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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 or treatment guidelines exist. Pediatric neurodegenerative disorders require symptomatic treatment for both the neurological and systemic symptoms. All treatment is supportive and palliative.

Anecdotal reports of benefit from coenzyme-Q10 in its reduced form (Ubiquinol), carnitine, succinate, riboflavin, thiamine, alpha lipoic acid, folinic acid, and ascorbic acid exist, but none have demonstrated sustained benefit.1-10 Management of mitochondrial disorders remains supportive.11 For example, give anticonvulsants for seizure control and replace hormones for endocrinopathies. Initiate physical, occupational, and speech therapy when needed to maximize function.

Permanent pacemaker implantation for patients with KSS and atrioventricular block is recommended under current guidelines.12

Thiamine (Vitamin B1) is the most common treatment for Leigh Syndrome with some patients experiencing temporary symptomatic improvement and minimal slowing of disease progression.1 Most often used AED for epilepsy in MERRF is levetiracetam.13

Certain medications should be avoided. Valproic acid has deleterious effects on mitochondrial function and should be avoided in seizures.14 Metformin often causes lactic acidosis. Propofol and other volatile general anesthetics may exacerbate dysfunction.11 Mitochondrial toxicity can result from aminoglycosides, linezolid, and alcohol.3,6, 7,15,

Acute exacerbations in MELAS can be triggered by febrile illness, thus all childhood vaccinations should be given in a timely manner.4

Nutrition and weight monitoring is essential as several of these disorders result in a hypermetabolic state leading to poor weight gain and growth delay.

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. Maximize function throughout the disease course. Prescribe 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 as needed, including 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, and MERRF. The Muscular Dystrophy Association also helps connect mitochondrial myopathy patients with the closest MDA clinics in their area.16

Emerging/unique interventions

Functional measures such as the Gross Motor Function Measure and Manual Ability Classification System 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

  1. Suspect mitochondrial disease in patients who present with weakness out of proportion to tone abnormalities.
  2. Suspect mitochondrial disease in patients who present with new onset metabolic disease and functional deficits.
  3. 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.
  4. 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.
  5. Upon suspicion of diagnosis, multi-organ evaluation should be done. This includes neuro exam with cognitive assessments, brain MRI, audiologic & ophthalmologic exams, growth assessment, echo and EKG, and endocrine screening (hypothyroidism, DM).3

Cutting Edge/ Emerging and Unique Concepts and Practice

Cutting edge concepts and practice

Genetic therapeutic techniques targeting the mtDNA and nDNA are actively being investigated.

In-vitro experiments with LHON cybrids have shown improvement in mitochondrial respiratory chain function, lower reactive oxygen species levels, and reduced apoptosis after treatment with phytoestrogens.17

Idebenone (coenzyme Q10 analogue) is the active substance of Ranexone which has been shown to be partially effective in acute stage of LHON with some patients experiencing clinically significant visual benefits.10, 17-19 Those with the m.1178 mutation and younger age of onset responded better than others. The involvement of the second eye was delayed after taking Ranexone.20 Idebenone has been studied in other mitochondrial disorders such as MELAS as it crosses the blood brain barrier.5

Current phase 3 gene therapy trials for LHON patients involve wild type mtDNA being delivered via viral vectors (adenovirus) directly into their eyes with intravitreal injection. The goal being incorporation into retinal ganglion cells, preserving them, and stabilization or improvement of vision.21-24 Recent studies have shown increased size of the visual field and improvement in visual acuity.10 Intravitreal injection of GS010 has shown promising improvement in visual acuity in those with onset of symptoms of up to 60 months in those with m.1178G>A mutation.20

Reduction in retinal ganglion cells lost and improvement in visual function, has been shown in mice models by MT-ND4 gene delivery via modified adeno-associated viral vectors (AAV2) in treatment of m.11778G>A mutations. Current clinical trials are recruiting patients to evaluate efficacy and optimal dosing.10,11,17

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.17

Nicotinamide riboside is promising in the treatment of mitochondrial diseases by way of increasing NAD synthesis or PARP inhibitors (that block NAD degradation).10,25

