Dystrophinopathies

[Includes: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), DMD-Associated Dilated Cardiomyopathy]

Clinical Diagnosis

In addition to a positive family history compatible with X-linked inheritance, the following clinical findings support the diagnosis of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy (DCM) in males:

Duchenne muscular dystrophy (DMD)

• Progressive symmetrical muscular weakness, proximal greater than distal, often with calf hypertrophy

• Symptoms present before age five years

• Wheelchair dependency before age 13 years

Becker muscular dystrophy (BMD)

• Progressive symmetrical muscle weakness and atrophy, proximal greater than distal, often with calf hypertrophy (weakness of quadriceps femoris may be the only sign)

• Activity-induced cramping (present in some individuals)

• Flexion contractures of the elbows (if present, late in the course)

• Wheelchair dependency (if present, after age 16 years)

• Preservation of neck flexor muscle strength (differentiates BMD from DMD)

Note: The presence of fasciculations or loss of sensory modalities excludes the diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair bound between ages 13 and 16 years.

DMD-associated dilated cardiomyopathy (DCM)

• Dilated cardiomyopathy (DCM) with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life

• Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD

• Rapid progression to death in several years in males and slower progression over a decade or more in females [Beggs 1997]

See also Dilated Cardiomyopathy Overview.

Testing

Serum creatine phosphokinase (CK) concentration (Table 1)

Electromyography (EMG) is useful in distinguishing a myopathic process from a neurogenic disorder. This is done by demonstrating short-duration, low-amplitude, polyphasic, rapidly recruited motor unit potentials. As the disease progresses, the interference pattern becomes incomplete because of reduced recruitment and eventually the muscle becomes electrically silent. However, these findings are nonspecific, occurring in all myogenic disorders. In practice, EMG is used only rarely in the diagnosis of dystrophinopathies.

Skeletal muscle biopsy

Histology. Muscle histology early in the disease shows nonspecific dystrophic changes, including variation in fiber size, foci of necrosis and regeneration, hyalinization, and, later in the disease, deposition of fat and connective tissue.

Western blot and immunohistochemistry are summarized in Table 2.

Cytogenetic analysis

Males. In rare instances, boys with DMD have other X-linked disorders including retinitis pigmentosa, chronic granulomatous disease, and McLeod red cell phenotype (see McLeod neuroacanthocytosis syndrome) [Francke et al 1985] or glycerol kinase deficiency and adrenal hypoplasia [Darras & Francke 1988] as part of contiguous gene deletion syndromes. Such boys warrant both high-resolution chromosome studies to look for visible cytogenetic deletions or rearrangements involving Xp21.2 and FISH analysis with probes (covering the GK and NRDB1 genes in addition to exons in the DMD gene).

Females. Girls with classic DMD may have an X-chromosome rearrangement or deletion involving Xp21.2, complete absence of an X chromosome (i.e., Turner syndrome), or uniparental disomy of the X chromosome. Girls with findings of typical DMD warrant high-resolution chromosome studies.

Molecular Genetic Testing

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Gene. DMD is the only gene known to be associated with DMD, BMD, and DMD-associated DCM.

Clinical testing

• Diagnostic testing

  • Deletion/duplication analysis
    
    Multiplex PCR [Multicenter Study Group 1992], Southern blotting [Darras et al 1988], and FISH (with probes covering DMD exons 3-6, 8, 12, 13, 17, 19, 32-34, 43-48, 50, 51, and 60) can be used to detect deletions, which account for approximately 65% of mutations in individuals with DMD and 85% in those with BMD. Approximately 98% of deletions are detectable by these methodologies.
    
    Southern blotting and quantitative PCR analysis can be used to detect duplications.
    Duplications may lead to in-frame or out-of-frame transcripts and account for the disease-causing mutations in approximately 6%-10% of males with DMD or BMD.
    In one study [Galvagni et al 1994], duplications were detected in 6.8% of individuals with BMD and 8.18% of individuals with DMD.
    In a series of individuals already screened for deletions and point mutations, duplications were detected in 87% of cases [White et al 2006].
    
    Multiple ligation probe amplification (MLPA) has been developed for deletion/duplication analysis of the DMD gene in probands and carrier females [Gatta et al 2005].

  • Mutation scanning or sequence analysis detect the small deletions or insertions, single-base changes, or splicing mutations that account for approximately 30%-35% of mutations in DMD [Bennett et al 2001, Mendell et al 2001, Dolinsky et al 2002].

  • New testing methods including single-condition amplification internal primer sequencing (SCAIP) [Flanigan et al 2003] and denaturing gradient gel electrophoresis (DGGE)-based whole-gene mutation scanning [Hofstra et al 2004] aim at detecting the remaining 30%-35% of the DMD mutations in a semiautomatic, rapid, accurate, and economical fashion.

  • A muscle biopsy-based diagnostic approach was developed and optimized to increase the mutation detection frequency to nearly 100% [Deburgrave et al 2007]. This method utilizes protein- and RNA-based analyses in combination with direct cDNA sequencing.
    
    Note: Data are currently insufficient to estimate the percentage of individuals with DMD-associated dilated cardiomyopathy with detectable DMD mutations.

• Carrier testing

  • When the proband's DMD mutation is known

    • Carrier testing for deletions and duplications may be performed using quantitative analysis for gene dosage.
      
      Note: This method may be difficult to perform and interpret. A reliable and simple method based on quantitative real-time PCR detects deletions/duplications in 100% of DMD/BMD carriers [Joncourt et al 2004].

    • Carrier testing for deletions may also be performed by FISH [Voskova-Goldman et al 1997].

