Coverage Policy Manual
Policy #: 2014012
Category: Laboratory
Initiated: May 2014
Last Review: August 2018
  Genetic Test: Mitochondrial Disorders

Description:
Mitochondrial disorders are multisystem diseases that arise from dysfunction in the mitochondrial protein complexes that are involved in oxidative metabolism. These disorders can be due to pathogenic mutations in the mitochondrial DNA that code for the protein complexes, or mutations in nuclear DNA that code for proteins involved in translation and assembly of mitochondrial complexes. Genetic sequencing of mitochondrial DNA and nuclear genes associated with mitochondrial processes is commercially available.
 
Background
Mitochondrial DNA. Mitochondria are organelles within each cell that contain their own set of DNA, distinct from the nuclear DNA 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 that are involved in the translation and/or assembly of the mitochondrial complex (Schon, 2012). In addition, there are over 1000 nuclear genes that code for proteins that support mitochondrial function (Wong, 2007). The protein products from these genes are produced in the nucleus and later migrate to the mitochondria.
 
Mitochondrial DNA differs from nuclear DNA in several important ways. Inheritance of mitochondrial DNA does not follow traditional Mendelian patterns. Rather, mtDNA is inherited only from maternal DNA so that disorders that result from mutations 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 only has 1 copy per cell. Because there are many copies of each gene, mutations 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 mutation, ranging from 0% to 100%. Clinical expression of the mutation will generally depend on a threshold effect, ie clinical symptoms will begin to appear when the percent of mutated genes exceeds a threshold amount (DiMauro, 2001).
 
Mitochondrial disorders. Primary mitochondrial disorders 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 that are 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 (Platt, 2014).
 
The prevalence of these disorders has been rising 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 disorders is at least 1 in 5000 (Schon, 2012; Falk, 2010).
 
Some of the specific mitochondrial disorders are listed below:
 
    • Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome;
    • Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome;
    • Kearns-Sayre (KSS) syndrome;
    • Leigh syndrome (LS);
    • Chronic progressive external ophthalmoplegia (CPEO);
    • Lieber hereditary optic neuropathy (LHON);
    • Neurogenic weakness with 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 of the defined mitochondrial disorders has a characteristic set of signs of 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.
 
The diagnosis of mitochondrial disorders 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 one particular syndrome (Chinnery, 2014). Biochemical testing is indicated for patients who do not have a clear clinical picture of one specific disorder. Measurement of serum lactic acid is often used as a screening test, but the test is neither sensitive nor specific for mitochondrial disorders (Wong, 2007).
 
A muscle biopsy can be performed if the diagnosis is uncertain after biochemical workup. However, this is an invasive test and is not definitive in all cases. The presence of “ragged red fibers” on histologic analysis is consistent with a mitochondrial disorder. Ragged red fibers represent a proliferation of defective mitochondrial (Schon, 2012). This characteristic finding may not be present in all types of mitochondrial disorders, and also may be absent early in the course of disease (Wong, 2007).
 
Treatment of mitochondrial disease is largely supportive, as there are no specific therapies than impact the natural history of the disorder (Chinnery, 2014). Identification of complications such as diabetes mellitus 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 empiric evidence of benefit is lacking (Chinnery, 2006). Exercise therapy for myopathy is often prescribed, but the effect on clinical outcomes is uncertain (Chinnery, 2014). The possibility of gene transfer therapy is under consideration, but is at an early stage of development and has not yet been tested in clinical trials.
 
Genetic testing for mitochondrial disorders. Genetic testing for mitochondrial disorders may involve testing for point mutations, deletion/duplication analysis, and/or whole mitochondrial exome sequencing. The type of testing done depends on the specific disorder being considered. For some primary mitochondrial disorders such as MELAS and MERFF, most mutations are point mutations, and there are a finite number of mutations associated with the disorder. When testing for one of these disorders, known pathogenic mutations can be tested for with polymerase chain reaction (PCR), or sequence analysis can be performed on the particular gene. For other mitochondrial disorders such as CPEO and KSS, the most common mutations are deletions, and therefore duplication/deletion analysis would be the first test when these disorders are suspected.
 
