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.
MELAS Known Familial Mutation Testing may be considered medically necessary when the following criteria are met:
- Genetic Counseling
- Pre and post-test counseling by an appropriate provider; and
- Previous Genetic Testing
- No previous genetic testing in the individual for MELAS; and
- MELAS pathogenic variant identified in 1st degree biological maternal relative; and
- Predictive Testing for Asymptomatic Individual:
- 18 years of age or older; or
- Under the age of 18 years; and
- Presymptomatic screening for diabetes mellitus is being considered; or
- Diagnostic Testing for Symptomatic Individual:
- Clinical exam and biochemical testing suggestive, but not confirmatory, of a diagnosis of MELAS; or
- Prenatal Testing for At-Risk Pregnancies:
- MELAS causing pathogenic variant in a previous child or in the mother.
MELAS Targeted Mutation Analysis (A3243G) may be considered medically necessary when the following criteria are met:
- Genetic Counseling
- Pre and post-test counseling by an appropriate provider; and
- Previous Testing:
- No previous genetic testing for MELAS; and
- No known MELAS pathogenic variants in the family; and
- Diagnostic Testing for Symptomatic Individuals:
- Clinical exam and biochemical testing suggestive, but not confirmatory, of a diagnosis of MELAS by one or more of the following:
- Lactic acidosis both in blood and in the CSF; and/or
- Muscle biopsy showing ragged red fibers; and/or
- Respiratory chain enzyme studies that are consistent with a diagnosis of MELAS; and/or
- Stroke-like episodes before the age of 40 years; and/or
- Encephalopathy with seizures and/or dementia; and
- Genetic testing is needed to confirm the diagnosis.
MELAS Targeted Mutation Analysis (G13513A, T3271C, and A3252G) may be considered medically necessary when the following criteria are met:
- Genetic Counseling
- Pre and post-test counseling by an appropriate provider; and
- Criteria for MELAS targeted mutation analysis (A3243G) is met; and
- No pathogenic variants identified in the targeted mutation analysis (A3243G).
Whole mtDNA Sequencing may be considered medically necessary when the following criteria are met:
- Genetic Counseling
- Pre and post-test counseling by an appropriate provider; and
- Criteria for MELAS targeted mutation analysis is met; and
- No pathogenic variants identified in the targeted mutation analysis (A3243G, G13513A, T3271C, and A3252G); and
- Paternal transmission has been ruled out.
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No specific evidence-based U.S. testing guidelines for MELAS were identified.
The Mitochondrial Medicine Society (2015) developed consensus recommendations for the diagnosis and management of mitochondrial disease. Testing strategies, including strategies for genetic testing, were discussed.
- 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 to guide genetic counseling. Heteroplasmy analysis in urine can selectively be more informative and accurate than testing in blood alone, especially in cases of MELAS due to the common m.3243A>G mutation.
- Recommendations for pathology testing:
- Muscle (and/or liver) biopsies should be performed in the routine analysis for mitochondrial disease when the diagnosis cannot be confirmed with DNA testing of other more accessible tissues.”
European Federation of Neurological Sciences (EFNS, 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 hybridization, real-time-PCR or single-gene sequencing are indicated
The clinical utility of genetic testing for MELAS was described by a workshop of the National Institute of Neurological Disorders and Stroke (2008):
- The diagnosis of mitochondrial diseases is complicated by their heterogeneous presentations and by the lack of screening procedures ordiagnostic 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 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.”
- Initial screening includes testing for blood lactate, urine amino acids, acylcarnitine profile, and MRI. "It is important to note that biochemical abnormalities may not be present during periods when the mitochondrial disease is quiescent/ dormant." The Clinical Molecular Genetics Society (CMGS) of UK (2008) provided practice-based guidelines for the molecular diagnosis of mitochondrial disease:
- In cases with strong clinical evidence, testing should begin with checking for the common 3243G mutation. Testing for the rare mutations including T3271C and A3252G is not routinely indicated unless there is strong clinical diagnosis of MELAS testing.
The Clinical Molecular Genetics Society (CMGS) of UK (2008) provided practice-based guidelines for the molecular diagnosis of mitochondrial disease:
- In cases with strong clinical evidence, testing should begin with checking for the common A3243G mutation. Testing for the rare mutations including T3271C and A3252G is not routinely indicated unless there is strong clinical diagnosis of MELAS testing.
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Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) Genetic Testing 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.