Bone marrow derived stem cell studies have been initiated in low sample studies with preliminary improvement of visual fields and visual acuity.20

Elamepretide corrects the reductive oxidative species and decreases cytochrome C release; therefore, it increases ATP production at the inner mitochondrial membrane and preliminarily demonstrates effect in mitochondrial disorders.10,20

Mitochondrial donation for female carriers of disease-causing mtDNA mutations are currently being investigated, with favorable results in primate models, and a clinic in the UK has recently been set up to provide this service.17

L-arginine and citrulline supplementation have been shown to improve symptoms in stroke-like episodes (headache, nausea/vomiting, consciousness, and visual disturbance). It is thought to possibly be due to increased nitrous oxide production and decreasing endothelial dysfunction.3,13,19,26-28 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.28 In addition, it has been shown to decrease cerebral hyperperfusion.3,27

Growth hormone therapy has shown favorable increase in height in Kearns-Sayre patients.29

Aerobic and endurance training with or without resistive exercise has been shown to increase mitochondrial mass and help activate mitochondrial biogenesis.5,10

A vitamin E derivative, KH176 showed improvement of attention and mood but not gait impairment.10

EPI-743 acts as an anti-oxidant and enhances the synthesis of glutathione. Several open label studies in patients with Leigh Syndrome, Pearson Syndrome and Leber Hereditary Optic Neuropathy have shown promising effects.10

Tetracyclines and their analogues such as doxycycline have shown improved fitness of cultured mitochondrial disease cells, decrease cell death, and mitigates Leigh Syndrome in a mouse model.30

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.31 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.32,33 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.

No guidelines exist regarding the use of botulinum toxin in patients with mitochondrial disorders. Case reports showing efficacy with no side effects, and those showing adverse side effects are both present in the literature.21,34,35 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 knowledge may inform the extent of potential sensitivity to botulinum toxin.

Additional studies on bone marrow derived stem cells with larger sample sizes will be beneficial in demonstrating efficacy in mitochondrial disorders.20Additional studies on neural stem cells within patients will be beneficial in demonstrating efficacy in neurodegenerative disorders involving glycoprotein degradative disorders.31

Citrulline elevates nitric oxide production more than arginine and may provide increased clinical effect; however, therapeutic trials have not yet been completed.5

Intractable seizures may be a result of mitochondrial disorders. There is limited evidence of low dose perampanel suppressing epileptic seizures as well as improving neurotropic function.36


