|MP 2.04.86||Genetic Testing for Duchenne and Becker Muscular Dystrophy|
Original Policy Date
|Last Review Status/Date
Created with literature search/ March 2013
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Mutations in the DMD gene, which encodes the protein dystrophin, may result in a spectrum of X-linked muscle diseases. The severe end of the spectrum includes the progressive muscle diseases Duchenne and Becker muscular dystrophy and dilated cardiomyopathy. Genetic testing can confirm a diagnosis of a dystrophinopathy and distinguish the less and more severe forms, as well as identify female carriers at risk.
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, they are classified as Duchenne or Becker muscular dystrophy and when the heart is primarily affected, as DMD-associated dilated cardiomyopathy (left ventricular dilation and heart failure).
Duchenne Muscular Dystrophy
Duchenne 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. (1) The incidence of DMD is estimated to be 1 in 3,500 newborn male births, (2) and approximately one-third of DMD cases arise from new mutations and have no known family history. (1) 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’s 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. The majority of 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.(1) Few individuals with DMD survive beyond the third decade.
Becker muscular dystrophy
Becker 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.
Females heterozygous for a DMD mutation can manifest symptoms of the disease. (3) An estimated 2.5% to 7.8% of female carriers are manifesting carriers who develop symptoms ranging from a mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy. (4) 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. (5) 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. (6) 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). (3)
The suspicion of DMD should be considered irrespective of family history, and is most commonly triggered by an observation of abnormal muscle function in a male child, the detection of an increase in serum creatine kinase tested for unrelated indications, or after the discovery 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 in rising from the floor or in tip-toe walking, and pseudo hypertrophy 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 10-20 times normal levels (between 5,000 and 150,000 IU/L), is non-specific to DMD but is always present in affected patients. (1) Electromyography and nerve-conduction were traditional parts of the assessment of neuromuscular disorders, but now these tests are no longer believed to be necessary for the specific assessment of DMD. (7) An open skeletal muscle biopsy is needed when a negative test for deletions or duplications to 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 on a muscle biopsy will always be abnormal in affected patients but is not specific to DMD.
Becker muscular dystrophy (BMD) has a clinical picture similar to DMD but is milder than DMD 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 (5-100 times the normal level).
DMD is the only gene in which mutations 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 most 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 (1) 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 mutational spectrum with over 5,000 different reported mutations, as well as a high spontaneous mutation rate. (8)
Treatment of Duchenne Muscular Dystrophy
There is no cure for Duchenne or Becker muscular dystrophy, and treatment is aimed at control of symptoms to improve quality of life. However, the natural history of the disease can be changed by several strategies such as corticosteroid therapy, proper nutrition or rehabilitative interventions. Glucocorticoids can slow the loss of muscle strength and may be started when a child is diagnosed or when muscle strength begins to decline. (7) 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. (1) 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 earlier therapy, before 5 years of age. (1)
New therapeutic trials require accurate diagnoses of these disorders, especially when the therapy is targeted toward specific mutations. (9) Several of these therapies are currently undergoing clinical trials with two of the most promising being anti-sense oligonucleotide induced exon-skipping and gene repair and replacement with an adeno-associated viral (AAV) vector. (10) Exon-skipping is a molecular therapy aimed at skipping the transcription of a targeted exon to restore a correct reading frame using antisense oligonucleotides. The result is a DMD protein that is formed without the mutated exon and a normal, non-shifted reading frame. Exon skipping may be able to restore DMD protein function so that the treated patient’s phenotypic expression more closely resembles BMD. Gene transfer using AAV vector therapy involves the transfer of a functional DMD gene to the patient using this nonpathogenic and low immune response vector. (11)
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. 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 (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
Genetic testing for DMD gene mutations 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 and Benefit Application)
- 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.
Heterozygous females 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.
Effective in 2013, there are CPT codes applicable to this testing:
81161 DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy) deletion analysis and duplication analysis, if performed
81408 includes DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy), full gene sequence
BlueCard/National Account Issues
BlueCard/National Account Issues
Some plans may have contract or benefit exclusions for genetic testing.
Recommendations from consensus Best Practice Guidelines for molecular diagnosis of DMD/BMD indicate that testing of an affected male (the index case) be performed so that carrier testing in female relatives at risk can focus on the mutation found in the affected family member. However, coverage for testing of the affected index case is dependent on contract benefit language.
Specific contract language must be reviewed and considered when determining coverage for testing. In some cases, coverage for testing the index case may be available through the contract that covers the at-risk individual who will benefit from knowing the results of genetic test.
This policy was created in February 2013, with a review of the literature through MEDLINE as of January 3, 2013.
