Mitochondrial Myopathies

Mitochondrial myopathies are conditions arising from dysfunction of the mitochondria (the energy-producing structures) and are characterized by prominent muscular symptoms and accompanied by various symptoms from organs with high energy requirements. The organs disproportionately affected include the skeletal muscles, brain, and heart. Mitochondrial myopathies are caused by mutations in the nuclear DNA or mitochondrial DNA, which typically result in reduced production of energy needed by cells. Presentation can be an isolated myopathy, encephalomyopathy, ophthalmoplegias, or a multisystem disease. Diagnosis involves in-depth medical and family history, along with laboratory and genetic studies. On biopsy, there is subsarcolemmal and intermyofibrillar proliferation of mitochondria seen as “ragged-red fibers.” This condition indicates a compensatory response to energy failure. There is no definitive treatment. Management consists of physical therapy and a multidisciplinary approach in addressing accompanying symptoms.

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Mitochondrial myopathies are diseases that arise from dysfunction of the mitochondria (the energy-producing structures). These diseases are characterized by prominent muscular symptoms (such as muscle weakness) and accompanied by various symptoms from organs with high energy requirements.


  • Mutation(s) involving the nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) with a general end result of impaired oxidative phosphorylation.
    • mtDNA-related mutation maternally inherited
    • Also occur sporadically
  • Defects involve:
    • Genes encoding respiratory chain proteins
    • Genes encoding respiratory chain ancillary proteins (e.g., required for assembly)
    • Mitochondrial RNA translation
    • Mitochondrial inner membrane lipid milieu
    • Depletion of mtDNA (defect in mtDNA maintenance)
    • Mitochondrial dynamics (fusion/fission)


  • In the United States: estimated 1000–4000 births with mitochondrial disorders each year 
  • Globally, it is difficult to determine exact prevalence due to:
    • Data in certain regions being less available
    • Less severe symptoms go unnoticed and thus are not reported.
  • From extrapolated data in studies done in northeast England and Australia, the estimated prevalence of mitochondrial disease is 13 in 200,000.



  • Organelles with multiple functions:
    • Produce energy (ATP) through oxidative phosphorylation
    • Involved in apoptosis, calcium homeostasis, and production of reactive oxygen species
    • Maintain the phospholipid membrane that serves as the boundary to the cytosol and site of the respiratory chain
    • Replicate, transcribe own DNA, and translate messenger RNA (mRNA) into protein(s)
  • While the mitochondrion has its own DNA, the majority of the proteins needed are encoded by the nDNA and are transported into the organelle.
Mitochondrion of the eukaryotic cell

Structure of a mitochondrion

Image: “Mitochondrion of the eukaryotic cell” by Mariana Ruiz Villarreal. License: Public Domain

Mitochondrial disease

  • Both nuclear and mitochondrial genes produce proteins necessary for mitochondria to perform their various functions.
  • Mutations in nDNA or mtDNA affect mitochondrial functions, ultimately causing reduced production of energy and increased risk of radical oxygen damage.
  • nDNA:
    • Mutations can be autosomal recessive, autosomal dominant, or X-linked.
    • De novo mutations also occur.
  • mtDNA:
    • A fertilized egg carries mitochondria predominantly from the mother; thus, the mitochondrial genotype is transmitted maternally.
    • Sporadic mutations can take place, indicating that the offspring can have mtDNA different from the mother’s.
    • Each cell has several mitochondria, and each mitochondrion has several DNA molecules.
      • Homoplasmy: mtDNAs are all identical.
      • Heteroplasmy: Mutation is present in some of the mtDNA copies.
    • Clinical expression of mutation(s) is variable owing to heteroplasmy.
  • Brain, heart, and muscles generally require high energy, so defects in mitochondrial function disproportionately affect these organs.
    • Muscle disease (myopathy) may be the predominant manifestation.
    • Other conditions have a multitude of manifestations depending on organs affected.

Clinical Presentation

General findings

Signs and symptoms correlate to organs or tissues affected:

  • Skeletal muscles:
    • Weakness
    • Fatigue
    • Exercise intolerance
    • Developmental delays
    • Stunted growth
  • Nervous system:
    • Seizures
    • Balance and coordination (ataxia)
    • Learning deficits
    • Hearing loss
  • Heart: 
    • Cardiomyopathy
    • Conduction abnormalities
  • Eyes: 
    • Ophthalmoplegia
    • Ptosis
    • Vision loss (optic atrophy)
  • GI disorders (altered motility), liver disease, pancreatic dysfunction (diabetes), and kidney problems (glomerulopathy)

