Mitochondrial Disorders Part One: Disease/Disorder, Essentials of Assessment

Disease/Disorder

Definition

Mitochondrial disorders are a subtype of pediatric neurodegenerative disorders which involve progressive deficits and/or regression of neurological function and overall development. . Biochemical location of the deficit and type of DNA affected are a few of the several classification systems. A classification system in 1985 grouped mitochondrial disorders according to the site of biochemical defect of substrate transport, substrate utilization, Krebs cycle (also known as citric acid cycle), respiratory or electron transport chain, and oxidation-phosphorylation coupling. Genetic classification on the basis of nuclear DNA (nDNA) versus mitochondrial DNA (mtDNA) defects exist and newer sources restrict the term to disorders of the respiratory chain.

Etiology

Mutations of the mtDNA and nDNA have been identified in numerous mitochondrial disorders. The mtDNA encodes 37 genes including subunits of the electron transport chain complexes and subunits, tRNAs, and rRNAs. The nDNA encodes all other mitochondrial proteins. mtDNA mutations may be due to large scale rearrangements, point mutations, or deletions which are inherited maternally, but phenotypic expression is variable because of threshold effect and heteroplasmy. The majority of nDNA mutations are inherited autosomal recessively though any inheritance pattern is possible.¹ More than 400 nuclear-encoded genes have also been linked to these disorders.¹ Childhood onset of mitochondrial disease is more likely due to mutations in nDNA (up to 50.4%) whereas older age of onset is more commonly due to mtDNA (up to 22%).^1,2 Most mutations are inherited (75%), but sporadic mutations (25%) are not uncommon especially in children.¹ Acquired mitochondrial disorders and adult onset disorders are beyond the scope of this review.

Epidemiology including risk factors and primary prevention

• Prevalence of symptomatic primary mitochondrial disorders for children is estimated to be 5 per 100,000 and estimated to be 12.5 per 100,000 for adults.^2-4 There is a prevalence of 1 per 5,000 for primary mitochondrial disorders which are at risk of disease.³ This estimation is conservative as those with mild disease may not always be captured in data collection.
• Childhood onset mitochondrial disease incidence is predicted to be 0.5-1.5 per 100,000 which is significantly less than adult onset mitochondrial disease.⁴ In the United States, the incidence is 1 in 4,000.⁵ Globally, the incidence is 1 in 5,000.⁵
• Minimal gender predilection
• Risk factors include positive family history, exposures to radiation, erythromycin, azidothymidine, excessive alcohol consumption, and heavy smoking.^8,9

Patho-anatomy/physiology

The primary function of the mitochondria is to generate ATP from ADP by utilizing the electron transport chain and oxidative phosphorylation. Pyruvate oxidation, fatty acid oxidation, and the Krebs cycle are other metabolic pathways within the mitochondria coupled to energy generation.^5-7 Over 90% of ATP required for cellular energy is produced by the mitochondria.^5-7 Cellular energy deficiency is the unifying biochemical defect. Tissues with high energy demand, such as the brain, nerves, muscle, heart, retina, cochlea and renal tubules, are disproportionately affected.^5,7 Specific pathological mechanisms leading to cell loss have not been completely elucidated. Apoptosis-induced cell loss, accumulation of reactive oxygen species, reduced synthesis of essential nucleotides, impaired protein synthesis, and altered calcium metabolism appear to be key processes in pathogenesis eventually leading to organ failure.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Heteroplasmy and phenotypic expression plays a large role in age of onset and which systems are affected in each individual. Most early childhood presentations initially present with developmental delay or regression. Cognition including social skills, motor, and sensory domains of the nervous system (NS), may be affected. Development of a milestone does not exclude nervous system degeneration.¹⁰ NS degeneration is responsible for neurological deterioration.¹⁰ Most well defined syndromes have multi-system involvement though younger age of presentation may demonstrate involvement of a single system initially.⁶ Patients are classified into either syndromic or nonsyndromic mitochondrial disorders, with most falling under the former. While nonsyndromic mitochondrial disorders are not uncommon, they are more nonspecific and thus, more difficult to diagnose.⁶ Progression and exacerbation risk factors include stress to the body, drugs, acute illness, surgery, and anesthesia. Therefore, prevention and early intervention is essential. Patients with higher levels of heteroplasmy have poorer prognosis.¹

