Author(s): Amanda Lindenberg, DO, MOT, Stephanie Barton, DO
Originally published: September 20, 2013 Last updated: April 10, 2025
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Disease/Disorder

See Mitochondrial Disorders: Part One

Essentials of Assessment

See Mitochondrial Disorders: Part One

Rehabilitation Management and Treatments

Available or current treatment guidelines

Currently, no curative treatments exist. Treatment guidelines for management of mitochondrial disorders are primarily supportive and palliative which target both the neurologic and systemic symptoms. Early treatment of organ specific symptoms is recommended as well as avoiding triggers.1,2 Individualized assessment and management is specific to each patient. Multi-disciplinary neuromuscular clinics may be an excellent resource for some patients given multiple needs.

Neurological management includes early seizure control with the use of antiepileptics. In patients with myoclonic epilepsy and ragged red fibers (MERRF), levetiracetam is the most commonly used anti-epileptic.3 Oxcarbazepine, carbamazepine, and phenytoin should be avoided as it may worsen myoclonus.3,4 Additionally, valproic acid inhibits carnitine uptake which contributes to liver failure and therefore should be avoided in seizure management of mitochondrial disorders.4

Early referral to cardiology should be placed for patients with Kearns-Sayre Syndrome (KSS) and those with arrhythmias such as Wolf Parkinson White or atrioventricular block. Permanent pacemakers have been implanted to avoid sudden cardiac death in children under current management guidelines. Supportive management of hypertension, heart failure and cardiomyopathy is crucial especially in the setting of acute crisis and treating the underlying cause of the crisis. Exercise stress testing and electrocardiogram is recommended in asymptomatic individuals as symptoms often present with advanced disease.1

Endocrinopathies such as diabetes mellitus, hormone deficiency and adrenal insufficiency should be managed by endocrinologists. Diabetes mellitus is typically due to insulin deficiency rather than resistance.1 Metformin should be avoided as it can worsen lactic acidosis and unmask metabolic stress.2,5 Short stature is often related to the growth hormone deficiency which also can be managed by endocrinology.1 Dieticians and/or gastroenterology should be involved for weight and diet management as several of these disorders result in a hypermetabolic state leading to poor weight gain and growth delay.

Physical therapy, occupational therapy, physical therapy and physiatrists should be consulted early for developmental delay, regression of development, to facilitate function and equipment needs associated with progression of disease. Aerobic and endurance training with or without resistive exercise has been shown to increase mitochondrial mass and help activate mitochondrial biogenesis which has translated to improved quality of life and activities of daily living.1,6 Resistance training demonstrated improved strength and aerobic capacity but did not have a significant effect on mutated mtDNA or myopathic fibers.1,6 Moreover, physical activity and exercise should be encouraged.

There are several supplements such as L-carnitine, succinate, riboflavin, other B vitamins, alpha lipoic acid, vitamin E, and folinic acid that have anecdotal report of benefit; however none have shown sustained benefits.1 Their use is controversial and requires individualization. Vitamin C has recently been shown to be an inadequate antioxidant and no longer recommended.7 L- carnitine should be restricted to Leigh syndrome (LS) and Mitochondrial Encephalopathy with Lactic Acidosis and Stroke Like Episodes (MELAS) due to risk of accelerated cardiac atherosclerosis.7 Coenzyme Q10 (CoQ10) is one of the most common supplements recommended despite a paucity of evidence for reversal of symptoms. It may delay progression of disease.6 There are a few mitochondrial disorders with deficits in CoQ10 biosynthesis defects and therefore supplementation is essential. Similarly, there are disorders that affect riboflavin transport and metabolism in which supplementation is necessary.8 One vitamin that has promising evidence of benefit is Thiamine (vitamin B1). It is a treatment for Leigh Syndrome due to nuclear DNA mutation demonstrating symptomatic improvement and minimal slowing of disease progression. This is likely due to improvement of transporter deficiency.9 These studies further support the need for individualization based on biochemical defect. Genetics teams often help with guidance of this individualized management.

