Genetic Testing for Mitochondrial Disorders

POLICY NUMBER

A.2.04.117

DESCRIPTION

Mitochondrial diseases are multisystem diseases that arise from dysfunction in the mitochondrial protein complexes involved in oxidative metabolism. There are many related but distinct syndromes, and some patients have overlapping syndromes. As a result, these disorders can be difficult to diagnose. Genetic testing has the potential to improve the accuracy of diagnosis for mitochondrial diseases. Genetic testing also has the potential to determine future risk of disease in individuals who have a close relative with a pathogenic variant.

Mitochondrial DNA

Mitochondria are organelles within each cell that contain their own set of DNA, distinct from the nuclear DNA (nDNA) that makes up most of the human genome. Human mitochondrial DNA (mtDNA) consists of 37 genes. Thirteen genes code for protein subunits of the mitochondrial oxidative phosphorylation complex, and the remaining 24 genes are responsible for proteins involved in the translation and/or assembly of the mitochondrial complex. Additionally, there are over 1,000 nuclear genes coding for proteins that support mitochondrial function. The protein products from these genes are produced in the nucleus and later migrate to the mitochondria.

Mitochondrial DNA differs from nuclear DNA (nDNA) in several important ways. Inheritance of mtDNA does not follow traditional Mendelian patterns. Rather, mtDNA is inherited only from maternal DNA so disorders that result from variants in mtDNA can only be passed on by the mother. Also, there are thousands of copies of each mtDNA gene in each cell, as opposed to nuclear DNA, which contains only one copy per cell. Because there are many copies of each gene, variants may be present in some copies of the gene but not others. This phenomenon is called heteroplasmy. Heteroplasmy can be expressed as a percentage of genes that have the variant ranging from 0% to 100%. Clinical expression of the variant will generally depend on a threshold effect (ie, clinical symptoms will begin to appear when the percentage of mutated genes exceeds a threshold amount).

Diagnostic genetic testing for mitochondrial disorders and carrier testing of known familial variants associated with mitochondrial disorders is addressed in this policy. Carrier screening for mitochondrial disorders associated with autosomal recessive inheritance of nDNA variants is addressed in the Carrier Screening for Genetic Diseases medical policy.

Mitochondrial Diseases

Primary mitochondrial diseases arise from dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is responsible for aerobic metabolism, and dysfunction, therefore, affects a wide variety of physiologic pathways dependent on aerobic metabolism. Organs with a high-energy requirement, such as the central nervous system, cardiovascular system, and skeletal muscle, are preferentially affected by mitochondrial dysfunction.

The prevalence of these disorders has risen over the last two decades as the pathophysiology and clinical manifestations have been better characterized. It is currently estimated that the minimum prevalence of primary mitochondrial diseases is at least 1 in 5000.

Some specific mitochondrial diseases are listed below:

• Mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms (MELAS) syndrome;

• Myoclonic epilepsy with ragged red fibers syndrome (MERFF);

• Kearns-Sayre syndrome;

• Leigh syndrome;

• Chronic progressive external ophthalmoplegia (CPEO);

• Leber hereditary optic neuropathy (LHON);

• Neuropathy, ataxia, and retinitis pigmentosa (NARP).

Most of these disorders are characterized by multisystem dysfunction, which generally includes myopathies and neurologic dysfunction and may involve multiple other organs. Each defined mitochondrial disease has a characteristic set of signs or symptoms. The severity of illness is heterogeneous and can vary markedly. Some patients will have only mild symptoms for which they never require medical care, while other patients have severe symptoms, a large burden of morbidity, and a shortened life expectancy.

DiagnosisThe diagnosis of mitochondrial diseases can be difficult. The individual symptoms are nonspecific, and symptom patterns can overlap considerably. As a result, a patient often cannot be easily classified into a particular syndrome. Biochemical testing is indicated for patients who do not have a clear clinical picture of a specific disorder. Measurement of serum lactic acid is often used as a screening test, but the test is neither sensitive nor specific for mitochondrial diseases.