There have been multiple case reports with overlap of two well defined syndromes which are defined as “plus” syndromes.^1,11,12

Some well-defined and common syndromes are

Leigh Syndrome (also known as subacute necrotizing encephalomyelopathy, LS)

• Genetics: Mutations in more than 115 genes in nDNA > mtDNA have been identified.^6,12 All but four genes were transmitted autosomal recessively. MT-ND and MT-ATP were the most commonly affected mutated mtDNA genes.¹³ SURF1 is the most common nDNA gene affected.¹³
• Onset: Usually between 3 months and 2 years.^12,14 Onset after 2 years old is rare and presents with atypical symptoms.¹⁴
• Presentation: Loss of previously acquired developmental skills is the most common presenting symptom.^2,10 Developmental delay, dysphagia, vomiting, diarrhea, failure to thrive, or seizures are other common presenting symptoms.^2,14
• Other symptoms: Ophthalmoplegia, optic atrophy, retinitis pigmentosa, hypotonia, dystonia, ataxia, peripheral neuropathy, hypertrophic or dilated cardiomyopathy, arrhythmias, respiratory insufficiency, lactic acidosis, hypertrichosis.^12,14
• Prognosis: Rapidly progressive in stepwise manner, usually death by 3 years old, although some live to early adulthood.^12,14 Median duration of onset to death is approximately 1.8 years. Onset prior to 6 months, lesions of the basal ganglia on initial MRI, and hospitalization in the intensive care unit carry a poor prognosis.¹⁴ Those with SURF1 and MTFMT mutations have an increased life expectancy and milder clinical phenotype.¹³

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes)

• Genetics: m.3242A>G of the MT-TL1 gene is responsible for 80% of pathogenic variants. ^3,15 29 other mtDNA point mutations have been identified.¹
• Onset: Typically before age 20 years (average 2-10 years old), adult onset possible.¹
• Presentation: Seizures and stroke-like episodes, lactic acidosis^15,16
• Other symptoms: Wide phenotype, Visual field deficits, hemiparesis (can be bilateral), ataxia, dementia, migraine headaches, hearing impairment, peripheral neuropathy, exercise intolerance, myopathy, myoclonus, mood disorders, cyclic vomiting, short stature, diabetes mellitus, incomplete atrioventricular block, Wolff-Parkinson-White, arrhythmias, left ventricular hypertrophy, cardiomyopathy in later stages, pulmonary hypertension.^2,15,16
• Prognosis: Episodic decline with intermittent potential for improvement and plateau. Poor prognosis is associated with multi-system involvement, heart disease, and early stroke-like episodes.^17,18 Median survival from onset of symptoms is 17 years.¹⁵

MERRF (Myoclonic Epilepsy with Ragged Red Fibers)

• Genetics: m.8433A>G of the MT-TK gene is responsible for 80% of pathogenic variants.¹ m.8256T>C, m.8363G>A, and m.8361 g>A of the MT-TK gene accounts for another 10% of pathogenic variants.¹⁹
• Onset: Childhood to early adulthood, insidious6
• Presentation: Myoclonic Epilepsy is the most prevalent feature.^1,6,19 This symptom distinguishes it from all other mitochondrial disorders.¹ Ataxia, hearing loss, and endocrinopathy most common presentation.⁶
• Other symptoms: Other seizure types, optic atrophy, pyramidal signs, limb-girdle weakness, exercise intolerance, re-entrant atrioventricular tachycardia, and multiple lipomas are also seen.⁶
• Prognosis: Variable progression, neurologic degeneration is often severe.

Kearns-Sayre Syndrome (KSS)

• Genetics: large mtDNA (1.3-10kb) deletions present in 90%.20-224977 bp deletion is the most common accounting for more than ⅓ of all cases.²⁰
• Onset: Before the age of 20 years old typically
• Presentation: Retinitis pigmentosa, progressive external ophthalmoplegia characterized by ptosis and ophthalmoplegia, conduction abnormalities, and skeletal muscle involvement Previously, onset before 20 years old was one of the diagnostic criteria that was recently updated.²¹
• Other symptoms: Ataxia, cognitive impairment, dementia, sensorineural hearing loss, dysphagia, endocrine abnormalities such as diabetes mellitus, short stature.^20-22
• Prognosis: Few survive beyond the age of 30. Sudden cardiac death is prevalent.^20,22