Idebenone (Raxone, Puldysa) is a synthetic short chain analogue of CoQ10 acting as an antioxidant, inhibits lipid peroxidation and further facilitates flux of electrons through the transport chain. It has been shown to be partially effective in acute, subacute and dynamic clinical stages of LHON with some patients experiencing clinically significant visual benefits.10-12 Those with the m.1178 mutation and older age of onset responded better than others.11,12 Consistent with natural history, younger age of onset have more spontaneous resolution of symptoms. Treatment is recommended for more than 24 months. Idebenone has been studied in other mitochondrial disorders such as MELAS, KSS as it crosses the blood brain barrier.6 It is the first European Medical Agency approved specific drug for LHON. At this time, use as a preventative agent is not recommended.1,10-12

For all patients, the following medications should be avoided as they can contribute to negative metabolic and mitochondrial effects: propofol, volatile general anesthetics, aminoglycoside antibiotics, linezolid, valproic acid, barbiturates, statins and metformin.4,7,13 Febrile illness and stress can trigger acute exacerbations and therefore childhood vaccinations should be given in a timely manner. While we promote inclusivity in the classroom, special consideration should be taken for homebound education and therapy services during certain seasons where acute illness is rapidly spread in the classroom to avoid exacerbation and irreversible decline.

At different disease stages

There are no consistent disease stages among the numerous mitochondrial disorders. Some show rapidly progressive multi-system failure. Others show slowly progressive single-organ degeneration or periods of relative stability with interval regressions often in the setting of metabolic stress or illness that may or may not be partially recovered.

It is vital to maximize function throughout the disease course with supportive prescriptions. Consider physical, occupational, and speech therapy as needed to maximize strength, range-of-motion, balance, coordination, endurance, and function.

For episodic disease such as MELAS or acute functional decline associated with intercurrent illness, consider acute inpatient rehabilitation to maximize functional recovery.

Manage tone issues such as dystonia and spasticity with a combination of stretching, bracing, oral medications, and chemodenervation. Consider invasive modalities such as intrathecal baclofen therapy and deep brain stimulation when appropriate.

Because of the progressive nature of the disease, apply assistive technology and environmental controls early as adjuncts to current function. Apply bracing and adaptive equipment together with physical therapy to maximize independent ambulation. Expeditious transition to adapted mobility device when patient loses efficient independent ambulation.

Frequent follow up for monitoring of their function, preventing irreversible complications, and improving their quality of life is essential.

Coordination of care

Multidisciplinary care is strongly recommended. The team should include physiatry, neurology, genetics, case management, and complex medical care to direct referrals to other subspecialties such as cardiology, ophthalmology, neurology, and endocrinology as well as timely initiation of physical, occupational, and speech therapy. Consider the integration of palliative care into the multidisciplinary team.

Patient & family education

Provide anticipatory guidance to the patient and family about the progressive nature of mitochondrial disorders. Encourage the patient and family to utilize services provided by organizations such as the United Mitochondrial Disease Foundation and the Muscular Dystrophy Association. Provide assistance to the patient and family with identification of emotional support system, financial assistance, respite care, in-home nursing, monitoring and consolidation of medical appointments, transportation, and community recreation. Also provide assistance with obtaining services, as entitled, through the Individuals with Disabilities Act, including 504 plan and Individual Education Plan at school.

The Muscular Dystrophy Association helps fund research into mitochondrial diseases as well as provides support and information to patients and families with mitochondrial myopathies. Some of the myopathies that MDA clinics help manage include Kearns-Sayre, Leigh, MELAS, TK2 deficiency and MERRF. The Muscular Dystrophy Association also helps connect mitochondrial myopathy patients with the closest MDA clinics in their area.14

Emerging/unique interventions

Functional measures such as the Gross Motor Function Measure and Manual Ability Classification System 6 minute walk test, North Star Ambulatory Scale, or Bayley Scale of Infant and Toddler Development may be utilized; however, they are not validated for mitochondrial disorders. Neuropsychological testing can also be useful in monitoring the progression of cognitive function.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • Suspect mitochondrial disease in patients who present with significant weakness out of proportion to tone abnormalities or relatively low CPK elevations.
  • Suspect mitochondrial disease in patients who present with new onset metabolic disease and functional deficits.
  • Coordinate care with a multidisciplinary team that stays abreast with current research to ensure the implementation of the most up-to-date and evidence-based management plan.
  • Patients with mitochondrial disorders have increased risk of developing metabolic crises. Aggressive medical intervention, including possible inpatient admission, should be initiated at the first signs of illness.
  • Upon suspicion of diagnosis, multi-organ evaluation should be done. This includes comprehensive neurologic exam with cognitive assessments, brain MRI, audiologic & ophthalmologic exams, growth assessment, echo and EKG, and endocrine screening (hypothyroidism, DM).1,2,7,9

Cutting Edge/Emerging and Unique Concepts and Practice

Genetic therapeutic techniques targeting the mtDNA and nDNA are actively being investigated and are one of the key areas of cutting edge research.

