one tablet daily). (See 'Antioxidant and cofactor supplements' above.)

●Exercise – For patients with mitochondrial disorders who are able to participate in physical activity, routine, moderate-level aerobic exercise and regular mild resistance training may be beneficial. Options for aerobic exercise include walking, running, cycling, or swimming. (See 'Exercise' above.)

●Ketogenic dietary therapy – This is an option for some patients with mitochondrial disorders, particularly those with concurrent epilepsy, and for patients with pyruvate dehydrogenase deficiency. (See 'Ketogenic dietary therapy' above.)

●Avoidance of mitochondrial toxins – Patients with mitochondrial disorders should avoid certain drugs if possible, as listed above. (See 'Potentially toxic agents' above.)

●Treatment of specific mitochondrial disorders

•CoQ10 deficiency – For patients with CoQ10 deficiency, we suggest high-dose oral CoQ10 treatment (Grade 2C). (See 'CoQ10 deficiency' above.)

•Leigh syndrome – While there is no proven treatment for Leigh syndrome, 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. It is also reasonable to treat Leigh syndrome empirically with a CoQ10, carnitine supplementation, riboflavin, alpha-lipoic acid, creatine monohydrate, and vitamin E. (See 'Leigh syndrome' above.)

•LHON – There is no proven effective treatment for Leber hereditary optic neuropathy (LHON). Idebenone is used by some experts and is approved in Europe for the treatment of visual impairment in adolescent and adult patients with LHON. (See 'LHON' above.)

•MELAS – For patients with the syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) who have seizures, we treat with intravenous levetiracetam (20 to 40 mg/kg, maximum 4500 mg) as our preferred antiseizure medication (Grade 2C). Other options are intravenous phenytoin, phenobarbital, or lacosamide. The role of antiseizure medications in patients with MELAS but without seizures is unclear. Additionally, some experts treat stroke-like episodes with intravenous L-arginine or normal saline and dextrose-containing fluids. (See 'MELAS' above.)

•MNGIE – Evidence of efficacy is limited for treatments of mitochondrial neurogastrointestinal encephalopathy (MNGIE). For younger patients who are early in the disease course, orthotopic liver transplantation may be considered. Peritoneal dialysis or enzyme replacement therapy (if available) can be used as a bridge to liver transplantation or offered to patients who are not eligible for liver transplantation. (See 'MNGIE' above.)

•TK2 deficiency – Oral deoxynucleoside supplementation is a potential therapy for thymidine kinase 2 (TK2) deficiency. (See 'TK2 deficiency' above.)

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