BlueCross BlueShield of Tennessee Medical Policy Manual

Genetic Testing for Mitochondrial Disorders

Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018


Mitochondrial disorder (MD) refers to approximately 40 different disorders, presenting mostly in childhood (usually by age 10), affecting one or more organ systems and varying in degree of dysfunction. All disorders are caused by mutations in either the mitochondrial and/or nuclear DNA. The prevalence of mitochondrial disorders is approximately 1 in 5000 births in the United States. No known cure exists for any of the disorders. Currently less than half of the named disorders have an identified genetic cause, and the presence of the gene variant does not predict the severity of the disorder. While larger expanded panels (e.g. GeneDx®) or mitochondrial genome sequencing may be useful in diagnosing a mitochondrial disorder, whole exome sequencing does not sequence mtDNA.

Some of the more common named mitochondrial disorders are: Leigh Syndrome (LS), mitochondrial encephalomyopathy lactic acidosis with stroke-like episodes (MELAS), Leber hereditary optic neuropathy (LHON), and neuropathy ataxia retinitis pigmentosa (NARP). The diagnosis of a mitochondrial disorder can be difficult, as symptoms often mimic other disorders such as Autism, and Parkinson’s. In addition, the symptoms of the various mitochondrial disorders often overlap. Standard tests used in diagnosing a mitochondrial disorder may include:

Treatment of mitochondrial disease is largely supportive, as there are no specific therapies that impact the natural history of the disorders.





Mitochondrial disorders are either inherited maternally, or when both parents carry the recessive trait. When a disorder is severe enough to cause impairment and/or disability in a sibling or previous child of either parent, genetic testing prior to future reproductive decisions is a reasonable choice.


BlueCross BlueShield Association. Evidence Positioning System. (10:2020). Genetic testing for mitochondrial disorders (2.04.117). Retrieved February 11, 2021 from (31 articles and/or guidelines reviewed)

Chang, x., Wu, Y., Zhou,J., Meng, H., Zhang, W., & Guo, J. (2020). A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. Medicine, 99 (5), e18634. (Level 1 evidence)

Clinical Molecular Genetics Society. (2004; last updated 2008). Practice guidelines for the molecular diagnosis of mitochondrial diseases. Retrieved May 21, 2019 from

Mitochondrial Medicine Society. (2014). Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Retrieved May 21, 2019 from

Ng, Y. S., Hardy, S. A., Shrier, V., Quaghebeur, G., Mole, D. R., Daniels, M. J., et al. (2016). Clinical features of the pathogenic m.5540G>A mitochondrial transfer RNA tryptophan gene mutation. Neuromuscular Disorders, 26 (10), 702-705. (Level 4 evidence)

Sanghivi, H., Singh, R., Morrin, H., & Rajkumar, A.P. (2020). Systematic review of genetic association studies in people with Lewy body dementia. International Journal of Geriatric Psychiatry, 35 (5), 436-448. (Level 2 evidence)




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