Specific disorders

  • Isolated myopathy (muscle symptoms only):
    • Weakness, fatigue, poor exercise tolerance
    • Usually involves proximal limbs
  • Chronic progressive external ophthalmoplegia (CPEO):
    • Progressive ophthalmoparesis with ptosis
    • Symptomatic overlap with other mitochondrial myopathies.
  • Kearns-Sayre syndrome (KSS):
    • External ophthalmoplegia (CPEO), pigmentary retinopathy before age 20 years
    • Also associated with:
      • Cardiac conduction defects
      • Sensorineural hearing loss
      • Anemia
      • Diabetes
      • Cognitive defects
  • Leber hereditary optic neuropathy (LHON):
    • Usually presents with bilateral optic neuropathy (permanent visual loss predominantly in young men)
    • Maternally inherited (associated with mtDNA point mutation)
    • Other features can include:
      • Seizures
      • Extrapyramidal syndrome
      • Ataxia
      • Intellectual disability
      • Peripheral neuropathy
      • Cardiac conduction defects
  • Severe encephalomyopathy of infancy or childhood:
    • Presents in infancy or early childhood
    • Commonly presents with encephalomyopathy: hypotonia, encephalopathy, seizures, and/or ophthalmopathy 
    • Poor prognosis
  • Multisystem disease (variable combination of manifestations, with Leigh syndrome and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as the most common):
    • Leigh syndrome:
      • Subacute necrotizing encephalomyelopathy, often in infancy and early childhood
      • Pathology: bilateral, symmetric necrotizing lesions with spongy changes in the basal ganglia, thalamus, brain stem, and spinal cord 
    • MELAS:
      • Varying degrees of cognitive impairment and dementia
      • Lactic acidosis
      • Stroke-like episodes (hemiparesis, hemianopia, or cortical blindness)
      • Hearing loss
      • Short stature
    • Myoclonic epilepsy and ragged-red fibers (MERRF):
      • Myoclonus
      • Epilepsy
      • Myopathy
      • Ataxia
      • Short stature
    • LHON
    • Maternally inherited deafness and diabetes (MIDD)
    • Neuropathy, ataxia, and retinitis pigmentosa (NARP)
    • Pearson syndrome (sideroblastic anemia and pancreatic dysfunction)
  • Coenzyme Q10 (CoQ10) deficiency:
    • Coenzyme Q10 is an important electron carrier, antioxidant, and important factor in DNA repair and cellular membrane regulation.
    • Mitochondrial disorder leads to reduced CoQ10 levels.
    • Can present with proximal muscle weakness only (isolated myopathy)
    • Can also have ataxia, encephalomyopathy, and nephrotic syndrome
Bilateral ptosis

Kearns-Sayre syndrome (KSS):
Patient with bilateral ptosis

Image: “Bilateral ptosis” by Department of Pediatric Neurology, Ghaem Medical Center, Mashhahd University of Medical Sciences, Mashhad, Iran. License: CC BY 3.0


  • History and examination:
    • Family history up to 3 generations, including neonatal or childhood deaths
    • Family conditions of maternal inheritance (transmitted by females only)
  • Labs:
    • Blood tests include CBC, metabolic panel, creatine kinase, lactic acid, uric acid, and amino acids.
    • CSF studies include lactate, pyruvate, amino acids, and 5-methyltetrahydrofolate.
    • Quantitative and qualitative urine organic acids
  • Genetic studies: In cases of classic presentation (e.g., LHON), genetic studies can be done initially.
  • Muscle biopsy:
    • Hallmark: 
      • Mitochondrial accumulation in the subsarcolemmal and intermyofibrillar region of muscle fibers
      • Mitochondria proliferate to compensate for the lack of energy production.
    • On Gomori trichome stains: Mitochondria are seen as red masses against a blue background (ragged-red fibers).
    • In succinate dehydrogenase (SDH)–reacted stains, mitochondrial proliferation is seen as ragged-blue fibers.
  • Additional tests depending on accompanying features:
    • Electrocardiography, echocardiography
    • Electromyography
    • Neuroimaging


  • General approach:
    • Mainly supportive
    • Regular exercise (if able to)
    • Physical therapy and occupational therapy
    • Genetic counseling
  • Depending on accompanying features:
    • Respiratory support: 
      • For those with associated respiratory difficulty
      • Noninvasive measures (e.g., continuous positive air pressure (CPAP))
      • In some cases, tracheostomy is necessary.
    • Ophthalmologic and audiologic evaluation
    • Cardiologic evaluation
    • Seizure control
  • Pharmacologic:
    • No proven treatment
    • In select cases, CoQ10, creatine, and L-carnitine are given.
    • Avoid certain drugs that interfere with respiratory chain function (e.g., carbamazepine, valproic acid, phenytoin, barbiturates, tetracyclines).
  • Gene therapy is a potential future option.

Differential Diagnosis

  • Seizures in children: occur when there is uncontrolled excessive synchronous neuronal activity in the brain that causes sudden transient changes in motor function, sensation, behavior, or mental status.  Diagnosis depends on thorough history, physical exam, and EEG findings. Most children that have a seizure recover without any sequelae. Different types are seen, including tonic, myoclonic, and atonic. The prognosis depends on the initial cause and the presence of underlying neurologic pathology. 
  • Friedreich ataxia: autosomal recessive disorder characterized by progressive spinocerebellar degeneration. Friedreich ataxia presents in the 1st–2nd decades of life with progressive gait ataxia, weakness, tremor, dysarthria, dysphagia, hypertrophic cardiomyopathy, and/or diabetes. The patient eventually becomes bedridden. Diagnosis is confirmed by genetic testing showing trinucleotide repeat expansion in the FXN gene. Treatment is supportive, and most patients die of heart disease in the 4th or 5th decade of life. 
  • Myotonic syndromes: group of heterogeneous, inherited disorders that primarily affect muscles. Myotonic dystrophy, a trinucleotide/tetranucleotide repeat expansion disorder, is the most important disorder in this group. Several types can present with muscle weakness, myotonia, and myalgias. Affected individuals may also manifest with cataracts, cardiac conduction abnormalities, and insulin resistance. Muscle biopsy and genetic studies help differentiate this condition.


  1. Ahuja A. S. (2018). Understanding mitochondrial myopathies: a review. Peer J 6:e4790.
  2. O’Ferrall, E. (2021). Mitochondrial structure, function and genetics. UpToDate. Retrieved June 14, 2021, from
  3. O’Ferrall, E (2021). Mitochondrial myopathies: clinical features and diagnosis. In J. F. Dashe (Ed.), UpToDate. Retrieved March 25th, 2021, from
  4. O’Ferrall, E. (2021). Mitochondrial myopathies: treatment. UpToDate. Retrieved June 14, 2021, from

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