Testing for the individual mutations associated with mitochondrial disorders is offered by numerous labs. Genetic panel testing is also available, with numerous different panels available. Some of these are disease-specific panels that include only a small number of genes associated with a particular mitochondrial disorder. For example, Transgenomics™ offers a MELAS panel consisting of 10 mutations that have specific associations with MELAS syndrome (Transgenomic Web Site, 2014).  
 
There are at least 7 labs that currently offer “expanded” panel testing for mitochondrial disorders by next-generation sequencing (Platt, 2014). The number of genes included in these panels varies widely, ranging from 37 to 1192. These types of panels include a larger number of genes that are associated with numerous different mitochondrial disorders. These expanded panels are often intended to be comprehensive panels that test for all known mitochondrial and nuclear genes associated with any mitochondrial disorder. All of the expanded panels, with the exception of MEDomics® include analysis of both mitochondrial genes and nuclear genes that are thought to be involved with mitochondrial function. The composition of these expanded panels vary widely in terms of the number of genes, the percent of genes that are “classic” mutations for mitochondrial disorders, and the inclusion of genes that are not associated with any disease phenotype (Platt, 2014).
 
The specific labs and number of genes tested are listed below:
 
Commercially Available Expanded Genetic Panels for Mitochondrial Disorders
 
  • Gene Dx® (Gaithersburg, MD) - 101 genes included in the panel  
  • Transgenomic® (New Haven, CT) - 447 genes included in the panel   
  • Courtagen® (Woburn, MA) - 1192 genes included in the panel (includes mtSEEK®, nucSEEK®, theraSEEK®)
  • ARUP® (Salt Lake City, UT) - 108  genes included in the panel   
  • Baylor® (Houston, TX) - BCM-MitomeNGS  162 genes included in the panel; MitoMetPlus aCGH Analysis
  • Medical Neurogenetics® (Atlanta, GA) - 393 genes included in the panel  
  • MEDomics® (Azusa, CA) - 37 genes included in the panel  
 
Regulatory Status
No U.S. Food and Drug Administration‒cleared genotyping tests were identified. The available commercial genetic tests for epilepsy are offered as laboratory-developed tests. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.
 
Mitochondrial Disorders, Clinical Manifestations, and Associated Pathogenic Genes
To maximize the positive and the negative predictive value of testing, testing should be restricted to patients with a clinical picture consistent with a specific disorder and to a small number of mutations that are known to be pathogenic for that disorder. Table 1 is a guide to clinical symptoms and particular genetic mutations that are associated with particular mitochondrial syndromes.
 
Table 1.  Syndromes, Associated Pathogenic Genes and Clinical Manifestations (Chinnery, 2014):
 
        1. MELAS  [MT-TL1, MT-ND5 (greater than 95%)] ; [MT-TF, MT-TH, MT-TK, MT-TQ, MT-TS1, MT-TS2, MT-ND1, MT-ND6 (rare)]
            1. Stroke-like episodes at age less than 40 years.
            2. Seizures and/or dementia
            3. Pigmentary retinopathy
            4. Lactic acidosis
        2. MERRF [ MT-TK (greater than 80%)]; [MT-TF, MT-TP(rare)]
            1. Myoclonus
            2. Seizures
            3. Cerebellar ataxia
            4. Myopathy
        3. CPEO [various deletions of MT-DNA]
            1. External ophthalmoplegia
            2. Bilateral ptosis
        4. KSS [various deletions of MT-DNA]
            1. External ophthalmoplegia less than 20 year old
            2. Pigmentary retinopathy
            3. Cerebellar ataxia
            4. Heart block
        5. LS [Mt-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MTCO3];[ MT-DNA deletions (rare)]
            1. Subacute relapsing encephalopathy
            2. Infantile onset
            3. Cerebellar/brain stem dysfunction
        6. LHON [Mt-ND-1, MT-ND4, MT-ND6]
            1. Painless bilateral visual failure
            2. Male predominance
            3. Dystonia
            4. Cardiac pre-excitation syndromes
        7. NARP [MT-ATP6]
            1. Peripheral neuropathy
            2. Ataxia
            3. Pigmentary retinopathy
 
Panels of mutations that are disease-specific, i.e. contain only mutations associated with a specific type of mitochondrial disorder, can be used in place of testing individual genes in sequence. Disease-specific panels should include a list of mutations that approximates (but may not be identical to) those listed in Table 1 for each specific disorder.
 
