Mitochondrial Diseases

Mitochondrial diseases are a group of disorders originating from variants in nuclear DNA or mitochondrial DNA (mtDNA) and resulting in a wide spectrum of pathological conditions, often with significant neurologic and myelopathic symptoms. Many commonly seen conditions can be classified as discrete clinical syndromes; however, the presentation and severity of the conditions may vary, creating challenges in diagnosis and treatment.

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Multiple complex neurologic features or a single neurological symptom with other system involvement
  • Lactic acidosis (in children)
  • Clinical symptoms characteristic of a specific mitochondrial disorder
  • Any progressive multisystem disorder of unknown etiology
  • Relatives with mitochondrial disease (ie, presymptomatic testing for at-risk family members)

Laboratory Testing

  • Metabolic evaluation generally precedes molecular genetic testing, unless a specific disorder is suspected from clinical presentation
    • Blood
      • Chemistry panel
      • Liver function studies
      • Blood lactate/pyruvate ratio
      • Ammonia
      • Creatine kinase (MM fraction) – rarely elevated
      • Plasma acylcarnitine profile
      • Ketone
      • Fasting glucose
      • Plasma amino acids
      • Coenzyme Q – deficient in isolated myopathy, cerebellar ataxia, encephalomyopathy, Leigh syndrome
    • Urine
      • Urinalysis
      • Organic acids
      • Amino acids
    • Cerebrospinal fluid (CSF)
      • Routine studies
      • Lactate/pyruvate ratio
      • Amino acids
  • Molecular genetic testing  – generally performed after other disorders are ruled out by metabolic evaluation
    • Testing for mitochondrial DNA (mtDNA) variants – may require testing on DNA extracted from skeletal muscle
    • Nuclear gene variants and some mtDNA variants – can be detected in DNA from peripheral blood
    • Mitochondrial genome variant scanning/sequencing and duplication/deletion testing
    • DNA testing for nuclear genes associated with mitochondrial disorders
    • Targeted testing for a family-specific variant in at-risk or symptomatic family members

Imaging Studies

  • Computed tomography (CT) of head often normal
    • May demonstrate punctate calcifications
    • May show edema or atrophy – cerebral or cerebellar
  • Magnetic resonance imaging (MRI) of head
    • May show T2 signal that resembles strokelike lesions
    • May demonstrate abnormal myelination

Other Testing

  • Specific biochemical testing
    • Analysis of electron transport chain activity
    • Adenosine triphosphate (ATP) synthesis measures in fibroblasts
    • Biochemical results may suggest further genetic testing
      • Complex I deficiency – analysis of mtDNA and nuclear encoded genes
      • Complex II deficiency – analysis of SDHA, SDHB, SDHC, SDHD
      • Complex III deficiency – analysis of BCS1L, MTCYB, 10 nuclear structural genes
      • Complex IV deficiency – analysis of mtDNA cytochrome c oxidase assembly factors (COX10, COX15, SCO1, SCO2, SURF1)
      • Complex V deficiency – analysis of ATPAF2
      • Multiple complex deficiencies – analysis of mtDNA and nuclear DNA mitochondrial maintenance and translation genes
      • Coenzyme Q deficiency – analysis of APTX, CABC1, COQ2, COQ9, ETFDH, PDSS1, PDSS2
  • Muscle biopsy (other acceptable tissue biopsies include liver, cardiac, skin)
    • Light microscopy – histochemistry
      • Detection of ragged red fibers (most common in mitochondrial variants) by Gomori trichrome stain – subsarcolemmal accumulation of mitochondria on muscle pathology
      • Cytochrome c oxidase-deficient fibers
    • Electron microscopy – increase in mitochondrial number or size, increased lipid and glycogen droplets, increased mitochondrial matrix
  • Neurophysiologic studies
    • Electroencephalography for individuals with suspected encephalopathy or seizures
    • Electromyography/nerve conduction velocity for individuals with limb weakness, sensory issues, or areflexia
  • Electrocardiography/echocardiography – evaluate cardiomyopathy or atrioventricular conduction defects
  • Auditory/ophthalmologic examinations to confirm defects

Differential Diagnosis


  • Prevalence – approximately 1/5,000 in U.S.
  • Age – all
  • Sex – M:F, equal


  • Mitochondrial disorders may be caused by variants in nuclear DNA or mtDNA
    • Nuclear gene defect inheritance may be autosomal recessive or autosomal dominant
    • mtDNA deletions generally occur de novo
    • mtDNA defects, point variations, and duplications are maternally inherited
  • Affected individuals with mtDNA variants often have a mixture of mutated and normal mtDNA within each cell (heteroplasmy)
    • Disease severity and age of onset are affected by amount of heteroplasmy and number and type of cells containing mtDNA variant
    • Females with heteroplasmy but no clinical symptoms may have affected offspring
  • Poor genotype/phenotype correlation exists; the same variant may cause different clinical syndromes


  • Mitochondria are ubiquitous, complex, intracellular organelles containing nonnuclear DNA
    • Each cell may contain hundreds to thousands of copies of mtDNA
  • Mitochondria are essential in many cell processes, including the generation of adenosine triphosphate during oxidative metabolism
    • Tissues most affected are dependent upon aerobic metabolism or have a high energy requirement
  • Variants in the mitochondrial genome or in nuclear DNA involved in the respiratory chain principally affect tissues that are heavily dependent on oxidative metabolism (eg, central nervous system, cardiovascular, musculoskeletal)

