Pediatric neurodegenerative disorders

Author(s): Simra Javaid, MD and Charles Pelshaw, MD

Originally published:09/20/2013

Last updated:02/14/2018

1. DISEASE/DISORDER:

Definition

Mitochondrial disorders are a heterogeneous group of diseases that share mitochondrial dysfunction as the etiology of their pathogenesis. A biochemical classification system introduced in 1985 grouped mitochondrial disorders according to the site of biochemical defect of substrate transport, substrate utilization, Krebs cycle, respiratory chain, and oxidation-phosphorylation coupling. A genetic classification system delineating nuclear DNA defects and mitochondrial DNA defects now exists. The recent trend restricts the term mitochondrial diseases to disorders of the respiratory chain.

Etiology

Mutations of the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) have been identified in numerous mitochondrial disorders. The mtDNA encodes 13 subunits of the electron transport chain complexes, 22 transfer RNAs, and 2 ribosomal RNAs. The nDNA encodes all other mitochondrial proteins. mtDNA mutations are inherited maternally, but phenotypic expression of the disease is variable because of mtDNA heteroplasmy and threshold effect. The majority of nDNA mutations have an autosomal recessive inheritance pattern. Recent studies have shown that up to 25% of mitochondrial disorders in children are due to nDNA mutations and 10-15% are due to mutations in mtDNA. More than 200 nuclear-encoded genes have also been linked to these disorders.1

Epidemiology including risk factors and primary prevention

  • Prevalence for all ages estimated to be 10 to 15 per 100,000.1
  • Prevalence for ages under 16 years estimated to be 5 per 100,000.2
  • Risk factors include positive family history, and exposures to radiation, rotenone, AZT, vpr-HIV.3,4,5,6,7,8
  • Heavy smoking and excessive alcohol consumption are major risk factors for visual loss in LHON mutation carriers.3

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. Over 90% of ATP required for cellular energy is produced by the mitochondria. Cellular energy deficiency is the unifying biochemical defect. Tissues with high energy demand, such as the brain, nerves, muscle, heart, retina, and renal tubules, are disproportionately affected. Specific pathological mechanism leading to cell loss has not been completely elucidated. Apoptosis-induced cell loss, accumulation of reactive oxygen species, and altered calcium metabolism appear to be key processes in the pathogenesis.

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

The phenotypic expression of mitochondrial disorders is highly variable, and can manifest as single-organ impairment or multi-system dysfunction, with onset ranging from infancy to adulthood. 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.1

Some well-defined syndromes are:

Leigh Syndrome:

  1. Genetics: Mutations in >75 genes in mtDNA and nDNA identified.10
  2. Onset: Usually between 3 months and 2 years.9,10,21
  3. Presentation: Inititally, loss of previously acquired motor skills.9,21,25 Dysphagia, vomiting, diarrhea, failure to thrive.
  4. Other symptoms: Ophthalmoplegia, optic atrophy, retinitis pigmentosa, hypotonia, dystonia, ataxia, peripheral neuropathy, hypertrophic cardiomyopathy, respiratory insufficiency, lactic acidosis.
  5. Prognosis: Rapidly progressive, usually death by age 3 years, although some live to early adulthood.10 Onset prior to age 1 and lesions in addition to basal ganglia on initial MRI are prognostic of poor clinical course.11,21,22,25

MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes):

  1. Genetics: m.3242A>G.
  2. Onset: Typically before age 20 years, adult onset possible.
  3. Presentation: Seizures and stroke-like episodes.
  4. Other symptoms: Visual field deficits, hemiparesis (can be bilateral, or “doubleâ€), ataxia. Dementia, recurrent headaches, hearing impairment, peripheral neuropathy, exercise intolerance & muscle weakness, cyclic vomiting, short stature.12,14
  5. Prognosis: Episodic decline with intermittent potential for improvement and plateau, especially with rehabilitation therapy.

