Author(s): Amanda Lindenberg, DO, OTR, Simra Javaid, DO, Kelli Chaviano, DO
Originally published: September 20, 2013 Last updated: October 28, 2021
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Disease/ Disorder

Definition

Pediatric neurodegenerative disorders are a large, heterogenous group of progressive neurological disorders which are due to central nervous system (CNS) deterioration. The classic presentation includes progressive deficits or regression of neurological development and cognition. These disorders include lipidoses, peroxisomal disorders, lysosomal disorders and mitochondrial disorders by which they are classified.

Mitochondrial disorders are a subtype of pediatric neurodegenerative disorders which share mitochondrial dysfunction as the etiology of their pathogenesis. There are several classification systems including the biochemical location of deficit and type of DNA affected.  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

Pediatric neurodegenerative disorders have a variety of etiologies which may include genetic mutations, biochemical deficits, infections or unknown etiology.

Mutations of the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) have been identified in numerous mitochondrial disorders. The mtDNA encodes for 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. mtDNA point mutations are inherited maternally, but phenotypic expression is variable because of mtDNA heteroplasmy and threshold effect. Heteroplasmy is defined as the proportion of mutant DNA in a cell, and it can vary from cell to cell, further explaining phenotypic and symptomatic presentation.1,2 The majority of nDNA mutations are inherited autosomal recessively.3 More than 200 nuclear-encoded genes have also been linked to these disorders.4 Childhood onset of mitochondrial disease is more likely due to mutations in nDNA whereas adult onset is more likely due to mtDNA.1,3,5

Epidemiology including risk factors and primary prevention

  • Prevalence of mitochondrial disorders for all ages estimated to be 10 to 15 per 100,000 and 5 per 100,000 for under 16 years.8,9
  • Minimal gender predilection
  • Risk factors include positive family history, exposures to radiation, rotenone, AZT, vpr-HIV, excessive alcohol consumption, and heavy smoking. 10-16

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, cochlea and renal tubules, are disproportionately affected. 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)

The phenotypic presentation of neurodegenerative disorders is dependent on the disorder with a variable presentation from infancy to adulthood.  Heteroplasmy and phenotypic expression plays a large role in age of onset and which systems are affected in each individual. All presentations initially present with loss or regression of neurologic function.  Cognition, including social skills, motor, and sensory domains of the central nervous system, may be affected.  Development of a milestone does not exclude central degeneration.17 CNS degeneration is responsible for neurological deterioration.17 Most well defined syndromes have multi-system involvement.  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.4 Progression and exacerbation risk factors include stress to the body, drugs, acute illness, surgery, and anesthesia. Patients with higher levels of heteroplasmy have poorer prognosis.18

There have been multiple case reports with “plus” syndromes or overlap between two of the well-defined syndromes.19-21

Some well-defined syndromes are:

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

  1. Genetics: Mutations in >95 genes in mtDNA and nDNAhave been identified.22-24 All but four genes were transmitted autosomal recessively. MT-ND and MT-ATP6 were the most commonly affected mutated mtDNA genes.22 SURF1 is the most common nDNA gene affected.5
  2. Onset: Usually between 3 months and 2 years.23-25 Onset after 2 years old is rare and presents with atypical symptoms.24
  3. Presentation: Loss of previously acquired developmental skills is the most common presenting symptom.23,25,26 Dysphagia, vomiting, diarrhea, failure to thrive, or seizures are other commonly presenting symptoms.
  4. Other symptoms: Ophthalmoplegia, optic atrophy, retinitis pigmentosa, hypotonia, dystonia, ataxia, peripheral neuropathy, hypertrophic cardiomyopathy, respiratory insufficiency, lactic acidosis, hypertrichosis.
  5. Prognosis: Rapidly progressive in stepwise manner, usually death by 3 years old, although some live to early adulthood.21,24 Median duration of onset to death is approximately 1.8 years. Onset prior to 6 months, lesions in addition to basal ganglia on initial MRI, and hospitalization in the intensive care unit are prognostic of poor clinical course.21-24 Those with SURF1 as well as MTFMT mutations have an increased life expectancy with a milder clinical phenotype.21,28,29

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

  1. Genetics: m.3242A>G of the mt-mRNA gene
  2. Onset: Typically before age 20 years (average 2-10 years old)30, adult onset possible.
  3. Presentation: Seizures and stroke-like episodes.
  4. Other symptoms: Visual field deficits, hemiparesis (can be bilateral), ataxia, dementia, recurrent headaches, hearing impairment, peripheral neuropathy, exercise intolerance and muscle weakness due to myopathy, myoclonus, mood disorders, cyclic vomiting, short stature, incomplete atrioventricular block, Wolff-Parkinson-White, arrhythmias, left ventricular hypertrophy in up to 55%, cardiomyopathy in later stages, pulmonary hypertension.2,31-34
  5. Prognosis: Episodic decline with intermittent potential for improvement and plateau, especially with rehabilitation therapy. Poor prognosis is associated with multi-system involvement, heart disease, and early stroke-like episodes.33,35