Phase 3 gene therapy trials for LHON patients involve wild type mtDNA being delivered via viral vectors (adenovirus) carrying NDH4 gene directly into their eyes with intravitreal injection. This is known as allotopic gene therapy. The goal being incorporation into retinal ganglion cells, preserving them, and stabilization or improvement of vision.12 Studies demonstratedincreased size of the visual field, sustained improvement in visual acuity in bilateral eyes despite treatment in one eye in those with onset of symptoms of up to 12 months in those with m.1178G>A mutation. Current clinical trials are recruiting patients to evaluate efficacy at various onsets of disease and optimal dosing.12

Mitochondrial donation for female carriers of disease-causing mtDNA mutations are currently being investigated, with favorable results in primate models. It is completed in healthy oocytes or fertilized egg. This service is currently available in the United Kingdom. It is not available elsewhere due to ethical concerns and perceived need for more advanced research.15

Mouse model studies were suggestive of benefit from both gene therapies and pyrimidine deoxynucleotides in the setting of TK2 deficiency. Preliminary studies have demonstrated improvement of thymine kinase activity in multiple affected tissues except the kidneys, with delayed onset of disease and prolonged lifespan.16 Thedeoxynucleotides treatment is currently available on compassionate basis and does show promising benefits in humans.16

Additional research continues to be done on pharmacological agents and supplements including antioxidant therapies. Dietary supplements unfortunately lack high quality studies and therefore their use as treatment remains in early phase trials.

Increasing mitochondria and nicotinamide adenine dinucleotide (NAD) within the cell to improve oxidative phosphorylation is one of the proposed mechanisms of novel pharmacologic agents. Bezafibrate initially showed promising effects on cardiac and skeletal muscle however there was an increase in biomarkers of mitochondrial disease. Therefore, additional studies are currently being completed.6

Everolimus, a treatment that inhibits the rapamycin (mTOR) pathway, has had evidence of extension of life expectancy and attenuation of pathologic and clinical progression of disease in the mouse model. The clinical results have been equivocal in a small number of patients with specific mitochondrial disorders such as LHON and MELAS and therefore not a generalized treatment.18

KH176, EPI-743, and Elamipretide aim to decrease reactive oxidative species and act as an antioxidant to absorb these species before they are absorbed by mitochondria.6 KH176, known as Sonlicromanol, safety profile has been studied and deemed safe. Phase 3 trials await. Early phase studies demonstrated improvement of attention, mood, cardiac function and mood but not gait impairment.7 EPI-743 (vitamin E analogue) also known as vatiquinone acts as an antioxidant and enhances the synthesis of glutathione. Several open label studies in patients with Kearns-Sayre Syndrome, Leigh Syndrome, Pearson Syndrome and Leber Hereditary Optic Neuropathy (LHON) have shown promising effects.12 Phase 2 studies in patients with Leigh Syndrome demonstrated improved neurological symptoms based on the Newcastle Pediatric Mitochondrial Disease Scale. There were no reported adverse effects.6A randomized, double blinded and placebo study was completed and awaiting results. Elamipretide corrects the reductive oxidative species and decreases cytochrome C release; therefore, it increases ATP production at the inner mitochondrial membrane and preliminarily demonstrates a good safety profile, improved visual acuity and color differentiation in LHON.1 Other preliminary studies demonstrated improved 6 minute walk test compared to placebo effect in non-specific mitochondrial disorder while others have not reproduced these results. Therefore it’s clinical use remains unclear.6,19,20

Implementation of vitamin B3 (NAD+ precursor nicotinamide) is shown to prevent retinal ganglion cell dysfunction and neuronal loss in mice models, which may translate to therapeutic treatment of mitochondrial optic neuropathies. A recent study revealed a consistent deficiency of vitamin B3 in those with LHON and remains a target of future intervention.21 Nicotinamide riboside is a vitamin B3 derivative shows promising results in the treatment of mitochondrial diseases by way of increasing NAD synthesis or PARP inhibitors (that block NAD degradation) in mice models. Additional trials are currently recruiting 10,21

