This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
Whole mtDNA Sequencing may be considered medically necessary when ALL of the following criteria are met:
- Pre and post-test counseling by an appropriate provider; and
- Member has not had previous whole mtDNA sequencing performed; and
- Biochemical testing appropriate for the suspected disorder has been performed and is not confirmatory of a diagnosis of a specific mitochondrial condition; and
- Member has multiple organ system involvement defined as altered function in two or more organ systems; and
- Member has one or more of the following clinical features: proximal myopathy, cardiomyopathy, encephalopathy, seizures, dementia, stroke-like episodes, ataxia, spasticity, ptosis, ophthalmoparesis, ophthalmoplegia, optic atrophy, pigmentary retinopathy, sensorineural hearing loss, diabetes mellitus, mid- or late pregnancy loss, MRI and/or MRS imaging results consistent with a mitochondrial process, and/or pathology results consistent with a mitochondrial process; and
- Member’s clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available (e.g. LHON); and
- Alternate etiologies have been considered and ruled out when possible (e.g.,environmental exposure, injury, infection); and
- Family history strongly suggests mitochondrial inheritance (e.g. paternal transmission has been ruled out).
Whole mtDNA Deletion/Duplication Analysis may be considered medically necessary when ALL of the following are met:
- Pre and post-test counseling by an appropriate provider; and
- Member has not had previous whole mtDNA deletion/duplication analysis performed; and
- Biochemical testing appropriate for the suspected disorder has been performed and is not confirmatory of a diagnosis of a specific mitochondrial condition; and
- Member has multiple organ system involvement defined as altered function in two or more organ systems; and
- Member has one or more of the following clinical features: proximal myopathy, cardiomyopathy, encephalopathy, seizures, dementia, stroke-like episodes, ataxia, spasticity, ptosis, ophthalmoparesis, ophthalmoplegia, optic atrophy, pigmentary retinopathy, sensorineural hearing loss, diabetes mellitus, mid- or late pregnancy loss, MRI and/or MRS imaging results consistent with a mitochondrial process, and/or pathology results consistent with a mitochondrial process; and
- Member’s clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available (e.g. LHON); and
- Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection); and
- Family history strongly suggests mitochondrial inheritance (e.g. paternal transmission has been ruled out).
Nuclear Encoded Mitochondrial Gene Sequencing Panel may be considered medically necessary when ALL of the following are met:
- Pre and post-test counseling by an appropriate provider; and
- Member has not had a previous nuclear encoded mitochondrial gene sequencing panel testing performed; and
- Biochemical testing appropriate for the suspected disorder has been performed and is not confirmatory of a diagnosis of a specific mitochondrial condition; and
- Member has multiple organ system involvement defined as altered function in two or more organ systems; and
- Member has one or more of the following clinical features: proximal myopathy, cardiomyopathy, encephalopathy, seizures, dementia, stroke-like episodes, ataxia, spasticity, ptosis, ophthalmoparesis, ophthalmoplegia, optic atrophy, pigmentary retinopathy, sensorineural hearing loss, diabetes mellitus, mid- or late pregnancy loss, MRI and/or MRS imaging results consistent with a mitochondrial process, and/or pathology results consistent with a mitochondrial process; and
- Member’s clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available (e.g. LHON); and
- Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection); and
- Family history DOES NOT strongly suggest mitochondrial inheritance (e.g. paternal transmission is observed, autosomal inheritance is likely).
- No specific evidence-based U.S. testing guidelines were identified.
- The Mitochondrial Medicine Society developed consensus recommendations using the Delphi method and published them in 2015.
- Recommendations for DNA testing
- Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology when testing mtDNA and should be performed in cases of suspected mitochondrial disease instead of testing for a limited number of pathogenic point mutations.
- Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and guides genetic counseling.
- When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease genes is preferred. Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.
- Recommendations for pathology testing
- Biopsy should only be considered when the diagnosis cannot be confirmed with DNA testing of other more accessible tissues. Muscle (and/or liver) biopsies are often not necessary and should be avoided when possible due to their invasive nature, unless other types of analyses such as pathology, enzymology, or mtDNA copy number analyses are required for diagnosis.
- The American College of Medical Genetics and Genomics (ACMG, 2013) states the following regarding testing individuals with isolated autism for mitochondrial disorders:
- “As with metabolic disorders, testing for mitochondrial disorders in persons with ASDs is recommended only if supporting symptoms or laboratory abnormalities are present.”
- The European Federation of Neurological Sciences (2009) provided molecular diagnostic consensus-based guidelines based on literature reviews: “If the phenotype suggests syndromic mitochondrial disease due to mtDNA point mutations (MELAS, MERRF, NARP, LHON) DNA-microarrays using allele-specific oligonucleotide hybridisation, real-time-PCR or single-gene sequencing are indicated.”
- The European Federation of Neurological Sciences (2009) provided molecular diagnostic consensus-based guidelines based on literature reviews: “If the phenotype suggests syndromic mitochondrial disease due to mtDNA point mutations (MELAS, MERRF, NARP, LHON) DNA-microarrays using allele-specific oligonucleotide hybridisation, real-time-PCR or single-gene sequencing are indicated.”
- The Clinical Molecular Genetics Society (CMGS) of the United Kingdom (2008) practice-based guidelines for the molecular diagnosis of mitochondrial disease state that: “ In cases with strong clinical evidence, testing should begin with checking for the common mutation, m.8344A>G. Subsequent testing for other mutations, such as m.8356T>C, may be indicated in cases with a strong clinical indication of MERRF”. “For routine referrals for NARP, presence of T8993G and T8993C mutations should be investigated.”
- A workshop of the National Institute of Neurological Disorders and Stroke (2008) summarizes:
- “The diagnosis of mitochondrial diseases is complicated by their heterogeneous presentations and by the lack of screening procedures or diagnostic biomarkers that are both sensitive and specific. The workshop panelists explained that diagnosis is often a lengthy process beginning with a general clinical evaluation followed by metabolic screening and imaging and finally by genetic tests and more invasive biochemical and histological analyses. The identification of known mitochondrial mutations in tissue has greatly aided diagnosis. However, even when clinical features and family history strongly suggest mitochondrial disease, the underlying genetic mutation can elude detection, and there is no current screening procedure that would be practical for all cases of suspected mitochondrial disease.”
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Mitochondrial genetic is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.
Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.