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  2. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh Syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016; 79(2): 190-203.
  3. El-Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Molecular Genetics and Metabolism. 2015; 116: 4-12.
  4. Lorenzoni PJ, Werneck LC, Kay CSK, et al. When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq Neurosiquiatr. 2015; 73(11): 959-67.
  5. El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017; 5:10.
  6. Finsterer J, Mahjoub SZ. Management of epilepsy in MERRF syndrome. Seizure. 2017; 50: 166-170.
  7. Finsterer J, Wakil SM. Stroke-like episodes, peri-episodic seizures, and MELAS mutations. European Journal of Paediatric Neurology. 2016; 20: 824-829.
  8. Lee JS, Kim H, Lim BC, et al. Leigh Syndrome in Childhood: Neurologic Progression and Functional Outcome. J Clin Neurol. 2016; 12(2) 181-187
  9. Fryer RH, Bain JM, De Vivo DC. Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatric Neurology. 2015; 56: 59-61.
  10. Hirano M, Emmanuele V, Quinzii CM. Emerging therapies for mitochondrial diseases. Essays Biochem. 2018;62(3):467-481.
  11. Enns GM. Pediatric mitochondrial diseases and the heart. Curr Opin Pediatr. 2017;29(5):541-551.
  12. Khambatta S, Nguyen DL, Beckman TJ, Wittich CM. Kearns-Sayre syndrome: a case series of 35 adults and children. International Journal of General Medicine. 2014; 7: 325-332.
  13. Finsterer J, Mahjoub SZ. Management of epilepsy in MERRF syndrome. Seizure. 2017; 50: 166-170.
  14. Pia S LF. MELAS Syndrome In. Stat Pearls Treasure Island, Florida Stat Pearls Publishing; 2020.
  15. Yu XL, Yan CZ, Ji KQ, et al. Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations. Chin Med J (Engl). 2018;131(22):2705-2712.
  16. Mitochondrial Myopathies. (2017, December 22). Retrieved from https://www.mda.org/disease/mitochondrial-myopathies.
  17. Jurkute N, Yu-Wai-Man R. Leber hereditary optic neuropathy: bridging the translational gap. Curr Opin Ophthalmol. 2017; 28: 403-409.
  18. Biousse V, Newman NJ. Diagnosis and clinical features of common optic neuropathies. Lancet Neurol. 2016; 15:1355-67.
  19. Magner M, Kolarova H, Honzik T, et al. Clinical Manifestations of Mitochondrial Diseases. Dev Period Med. 2015; 4:441-449.
  20. Zuccarelli M, Vella- Szijj, J.,  Serracino-Inglott, A., Borg, J. Treatment of Leber’s Hereditary Optic Neuropathy:An Overview of Recent Developments European Journal Of Ophthalmology 2020;30(6):7.
  21. Bonfante E, Koenig MK, Adejumo RB, et al. The neuroimaging of Leigh syndrome: case series and review of the literature. Pediatr Radiol. 2016; 46: 443-451
  22. Feuer WJ, Schiffman JC,, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy : initial results. Ophthalmology. 2016; 123: 558-70.
  23. Wan X, Pei H, Zhao MJ, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016; 6: 21587.
  24. Pia S LF. MELAS Syndrome In. Stat Pearls Treasure Island, Florida Stat Pearls Publishing; 2020.
  25. Mirabelli-Badenier M, Morana G, Bruno C, et al. Inferior Olivary Nucleus Involvement in Pediatric Neurodegenerative Disorders: Does It Play a Role in Neuroimaging Pattern-Recognition Approach? Neuropediatrics. 2015; 46: 104-109.
  26. Lorenzoni PJ, Werneck LC, Kay CSK, et al. When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq Neurosiquiatr. 2015; 73(11): 959-67.
  27. Fryer RH, Bain JM, De Vivo DC. Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report and Critical Reappraisal of Treatment Options. Pediatric Neurology. 2015; 56: 59-61.
  28. Koga Y, Povalko N, Inoue E, et al. Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research. J Neurol. 2018;265(12):2861-2874.
  29. Quintos JB, Hodax JK, Gonzales-Ellis BA, et al. Efficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience. J Pediatr Endocrinol Metab. 2016; 29(11): 1319-1324.
  30. Perry EA, Bennett CF, Luo C, et al. Tetracyclines promote survival and fitness in mitochondrial disease models. Nat Metab. 2021;3(1):33-42.
  31. Aulbert W, Weigt-Usinger K, Thiels C, et al. Long Survival in Leigh Syndrome: New Cases and Review of Literature. Neuropediatrics. 2014; 45(3): 346-353.
  32. Sofou K, De Coo IFM, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet Journal of Rare Diseases. 2014; 9:52.
  33. Henry C, Patel N, Shaffer W, et al. Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes – MELAS Syndrome. Ochsner Journal. 2017; 17:296-301.
  34. Whitehead MT, Wien M, Lee B, et al. Black Toenail Sign in MELAS Syndrome. Pediatr Neurol. 2017; 75: 61-65
  35. Whitehead MT, Wien M, Lee B, et al. Cortical venous disease severity in MELAS syndrome correlates with brain lesion development. Pediatr Neurol. 2017; 59: 813-818.
  36. Kimura S, Shiraishi H, Egawa K, Uchida M, Ueno M. Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report. Brain Dev. 2021;43(1):157-159.


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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.

Author Disclosure

Amanda Lindenberg, DO, OTR
Nothing to Disclose

Simra Javaid, DO
Nothing to Disclose

Kelli Chaviano, DO
Nothing to Disclose