“Expanded” panels refer to panels of many genes that are associated with numerous different types of mitochondrial disorders, typically including both mitochondrial and nuclear genes. These expanded panels are contrasted with the smaller number of genes associated with any particular disorder. Examples of commercially available expanded panel testing are provided above in this policy section.
  
Coding
Effective in 2015, there are CPT codes for genomic sequencing procedures (or “next-generation
sequencing” panels) for mitochondrial disorders. If the panel complies with the requirements in the code
descriptor, these codes may be used:
 
81440: Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic
sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10,
DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1,
TAZ, TK2, and TYMP
 
81460: Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF],
neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic
sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection
 
81465: Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic
progressive external ophthalmoplegia), including heteroplasmy detection, if performed
 
If the panel does not meet the requirements in the codes above or the test is not a panel, there are
several mitochondrial tests listed in the CPT tier 2 molecular pathology codes.
 
Code 81401 includes:
 
MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C)
 
MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C)
 
MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C)
 
MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A)
MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C)
 
MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G)
 
Code 81403 includes:
MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), full gene sequence
MT-TS1 (mitochondrially encoded tRNA serine 1) (eg, nonsyndromic hearing loss), full gene sequence
 
If there is no specific listing in the CPT molecular pathology code list for the mitochondrial DNA test that is performed, the unlisted molecular pathology code 81479 may be reported. If multiple unlisted mitochondrial DNA tests are performed, the unlisted code is only reported once for all of the unlisted tests. Other CPT codes that might be billed for this testing include: 81228, 81404, 81405, 81406, 81407 and 81408.
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing to confirm the diagnosis of a mitochondrial disorder meets member benefit certificate primary coverage criteria as an alternative to muscle biopsy under the following conditions:
 
    • Clinical signs and symptoms are consistent with a specific mitochondrial disorder (see Description), 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 Description)
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for mitochondrial disorders in at risk relatives is not covered. Genetic testing to determine the presence of a disease or condition in a relative is a contract exclusion in most member benefit certificates of coverage.
 
Genetic testing for mitochondrial disorders using expanded panel testing does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Note: “Expanded” panels refer to panels of many genes that are associated with numerous different types of mitochondrial disorders, typically including both mitochondrial and nuclear genes. These expanded panels are contrasted with the smaller number of genes associated with any particular disorder. Examples of commercially available expanded panel testing are provided above in this policy section.
 
For members with contracts without primary coverage criteria, genetic testing for mitochondrial disorders using expanded panel testing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for mitochondrial disorders in all other situations do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing for mitochondrial disorders is considered investigational in all other situations when the criteria for medical necessity are not met.
 

Rationale:
The evaluation of a genetic test focuses on 3 main principles: 1) analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); 2) clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and 3) clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes).
 
Analytic Validity
The analytic validity of testing for mitochondrial DNA may vary by the type of testing performed, the type of mutation present, and the particular gene being evaluated. The 2 main types of genetic testing are polymerase chain reaction (PCR) analysis and next generation sequencing. Both of these are, in general, associated with high analytic validity of greater than 95%.
 
The Courtagen® web page cites a sensitivity of greater than 99% and a specificity of greater than 99% (Courtagen, 2014). No further information is provided, but this presumably refers to the analytic validity of the Courtagen panel to detect mutations that are present and exclude mutations that are not present. In addition to determining the presence of the mutation, another important component of analytic validity is whether the degree of heteroplasmy has been accurately measured. The proportion of DNA that is mutated is an important component of whether clinical symptoms will develop and is generally reported along with the presence or absence of the mutation. No information was available to judge the accuracy of heteroplasmy determination for mutations in mitochondrial DNA.
 
Clinical Validity
The evidence on the clinical sensitivity and specificity of genetic testing for mitochondrial disorders is limited. There are some small case series of patients with well-defined syndrome such as mitrochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, and there are some studies that include larger numbers of patients with less specific clinical diagnose. There are wide variations reported in the yield of testing, probably reflecting the selection process used to select patients for testing. Some of the representative information that is pertinent to clinical validity is reviewed here.
 