Leber Hereditary Optic Neuropathy (LHON)

• Genetics: m.11778G>A mt-ND4, m.3460G>A mt-ND1, m.14484T>C mt-ND6 account for 90% of cases.22-24m.11778 locus mutation is most common (~60%) and associated with worst prognosis.^{1, 23} It is the most common mtDNA disorder and often homoplasmic compared to other mtDNA disorders that are heteroplasmic.^1,23
• Onset: Late adolescence, early adulthood. Usually between ages of 15-35. Less than 10% are younger than 12 years old.²⁵
• Presentation: Subacute to acute painless loss of central and color vision in one eye then the other within days to months. Males>females between 6 and 45 years old.^24-26 If pale optic disc on exam, one should be highly suspicious.²⁵
• Other symptoms: Cardiac conduction abnormalities, encephalopathy, dystonia.6
• Prognosis: Most progress within the first 6-9 months. Nearly all are blind by 50 years old. Better visual prognosis for childhood-onset with m.3460 or m.14484 (~30-50%) mutations.^23,24

Thymidine Kinase 2 Deficiency (also known as mitochondrial depletion syndrome 2, TK2)

• Genetics: Thymidine Kinase 2 (TK2) gene is located on chromosome 16. Autosomal recessive inheritance. p.Arg130Trp is associated with infantile onset/most severe symptoms.²⁵ p.Thr108Met is the most common pathogenic variant,^25,26 p.Asn58Ser, p.Arg130Trp are other common pathogenic variants.²⁵
• Onset: Less than one year old (infantile onset) up to 12 years old (childhood onset) as well as late onset which is after 12 years old.²⁷
• Presentation: Hypotonia, progressive and proximal weakness in bilateral upper and lower extremities
• Other symptoms: Facial weakness, progressive external ophthalmoplegia, dysphagia, dysarthria, peripheral neuropathy, respiratory failure (restrictive lung disease). Isolated myopathic presentation is most common but also may have seizures, sensorineural hearing loss, liver failure, kidney disease, arrhythmias, and ventricular hypertrophy^25-27
• Prognosis: Dependent on age onset subtype of which all are progressive. Median survival of 2 years for infantile onset.²⁵ Those with childhood onset are wheelchair dependent by 10 years old. Respiratory failure is a common cause of death.

Specific secondary or associated conditions and complications

• Neurologic: encephalopathy, seizures, ataxia, chorea, dystonia, spasticity, myoclonus, migraine, deafness, cognitive impairment, developmental delay, cranial nerve abnormalities.^6,29,22
• Visual: ophthalmoplegia, ptosis, optic atrophy, retinitis pigmentosa.
• Musculoskeletal: weakness, hypotonia, fatigability, exercise intolerance, contractures.
• Cardiopulmonary: arrhythmia, conduction defects, cardiomyopathy with hypertrophic being the most common,⁶ respiratory failure, and pulmonary hypertension. Those with skeletal myopathy and failure to thrive are more likely to have involvement of the cardiopulmonary system.¹⁸
• Gastrointestinal: recurrent vomiting, constipation, pseudo-obstruction
• Renal: renal tubular dysfunction.
• Endocrine: short stature, diabetes mellitus, exocrine pancreatic failure, thyroid dysregulation, adrenal insufficiency.²⁹
• Hematologic: neutropenia, pancytopenia, sideroblastic anemia, thrombocytopenia.

Essentials of Assessment

History

• Determine the age of onset of regression and age of milestones met prior to regression.
• Recognize well-defined syndromes.
• Suggestive features, especially when presenting in clusters, include myoclonus, generalized seizures including neonatal seizures, continuous partial seizures, ataxia, myopathy, exercise intolerance, abnormal tone (either increased, decreased or mixed), ophthalmoplegia, ptosis, hearing loss, diabetes, lactic acidosis, developmental delay, and neonatal complications such as jaundice or hypoglycemia.
• Other suggestive historical findings include positive family history involving at least three generations if possible, progressive symptoms in unrelated organ systems, and acute loss of functional skills with intercurrent illness, especially with fever and dehydration.

