Genetic Testing for Duchenne and Becker Muscular Dystrophy

POLICY NUMBER

A.2.04.86

DESCRIPTION

Variants in the Duchenne muscular dystrophy (DMD) gene, which encodes the protein dystrophin, may result in a spectrum of X-linked muscle diseases, including the progressive diseases Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) and dilated cardiomyopathy. Genetic testing can confirm a diagnosis of a dystrophinopathy and distinguish the less from more severe forms, as well as identify female carriers at risk.

Dystrophinopathies

The dystrophinopathies include a spectrum of muscle diseases. The mild end of the spectrum includes asymptomatic increases in serum concentration of creatine phosphokinase and clinical symptoms such as muscle cramps with myoglobinuria and/or isolated quadriceps myopathy. The severe end of the spectrum includes progressive muscle diseases that lead to substantial morbidity and mortality. When skeletal muscle is primarily affected, the disease is classified as Duchenne (DMD) or Becker muscular dystrophy (BMD); when the heart is primarily affected, the disease is classified as DMD-associated dilated cardiomyopathy (left ventricular dilation and heart failure).

Duchenne Muscular DystrophyDuchenne muscular dystrophy (DMD), the most common muscular dystrophy, is a severe childhood X-linked recessive disorder that results in significant disability due to skeletal myopathy and cardiomyopathy. The disease is characterized by progressive, symmetric muscle weakness and gait disturbance resulting from a defective dystrophin gene. According to a 2022 systematic review and meta-analysis, the global prevalence of DMD is estimated at 4.8 cases (95% confidence interval [CI], 3.6 to 6.3) per 100,000 people. Approximately one-third of DMD cases arise from de novo variants and have no known family history. Infant males with DMD are often asymptomatic. Manifestations may be present as early as the first year of life in some patients, but clinical manifestations most often appear during preschool, from years 2 to 5. Affected children present with gait problems, calf hypertrophy, positive Gower sign, and difficulty climbing stairs. The affected child’s motor status may plateau between 3 and 6 years of life with deterioration beginning at 6 to 8 years. Most patients will be wheelchair bound by ages 9 to 12 years, but will retain preserved upper-limb function until a later period. Cardiomyopathy occurs after 18 years of age. Late complications are cardiorespiratory (e.g. decreased pulmonary function as a result of respiratory muscle weakness and cardiomyopathy). These severe complications commonly appear in the second decade of life and eventually lead to death. Few individuals with DMD survive beyond the third decade.

Becker Muscular DystrophyBecker muscular dystrophy (BMD) is characterized by later onset skeletal muscle weakness. Individuals remain ambulatory into their 20s. Despite the milder skeletal muscle involvement, heart failure from cardiomyopathy is a common cause of morbidity and the most common cause of death in these patients, with a mean age of death in the mid-40s. According to a 2022 systematic review and meta-analysis, the global prevalence of BMD is estimated at 1.6 cases (95% CI, 1.1 to 2.4) per 100,000 people.

Female CarriersFemales heterozygous for a DMD disease-associated variant can manifest symptoms of the disease. An estimated 2.5% to 7.8% of female carriers are manifesting carriers who develop symptoms ranging from mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy. Female carriers are at increased risk for dilated cardiomyopathy. Most heterozygous women do not show severe myopathic features of DMD, possibly due to compensation by a normal X chromosome with inactivation of the mutated DMD gene in the affected X chromosome. In some cases, this compensation can be reversed by a non-random or skewed inactivation of X chromosome, resulting in greater expression of the affected X chromosome and some degree of myopathic features. Other mechanisms of manifesting female carriers include X chromosome rearrangement involving the DMD gene and complete or partial absence of the X chromosome (Turner syndrome).

Clinical Diagnosis

Duchenne Muscular DystrophySuspicion of DMD should be considered irrespective of family history; it is most commonly triggered by the observation of abnormal muscle function in a male child, the detection of an increase in serum creatine kinase tested for unrelated indications, or thedetection of increased serum transaminases (aspartate aminotransferase and alanine aminotransferases). Clinical examination by a neuromuscular specialist for DMD includes visual inspection of mechanical function such as running, jumping, climbing stairs, and getting up from the floor. Common presenting symptoms include abnormal gait with frequent falls, difficulties rising from the floor or tip-toe walking, and pseudohypertrophy of the calves. A clinical examination may reveal decreased or lost muscle reflexes and, commonly, a positive Gower sign. An elevation of serum creatine kinase, at least 10 to 20 times normal levels (between 5,000 IU/L and 150,000 IU/L), is non-specific to DMD, but is always present in affected patients. Electromyography and nerve conduction studies were traditional parts of the assessment of neuromuscular disorders, but these tests may not be necessary for assessment of DMD. An open skeletal muscle biopsy is needed when a test for deletions or duplications of the DMD gene is negative. The biopsy will provide general signs of muscular dystrophy, including muscle fiber degeneration, muscle regeneration, and increased content of connective tissue and fat. Dystrophin analysis of a muscle biopsy will always be abnormal in affected patients but is not specific to DMD.

Becker Muscular DystrophyBecker muscular dystrophy (BMD) is clinically similar to DMD, but is milder and has a later onset. BMD presents with progressive symmetric muscle weakness, often with calf hypertrophy, although weakness of quadriceps femoris may be the only sign. Activity-induced cramping may be present in some individuals, and flexion contractures of the elbows may be present late in the course. Neck flexor muscle strength is preserved, which differentiates BMD from DMD. Serum creatine kinase shows moderate-to-severe elevation (5 to 100 times the normal level).