MERRF (Myoclonic Epilepsy with Ragged Red Fibers):

  1. Genetics: m.8433A>G.
  2. Onset: Childhood to early adulthood.
  3. Presentation: Myoclonic Epilepsy is most prevalent feature. 16
  4. Other symptoms: optic atrophy, hearing loss, pyramidal signs, ataxia, limb-girdle weakness, re-entrant atrioventricular tachycardia, multiple lipomas.
  5. Prognosis: Variable progression, neurologic degeneration is often severe.

Kearns-Sayre Syndrome:

  1. Genetics: large mtDNA (1.3-10kb)4,23 deletions.
  2. Onset: Before age 20 years.
  3. Presentation: Triad of age before 20 years, retinitis pigmentosa, progressive external ophthalmoplegia. Heart block/cardiac conduction abnormalities23, cerebellar ataxia, or increased CSF protein (>100 mg/dL) must be present to make diagnosis.4
  4. Other symptoms: Ataxia, cognitive impairment, deafness, ptosis, cricopharyngeal dysphagia.4
  5. Prognosis: Few survive beyond age 30 years. Sudden cardiac death prevalent.4,23

Leber’s Hereditary Optic Neuropathy:

  1. Genetics: m.11778G>A, m.3460G>A, m.14484T>C. 11778 locus mutation is most common and associated with worst prognosis.6
  2. Onset: Late adolescence, early adulthood. Usually between ages of 15-35.6 Less than 10% <12 years old.2,3
  3. Presentation: Subacute to acute bilateral loss of central vision. Males>females. 2,3,6,27
  4. Other symptoms: Cardiac conduction abnormalities, encephalopathy, dystonia.
  5. Prognosis: Nearly all are blind by age 50 years. Better visual prognosis for childhood-onset with some visual recovery with 3460 or 14484 mutations.2,3,6

Specific secondary or associated conditions and complications

  1. Neurologic: encephalopathy, seizures, ataxia, chorea, dystonia, spasticity, myoclonus, migraine, deafness, cognitive impairment, developmental delay1.
  2. Visual: ophthalmoplegia, ptosis, optic atrophy, retinitis pigmentosa.
  3. Musculoskeletal: weakness, hypotonia, fatiguability, exercise intolerance, contractures.
  4. Cardiopulmonary: arrhythmia, conduction defects, cardiomyopathy, respiratory failure.
  5. Gastrointestinal: recurrent vomiting, constipation, pseudo-obstruction, hepatic dysfunction.
  6. Renal: renal tubular dysfunction.
  7. Endocrine: short stature, diabetes mellitus, exocrine pancreatic failure, thyroid dysregulation, adrenal insufficiency4.
  8. Hematologic: neutropenia, pancytopenia, sideroplastic anemia.

2. ESSENTIALS OF ASSESSMENT

History

  1. Recognize well-defined syndromes.
  2. Suggestive features, especially when presenting in clusters, include myoclonus, generalized seizures, ataxia, myopathy, abnormal tone – either increased or decreased or mixed, ophthalmoplegia, hearing loss, diabetes, lactic acidosis, and developmental delay.
  3. Other suggestive historical findings include positive family history, progressive symptoms in unrelated organ systems, acute loss of functional skills with intercurrent illness, especially with fever and dehydration.

Physical examination

Physical examination findings are highly variable, and may include:

  1. Mental Status/ Cognition: decreased arousal, impaired attention, delayed language, intellectual disability.
  2. Cranial Nerves: ptosis, ophthalmoplegia, visual field deficits, hearing loss, weak suck.
  3. Tone: hypotonia, spasticity, dystonia; can present in various patterns in the trunk and limbs.
  4. Movement: ataxia, myoclonic jerks.
  5. Fundoscopic: pigmentary retinitis, optic atrophy. Hyperaemic optic disc with peripapillary telangiectasias and vascular tortuosity of central retinal vessels. 3,6
  6. Strength: mild to profound weakness.
  7. Cardiovascular: arrhythmia, edema, cyanosis.
  8. Dermatologic: acrocyanosis, mottled pigmentation of photo-exposed areas, alopecia.

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.

