Mitochondrial Diseases

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

Indications for Testing

  • Individuals with multiple complex neurologic features or a single neurological symptom with other system involvement
  • Children presenting with lactic acidosis
  • Individuals with clinical symptoms characteristic of a specific mitochondrial disorder
  • Individuals with any progressive multisystem disorder of unknown etiology
  • 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
      • Routine studies
      • Lactate/pyruvate ratio
      • Amino acids
  • Molecular genetic testing
    • Molecular testing for mitochondrial DNA (mtDNA) mutations may require testing on DNA extracted from skeletal muscle; nuclear gene mutations and some mtDNA mutations can be detected in DNA from peripheral blood
    • Mitochondrial genome mutation scanning/sequencing and duplication/deletion testing
    • DNA testing for nuclear genes associated with mitochondrial disorders
    • Targeted testing for a family-specific mutation in at-risk or symptomatic family members

Imaging Studies

  • CT of head often normal
    • May demonstrate punctate calcifications
    • May see edema or atrophy – cerebral or cerebellar
  • MRI of head
    • T2 signal that resembles stroke-like lesions
    • Abnormal myelination

Other Testing

  • Specific biochemical testing
    • Analysis of electron transport chain activity
    • ATP synthesis measures in fibroblasts
    • Biochemical results may suggest further genetic testing
      • Complex I deficiency – analysis of mitochondrial DNA 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 mitochondrial DNA cytochrome coxidase assembly factors (COX10, COX15, SCO1, SCO2, SURF1)
      • Complex V deficiency – analysis of ATPAF2
      • Multiple complex deficiencies – analysis of mitochondrial DNA and nuclear DNA mitochondrial maintenance and translation genes
      • Coenzyme Q deficiency – analysis of APTX, CABC1, COQ2, COQ9, ETFDH, PDSS1, PDSS2
  • Muscle biopsy
    • Light microscopy – histochemistry
      • Detection of ragged red fibers (most common in mitochondrial mutations) by Gomori trichrome stain
        • Subsarcolemmal accumulation of mitochondria on muscle pathology
      • Cytochrome coxidase-deficient fibers
    • Electron microscopy
      • Increase in mitochondrial number or size, increased lipid and glycogen droplets, increased mitochondrial matrix
    • Other acceptable tissues – liver, cardiac, and skin biopsy
  • 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

Mitochondrial diseases are a group of disorders originating from mutations 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.


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


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


  • Mitochondria are ubiquitous, complex, intracellular organelles containing non-nuclear 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
  • Mutations 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 mutations 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


Not determined or evaluated

  • Genes other than those listed in Table 2 of Additional Technical Information bulletin
  • Variants in the mitochondrial DNA
  • Large deletions and duplications in the EMD and TAZ genes
  • Deep intronic and regulatory region variants
  • Breakpoints of large deletions/duplication
  • Small deletions or insertions may not be detected by massively parallel sequencing

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene variant does not exclude a heritable form of cardiomyopathy or arrhythmia

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


Diagnosis of mitochondrial disorders may be tissue specific

Not detected

  • Mutations in genes not analyzed
  • Regulatory region and deep intronic mutations
  • Mutations within the nuclear genes

Not reported

  • Variants in the mitochondrial D-loop

mtDNA mutations 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

Mitochondrial Disorders (121 Nuclear Genes) Sequencing 2006050
Method: Massively Parallel Sequencing


Not detected

  • Mutations in genes not analyzed
  • Regulatory region and deep intronic mutations
  • Mutations within the mitochondrial genome

Not reported

  • Mosaic mutations in nuclear genes

Sequencing may detect variants of unknown clinical significance

Diagnostic errors can occur due to rare sequence variations

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: December 2016