Clinical Presentation

  • Many mitochondrial diseases can be classified as discrete clinical syndromes based on characteristic clinical features; however, clinical overlap occurs
  • Some mitochondrial disorders affect only a single organ (eg, Leber hereditary optic neuropathy [LHON] and nonsyndromic sensorineural deafness)
  • Mitochondrial disorders may present at any age
    • Presentation of nuclear DNA variants typically occurs in childhood
    • mtDNA abnormalities are more likely to present in late childhood or adulthood
  • Clinical presentation is highly variable
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Mitochondrial Disorders Panel (mtDNA by Sequencing and Deletion/Duplication, 121 Nuclear Genes by Sequencing, 119 Nuclear Genes by Deletion/Duplication) 2006054
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-Based CGH Microarray


Variants in genes are not analyzed, and regulatory region and deep intronic variants and large deletions/duplications in LARS2 or NDUFA2 are not detected

mtDNA variants present at <10% heteroplasmy may not be detected

Sequencing may detect variants of unknown clinical significance

Diagnostic errors can occur due to rare sequence variations

Presence of a highly homologous pseudogene may interfere with variant detection in WFS1

Variants in mitochondrial D-loop and mosaic variants in nuclear genes are not reported

Mitochondrial Disorders (mtDNA) Sequencing 2006065
Method: Massively Parallel Sequencing


Variants in genes are not analyzed, and regulatory region and deep intronic variants and large deletions/duplications in LARS2 or NDUFA2 are not detected

mtDNA variants present at <10% heteroplasmy may not be detected

Sequencing may detect variants of unknown clinical significance

Diagnostic errors can occur due to rare sequence variations

Presence of a highly homologous pseudogene may interfere with variant detection in WFS1

Variants in mitochondrial D-loop are not reported

Cytogenomic SNP Microarray 2003414
Method: Genomic Microarray (Oligo-SNP Array)


Finsterer J, Harbo HF, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder J, Gasser T, European Federation of Neurological Sciences. EFNS guidelines on the molecular diagnosis of mitochondrial disorders. Eur J Neurol. 2009; 16(12): 1255-64. PubMed

General References

Craigen WJ. Mitochondrial DNA mutations: an overview of clinical and molecular aspects. Methods Mol Biol. 2012; 837: 3-15. PubMed

Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics. 2007; 120(6): 1326-33. PubMed

Keogh MJ, Chinnery PF. How to spot mitochondrial disease in adults. Clin Med. 2013; 13(1): 87-92. PubMed

Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and management. Dev Med Child Neurol. 2010; 52(5): 422-33. PubMed

Koenig MK. Presentation and diagnosis of mitochondrial disorders in children. Pediatr Neurol. 2008; 38(5): 305-13. PubMed

McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease. Lancet Neurol. 2010; 9(8): 829-40. PubMed

Rahman S, Hanna MG. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J Neurol Neurosurg Psychiatry. 2009; 80(9): 943-53. PubMed

Scaglia F. Nuclear gene defects in mitochondrial disorders. Methods Mol Biol. 2012; 837: 17-34. PubMed

Siciliano G, Pasquali L, Mancuso M, Murri L. Molecular diagnostics and mitochondrial dysfunction: a future perspective. Expert Rev Mol Diagn. 2008; 8(4): 531-49. PubMed

Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta. 2010; 1797(2): 113-28. PubMed

Wong LC. Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion. 2013; 13(4): 379-87. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Dames S, Chou L, Xiao Y, Wayman T, Stocks J, Singleton M, Eilbeck K, Mao R. The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders. J Mol Diagn. 2013; 15(4): 526-34. PubMed

Dames S, Eilbeck K, Mao R. A high-throughput next-generation sequencing assay for the mitochondrial genome. Methods Mol Biol. 2015; 1264: 77-88. PubMed

Dimmock DP, Zhang Q, Dionisi-Vici C, Carrozzo R, Shieh J, Tang L, Truong C, Schmitt E, Sifry-Platt M, Lucioli S, Santorelli FM, Ficicioglu CH, Rodriguez M, Wierenga K, Enns GM, Longo N, Lipson MH, Vallance H, Craigen WJ, Scaglia F, Wong L. Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Hum Mutat. 2008; 29(2): 330-1. PubMed

Dobrowolski SF, Hendrickx AT, van den Bosch BJ, Smeets HJ, Gray J, Miller T, Sears M. Identifying sequence variants in the human mitochondrial genome using high-resolution melt (HRM) profiling. Hum Mutat. 2009; 30(6): 891-8. PubMed

Longo N, Schrijver I, Vogel H, Pique LM, Cowan TM, Pasquali M, Steinberg GK, Hedlund GL, Ernst SL, Gallagher RC, Enns GM. Progressive cerebral vascular degeneration with mitochondrial encephalopathy. Am J Med Genet A. 2008; 146A(3): 361-7. PubMed

Viau KS, Ernst SL, Pasquali M, Botto LD, Hedlund G, Longo N. Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2013; 110(3): 255-62. PubMed

Medical Reviewers

Last Update: October 2017