Analytic validity (refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
Deletions of one or more exons account for 60-70% of mutations in individuals with DMD and BMD. (12)
Duplications account for 5-10% of mutations in DMD and BMD. (12)
Multiplex PCR may be used to amplify exons known to be most frequently deleted in DMD-affected patients. Results obtained from testing two polymerase chain reaction (PCR) multiplex sets suggest a detection rate of approximately 98% with this methodology. (13, 14) Multiplex PCR is the most widely available testing choice but is only able to detect deletions. In addition, this method does not cover the whole gene, so a deletion might not always be fully characterized. (7) An alternative to multiplex PCR is the use of a quantitative assay (e.g. multiplex ligation-dependent probe amplification or comparative genomic hybridization [also called chromosomal microarray or CMA]) of all exons. These methods have the advantage of being able to detect whole exon deletions, as well as duplications.
Point mutations (small deletions or insertions, single-base changes, and splicing mutations) account for approximately 25-35% of mutations in males with DMD and about 10-20% of males with BMD.
If deletion/duplication detection is negative, then dystrophin gene sequencing should be done to look for point mutations or small deletions/insertions. (7)
Sequencing of the entire DMD gene to detect point mutations can be performed by traditional PCR and Sanger sequencing, or by more automated methods such as universal long PCR combined with massive pyrosequencing.
There is a lack of published studies in the peer-review literature that evaluate analytic validity. According to information from the website of a large reference laboratory, deletion/duplication analysis by CMA and point mutations by full gene sequencing detects 98-99% of mutations in both males and females. (15)
Certain types of assays may cause false-positive results if the method identifies an apparent single-exon deletion or duplication based on the absence or increased amplification, respectively, of a single PCR amplification, or hybridization; when this occurs, the result must be confirmed using an alternative assay. This different assay will verify whether the initial result could have been caused by a sequence variant preventing hybridization of a primer, probe, etc., or for duplications, if the result was an anomaly. Therefore, false positives are expected to be infrequent.
Clinical validity (refers to the diagnostic performance of the test—sensitivity, specificity, positive and negative predictive values)
Virtually all males with DMD/BMD have identifiable DMD mutations, indicating a high clinical sensitivity for genetic testing. In males with DMD and BMD, phenotypes are best correlated with the degree of expression of dystrophin, largely determined by the reading frame of the spliced message obtained from the deleted allele.
A reading frame is the way in which a messenger RNA sequence of nucleotides can be read as a series of base triplets, and affects which protein is made. In DMD, the function of the dystrophin protein is completely lost due to mutations that disrupt the reading frame. Therefore, prematurely truncated, unstable dystrophins are generated. In contrast, patients with BMD have low levels of full-length dystrophin or carry in-frame mutations that allow for the generation of partially functional proteins. This so-called reading frame rule explains the phenotypic differences between DMD and BMD patients. Since this rule was postulated in 1988, (16) thousands of mutations have been reported for DMD and BMD, of which an estimated 90% fit this rule. (17)
To establish the diagnosis of a proband with DMD or BMD in a male with clinical findings that suggest a dystrophinopathy:
- Perform DMD genetic testing for deletion/duplication analysis first.
- If a mutation is not identified, perform sequence analysis for a point mutation.
- If a disease-causing DMD mutation is identified, the diagnosis of a dystrophinopathy is established.
- In cases where a distinction between DMD and BMD is difficult, the reading frame “rule” states that the type of deletion/duplication (those that alter the reading frame [out-of-frame], which correlates with the more severe phenotype of DMD versus those that do not alter the reading frame [in-frame] which correlate with the milder BMD phenotype) can distinguish the DMD and BMD phenotypes with 91-92% accuracy.
- If no disease-causing DMD mutation is identified, skeletal muscle biopsy is warranted for western blot and immunohistochemistry studies of dystrophin.
For carrier testing in at-risk female relatives:
- When the proband’s DMD mutation is known, test for that deletion/duplication or point mutation using appropriate testing method.
- When an affected male is not available for testing, perform testing by deletion/duplication first and if no mutation is identified, by sequence analysis.
The evaluation of relatives at risk includes females who are the sisters or maternal female relatives of an affected male and females who are a first-degree relative of a known or possible carrier female.
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)
The clinical utility of testing for DMD gene mutations for the index case includes:
- Establishing the diagnosis and initiating/directing treatment of the disease, such as glucocorticoids, evaluation by a cardiologist, avoidance of certain agents (e.g. botulinum toxin injections), and prevention of secondary complications (immunizations, reducing risk of fractures).
- Distinguishing between DMD and BMD.
- Avoidance of a muscle biopsy in the majority of cases.
The clinical utility of testing for DMD gene mutations for at-risk female relatives includes
- Testing to identify heterozygous females to confirm or exclude the need for cardiac surveillance.