Physical examination

Physical examination findings are highly variable, and may include

• Mental Status/Cognition: decreased arousal, impaired attention, delayed language, intellectual disability.
• Cranial Nerves: ptosis, ophthalmoplegia, saccades, visual field deficits, hearing loss, weak suck.
• Tone: hypotonia, spasticity, dystonia; can present in various patterns in the trunk and limbs.
• Movement: ataxia, myoclonic jerks.
• Fundoscopic: pigmentary retinitis, optic atrophy, hyperemic optic disc with peripapillary telangiectasias and vascular tortuosity of central retinal vessels, cherry red spots
• Strength: mild to profound weakness.
• Cardiovascular: arrhythmia, edema, cyanosis.
• Dermatologic: acrocyanosis, mottled pigmentation of photo-exposed areas, alopecia, evidence of bleeding

Functional assessment

Functional impairment can occur in all domains. Expected course is progressive decline, though plateaus of varying length can occur. No functional outcome measures have been normalized for mitochondrial disease. The multi-disciplinary team may use standardized assessments such as pediatric evaluation of disabilities inventory, the Denver developmental screening test, 6 minute walk test to evaluate global function.³⁰

Laboratory studies

Biochemical and molecular tests are available. Currently no standardized diagnostic serum panel exists. Initial laboratory studies frequently include plasma lactate, pyruvate, ketone bodies, acylcarnitine, CPK, creatinine, and plasma and urine organic acids. Specific measures must be taken to obtain an appropriate sample such as obtaining without tourniquet, sample on ice, and sample collection device.³¹CPK may or may not be elevated in mitochondrial myopathies as dysfunction is with energy production i.e. Krebs cycle rather than a structural problem. Carbohydrate loading with glucose or fructose, followed by serial plasma lactate, pyruvate, and alanine measurements, is a provocative test that can unmask mitochondrial disorders. An elevated CSF lactate-to-pyruvate ratio can suggest a mitochondrial disorder as well.⁶ In Leigh syndrome, elevated lactate in CSF is more consistent than plasma levels.⁶ While elevated lactate is frequently seen in mitochondrial disorders, some patients have normal serum/plasma and CSF lactate. In addition to lactate to pyruvate ratio, particular and individual attention to other amino acid ratios is a necessary part of the laboratory workup. Further biomarker workup includes growth differentiation factor-15 (GDF-15), fibroblast growth factor 21 (FGF-21). glutathione, malondialdehyde, gelsolin, neurofilament light chain of the plasma and CSF, and circulating cell free mtDNA.³²

Arginine deficiency has been demonstrated in those with MELAS as well as carriers of the mutation.¹⁵

Imaging

• MRI is the gold standard imaging for neurodegenerative and mitochondrial disorders. There is a lower likelihood of a mitochondrial disorder if the MRI is normal however it does not rule it out.⁶ CT of the brain may reveal hypodensities.
  • Hallmark findings on MRI in LS include bilateral, symmetrical gray matter lesions mainly in the basal ganglia (striatum) but also in the brain stem, thalamus, cerebellum and posterior columns of the spinal cord. T2 weighted images reveal hyperintensities and hypointensities on T1 weighted images.^6,14 White matter lesions may suggest advanced LS.^6,33
  • Stroke-like lesions are most often seen in MELAS syndrome but can also be seen in MERRF, KSS, LS and LHON. The lesions which do not follow a vascular distribution are dynamic initially with hyperintensity on T2/Flair and diffuse weighted MRI sequences. The diffusion coefficient is increased compared to decreased in ischemic strokes.^{2,15, 33,34} Both gray and white matter changes can be seen similar to ischemic strokes. Multiple areas of cortical necrosis with diffuse cortical atrophy of the cerebral hemispheres and cerebellum known as the black toenail sign on T2/FLAIR sequences is a classic pathological finding in MELAS.^13,15,33 MRSPECT studies demonstrate focal hyperperfusion. The occipital, parietal, and temporal lobes are most commonly affected.^13,34
  • MRI of patients with LHON may reveal gray and white matter lesions, cerebral atrophy, and optic nerve atrophy.¹³
• Spinal cord MRI may reveal spinocerebellar, corticospinal, and dorsal column tract involvement.^8,34
• MR angiography is generally normal in MELAS.^3,5
• Cardiac magnetic resonance imaging (CMR) has garnered use in identifying subclinical myocardial defects. For example, identification of mitral valve prolapse and concentric remodeling of the left ventricle in KSS and abnormalities in mid anterior and anterolateral walls in MELAS before clinical manifestations have been reported in literature.^3,6
• Proton magnetic resonance spectroscopy may show positive N-acetyl-L-aspartate, and succinate peaks.^33,34
• Phosphorus magnetic resonance spectroscopy may show abnormal ATP and phosphocreatine activity.^33,34
• Hydrogen magnetic resonance spectroscopy may show elevated lactate in the cerebral cortex in those with mitochondrial disorders though it is non-specific. It is an indicator of severe neurological impairment. Lactate is sometimes elevated in the ventricles of patients with Leber Hereditary Optic Neuropathy.³⁴
• Calcifications, though non-specific, are commonly seen in the basal ganglia of patients with KSS and MELAS. Calcifications are more easily visualized on CT^.34
• Optical coherence tomography (OCT) and OCT angiography (OCT-A) can help identify morphological changes in the retinal nerve fiber layer (RNFL) and retinal vasculature in various pathological states, respectively.²⁸