L-arginine, citrulline, and taurine supplementation have been shown to improve symptoms in stroke-like episodes (headache, nausea/vomiting, consciousness, and visual disturbance).22 It is thought to increase nitrous oxide production and decrease endothelial dysfunction.1 It is used in both the acute setting via IV and orally in the chronic setting. In the acute setting, it has decreased the severity and increased the time between stroke-like episodes in those with MELAS.26 In addition, it has been shown to decrease cerebral hyperperfusion.3,23, 24

Bone marrow derived stem cell studies have been initiated in low sample studies with preliminary improvement of visual fields and visual acuity within 24 months however long term results were unable to be obtained.11

An innovative antioxidant therapy involving near-infrared light-emitting diode therapy as a means of energy production and antioxidant protection has been performed but results have not yet been published.6,11

The ketogenic diet is being explored as a use of treatment for mitochondrial disorders. It has a well-known effect on epilepsy which is demonstrated in studies in the mitochondrial disorders population. A small study demonstrated effects on ataxia, speech and language function, sleep, social function, and number of hospitalizations.6 Additional research is needed. The low residual diet and high nitrate diets are additionally being studied in the primary mitochondrial disorders.6

Tetracyclines and their analogues such as doxycycline have shown improved fitness of cultured mitochondrial disease cells, decreased cell death, and mitigates Leigh Syndrome in a mouse model.24

Gaps in the Evidence-Based Knowledge

The role of endurance and resistance exercise remains poorly defined and no guidelines exist for exercise prescription. Exercise has been reported to be both beneficial in improving strength and endurance, improving quality of life, and detrimental in causing metabolic crisis.1,6  At the genetic level, some studies showed favorable mtDNA gene-shifting by selectively promoting satellite cell differentiation through resistive exercise while other studies showed increased mutant mtDNA load despite improved clinical symptoms.1,6 Exercise should, therefore, be prescribed with caution and followed closely; ideally, this should be coordinated with mitochondrial specialists whose genetic knowledge may inform the severity of exercise intolerance.

The use of botulinum toxin has been recommended in the current care guidelines however dosing and additional studies in this population would be beneficial.26 Neuromuscular junction dysfunction is observed to occur in certain cases of mitochondrial disorders, and this is hypothesized to be the cause of adverse hypersensitivity to botulinum toxin. Botulinum toxin should, therefore, be injected with caution; ideally, this should be coordinated with mitochondrial specialists whose genetic expertise may guide the extent of potential sensitivity to botulinum toxin.

Additional large population and higher quality studies on bone marrow derived stem cells with larger sample sizes will be beneficial in demonstrating efficacy in mitochondrial disorders.11

Dietary supplements continue to be controversial in patients with mitochondrial disorders. The current data supports arginine, citrulline, and taurine in MELAS. However, other dietary supplements such as COQ10 require additional evaluation of efficacy.

Gene therapy and mitochondrial donation are critical areas of future research which may help reduce the levels of mutant mtDNA and nDNA leading to decreased phenotypic mitochondrial disorders.