Laboratory studies

Biochemical and molecular tests are available. Currently no standardized diagnostic panel exists. Initial laboratory studies frequently include: plasma lactate, pyruvate, ketone bodies, acylcarnitine, and plasma and urine organic acids. 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.1,12,14

Unlike most mitochondrial diseases, MELAS ragged red fibers stain positively with cytochrome c oxidase.12,14

Imaging

  1. In general, MRI of the brain shows non-specific and heterogenous findings.
  2. A small number of mitochondrial disorders show characteristic MRI features.
  3. Inferior olivary nucleus involvement on MRI is not rare in mitochondrial disorders, but does not suggest a specific diagnosis.5
  4. Characteristic findings on MRI in Leigh syndrome include bilateral, symmetrical hyperintensities mainly in the basal ganglia, but also in the brain stem and peduncles18,22,25
  5. MRA is usually normal in MELAS12
  6. CT and MRI show changes in gray matter in MELAS patients, simulating ischemic strokes. Most common pathological finding is multiple areas of cortical necrosis with diffuse cortical atrophy in cerebral hemispheres and cerebellum.14,15,20,27
  7. Proton magnetic resonance spectroscopy may show positive N-acetyl-L-aspartate and succinate peaks.
  8. Phosphorus magnetic resonance spectroscopy may show abnormal ATP and phosphocreatine activity.
  9. Optical coherence tomography (OCT) and OCT angiography (OCT-A) can help identify morphological changes in retinal nerve fiber layer (RNFL) and retinal vasculature in various pathological states, respectively.3
  10. Cardiac magnetic resonance imaging (CMR) has garnered use in identifying sub-clinical myocardial defects before clinical presentation or finding on echo. For example, identification of mitral valve prolapse in KSS and abnormalities in mid anterior and anterolateral walls in MELAS before clinical manifestations have been reported in literature.23
  11. The Black Toenail Sign is a common image on T2/FLAIR sequences in MELAS. It represents gyral necrosis and the extent correlates with disease duration.23 Disease severity can be seen by abnormal venous signals.24

Supplemental assessment tools

  1. Modified Walker Criteria or Mitochondrial Diagnostic Criteria (MDC) for mitochondrial disorders in children1
  2. Genomic sequencing of the nDNA and mtDNA.
  3. Muscle biopsy for structural and biochemical evaluation, and quantification of respiratory chain complex enzymatic activity. Microscopic examination can reveal abnormal mitochondrial configurations and/or subsarcolemmal abnormal mitochondrial accumulation.1
  4. EMG for evaluation of myopathy and peripheral neuropathy.
  5. EEG for evaluation of seizure activity.
  6. Echocardiogram and EKG for evaluation of cardiomyopathy, conduction defects, arrhythmias.

Early predictions of outcomes

Diagnosis-dependent, but in general, the younger the onset, the more rapid the progression, and the worse the outcome.

In recent literature, Leigh syndrome patients with mutations close to the C-terminus with varying residual COX activity have been shown to have longer survival rates and a better prognosis.18

Several cases in recent literature with m.10191T>C mutation have been noted to survive into adolescenceand early adulthood.19

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 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 patient’s interest in recreational activities in order to develop adaptive programs as needed.

Professional Issues

  1. Genetic counseling is valuable for family planning.
  2. Prediction of disease expression in mtDNA mutation is complicated by variability of phenotypic expression.
  3. Genetic counseling is also valuable for therapeutic planning.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Currently, no curative treatments or treatment guidelines exist. Anecdotal reports of benefit from coenzyme-Q10, carnitine, succinate, riboflavin, thiamine, and ascorbic acid exist, but none have demonstrated sustained benefit.9,10,11,12,13,14,15,16,17 Management of mitochondrial disorders remains supportive. 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.4

Thiamine (Vitamin B1) is the most common treatment for Leigh syndrome with some patients experiencing temporary symptomatic improvement and minimal slowing of disease progression.9

Most often used AED for epilepsy in MERRF is levetiracetam.16

Certain medications should be avoided. Valproic acid has deleterious effects on mitochondrial function and should be avoided in seizures. Metformin often causes lactic acidosis. Mitochondrial toxicity can result from aminoglycosides, linezolid, and alcohol.12,14,15,16,20

Acute exacerbations in MELAS can be triggered by febrile illness, thus all childhood vaccinations should be given in a timely manner.14

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 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. Expeditiously transition to adapted mobility device when patient loses efficient independent ambulation.