A muscle biopsy can be performed if the diagnosis is uncertain after biochemical workup. However, this invasive test is not definitive in all cases. The presence of “ragged red fibers” on histologic analysis is consistent with a mitochondrial disease. Ragged red fibers represent a proliferation of defective mitochondria. This characteristic finding may not be present in all types of mitochondrial disorders and also may be absent early in the course of disease.

TreatmentTreatment of mitochondrial disease is largely supportive because there are no specific therapies that impact the natural history of the disorder. Identification of complications such as diabetes and cardiac dysfunction is important for early treatment of these conditions. A number of vitamins and cofactors (eg, coenzyme Q, riboflavin) have been used, but empirical evidence of benefit is lacking. Exercise therapy for myopathy is often prescribed, but the effect on clinical outcomes is uncertain. The possibility of gene transfer therapy is under consideration, but is at an early stage of development and untested in clinical trials.

Genetic TestingMitochondrial diseases can be caused by pathogenic variants in the maternally inherited mtDNA or one of many nDNA genes. Genetic testing for mitochondrial diseases may involve testing for point mutations, deletion and duplication analysis, and/or whole exome sequencing of nuclear or mtDNA. The type of testing done depends on the specific disorder being considered. For some primary mitochondrial diseases such as mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms and myoclonic epilepsy with ragged red fibers, most variants are point mutations, and there is a finite number of variants associated with the disorder. When testing for one of these disorders, known pathogenic variants can be tested for with polymerase chain reaction, or sequence analysis can be performed on the particular gene. For other mitochondrial diseases, such as chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome, the most common variants are deletions, and therefore duplication and deletion analysis would be the first test when these disorders are suspected. The table below provides examples of clinical symptoms and particular genetic variants in mtDNA or nDNA associated with particular mitochondrial syndromes. A repository of published and unpublished data on variants in human mtDNA is available in the MITOMAP database. Lists of mtDNA and nDNA genes that may lead to mitochondrial diseases and testing laboratories in the United States are provided at Genetic Testing Registry of the National Center for Biotechnology Information website.

Examples of Mitochondrial Diseases, Clinical Manifestations, and Associated Pathogenic Genes

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic testing for mitochondrial diseases is under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Genetic testing to establish a genetic diagnosis of a mitochondrial disorder may be considered medically necessary when signs and symptoms of a mitochondrial disorder are present and genetic testing may eliminate the need for muscle biopsy.

Targeted genetic testing for a known familial variant in at-risk relatives may be considered medically necessary as preconceptional carrier testing under the following conditions:

• There is a defined mitochondrial disorder in the family of sufficient severity to cause impairment of quality of life or functional status; AND

• A variant that is known to be pathogenic for that specific mitochondrial disorder has been identified in the index case.

Genetic testing for mitochondrial disorders is considered investigational in all other situations when the criteria for medical necessity are not met.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Mitochondrial disorders can be caused by variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). A 3-generation family history may suggest a mode of inheritance. A family history in which affected women transmit the disease to male and female children and affected men do not transmit the disease to their children suggests the familial variant(s) is in the mtDNA. A family history consistent with Mendelian autosomal dominant or autosomal recessive inheritance or with X-linked inheritance suggests the familial variant(s) is in the nDNA. De novo pathogenic variants are also possible.

Carrier screening for mitochondrial disorders associated with autosomal recessive inheritance of nDNA variants is addressed in the Carrier Screening for Genetic Diseases medical policy.

Testing Strategy

Individuals With a Suspected Mitochondrial DisorderIf the phenotype is highly suggestive of a specific disorder that is supported by the inheritance pattern noted in the family history, it would be reasonable to begin genetic testing with single genes or targeted multigene panels that test for pathogenic variants specific for that disorder.

