Highmark Commercial Medical Policy - Pennsylvania


 
Printer Friendly Version

Medical Policy: L-235-001
Topic: Polymerase Gamma (POLG) Related Disorders Genetic Testing
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

POLG-related disorders encompass a wide spectrum of disorders involving multiple organ systems, with variable severity and age of onset. All six (6) POLG-related disorders are caused by mutations in the POLG gene. However, inheritance varies.

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.

Known POLG Family Mutation Testing may be considered medically necessary when the following are met:

  • Genetic Counseling:
    • Pre and post-test counseling by an appropriate; and
  • Diagnostic Testing for Symptomatic Individuals
    • No previous genetic testing of POLG; and
    • If adPEO is suspected:
      • Clinical examination is consistent with a diagnosis of adPEO; and
      • POLG mutation identified in 1st degree biological relative; or
    • If AHS, MCHS, MEMSA, ANS, or arPEO is suspected:
      • Clinical examination is consistent with a diagnosis of AHS, MCHS, MEMSA, ANS, or arPEO; and
      • Two POLG mutations identified in a sibling; or
      • One POLG mutation identified in both parents.
Procedure Codes
81406



POLG Full Gene Sequencing may be considered medically necessary when the following are met:

  • Genetic Counseling:
    • Pre and post-test counseling by an appropriate; and
  • Previous Testing:
    • No previous genetic testing for POLG; and
    • No known POLG mutation in the family; and
  • Diagnostic Testing for Symptomatic Individuals:
    • If adPEO is suspected:
      • Clinical examination is consistent with a diagnosis of adPEO; and
      • Genetic testing is needed to confirm the diagnosis; or
    • If AHS, MCHS, MEMSA, ANS, or arPEO is suspected:
      • Clinical examination is consistent with a diagnosis of AHS, MCHS, MEMSA, ANS, or arPEO; and
      • Genetic testing is needed to confirm the diagnosis; or
    • If evaluating the risk for valproate-induced hepatic toxicity:
      • The member has epilepsy; and
      • There is suspicion for a POLG-related disorder based on the presence of at least ONE of the following:
        • unexplained encephalopathy; or
        • refractory epilepsy; or
        • status epilepticus at presentation; or
        • developmental delays; or
        • psychomotor regression; or
        • axonal sensorimotor neuropathy; or
        • myopathy and/or hypotonia; or
        • progressive spastic paraparesis; or
        • renal tubular acidosis; or
        • sensorineural hearing loss; or
        • cyclic vomiting; or
        • pancreatitis; or
        • cerebellar ataxia; or
        • ophthalmoplegia and/or ptosis; or
        • complicated migraine with occipital aura; and
      • The member is currently on Depakene (valoproate) or Depakote ER (divalproex sodium) therapy, or the use of one of these medications is being proposed.
Procedure Codes
81406



POLG Deletion/Duplication Analysis may be considered medically necessary when the following are met:

  • Genetic Counseling:
    • Pre and post-test counseling by an appropriate provider; and
  • Criteria for POLG Full Gene Sequencing is met; and
  • If adPEO is suspected:
    • No mutations found on POLG Full Gene Sequencing; or
  • If AHS, MCHS, MEMSA, ANS, or arPEO is suspected:
    • No mutations or only one mutation found on POLG Full Gene Sequencing; or
  • If evaluating the risk for valproate-induced hepatic toxicity:
    • No mutations or only one mutation found on POLG Full Gene Sequencing
Procedure Codes
81479

Professional Statements and Societal Positions


  • The Food and Drug Administration (FDA, 2017) states that Depakene (valoproate) and Depakote ER (divalproex sodium) are contraindicated for patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder:

  • “Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents.”

  • “POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.”

  • Although not specific to genetic testing for POLG, 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:

    • “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/European Neurological Society (EFNS/ENS) 2014 consensus guidelines on the diagnosis and management of chronic ataxias in adulthood recommend POLG testing in the following evaluation of individuals with autosomal recessive cerebellar ataxia:

    • “Step 1: mutation analysis of the FRDA gene for Friedreich’s ataxia (although one can refrain from this in the case of severe cerebellar atrophy), and biochemical testing that includes cholestanol, vitamin E, cholesterol, albumin, creatine kinase (CK) and a-fetoprotein. Also consider doing nerve conduction studies/EMG (presence versus absence of peripheral neuropathy, axonal versus demyelinating) and referral to an ophthalmologist (retinitis pigmentosa, cataract, cherry red spot etc.) (Table S2) (good practice point).”

