Highmark Commercial Medical Policy - Pennsylvania

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Medical Policy: L-198-002
Topic: Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)
Section: Laboratory
Effective Date: November 13, 2017
Issue Date: November 13, 2017
Last Reviewed: March 2017

MNGIE is a multisystem mitochondrial disease typically characterized by progressive gastrointestinal dysmotility, which may present with nausea, dysphagia, reflux, early satiety, vomiting after a meal, episodic abdominal pain, bloating, and/or diarrhea. Additionally individuals may present with cachexia (a wasting syndrome), ptosis/ophthalmoplegia (drooping/weakness of the eyelid), leukoencephalopathy on brain MRI, or peripheral neuropathy (tingling, numbness, and/or pain in the extremities).Symptoms may first occur between the first and fifth decade of life and may not appear in any particular order.

MNGIE is caused by biallelic mutations in the TYMP gene and is inherited in an autosomal recessive pattern, meaning parents of an affected individual must be obligate carriers. The chance of having another child with MNGIE to the same parents is 25%.

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.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

TYMP known familial mutation testing may be considered medically necessary when the following criteria have been met:

  • Genetic Counseling:
    • Pre and post-test counseling by an appropriate provider; and 
  • Previous Genetic Testing:
    • No previous genetic testing in the individual for MNGIE; and
    • TYMP pathogenic variant(s) identified in parents and/or sibling(s); and
  • Predictive Testing for Asymptomatic Individual:
    • 18 years of age or older; or
  • Diagnostic Testing for Symptomatic Individual:
    • Clinical exam and/or biochemical testing suggestive, but not confirmatory, of a diagnosis of MNGIE.  

TYMP sequencing may be considered medically necessary when ALL of the following criteria have been met:

  • Genetic Counseling
    • Pre and post-test counseling by an appropriate provider; and
  • Previous Testing:
    • No previous genetic testing for MNGIE; and
    • No known TYMP pathogenic variants in the family; and 
  • Diagnostic Testing for Symptomatic Individuals:
    • Clinical exam and/or biochemical testing suggestive, but not confirmatory, of a diagnosis of MNGIE; and 
    • Genetic testing is needed to confirm the diagnosis.

TYMP deletion/duplication may be considered medically necessary when ALL of the following criteria have been met:

  • Genetic Counseling:
    • Pre and post-test counseling by an appropriate provider; and
  • Criteria for TYMP sequencing is met; and
  • No pathogenic variants identified in the NARP targeted mutation analysis.
Procedure Codes
81403, 81405, 81479

Professional Statements and Societal Positions

Guidelines and Evidence

  • No specific evidence-based U.S. testing guidelines were identified.
  • Although not specific to genetic testing for MNGIE, 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 include the following:
      • “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.3243 A>G mutation.”
      • "When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease gene 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.”
  • The European Federation of Neurological Sciences (2009) provided molecular diagnostic consensus-based guidelines based on literature reviews: "Sequencing of TYMP should be performed only if serum thymidine is elevated."
  • Evidence from three different peer reviewed journals provides symptoms, clinical findings, imaging, and family history suggestive of MNGIE.
    • Severe gastrointestinal dysmotility, cachexia, ptosis, external ophthalmoparesis/ophthalmoplegia, and sensorimotor neuropathy.
    • Brain MRI that demonstrates abnormal brain white matter (increased FLAIR or T2-weighted signal) consistent with asymptomatic leukoencophalopathy.
    • Family history consistent with autosomal recessive inheritance.

Place of Service: Outpatient

MNGIE 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.

The policy position applies to all commercial lines of business

Denial Statements

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.


Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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