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.

Patient & family education

Provide anticipatory guidance to the patient and family about the progressive nature of mitochondrial disorders. Encourage patient and family to utilize services provided by organizations such as the United Mitochondrial Disease Foundation and the Muscular Dystrophy Association. Provide assistance to 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.28

Emerging/unique Interventions

Functional measures such as the Gross Motor Function Measure and Manual Ability Classification System may be utilized, keeping in mind that 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 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)12

4. 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.3

Idebenone shown to be partially effective in acute stage of LHON with some patients experiencing clinically significant visual benefits.3,6,12,27

Current phase 3 gene therapy trials for LHON patients involve wild type mtDNA being delivered via viral vectors directly into their eyes with intravitreal injection. The goal being incorporation into retinal ganglion cells and stabilization or improvement of vision.6,7,8

Implementation of vitamin B3 (NAD+ precursor nicotinamide) shown to prevent retinal ganglion cell dysfunction and neuronal loss in mice models, which may translate to therapeutic treatment of mitochondrial optic neuropathies.3

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

Reduction in retinal ganglion cells lost, with associated 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.3

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.3

L-arginine and citrulline supplementation has been shown to improve symptoms in stroke-like episodes possibly due to increased nitrous oxide production.12,13,14,16,17,27

Growth hormone therapy has shown favorable increase in height in Kearns-Sayre patients.26

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

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 and improving quality of life, and detrimental in causing metabolic crisis.18,19 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.20,21 Exercise should therefore be prescribed with caution, and followed closely, ideally in coordination 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.22,23,24 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 be therefore be injected with caution, ideally in coordination with mitochondrial specialists whose genetic knowledge may inform the extent of potential sensitivity to botulinum toxin.

REFERENCES

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  6. Biousse V, Newman NJ. Diagnosis and clinical features of common optic neuropathies. Lancet Neurol. 2016; 15:1355-67.
  7. Feuer WJ, Schiffman JC,, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy : initial results. Ophthalmology. 2016; 123: 558-70.
  8. 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.
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  13. 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.
  14. 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.
  15. Finsterer J, Wakil SM. Stroke-like episodes, peri-episodic seizures, and MELAS mutations. European Journal of Paediatric Neurology. 2016; 20: 824-829.
  16. Finsterer J, Mahjoub SZ. Management of epilepsy in MERRF syndrome. Seizure. 2017; 50: 166-170.
  17. El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017; 5:10.
  18. 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.
  19. Levy RJ, Rios PG, Akman HO, et al. Long Survival in Patients with Leigh Syndrome and the m.10191T>C Mutation in MT-ND3 : A Case Report and Review of the Literature. J Child Neurol. 2014; 29(10): 105-110.
  20. 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.
  21. 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.
  22. 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.
  23. Whitehead MT, Wien M, Lee B, et al. Black Toenail Sign in MELAS Syndrome. Pediatr Neurol. 2017; 75: 61-65.
  24. 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.
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  26. 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.
  27. Magner M, Kolarova H, Honzik T, et al. Clinical Manifestations of Mitochondrial Diseases. Dev Period Med. 2015; 4:441-449.
  28. Mitochondrial Myopathies. (2017, December 22). Retrieved from https://www.mda.org/disease/mitochondrial-myopathies.

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Original Version of the Topic

Sarah H. Evans, MD, Thomas Chang, MD, Adeline Vanderver, MD. Pediatric neurodegenerative disorders. 09/20/2013.

Author Disclosure

Simra Javaid, MD
Nothing to Disclose

Charles Pelshaw, MD
Nothing to Disclose

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