Supplemental assessment tools

• The Modified Walker Criteria was created in 2002 and the Mitochondrial Diagnostic Criteria (MDC) was created in 2006 are diagnostic tools to help facilitate diagnosis of mitochondrial disorders in children.⁸ The Modified Walker criteria assigns major or minor criteria for clinical, pathological, enzymatic, functional, molecular, and metabolic parameters. It is a scoring system of clinical, laboratory, pathologic, and biochemical findings.³⁶
• Genetic testing includes sequencing of both the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)as first line rather than muscle biopsy being more readily available and allowing earlier and specific diagnosis.³ If the clinical presentation is suspicious for mitochondrial disorder or if it is a non-urgent situation, targeted mtDNA testing may be the most appropriate first line genetic testing³ but whole exome (WES- just the coding and splice areas) or whole genome testing (WGS) can be considered; diagnosis rates  range up to 50%.^1,3 Trio WES or WGS is ideal to assess whether nDNA mutations are in cis or trans for recessive disease which may help determine pathogenicity of new variants. Mitochondrial sequencing is not automatically included in test panels but is necessary for quantification of mutant mtDNA to allow for estimation of disease severity, and maternal testing can also clarify whether a specific mtDNA mutation is pathogenic.
• If genetic testing is non-diagnostic, a muscle biopsy should be considered as mutations may not be present in leukocytes. Muscle should be sent for quantification of respiratory chain complex enzymatic activity as well as structural and biochemical evaluation.² Abnormal mitochondrial configurations and/or subsarcolemmal abnormal mitochondrial accumulation may be best appreciated with electron microscopy² but muscle fiber stains may reveal mitochondrial proliferation also known as ragged red fibers.^15,19 Unlike most mitochondrial diseases, MELAS ragged red fibers stain positively with cytochrome c oxidase.^15,19 In TK2, biopsy may demonstrate more severe dystrophy with both necrotic and regenerating myofibrils, variability in myofibril size, and replacement with connective and adipose tissue which is more severe than other mitochondrial myopathies.²⁵ For some infants and children who are critically ill with suspicion of primary mitochondrial disorders urgent muscle biopsy before genetic testing can be indicated if it will avoid delays in diagnosis where expedited sequencing is not available.
• EMG for evaluation of myopathy and peripheral neuropathy.
• EEG for evaluation of seizure activity. Despite focal or generalized seizures clinically, focal findings may or may not be present.^6,15 In Leigh Syndrome, EEG revealed diffuse background slowing.¹² In MERRF there was generalized epilepsy and EEG spikes.¹⁹
• Echocardiogram and EKG for evaluation of cardiomyopathy, conduction defects, arrhythmias.
• Electroretinography evaluates the photonic code responses and scotopic responses of the retina.²⁰

Early predictions of outcomes

Diagnosis-dependent, but in general, the younger the onset, the more rapid the progression, and the worse the outcome. Unfortunately, therapeutic options are limited. Early identification of clinical diagnosis and regular follow up can improve quality of life in this population. A mean of 74% of patients with a mitochondrial disorder pass away within 10 years of diagnosis.⁶

Lesions in the thalamus, multi-system involvement and a diagnosis of Leigh Syndrome were associated with early death (in those less than 6 years old).³⁹

In recent literature, Leigh Syndrome patients with mutations close to the C-terminus with varying residual COX activity and SURF1 have been shown to have longer survival rates and a better prognosis.^12,15,38

In MELAS patients, status epilepticus is associated with death.³⁹

Cause of death in patients with mitochondrial disorders may be similar to the general population but with sepsis being the most common. Therefore, close attention to scheduled immunizations and counseling of infection prevention is essential. Rapid treatment of infection and support of mitochondrial function is necessary to prevent irreversible deficits and/or death as above. Sudden death may also occur in those with comorbid neurological disorders including seizures.³⁹

Environmental

Evaluate the physical environment of the home, the school, and if applicable, the workplace for accessibility and for safety and efficacy with performance of activities of daily living.