Clinical Sensitivity. Several series of patients with mixed diagnoses, or suspected mitochondrial disorders, have been published. Qi et al studied 552 patients with mitochondrial encephalopathies and tested them for the presence of 4 of the most common mitochondrial mutations (Qi, 2007). Patients had a diagnosis of MELAS, myoclonic epilepsy with ragged-red fibers (MERRF) syndrome, Leigh syndrome (LS), Lieber hereditary optic neuropathy (LHON), or an overlap syndrome. A total of 64 patients (11.6%) had a pathogenic mutation, most of which (57/64) were the n3243 mutation.
 
Lieber et al studied 102 patients with heterogeneous clinical symptoms that were suspected to be due to mitochondrial disorders (Lieber, 2013). Using next generation sequencing, the authors sequenced the entire mitochondrial genome and the exons of 1598 nuclear genes. A total of 22 patients (22.4%) were found to have mutations thought to be pathogenic. An additional 26 variants were identified that were of uncertain clinical significance.
 
For patients with a well-defined syndrome, smaller case series have been published. For MELAS syndrome, a high proportion of patients who are diagnosed clinically with the disorder test positive for a pathogenic mutation. The most common mutation is an A to G base pair substitution at nucleotide pair 3,243. Goto et al tested 31 nonrelated patients with MELAS for the presence of this point mutation and reported that 83.9% (26/31) were positive (Goto, 1990).  
 
For MERRF, it is commonly cited that more than 80% of patients with the clinically defined syndrome will have a mutation in the MT-TK gene, with an A to G substitution at (nt)8344, and that an additional 10% of patients with MERRF will have 1 of 3 other mutations in the MT-TK gene (DiMauro, 2009). However, there is a lack of published evidence that supports this claim.
 
LS has criteria for diagnosis that include 1) Nneurodegenerative disease with symptoms of mitochondrial dysfunction, 2) hereditary pattern of disease, and 3) bilateral central nervous system (CNS) lesions on imaging (Thorburn, 1993). There are at least 12 genes that have been associated with LS, with each gene accounting for only a small minority of cases. The most common gene involved is the MT-ATP6 gene, which is implicated in approximately 10% of cases (Thorburn, 1993).  
 
Clinical Specificity. The clinical specificity of genetic testing for mitochondrial disorders is largely unknown, but false positive results have been reported (Deschauer, 2004). Some epidemiologic evidence is available on the population prevalence of pathogenic mutations, which provides some indirect evidence on the potential for false positive results.
 
A study of population-based testing reported that the prevalence of pathogenic mutations is higher than the prevalence of clinical disease. In this study, 3168 consecutive newborns were tested for the presence of 1 or more of the 10 most common mitochondrial DNA mutations thought to be associated with clinical disease (Elliott, 2008). At least 1 pathogenic mutation was identified in 15/3168 people (0.54%, 95% CI, 0.30% to 0.89%). This finding implies that there are many more people with a mutation who are asymptomatic than there are people with clinical disease and raises the possibility of false positive results on genetic testing.
 
An earlier population-based study evaluated the prevalence of the n3243 mutation that is associated with MELAS syndrome (Majamaa, 1998). This study included 245,201 subjects from Finland. Participants were screened for common symptoms associated with MELAS and screen-positive patients were tested for the mutation. The population prevalence was estimated at 16.3/100,000 (0.16%). This study may have underestimated the prevalence because patients who screened negative were not tested for the mutation. In addition to false positive results, there are variants of uncertain significance that are detected in substantial numbers of patients. The number of variants increases when next generation sequencing methods are used to examine a larger portion of the genome. In 1 study using targeted exome sequencing, variants of uncertain significance were far more common than definite pathogenic mutations (DaRe, 2013). In that study, 148 patients with suspected or confirmed mitochondrial disorders were tested by a genetic panel including 447 genes. A total of 13 patients were found to have pathogenic mutations. In contrast, variants of unknown significance were very common, occurring at a rate of 6.5 per patient.
 
A further consideration is the clinical heterogeneity of mutations known to be pathogenic. Some mutations associated with mitochondrial disorders can result in heterogenous clinical phenotypes, and this may cause uncertainty about the pathogenicity of the mutation detected. For example, the (nt)3243 mutation in the MT-TL1 gene is found in most patients with clinically defined MELAS syndrome (DiMauro, 2013).  However, this same mutation has also been associated with chronic progressive external ophthalmoplegia (CPEO) and LS (Jean-Francois, 1994). Therefore, the more closely the clinical syndrome matches MELAS, the more likely a positive genetic test will represent a pathogenic mutation.
 