If a mitochondrial disorder is suspected, but the phenotype is nonspecific, broader genetic testing is appropriate under the guidance of a clinical geneticist and genetics counselor. For individuals in whom the family history is suggestive of a disorder due to pathogenic variant(s) in mtDNA, multigene panels or sequencing of the mitochondrial genome may be appropriate. If multiple mtDNA deletions are noted, or the family history is suggestive of a disorder due to variants in nDNA, then multigene panels covering known nuclear genes associated with mitochondrial disease may be appropriate. Testing using whole exome sequencing is reviewed in the  Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders medical policy.

Individuals With a Family Member With a Mitochondrial Disorder and Known Familial VariantTargeted testing of the parents of a proband with a mitochondrial disorder and a confirmed pathogenic/likely pathogenic gene variant is done to identify mode of transmission [germline (autosomal recessive, autosomal dominant, X-linked, mitochondrial) vs. de novo] thereby indicating risk for future offspring and other family members. Targeted testing for a known familial variant in parents and other at-risk relatives as part of preconceptional carrier testing is appropriate. At-risk relatives include only female relatives if the familial pathogenic variant is in the mtDNA but includes both male and female relatives if the familial pathogenic variant is in the nDNA.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1.) The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—"pathogenic," likely pathogenic," "uncertain significance," "likely benign," and "benign"—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/17/2014: Approved by Medical Policy Advisory Committee.

08/31/2015: Medical policy revised to add ICD-10 codes. Added ICD-9 diagnosis codes 330.8, 377.16, and 378.55 to the Code Reference section.

09/24/2015: Policy description updated regarding expanded genetic panels for mitochondrial disorders. First medically necessary policy statement revised. It previously stated: Genetic testing to confirm the diagnosis of a mitochondrial disorder may be considered medically necessary as an alternative to muscle biopsy under the following conditions: Clinical signs and symptoms are consistent with a specific mitochondrial disorder (see Policy Guidelines), but the diagnosis cannot be made with certainty by clinical and/or biochemical evaluation; AND; Genetic testing is restricted to the specific mutations that have been documented to be pathogenic for the particular mitochondrial disorder being considered (see Policy Guidelines). Second medically necessary statement revised to change "as part of a preconceptual evaluation" to "as preconceptual carrier testing." Policy Guidelines updated to add testing information and medically necessary and investigative definitions.

06/07/2016: Policy number A.2.04.117 added.

08/18/2016: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy Guidelines updated to add genetic counseling information.

06/26/2017: Code Reference section updated to revise code description for CPT code 81401, effective 07/01/2017.

08/28/2017: Policy description updated regarding examples of mitochondrial disorders, clinical manifestations, and associated pathogenic genes. Revised policy statements so that genetic testing is not restricted to a set of specific mutations documented for a particular mitochondrial disorder. First policy statement revised to state that genetic testing to establish a genetic diagnosis of a mitochondrial disorder may be considered medically necessary when signs and symptoms of a mitochondrial disorder are present and genetic testing may eliminate the need for muscle biopsy. Second medically necessary statement updated to change "Genetic testing of at-risk female relatives" to "Targeted genetic testing for a known familial variant of at risk relatives." Removed the following statement: Genetic testing for mitochondrial disorders using expanded panel testing is considered investigational. Policy Guidelines updated regarding testing strategies and genetics nomenclature.

12/22/2017: Code Reference section updated to revise description for CPT code 81401 effective 01/01/2018.

07/03/2018: Policy description updated to change "disorders" to "diseases." Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

07/15/2019: Policy reviewed. Correction made to policy statement: "preconceptual" changed to "preconceptional." Policy statements otherwise unchanged.

10/12/2020: Policy reviewed; no changes.

12/29/2021: Policy description updated regarding mitochondrial diseases. Policy statements unchanged. Policy Guidelines updated regarding individuals with a family member with a mitochondrial disorder and known familial variant.

11/17/2022: Policy description updated. Policy statements unchanged. Policy Guidelines updated to add related medical policy and information regarding genetic counseling.

09/29/2023: Code Reference section updated to add new ICD-10 diagnosis code, E88.43, effective 10/01/2023.

10/10/2023: Policy reviewed; no changes.

12/11/2024: Policy description updated. Policy statements unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.117

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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