Molecular DiagnosisDMD is the only gene of which variants are known to cause DMD, BMD, and DMD-associated cardiomyopathy. Molecular genetic testing of DMD can establish the diagnosis of a dystrophinopathy without muscle biopsy in approximately 95% of patients with DMD and BMD.

The dystrophinopathies are X-linked recessive and penetrance is complete in males. The gene that codes for dystrophin is the largest known human gene. A molecular confirmation of DMD and BMD is achieved by confirming the presence of a pathogenic variant in this gene by a number of available assays. The large size of the dystrophin gene results in a complex variant spectrum with over 5,000 reported disease-associated variants, as well as a high spontaneous de novo variant rate.

TreatmentThere is no cure for DMD or BMD. Treatment is aimed at controlling symptoms to improve quality of life. However, the natural history of the disease can be changed by strategies such as corticosteroid therapy, proper nutrition, or rehabilitative interventions. Glucocorticoids were shown in a 1991 randomized controlled trial to prolong the period of independent ambulation by 3 years. The goal of this therapy is to preserve ambulation and minimize later respiratory, cardiac, and orthopedic complications. Glucocorticoids work by decreasing inflammation, preventing fibrosis, improving muscle regeneration, improving mitochondrial function, decreasing oxidative radicals, and stopping abnormal apoptosis pathways. Bone density measurement and immunization are prerequisites for corticosteroid therapy initiation, which typically begins at 2 to 5 years of age, although there has been no demonstrated benefit of therapy before 5 years of age.

New therapeutic trials require accurate diagnoses of these disorders, especially when the therapy is targeted at specific pathogenic variants. Exon-skipping is a molecular therapy aimed at skipping the transcription of a targeted exon to restore a correct reading frame using antisense oligonucleotides. Exon-skipping may result in a DMD protein without the mutated exon and a normal, non-shifted reading frame. Exon-skipping may also restore DMD protein function so that the treated patient’s phenotypic expression more closely resembles BMD. Several therapies are currently in clinical trials. Exon-skipping therapy using antisense oligonucleotides approved by the U.S. Food and Drug Administration include: eteplirsen (Exondys 51) for treatment for patients who have a confirmed variant of the dystrophin gene amenable to exon 51 skipping, golodirsen (Vyondys 53), and viltolarsen (Viltepso) for patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, and casimersen (Amondys 45), for patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. These approvals were based on improvements in the surrogate outcome of increased dystrophin production in skeletal muscle and benefits in clinical outcomes have not yet been established.

A gene therapy, delandistrogene moxeparvovec-rokl (Elevidys), was also approved in 2023 to treat ambulatory children 4 to 5 years of age with DMD and a confirmed mutation in the DMD gene.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA 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 for DMD gene variants may be considered medically necessary under the following conditions:

• In a male with signs and symptoms of a dystrophinopathy in order to confirm the diagnosis and direct treatment.

• For at-risk female relatives: (see Policy Guidelines)

  • To confirm or exclude the need for cardiac surveillance.

  • For preconception testing to determine the likelihood of an affected offspring in a woman considering a pregnancy.

• For at-risk male offspring (see Policy Guidelines)

  • To confirm or exclude the need for medical and cardiac surveillance.

Genetic testing for DMD gene variants is considered investigational in all other situations.

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.

DMD Gene Testing

Females heterozygous for a Duchenne muscular dystrophy (DMD) disease-associated variant are at increased risk for cardiomyopathy and need routine cardiac surveillance and treatment.

At-risk females are defined as first- and second-degree female relatives and include the proband’s mother, female siblings of the proband, female offspring of the proband, the proband’s maternal grandmother, maternal aunts, and their offspring.

An at-risk male is defined as an asymptomatic male offspring of a female carrier or an asymptomatic male sibling of a patient with a DMD-associated dystrophinopathy.

Genetic Counseling

Experts recommend formal genetic counseling for individuals who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some individuals. Therefore, genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that 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

07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.

05/01/2014: Policy reviewed; no changes.

08/18/2015: Medical policy revised to add ICD-10 codes.

09/16/2015: Policy reviewed. Added the following policy statement: Genetic testing for DMD gene mutations is considered investigational in all other situations. Policy Guidelines updated to add medically necessary and investigative definitions.

04/19/2016: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add genetic counseling information.

06/07/2016: Policy number A.2.04.86 added.

07/13/2017: Policy description and policy statements updated to change "mutations" to "variants." Medically necessary policy statement updated to add an indication for at-risk male offspring. Policy guidelines updated to define an at-risk male and to add standard terminology for variant classification.

04/06/2018: Policy description updated regarding treatment for Duchenne and Becker muscular dystrophy. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

09/26/2018: Code Reference section updated to add new ICD-10 diagnosis codes G71.00, G71.01, and G71.09, effective 10/01/2018.

04/05/2019: Policy reviewed; no changes.

04/15/2020: Policy reviewed. Policy statements unchanged. Code Reference section updated to remove deleted ICD-10 diagnosis code G71.0 and ICD-9 diagnosis code 359.1.

09/22/2020: Code Reference section updated to add new CPT code 0218U, effective 10/01/2020.

05/26/2021: Policy description updated regarding treatment. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature information and to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

08/24/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding DMD gene testing. Code Reference section updated to add CPT code 81408.

04/17/2023: Policy description updated regarding the prevalence of Duchenne Muscular Dystrophy and Becker Muscular Dystrophy. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

04/18/2024: Policy description updated regarding treatments. Policy statements unchanged.

04/17/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.86

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.

Covered Codes

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