Clinical Utility
No direct evidence on clinical utility was identified. There are 2 ways that clinical utility might be demonstrated from an indirect chain of evidence. First, confirmation of the diagnosis may have benefits in ending the need for further clinical workup and eliminating the need for a muscle biopsy. Second, knowledge of mutation status may have benefits for family members in determining their risk of developing disease.
 
Confirmation of diagnosis. For patients with signs and symptoms that are consistent with a defined mitochondrial syndrome, testing can be targeted to those mutations associated with that particular syndrome. In the presence of a clinical picture consistent with the syndrome, the presence of a known pathogenic mutation will confirm the diagnosis with a high degree of certainty. Confirmation of the diagnosis by genetic testing can result in reduced need for further testing, especially a muscle biopsy. The clinical utility of testing will be maximized if patients are selected who have at least a moderate to high pretest probability of disease. If confirmation of the diagnosis depends on both on the presence of signs of and symptoms of a specific disorder in conjunction with the presence of a known pathogenic mutation, then the problem of potential false positive results will be minimized.
 
There is no specific therapy for mitochondrial disorders. Treatment is largely supportive management for complications of the disease. It is possible that confirmation of the diagnosis by genetic testing leads to management changes, such as increased surveillance for complications of disease and/or the prescription of exercise therapy or antioxidants. However, the impact of these management changes on health outcomes is not known.
 
Testing of at-risk relatives. Confirmation of a genetic mutation has implications for family members of the affected person. Knowledge of mutation status will clarify the inheritance pattern of the mutation, thus clarifying risk to family members. For example, for a male patient with MELAS syndrome, confirmation of a pathogenic mutation in the mitochondrial DNA would indicate that his offspring are not at risk for inheriting the mutation, because inheritance of the mitochondrial mutation could only occur through the mother. In contrast, identification of a pathogenic mutation in nuclear DNA would indicate that his offspring are at risk for inheriting the mutation.
 
When there is disease of moderate severity or higher, it is reasonable to assume that many patients will consider results of testing in reproductive decision making. Prevention of disease through genetic testing is one way in which the burden of illness can be reduced. Nesbitt et al published a retrospective review of 62 patients who underwent prenatal genetic testing for mitochondrial disorders at a European center (Nesbitt, 2014). Based on test results and their review of records, the authors estimated that at least 11 cases of mitochondrial disorder had been prevented.
 
Expanded Panel Testing and Whole Exome Sequencing
Expanded panels are defined as panels that include many more genes than are associated with any specific disorder. They are sometimes promoted for individuals with signs and/or symptoms that are not consistent with any specific disorder. When these panels are used in individuals with nonspecific signs and symptoms that are not consistent with a “classic” presentation of a mitochondrial disorder, the probability of finding a pathogenic mutation is considerably less. Conversely, the likelihood of a false-positive result and the number of VUS may be substantially increased (O’Brien, 2014).
 
Whole exome sequencing has also been examined to detect mutations associated with mitochondrial Disorders (Taylor, 2014; Ohtake, 2014). This technique is likely to increase the detection rate but will also increase the rate of VUS. In 1 study from the U.K. of 53 patients who had biochemical evidence of a mitochondrial disorder but were negative on genetic testing of the primary mitochondrial disorder, mutations underwent whole exome sequencing (Taylor, 2014). Probable pathogenic mutations causative of a mitochondrial disorder were identified in 28 patients (53%), and there were an additional 4 patients who had variants that were possibly pathogenic.
 
Further research is needed into the benefits and harms of expanded panel testing and whole exome sequencing for the diagnosis of mitochondrial disorders. At present, due the uncertainty about the balance of benefits and harms, it is not possible to determine whether there is a net health outcome benefit.
  
Practice Guidelines and Position Statements
The Foundation for Mitochondrial Medicine published an overview of mitochondrial disease in 2013; genetic testing was specifically addressed (Foundation for Mitochondrial medicine, 2013). Mitochondrial disease can look like a number of different diseases such as autism, Parkinson disease, Alzheimer disease, Lou Gehrig disease, muscular dystrophy, and chronic fatigue. No one approach is sufficient for an accurate diagnosis. There are 3 categories of diagnostic criteria: clinical, biochemical, and genetic. A diagnosis of mitochondrial disease requires an integrated approach; there is no single test to diagnose mitochondrial disease in most patients. Genetic testing, alone, is not generally sufficient to diagnose mitochondrial disease.
  