- Preconception testing in a woman considering offspring who would alter reproductive decision-making based on test results.
The analytic and clinical validity of genetic testing for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are high. DMD is the only gene in which mutations cause the dystrophinopathies, and molecular genetic testing can establish the diagnosis in most patients. Nearly all affected individuals will be found to have a DMD mutation, and false positives are expected to be rare.
The clinical utility of DMD gene testing can be established for the index case and for at-risk female relatives. For the index case, utility lies in confirmation of the diagnosis without a muscle biopsy, initiation of effective treatment, and in distinguishing between DMD and the less severe BMD. For at-risk female relatives, the test can confirm or exclude the need to undergo routine cardiac surveillance, and can indicate the likelihood of an affected offspring in women considering children.
Therefore, genetic testing for DMD gene mutations may be considered medically necessary to establish a diagnosis in a male with clinical signs and symptoms suggestive of a dystrophinopathy and as testing for at-risk female relatives.
Practice Guidelines and Position Statements
A meeting of 29 senior scientists from Europe, the US, India, and Australia established consensus Best Practice Guidelines for the molecular diagnosis of DMD/BMD. The recommendations for testing are, if there is a clinical suspicion of a dystrophinopathy, first screen for deletions and duplications. If no deletion or duplication is detected, but the clinical diagnosis is verified, screening for point mutations should be performed. (9)
- Verma S, Anziska Y, Cracco J. Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community. Clin Pediatr (Phila) 2010; 49(11):1011-7.
- Kalman L, Leonard J, Gerry N et al. Quality assurance for Duchenne and Becker muscular dystrophy genetic testing: development of a genomic DNA reference material panel. J Mol Diagn 2011; 13(2):167-74.
- Yoon J, Kim SH, Ki CS et al. Carrier woman of Duchenne muscular dystrophy mimicking inflammatory myositis. J Korean Med Sci 2011; 26(4):587-91.
- Soltanzadeh P, Friez MJ, Dunn D et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord 2010; 20(8):499-504.
- Bonilla E, Schmidt B, Samitt CE et al. Normal and dystrophin-deficient muscle fibers in carriers of the gene for Duchenne muscular dystrophy. Am J Pathol 1988; 133(3):440-5.
- Yoshioka M, Yorifuji T, Mituyoshi I. Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet 1998; 53(2):102-7.
- Bushby K, Finkel R, Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010; 9(1):77-93.
- Mah JK, Selby K, Campbell C et al. A population-based study of dystrophin mutations in Canada. Can J Neurol Sci 2011; 38(3):465-74.
- Abbs S, Tuffery-Giraud S, Bakker E et al. Best practice guidelines on molecular diagnostics in Duchenne/Becker muscular dystrophies. Neuromuscul Disord 2010; 20(6):422-7.
- Laing NG. Genetics of neuromuscular disorders. Crit Rev Clin Lab Sci 2012; 49(2):33-48.
- Bowles DE, McPhee SW, Li C et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 2012; 20(2):443-55.
- Takeshima Y, Yagi M, Okizuka Y et al. Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J Hum Genet 2010; 55(6):379-88.
- Beggs AH, Koenig M, Boyce FM et al. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet 1990; 86(1):45-8.
- Chamberlain JS, Gibbs RA, Ranier JE et al. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res 1988; 16(23):11141-56.
- http://genetics.emory.edu/egl/tests/?testid=120. Last accessed March 2013.
- Monaco AP, Bertelson CJ, Liechti-Gallati S et al. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 1988; 2(1):90-5.
- Aartsma-Rus A, Van Deutekom JC, Fokkema IF et al. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 2006; 34(2):135-44.
DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy) deletion analysis and duplication analysis, if performed
|81408||Molecular pathology procedure, Level 9 (e.g., analysis of >50 exons in a single gene by DNA sequence analysis) --includes DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy), full gene sequence|
ICD-9 CM Diagnosis
Hereditary progressive muscular dystrophy (includes Duchenne muscular dystrophy)
Other symptoms concerning nutrition, metabolism, and development (includes dystrophy NOS)
Testing of female genetic disease carrier status
|ICD-10-CM (effective 10/01/14)||G71.0||Muscular dystrophy|
|R62.59||Other lack of expected normal physiological development in childhood|
|Z31.430||Encounter of female for testing for genetic disease carrier status for procreative management|
|ICD-10-PCS (effective 10/01/14)||Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.|
Genetic Testing, Muscular Dystrophy
|03/14/13||New policy||Policy created with literature search through January 3, 2013. Medically necessary to establish a diagnosis in a male with clinical signs and symptoms suggestive of a dystrophinopathy and in at-risk female relatives.|