Social role and social support system

Explore whether the patient and family have an adequate emotional support system. Determine needs for financial assistance, respite care, in-home nursing, monitoring and coordination of medical appointments and/or transportation. Explore the patient’s interest in recreational activities in order to develop adaptive programs as needed.

Professional issues

• Genetic counseling is valuable for family and therapeutic planning
• Prediction of disease expression in mtDNA mutation is complicated by variability of phenotypic expression.

Rehabilitation Management and Treatments

See Mitochondrial Disorders: Part Two

Cutting Edge/Emerging and Unique Concepts and Practice

See Mitochondrial Disorders: Part Two

Gaps in the Evidence-Based Knowledge

See Mitochondrial Disorders: Part Two

References

1. Schlieben, L, Prokisch, H. Genetics of mitochondrial diseases: current approaches for the molecular diagnosis. Dimmock DP, Lawlor MW. Presentation and Diagnostic Evaluation of Mitochondrial Disease. Pediatr Clin North Am. 2017;64(1):161-171.
2. Barca E, Long Y, Cooley V, et al. Mitochondrial diseases in North America: An analysis of the NAMDC Registry. Neurol Genet. 2020;6(2):e402. Published 2020 Mar 2. doi:10.1212/NXG.0000000000000402
3. Mavraki E, Labrum R, Sergeant K, et al. Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines. Eur J Hum Genet. 2023;31(2):148-163. doi:10.1038/s41431-022-01249-w
4. Schaefer, A., Lim, A., Gorman, G. (2019). Epidemiology of Mitochondrial Disease. In: Mancuso, M., Klopstock, T. (eds) Diagnosis and Management of Mitochondrial Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-05517-2_4
5. United Mitochondrial Disease Foundation. Understanding and Navigating Mitochondrial Disease, United Mitochondrial Disease Foundation. 2023 Accessed: 1/9/2025 https://umdf.org/what-is-mitochondrial-disease-2/
6. 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.
7. Ahuja AS. Understanding mitochondrial myopathies: a review. PeerJ. 2018;6:e4790. Published 2018 May 21. doi:10.7717/peerj.4790
8. 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
9. Carey, A.R. (2021). Hereditary Optic Neuropathy. In: Henderson, A.D., Carey, A.R. (eds) Controversies in Neuro-Ophthalmic Management. Springer, Cham. https://doi-org.ezproxy.library.wisc.edu/10.1007/978-3-030-74103-7_9
10. Mishra S, Mishra A,Approach to Neurodegenerative Disease in Children: A Short Review. Prog Asp in Pediatric & Neonat 2018; 1(5). DOI: 10.32474/PAPN.2018.01.000121.
11. Shen C, Xian W, Zhou H, Li X, Liang X, Chen L. Overlapping Leigh Syndrome/Myoclonic Epilepsy With Ragged Red Fibres in an Adolescent Patient With a Mitochondrial DNA A8344G Mutation. Front Neurol. 2018;9:724
12. Rahman S. Leigh syndrome. Handb Clin Neurol. 2023;194:43-63. doi:10.1016/B978-0-12-821751-1.00015-4
13. Lim AZ, Ng YS, Blain A, et al. Natural History of Leigh Syndrome: A Study of Disease Burden and Progression. Ann Neurol. 2022;91(1):117-130. doi:10.1002/ana.26260
14. 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/
15. Pia S, Lui F. Melas Syndrome. [Updated 2024 Jan 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532959/
16. Fan H-C, Lee H-F, Yue C-T, Chi C-S. Clinical Characteristics of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes. Life. 2021; 11(11):1111. https://doi.org/10.3390/life11111111
17. Zhang Z, Zhao D, Zhang X, et al. Survival analysis of a cohort of Chinese patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) based on clinical features. J Neurol Sci. 2018;385:151-155.