Summary
Mitochondrial disorders are multisystem diseases that can present with a variety of symptoms and which can be difficult to diagnose. There are many different related but distinct syndromes, and some patients have overlapping syndromes. The “classic” forms of these disorders arise from mutations in mitochondrial DNA. Numerous other types of mitochondrial disorders arise from mutations in nuclear DNA that have a role in assembly or function of the mitochondria.
 
There is a lack of published data on analytic validity, but commercial testing uses methods that are expected to have high analytic validity. There is some evidence on clinical validity that varies by the specific disorder. For example, for the most well understood disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, small series of patients with a clinically diagnosed disorder have reported that a high proportion of patients have a pathogenic mutation. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain mutations exceeds the prevalence of clinical disease, suggesting that the mutation will be found in some people without clinical disease (false positives). Variants of unknown significance occur commonly, especially with the use of next generation sequencing.
 
Clinical utility is relatively high for confirming the diagnosis of mitochondrial disorders in people who have signs and symptoms indicating a moderate to high pretest likelihood of disease. In these patients, a positive result on genetic testing can avoid a muscle biopsy and can eliminate the need for further clinical workup. For testing of at-risk family members, clinical utility can also be demonstrated. When disease is present that is severe enough to cause impairment and/or disability, genetic testing for reproductive decision making is a reasonable choice that may prevent transmission of disease to offspring.
 
2016 Update
A literature search conducted through July 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Clinical Sensitivity
Kohda and colleagues evaluated a cohort of 142 children with early onset respiratory chain disease using next-generation sequencing of the entire mitochondrial DNA together with whole exome sequencing of the nuclear DNA (Kohda, 2016). There were 37 patients (26.1%) who had a likely pathogenic mutation identified. The majority of these (37/42, 88.1%) were novel mutations that were discovered in the mitochondrial DNA. There were 2 patients (1.4%) who were found to have a known pathogenic mutation in a mitochondrial gene.
 
Remenyi and colleagues evaluated a population of patients with heterogeneous symptoms and suspected mitochondrial disease (Remenyl, 2015). In this study, 1328 patients from China were tested for the 5 most common mitochondrial mutations. A pathogenic mutation was found in 22.5% of patients. The most common mutations were those associated with Leber hereditary optic neuropathy, occurring in 17.9% of patients.
 
Section Summary: Clinical Validity
Case series and cohort studies provide information on the clinical sensitivity of testing. For patients with signs and symptoms of mitochondrial disorders, but without a well-defined clinical syndrome, the mutations detection rate is low, ranging from 11.6-26.1%. This rate is an underestimation of clinical sensitivity since at least some of the patients probably do not have a mitochondrial disorder, but the degree to which it approximates clinical sensitivity is uncertain. For patients with a defined clinical syndrome, the clinical sensitivity is higher, in the range of 80% or higher. However, clinical sensitivity has not been reported for all of the types of mitochondrial disorders. There is very little evidence on clinical specificity, but there have been false positive tests reported.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81228Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (eg, bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)
81401MOLECULAR PATHOLOGY PROCEDURE LEVEL 2
81403MOLECULAR PATHOLOGY PROCEDURE LEVEL 4
81404MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
81406MOLECULAR PATHOLOGY PROCEDURE LEVEL 7
81407MOLECULAR PATHOLOGY PROCEDURE LEVEL 8
81408MOLECULAR PATHOLOGY PROCEDURE LEVEL 9
81440Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP
81460Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection
81465Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed
81479Unlisted molecular pathology procedure

References: Chinnery P, Majamaa K, Turnbull D et al.(2006) Treatment for mitochondrial disorders. Cochrane Database Syst Rev 2006; (1):CD004426.

Chinnery PF.(2014) Mitochondrial Disorders Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)2014.

Courtagen Web site.(2014) Physician Overview. 2014. Available online at: http://www.courtagen.com/professionals-overview.htm. Last accessed April 20, 2014.