MERRF (Myoclonic Epilepsy with Ragged Red Fibers):

  1. Genetics: m.8433A>G of the MT-TK gene is responsible for 80% of pathogenic variants. m.8256T>C, m.8363G>A, and m.8361 g>A of the MT-TK gene accounts for another 10% of pathogenic variants.36
  2. Onset: Childhood to early adulthood
  3. Presentation: Myoclonic Epilepsy is the most prevalent feature.37 This symptom distinguishes it from all other mitochondrial disorders.36
  4. Other symptoms: optic atrophy, hearing loss, pyramidal signs, ataxia, limb-girdle weakness, re-entrant atrioventricular tachycardia, and multiple lipomas.
  5. Prognosis: Variable progression, neurologic degeneration is often severe.

Kearns-Sayre Syndrome (KSS):

  1. Genetics: large mtDNA (1.3-10kb) deletions.11,38 4977 bp deletion is the most common.39
  2. Onset: Before the age of 20 years old
  3. Presentation: Triad of age before 20 years, retinitis pigmentosa, and progressive external ophthalmoplegia characterized by ptosis and paralysis of extraocular muscles.38 They must have at least one of the following: Heart block/cardiac conduction abnormalities,2,3,26,38,39 cerebellar ataxia, or increased CSF protein (>100 mg/dL) to make diagnosis.11
  4. Other symptoms: Ataxia, cognitive impairment, sensorineural hearing loss, ptosis, cricopharyngeal dysphagia, endocrine abnormalities such as diabetes mellitus, short stature, or growth hormone deficiency.11,39
  5. Prognosis: Few survive beyond the age of 30. Sudden cardiac death is prevalent.11,38

Leber Hereditary Optic Neuropathy (LHON):

  1. Genetics: m.11778G>A, m.3460G>A, m.14484T>C. 11778 locus mutation is most common (~70%) and associated with worst prognosis.13 It is the most common mtDNA disorder.16
  2. Onset: Late adolescence, early adulthood. Usually between ages of 15-35.15,19 Less than 10% are younger than12 years old.8,10
  3. Presentation: Subacute to acute painless loss of central vision in one eye then the other within days to months. Males>females between 6 and 45 years old.8,10,13,16,30,40,41   If pale optic disc on exam, one should be highly suspicious.16
  4. Other symptoms: Cardiac conduction abnormalities, encephalopathy, dystonia.
  5. Prognosis: Most progress within the first 6 months and may stabilize after about 9 months.40 Nearly all are blind by 50 years old. Better visual prognosis for childhood-onset with m.3460 or m.14484 (~30-50%) mutations.10,12,13,16, 41,42

Specific secondary or associated conditions and complications

  1. Neurologic: encephalopathy, seizures, ataxia, chorea, dystonia, spasticity, myoclonus, migraine, deafness, cognitive impairment, developmental delay, cranial nerve abnormalities.4,7,43
  2. Visual: ophthalmoplegia, ptosis, optic atrophy, retinitis pigmentosa.
  3. Musculoskeletal: weakness, hypotonia, fatigability, exercise intolerance, contractures.
  4. Cardiopulmonary: arrhythmia, conduction defects, cardiomyopathy with hypertrophic being the most common,3 respiratory failure, and pulmonary hypertension. Those with skeletal myopathy and failure to thrive are more likely to have involvement of the cardiopulmonary system.33
  5. Gastrointestinal: recurrent vomiting, constipation, pseudo-obstruction
  6. Renal: renal tubular dysfunction.
  7. Endocrine: short stature, diabetes mellitus, exocrine pancreatic failure, thyroid dysregulation, adrenal insufficiency.11
  8. Hematologic: neutropenia, pancytopenia, sideroblastic anemia, thrombocytopenia.

