Mitochondrial disorder (MD) refers to approximately 40 different disorders, presenting mostly in childhood (usually by age 10), effecting one or more organ systems and varying in degree of dysfunction; all caused by mutations in either the mitochondrial and/or nuclear DNA. The prevalence of mitochondrial disorders is approximately 1 in 5000 births in the US. 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:
Levels of certain substances in a sample of blood or cerebrospinal fluid
Magnetic resonance spectroscopy (detects abnormalities in the brain's chemical makeup)
Imaging studies of the brain such as MRI or CT scan
Electrocardiography and echocardiography
Treatment of mitochondrial disease is largely supportive, as there are no specific therapies that impact the natural history of the disorders.
Genetic testing (single gene or multi-gene panels) to confirm the diagnosis of a mitochondrial disorder may be considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Targeted genetic testing for a known familial variant of at-risk relatives may be considered medically necessary as part of a preconceptual evaluation if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Pre- and post- genetic counseling as an adjunct to genetic testing itself is considered medically necessary.
Genetic testing of a mitochondrial disorder is considered medically appropriate if ANY ONE of the following criteria are met:
To confirm the diagnosis of a mitochondrial disorder with ALL of the following:
Clinical signs and symptoms are consistent with a specific mitochondrial disorder
The diagnosis cannot be made with certainty by clinical and/or biochemical evaluation (e.g., one or more of the standard tests such as metabolite analysis of blood and/or urine sample)
At-risk relatives as part of a preconceptual evaluation if ALL of the following:
There is a diagnosed mitochondrial disorder in a parent, sibling, or previous child of sufficient severity to cause impairment of quality of life or functional status
The specific genetic variance has been documented to be associated with a mitochondrial disorder
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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.
American College of Medical Genetics and Genomics (2013, March) ACMG position statement on prenatal/preconception expanded carrier screening. Genetics in Medicine; 15(6):482-483.
American College of Medical Genetics and Genomics (2015, March) ACMG Policy Statement: Clinical utility of genetic and genomic services. Genetics in Medicine; (17)6: 505-7.
Bindu, P., Arvinda, H., Taly, A., Govindaraju, C., Sonam, K., Chiplunkar, S., et al. (2015). Magnetic resonance imaging correlates of genetically characterized patients with mitochondrial disorders: A study from south India. Mitochondrion, 25, 6-16. Abstract retrieved January 7, 2016 from PubMed database.
BlueCross BlueShield Association. Medical Policy Reference Manual. (6:2017). Genetic Testing of Mitochondrial Disorders (2.04.117). Retrieved June 29, 2017 from BlueWeb. (30 articles and/or guidelines reviewed)
Carrasco, S. P., Palma, M. C., López, M. J., Benito, C., Franco, F. S., & López, S. J. (2016). Leber hereditary optic neuropathy: Usefulness of next generation sequencing to study mitochondrial mutations on apparent homoplasmy. Medicina Clínica (Barcelona), 146 (4), 163-166. Abstract retrieved November 15, 2016 from PubMed database.
Chinnery, P. and Hudson, G. (2013, April). Mitochondrial genetics. British Medical Bulletin; 106: 135–159. (Level 5 evidence)
Chu, H., Hsiao, W., Tsao, T., Chang, C., Liu, Y., et. al., (2012, October) Quantitative assessment of mitochondrial DNA copies from whole genome sequencing. BMC Genomics, 13(Supplement 7):55. (Level 4 evidence)
Khan, N., Govindaraj, P., Meena, A. and Thangaraj, T. (2015, January) Mitochondrial disorders: Challenges in diagnosis & treatment. Indian Journal of Medical Research; 141(1): 13–26. (Level 5 evidence)
Legati A , Reyes A , Nasca A , Invernizzi F , Lamantea E , Tiranti V (2016, August) New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochemical and Biophysical Acta Journal;1857(8):1326-35. Abstract retrieved June 14, 2017 from PubMed database.
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)
Palmetto Government Benefit Administrators, LLC. (2011, November). Local Coverage Article: MolDX: Mitochondrial Nuclear Gene Tests Coding and Billing Guidelines (A53669). Retrieved June 14, 2017 from https://www.cms.gov.
Pronicka E , Piekutowska-Abramczuk D , Ciara E , Trubicka J , Rokicki D , Karkucińska-Więckowska, A. (2016, June) New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. Journal of Translational Medicine; 14(1):174. Abstract retrieved June 14, 2017 from PubMed database.
ORIGINAL EFFECTIVE DATE: 1/10/2015
MOST RECENT REVIEW DATE: 10/1/2017
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