DaRe JT, Vasta V, Penn J et al.(2013) Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity. BMC medical genetics 2013; 14:118.

Deschauer M, Krasnianski A, Zierz S et al.(2004) False-positive diagnosis of a single, large-scale mitochondrial DNA deletion by Southern blot analysis: the role of neutral polymorphisms. Genetic testing 2004; 8(4):395-9.

DiMauro S, Hirano M. Merrf. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)2009.

DiMauro S, Schon EA.(2001) Mitochondrial DNA mutations in human disease. Am J Med Genet 2001; 106(1):18-26.

Elliott HR, Samuels DC, Eden JA et al.(2008) Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008; 83(2):254-60.

Falk MJ, Sondheimer N.(2010) Mitochondrial genetic diseases. Curr Opin Pediatr 2010; 22(6):711-6.

Fang F, Liu Z, Fang H, et al.(2017) The clinical and genetic characteristics in children with mitochondrial disease in China. Sci China Life Sci. Jul 2017;60(7):746-757. PMID 28639102

Foundation for Mitochondrial Medicine.(2013) Mitochondrial Disease. 2013; http://mitochondrialdiseases.org/mitochondrial-disease/. Accessed March, 2015.

Goto Y, Nonaka I, Horai S.(1990) A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990; 348(6302):651-3.

Jean-Francois MJ, Lertrit P, Berkovic SF et al.(1994) Heterogeneity in the phenotypic expression of the mutation in the mitochondrial tRNA(Leu) (UUR) gene generally associated with the MELAS subset of mitochondrial encephalomyopathies. Aust N Z J Med 1994; 24(2):188-93.

Kohda M, Tokuzawa Y, Kishita Y, et al.(2016) A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. Jan 2016;12(1):e1005679. PMID 26741492

Lieber DS, Calvo SE, Shanahan K et al.(2013) Targeted exome sequencing of suspected mitochondrial disorders. Neurology 2013; 80(19):1762-70.

Majamaa K, Moilanen JS, Uimonen S et al.(1998) Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 1998; 63(2):447-54.

Nesbitt V, Alston CL, Blakely EL et al.(2014) A national perspective on prenatal testing for mitochondrial disease. European journal of human genetics : EJHG 2014.

O'Brien M, Cryan J, Brett F, et al.(2014) Ten years on: genetic screening for mitochondrial disease in Ireland. Clin Neuropathol. Jul-Aug 2014;33(4):279-283. PMID 24986207

Ohtake A, Murayama K, Mori M, et al.(2014) Diagnosis and molecular basis of mitochondrial respiratory chain disorders: exome sequencing for disease gene identification. Ohtake A, Murayama K, Mori M, et al.

Platt J, Cox R, Enns GM.(2014) Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms. J Genet Couns 2014.

Platt J, Cox R, Enns GM.(2014) Points to consider in the clinical use of NGS panels for mitochondrial disease: an analysis of gene inclusion and consent forms. J Genet Couns. Aug 2014;23(4):594-603. PMID 24399097

Qi Y, Zhang Y, Wang Z et al.(2007) Screening of common mitochondrial mutations in Chinese patients with mitochondrial encephalomyopathies. Mitochondrion 2007; 7(1-2):147-50.

Remenyi V, Inczedy-Farkas G, Komlosi K, et al.(2015) Retrospective assessment of the most common mitochondrial DNA mutations in a large Hungarian cohort of suspect mitochondrial cases. Mitochondrial DNA. Aug 2015;26(4):572-578. PMID 24438288

Schon EA, DiMauro S, Hirano M.(2012) Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 2012; 13(12):878-90.

Taylor RW, Pyle A, Griffin H, et al.(2014) Use of whole-exome sequencing to determine the genetic basis of multiplemitochondrial respiratory chain complex deficiencies. JAMA. Jul 2 2014;312(1):68-77. PMID 25058219

Thorburn DR, Rahman S.(1993) Mitochondrial DNA-Associated Leigh Syndrome and NARP. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)1993.

Transgenomic Web Site.(2014) Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 2014. Available online at: http://www.transgenomic.com/labs/neurology/melas. Last accessed 5/27/14, 2014.

Wong LJ.(2007) Diagnostic challenges of mitochondrial DNA disorders. Mitochondrion 2007; 7(1-2):45-52.


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