18. Brambilla A, Favilli S, Olivotto I, et al. Clinical profile and outcome of cardiac involvement in MELAS syndrome. Int J Cardiol. 2019;276:14-19.
19. Finsterer J, Zarrouk-Mahjoub S, Shoffner JM. MERRF Classification: Implications for Diagnosis and Clinical Trials. Pediatr Neurol. 2018;80:8-23
20. 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/
21. Hirano M, Pitceathly RDS. Progressive external ophthalmoplegia. Handb Clin Neurol. 2023;194:9-21. doi:10.1016/B978-0-12-821751-1.00018-X
22. 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.
23. 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
24. Olitsky,S, Marsh, J. Abnormalities of the optic nerve. In: Behrman RE, Kliegman RM, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2024
25. Berardo A, Domínguez-González C, Engelstad K, Hirano M. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. Journal of Neuromuscular Diseases. 2022;9(2):225-235. doi:10.3233/JND-210786
26. Ceballos F, Serrano-Lorenzo P, Bermejo-Guerrero L, et al. Clinical and Genetic Analysis of Patients With TK2 Deficiency. Neurol Genet. 2024;10(2):e200138. Published 2024 Mar 25. doi:10.1212/NXG.0000000000200138
27. El-Hattab. Thiamine Kinase 2 Deficiency. National Organization of Rare Disease. 2022. Updated Sept. 14 2022. Accessed 1/3/2025 https://rarediseases.org/rare-diseases/thymidine-kinase-2-deficiency/#synonyms
28. Carelli V, La Morgia C, Yu-Wai-Man P. Mitochondrial optic neuropathies. Handb Clin Neurol. 2023;194:23-42. doi:10.1016/B978-0-12-821751-1.00010-
29. Danhelovska T, Kolarova H, Zeman J, et al. Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I. BMC Pediatr. 2020;20(1):41.
30. Lindenschot M, de Groot IJM, Koene S, Satink T, Steultjens EMJ, Nijhuis-van der Sanden MWG. Everyday Activities for Children with Mitochondrial Disorder: A Retrospective Chart Review. Occup Ther Int. 2018;2018:5716947.
31. Ganetzky R, McCormick EM, Falk MJ. Primary Pyruvate Dehydrogenase Complex Deficiency Overview. 2021 Jun 17. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK571223/
32. Shayota BJ. Biomarkers of mitochondrial disorders. Neurotherapeutics. 2024;21(1):e00325. doi:10.1016/j.neurot.2024.e00325
33. Distelmaier F, Klopstock T. Neuroimaging in mitochondrial disease. Handb Clin Neurol. 2023;194:173-185. doi:10.1016/B978-0-12-821751-1.00016-6
34. Finsterer J, Zarrouk-Mahjoub S. Cerebral imaging in paediatric mitochondrial disorders. Neuroradiol J. 2018;31(6):596-608.
35. Cheng W, Zhang Y, He L. MRI Features of Stroke-Like Episodes in Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes. Front Neurol. 2022;13:843386. Published 2022 Feb 9. doi:10.3389/fneur.2022.843386
36. Zuccarelli M, Vella- Szijj, J., Serracino-Inglott, A., Borg, J.Treatment of Leber’s Hereditary OpticNeuropathy:An Overview of Recent Developments European Journal Of Ophthalmology 2020;30(6):7.
37. Chi CS. Diagnostic approach in infants and children with mitochondrial diseases. Pediatr Neonatol. 2015;56(1):7-18. doi:10.1016/j.pedneo.2014.03.009
38. Horvrath R, Mirano H, Chinnery PF. Chapter 1-17: Mitochondrial diseaseHandb Clin Neurol. 2023;194. doi:10.1016/B978-0-12-821751-1.00001-4
39. Eom S, Lee HN, Lee S, et al. Cause of Death in Children With Mitochondrial Diseases. Pediatric Neurology.2017;66: 82-88

Bibliography

Molnar C., Gair J. Chapt 4: How Cells Obtain Energy In: Concepts of Biology. 1st Edition, BC Campus; 2015,

Sharma S, Goldstein A, Falk M., Mitochondrial Disease. In: Kellerman’s ed. Conn’s Current Therapy. 2025 edition. Elsevier; 2025.1388-1396

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