Mitochondrial diseases are complex, clinically heterogeneous disorders that are caused by dysfunction of the mitochondrial respiratory chain. These diseases are often challenging to diagnose because they can be caused by pathogenic variants in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Given that mitochondria are present in almost all cells of the body, clinical symptoms are diverse and can present in isolated organs or with multiple system involvement. There are no specific metabolic markers to identify a particular genetic defect. Initial laboratory tests such as lactate, pyruvate, urine organic acids, and plasma amino acids can guide the clinician toward possible mitochondrial disease and inform the genetic testing strategy. However, initial biochemical tests are not diagnostic, and genetic testing is required for definitive diagnosis.
Quick Answers for Clinicians
Because mitochondrial disorders can arise from pathogenic variants in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), inheritance patterns vary widely. Mutations in nDNA can result in autosomal recessive, autosomal dominant, or X-linked recessive inheritance. mtDNA deletions are generally de novo, but can also be inherited from the mother. mtDNA defects, point variations, and duplications are typically maternally inherited. Additionally, individuals with mtDNA variants often display heteroplasmy (the coexistence of normal and mutant mtDNA in the same cell). Inheritance patterns are suggestive of specific mitochondrial disorders and as such can inform the testing strategy.
Indications for Testing
In general, testing for mitochondrial disease should be considered when a patient presents with a progressive multisystem disorder or a cluster of clinical features that indicate a discrete clinical syndrome. Some common clinical features of mitochondrial diseases include ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The table below lists some common mitochondrial disorders and their major clinical features.
|Disorder||Major Clinical Features|
|Chronic progressive external ophthalmoplegia||
Mild proximal myopathy
Progressive external ophthalmoplegia onset <20 years of age
CSF protein >1 g/L
Heart block (cardiac conduction defect)
|Leber hereditary optic neuropathy||
Subacute painless bilateral visual failure
Median age of onset 24 years
Progressive neurologic disease with motor and intellectual developmental delay
Cerebellar and brain stem signs
|Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes||
Strokelike episodes <40 years of age
Encephalopathy with seizures and/or dementia
Mitochondrial myopathy, evidenced by lactic acidosis and/or ragged-red fibers
|Myoclonic epilepsy with ragged-red fibers||
|Neurogenic weakness with ataxia and retinitis pigmentosa||
Late childhood-onset or adult-onset peripheral neuropathy
Sideroblastic anemia of childhood
Exocrine pancreatic failure
|CSF, cerebrospinal fluid|
Biochemical laboratory results often raise suspicion of a mitochondrial disorder and can be useful to monitor disease progression in such disorders. The Mitochondrial Medicine Society recommends evaluation of selected mitochondrial biomarkers in blood, urine, and CSF to aid in disease investigation.
Lactate measurements in blood and CSF may be elevated in some mitochondrial disorders; however, normal lactate levels do not exclude the possibility of a mitochondrial disorder. Measurement of lactate both preprandially and postprandially is useful to distinguish a mitochondrial disorder from a glycogen metabolism condition. Additionally, the lactate/pyruvate ratio can help distinguish respiratory chain dysfunction from pyruvate metabolism disorders such as pyruvate dehydrogenase deficiency.
Measurement of urine organic acids can be used to identify lactic aciduria, excess ketones (which build up because they are not properly utilized by dysfunctional mitochondria), and the presence of unusual compounds, which reflects impairment of the metabolic reactions that occur within mitochondria.
Amino acid analysis in blood or CSF can be used to identify an elevation in alanine, glycine, proline, and threonine with respiratory chain dysfunction. Urine amino acid analysis can reveal generalized amino aciduria, a sign of mitochondrial renal tubular dysfunction.
Measurement of plasma acylcarnitines can be used to differentiate between mitochondrial disorders and other causes of lactic acidosis such as organic acidemia and fatty acid oxidation defects. This is particularly useful in patients with phenotypes that overlap with other inborn metabolic errors for which acylcarnitine analysis is diagnostic.
Other markers such as creatine phosphokinase, creatine, carnitine, and albumin may also be useful to evaluate mitochondrial disease and to monitor effects of supplementation. The Mitochondrial Medicine Society provides more information in the Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.
Genetic testing is essential for the diagnosis of mitochondrial diseases. Next generation sequencing with gene dosage of nDNA and mtDNA in blood or affected tissues (muscle, buccal swab, urine sediment, liver biopsy) is recommended over testing for specific point mutations in cases of suspected mitochondrial disease. Tissue-based testing may identify mtDNA mutations, rearrangements, or deletions that are tissue specific. Genetic consultation is also advised.
ARUP Laboratory Tests
Quantitative Liquid Chromatography/Tandem Mass Spectrometry
Quantitative Liquid Chromatography/Tandem Mass Spectrometry
Tandem Mass Spectrometry
Next Generation Sequencing
Craven L, Alston CL, Taylor RW, et al. Recent advances in mitochondrial disease. Annu Rev Genomics Hum Genet. 2017;18:257-275.
Chinnery PF. Mitochondrial Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews, University of Washington; 1993-2020. [Last Update: Aug 2014; Accessed: Feb 2020]
Wortmann SB, Mayr JA, Nuoffer JM, et al. A guideline for the diagnosis of pediatric mitochondrial disease: the value of muscle and skin biopsies in the genetics era. Neuropediatrics. 2017;48(4):309-314.
Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701.
Davison JE, Rahman S. Recognition, investigation and management of mitochondrial disease. Arch Dis Child. 2017;102(11):1082-1090.