References

  1. Kornblum C, Lamperti C, Parikh S. Currently available therapies in mitochondrial disease. Handb Clin Neurol. 2023;194:189-206. doi:10.1016/B978-0-12-821751-1.00007-5
  2. Enns GM. Pediatric mitochondrial diseases and the heart. Curr Opin Pediatr. 2017;29(5):541-551.
  3. Finsterer J, Mahjoub SZ. Management of epilepsy in MERRF syndrome. Seizure. 2017; 50: 166-170.
  4. Hameed S, Tadi P. Myoclonic Epilepsy and Ragged Red Fibers. [Updated 2023 Jul 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK555923/
  5. Xin Z, Trisha M, Gordon IMetabolic stress due to metformin as a possible precipitating factor in MELAS: a case reportJournal of Neurology, Neurosurgery & Psychiatry 2023;94:A79.
  6. Tinker, R.J., Lim, A.Z., Stefanetti, R.J. et al. Current and Emerging Clinical Treatment in Mitochondrial Disease. Mol Diagn Ther 25, 181–206 (2021). https://doi.org/10.1007/s40291-020-00510-6
  7. Barcelos I, Shadiack E, Ganetzky RD, Falk MJ. Mitochondrial medicine therapies: rationale, evidence, and dosing guidelines. Curr Opin Pediatr. 2020;32(6):707-718. doi:10.1097/MOP.0000000000000954
  8. Rahman S (Paediatric Metabolic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK). Mitochondrial disease in children (Review Symposium). J Intern Med 2020; 287: 609–633.
  9. Fecek C, Samanta D. Subacute Necrotizing Encephalomyelopathy. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559164/
  10. Shemesh A, Margolin E. Kearns-Sayre Syndrome. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482341/
  11. Catarino CB, von Livonius B, Priglinger C, et al. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy. J Neuroophthalmol. 2020;40(4):558-565. doi:10.1097/WNO.0000000000001023
  12. Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J. Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy. Cells. 2023;12(15):2013. Published 2023 Aug 7. doi:10.3390/cells12152013
  13. Finsterer J. Mitochondrial disorders are prone to propofol infusion syndrome. Acute Med Surg. 2020;7(1):e495. Published 2020 Feb 28. doi:10.1002/ams2.495
  14. Mitochondrial Myopathies. (2024). Retrieved from https://www.mda.org/disease/mitochondrial-myopathies.
  15. Saxena N, Taneja N, Shome P, Mani S. Mitochondrial Donation: A Boon or Curse for the Treatment of Incurable Mitochondrial Diseases. J Hum Reprod Sci. 2018;11(1):3-9. doi:10.4103/jhrs.JHRS_54_17
  16. Lopez-Gomez, C., Sanchez-Quintero, M.J., Lee, E.J., Kleiner, G., Tadesse, S., Xie, J., Akman, H.O., Gao, G. and Hirano, M. (2021), Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency. Ann Neurol, 90: 640-652. https://doi-org.ezproxy.library.wisc.edu/10.1002/ana.26185
  17. Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem. 2018;62(3):467-481.
  18. Sage-Schwaede, A., Engelstad, K., Salazar, R., Curcio, A., Khandji, A., Garvin Jr, J.H. and De Vivo, D.C. (2019), Exploring mTOR inhibition as treatment for mitochondrial disease. Ann Clin Transl Neurol, 6: 1877-1881. https://doi.org/10.1002/acn3.50846
  19. Karaa A, Bertini E, Carelli V, et al. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023;101(3):e238-e252. doi:10.1212/WNL.0000000000207402
  20. Viscomi C, Zeviani M (University of Padova, Padova; and Venetian Institute of Molecular Medicine, Padova, Italy). Strategies for fighting mitochondrial diseases (Review-Symposium). J Intern Med 2020; 287: 665–684.
  21. Bocca C, Le Paih V, Chao de la Barca JM, et al. A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies. Hum Mol Genet. 2021;30(1):21-29. doi:10.1093/hmg/ddab013
  22. Pitceathly RDS, Keshavan N, Rahman J, Rahman S. Moving towards clinical trials for mitochondrial diseases. J Inherit Metab Dis. 2021;44(1):22-41. doi:10.1002/jimd.12281
  23. Ohsawa Y, Hagiwara H, Nishimatsu SI, et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial. J Neurol Neurosurg Psychiatry. 2019;90(5):529-536. doi:10.1136/jnnp-2018-317964
  24. El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017; 5:10.
  25. Perry EA, Bennett CF, Luo C, et al. Tetracyclines promote survival and fitness in mitochondrial disease models. Nat Metab. 2021;3(1):33-42.
  26. Parikh S, Goldstein A, Karaa A, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12):10.1038/gim.2017.107. doi:10.1038/gim.2017.107

Bibliography

Pia S LF. MELAS Syndrome In. Stat Pearls Treasure Island, Florida Stat Pearls Publishing; 2023.

Rahman S TD. Gene Reviews In: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.2023: https://www.ncbi.nlm.nih.gov/books/NBK320989/?report=classic.

Original Version of the Topic

Sarah H. Evans, MD, Thomas Chang, MD, Adeline Vanderver, MD. Pediatric neurodegenerative disorders. 9/20/2013.

Previous Revision(s) of the Topic

Simra Javaid, DO, Charles Pelshaw, MD. Pediatric neurodegenerative disorders. 2/14/2018.

Amanda Lindenberg, DO, OTR, Simra Javaid, DO, Kelli Chaviano, DO. Mitochondrial Disorders Part One: Disease/Disorder, Essentials of Assessment. 10/28/2021.

Author Disclosure

Amanda Lindenberg, DO, MOT
Nothing to Disclose

Stephanie Barton, DO
Nothing to Disclose