Essentials of Assessment

History

  1. Determine the age of onset of regression and age of milestones met prior to regression.
  2. Recognize well-defined syndromes.
  3. Suggestive features, especially when presenting in clusters, include myoclonus, generalized seizures including neonatal seizures, ataxia, myopathy, abnormal tone (either increased, decreased or mixed), ophthalmoplegia, hearing loss, diabetes, lactic acidosis, developmental delay, and neonatal complications such as jaundice or hypoglycemia.
  4. 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:

  1. Mental Status/Cognition: decreased arousal, impaired attention, delayed language, intellectual disability.
  2. Cranial Nerves: ptosis, ophthalmoplegia, saccades, 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, hyperemic optic disc with peripapillary telangiectasias and vascular tortuosity of central retinal vessels, cherry red spots
  6. Strength: mild to profound weakness.
  7. Cardiovascular: arrhythmia, edema, cyanosis.
  8. 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 or the Denver developmental screening test to evaluate global function.43, 44

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.4,31,32 In Leigh syndrome, elevated lactate in CSF is more consistent than plasma levels.2

Unlike most mitochondrial diseases, MELAS ragged red fibers stain positively with cytochrome c oxidase.31,32 Arginine deficiency has been demonstrated in those with MELAS as well as carriers of the mutation.34,45

Imaging

  1. In general, MRI of the brain shows non-specific and heterogeneous findings. A small number of neurodegenerative disorders show characteristic MRI features. It is the gold standard imaging for neurodegenerative disorders.5 CT of the brain may reveal hypodensities.
  2. Inferior olivary nucleus involvement on MRI is not rare in mitochondrial disorders but is non-specific.12
  3. Characteristic findings on MRI in LS include bilateral, symmetrical gray matter lesions mainly in the basal ganglia, but also in the brain stem, thalamus and peduncles.22,23,27,46,47 T2 weighted images reveal hyperintensities and hypointensities on T1 weighted images.5,48 White matter lesions may suggest advanced LS.9
  4. Stroke-like lesions are most often seen in MELAS syndrome but can also be seen in MERRF, KSS, LS and LHON. These lesions 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 SPECT studies demonstrate focal hyperperfusion. The occipital, parietal, and temporal lobes are most commonly affected.9 They do not follow a specific vascular territory.2
  5. Spinal cord MRI may reveal spinocerebellar, corticospinal, and dorsal column involvement.22 There has been no evidence of atrophy or gallodium enhancement of those with mitochondrial disorders; however, atrophy may be present in lysosomal storage disorders.49
  6. MRI of patients with LHON may reveal gray and white matter lesions, cerebral atrophy, and optic nerve atrophy.9
  7. MRA is usually normal in MELAS.31
  8. CT and MRI show changes in gray and white 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. This is known as the black toenail sign on T2/FLAIR sequences. Severity may be measured with abnormal venous signals.27,32,49-51
  9. Proton magnetic resonance spectroscopy may show positive N-acetyl-L-aspartate and succinate peaks.9
  10. Phosphorus magnetic resonance spectroscopy may show abnormal ATP and phosphocreatine activity.9
  11. 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.9
  12. Calcifications, though non-specific, are commonly seen in the basal ganglia of patients with KSS and MELAS. Calcifications are more easily visualized on CT.9
  13. 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.10
  14. 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.41,42

Supplemental assessment tools

  1. Modified Walker Criteria or Mitochondrial Diagnostic Criteria (MDC) for mitochondrial disorders in children.4
  2. Comprehensive genetic testing includes exome sequencing and genomic sequencing of the nDNA and mtDNA.22 Whole genomic sequencing allows for quantification of mutant mtDNA which allows for evaluation of disease severity. Next generation and whole genome sequencing allows for evaluation of new variants, characterization of carriers, and confirms diagnosis earlier.1,6,39,43
  3. Muscle biopsy for structural and biochemical evaluation as well as quantification of respiratory chain complex enzymatic activity. Microscopic examination can reveal abnormal mitochondrial configurations and/or subsarcolemmal abnormal mitochondrial accumulation.2 Whole genome sequencing is being done more frequently, and muscle biopsy is less favorable.52 Muscle fiber stains may reveal mitochondrial proliferation also known as ragged red fibers or cytochrome c oxidase deficiency in several mitochondrial diseases.30,36,39
  4. EMG for evaluation of myopathy and peripheral neuropathy.
  5. EEG for evaluation of seizure activity. Despite focal or generalized seizures clinically, focal findings may or may not be present.30,53 In Leigh Syndrome, EEG revealed diffuse background slowing. In MERRF there was generalized epilepsy and EEG spikes.53
  6. Echocardiogram and EKG for evaluation of cardiomyopathy, conduction defects, arrhythmias.
  7. Electroretinography evaluates the photonic code responses and scotopic responses of the retina.39

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.

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).54

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.21

Several cases in recent literature with m.10191T>C mutation have been noted to survive into adolescence and early adulthood.22

In MELAS patients, status epilepticus is associated with death.54

The cause of death in patients with mitochondrial disorders is similar to the general population with sepsis being the most frequent. Sudden onset death is also common in patients with mitochondrial disorders, especially those with comorbid neurological disorders.54

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

  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.

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

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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