    • “Step 2: mutation analysis of the SACS, POLG, Aprataxin (APTX) and SPG7 genes (taking into account specific phenotypes, as given in Table S2), and biochemical testing for white cell enzymes, phytanic acid and long chain fatty acids (good practice point).”

    • “Step 3: referral to a specialized centre, e.g. for skin or muscle biopsy targeted at diagnoses such as Niemann-Pick type C, recessive ataxia with coenzyme Q deficiency [aarF domain containing kinase 3 (ADCK3)/autosomal recessive spinocerebellar ataxia 9 (SCAR9)] and mitochondrial disorders, or for extended genetic screening using gene panel diagnostics (good practice point).”



  • A 2014 expert-authored review suggests the following testing strategy for those with a known or suspected diagnosis of a POLG related disorder:

    • “Standard clinical investigations can identify findings that, in the context of an appropriate family history, can suggest one of the POLG-related phenotypes.”

    • “Confirmation of the diagnosis of a POLG-related disorder requires identification of POLG pathogenic variants by molecular genetic testing.”

    • “One of the following two approaches can be used:”

      • “Direct sequencing of POLG”

      • “Two tiered analysis: targeted analysis for the common POLG pathogenic variants p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser, followed by sequence analysis of the entire coding region if no pathogenic variants or only one pathogenic variant is found.”



    • “In persons meeting the diagnostic criteria of an autosomal recessive POLG related disorder but in whom sequence analysis identifies only one disease causing “POLG” allele, further testing may be considered to search for a second pathogenic variant in regulatory regions (e.g., the POLG promoter) or in relate mitochondrial DNA replication genes such as C10orf2 (formerly PEO1; (encodes the twinkle helicase) and POLG2 to investigate the possibility of digenic inheritance. ”

      • “Digenic inheritance has been reported in arPEO in a simplex case with pathogenic variants in POLG and C10orf2.”

      • “Oligonucleotide array should be strongly considered as microdeletions involving intragenic regions of POLG are reported and therefore relevant in a symptomatic individual with a single heterozygous pathogenic variant.”



    • “An alternative genetic testing strategy is use of a multi-gene panel that includes POLG and other genes of interest.”





Place of Service: Outpatient

POLG 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.


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.

Links





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.

Discrimination is Against the Law
The Claims Administrator/Insurer complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. The Claims Administrator/Insurer does not exclude people or treat them differently because of race, color, national origin, age, disability, or sex. The Claims Administrator/ Insurer:
  • Provides free aids and services to people with disabilities to communicate effectively with us, such as:
    • Qualified sign language interpreters
    • Written information in other formats (large print, audio, accessible electronic formats, other formats)
  • Provides free language services to people whose primary language is not English, such as:
    • Qualified interpreters
    • Information written in other languages
If you need these services, contact the Civil Rights Coordinator.

If you believe that the Claims Administrator/Insurer has failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with: Civil Rights Coordinator, P.O. Box 22492, Pittsburgh, PA 15222, Phone: 1-866-286-8295, TTY: 711, Fax: 412-544-2475, email: CivilRightsCoordinator@highmarkhealth.org. You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, the Civil Rights Coordinator is available to help you.

You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at:

U.S. Department of Health and Human Services
200 Independence Avenue, SW
Room 509F, HHH Building
Washington, D.C. 20201
1-800-368-1019, 800-537-7697 (TDD)

Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html.

Insurance or benefit/claims administration may be provided by Highmark, Highmark Choice Company, Highmark Coverage Advantage, Highmark Health Insurance Company, First Priority Life Insurance Company, First Priority Health, Highmark Benefits Group, Highmark Select Resources, Highmark Senior Solutions Company or Highmark Senior Health Company, all of which are independent licensees of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield plans.

Highmark retains the right to review and update its medical policy guidelines at its sole discretion. These guidelines are the proprietary information of Highmark. Any sale, copying or dissemination of the medical policies is prohibited; however, limited copying of medical policies is permitted for individual use.



back to top