    • Carrier testing for point mutations may be performed by sequence analysis.

  • When the proband's DMD mutation is not known. Linkage analysis can be offered to at-risk females to determine carrier status in families with more than one affected male with the unequivocal diagnosis of DMD/BMD/DMD-associated DCM. Linkage studies are based on accurate clinical diagnosis of DMD/BMD/DMD-associated DCM in the affected family members and accurate understanding of the genetic relationships in the family. Linkage analysis relies on the availability and willingness of family members to be tested. The markers used for linkage in DMD/BMD/DMD-associated DCM are highly polymorphic and informative, and lie both within and flanking the DMD locus; thus, they can be used in most families with DMD/BMD/DMD-associated DCM [Kim et al 2002].
    
    Note: The large size of the DMD gene leads to an appreciable risk of recombination. It has been estimated that the gene itself spans a genetic distance of 12 centimorgans [Abbs et al 1990]; thus, multiple recombination events among different members of a family may complicate the interpretation of a linkage study. Linkage testing is not available to families in which there is a single affected male.

Table 3 summarizes molecular genetic testing for this disorder.

Table 3. Molecular Genetic Testing Used in the Dystrophinopathies

Test Method	Mutations Detected	Mutation Detection Frequency in Males by Phenotype and Test Method			Test Availability
		DMD	BMD	XLDCM
Deletion/duplication analysis	Deletion of one or more exons of DMD gene	~65%	~85%	Unknown	Clinical
	Duplication of one or more exons of DMD	~7%-10%	~6%-10%	Unknown
Mutation scanning and/or sequence analysis	Small insertions/deletions/point mutations/splicing mutations of DMD gene	~25%-30%	~5%-10%	Unknown

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis of a dystrophinopathy. For individuals with clinical findings suggesting a dystrophinopathy and an elevated serum CK concentration, the first step in diagnosis is molecular genetic testing of the DMD gene:

• If a disease-causing mutation is identified, the diagnosis is established; evaluation of muscle tissue in this instance may be considered to help distinguish between the DMD and BMD phenotypes in younger individuals with a negative family history.

• If no DMD disease-causing mutation is identified, skeletal muscle biopsy of individuals with suspected DMD or BMD is warranted for western blot and immunohistochemistry studies of dystrophin.

Identifying the origin of a de novo mutation. In families with a dystrophinopathy in one family member only, the origin of a de novo mutation can often be identified by performing deletion/duplication analysis or sequencing in conjunction with linkage analysis. The haplotype associated with the mutated DMD allele in the affected individual can be tracked back through the mother and, if necessary, through maternal grandparents to identify the individual in whom the mutation originated [Ferreiro et al 2004].

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder.

Prenatal diagnosis and preimplantation diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in DMD.

Natural History

Genotype-Phenotype Correlations

In males with DMD and BMD, phenotypes are best correlated with the degree of expression of dystrophin, which is largely determined by the reading frame of the spliced message obtained from the deleted allele [Monaco et al 1988, Koenig et al 1989].

DMD. Very large deletions may lead to absence of dystrophin expression. Mutations that disrupt the reading frame include stop mutations, some splicing mutations, and deletions or duplications. They produce a severely truncated dystrophin protein molecule that is degraded, leading to the more severe DMD phenotype. Exceptions to this "reading frame rule" are deletions in protein-binding domains that may severely affect function even in in-frame [Hoffman et al 1991] and exon-skipping events in which apparently out-of-frame deletions behave as in-frame deletions or vice versa [Chelly et al 1990]. The accuracy of phenotype prediction using this rule is in the range of 91%-92% [Aartsma-Rus et al 2006b].

Data suggest that dystrophin deletions involving the brain distal isoform Dp140 are associated with intellectual impairment [Felisari et al 2000].

BMD. The BMD phenotype occurs when some dystrophin is produced, usually resulting from deletions or duplications that juxtapose in-frame exons, some splicing mutations, and most non-truncating single-base changes that result in translation of a protein product with intact N and C termini. The shorter than normal dystrophin protein molecule, which retains partial function, produces the milder BMD phenotype [Deburgrave et al 2007].

DMD-associated DCM. DMD-associated DCM is caused by mutations in DMD that affect the muscle promoter (P_M) and the first exon (E1), resulting in no dystrophin transcripts being produced in cardiac muscle; however, two alternative promoters that are normally only active in the brain (P_B) and Purkinje cells (P_P) are active in the skeletal muscle, resulting in dystrophin expression sufficient to prevent manifestation of skeletal muscle symptoms [Beggs 1997, Towbin 1998, Yoshida et al 1998].

DMD-associated DCM may also be caused by alteration of epitopes in a region of the protein of particular functional importance to cardiac muscle [Ortiz-Lopez et al 1997] or possibly by mutations in hypothetical cardiac-specific exons. Abnormalities in cardiac conduction noted in persons with dystrophinopathies may be related to reduced expression of cardiac sodium channel NA(v)1.5 secondary to dystrophin deficiency [Gavillet et al 2006].

See also Dilated Cardiomyopathy Overview.

Penetrance

Penetrance of dystrophinopathies is complete in males.

Penetrance in carrier females varies, depending on patterns of X-chromosome inactivation.

Anticipation

Anticipation is not observed in the dystrophinopathies.

Nomenclature

The term "pseudohypertrophic muscular dystrophy" was used in the past; however, it is not used currently because pseudohypertrophy is not unique to the DMD or BMD phenotype.

Prevalence

The birth prevalence of DMD in northern England is one in 5,618 live male births, and that of BMD is one in 18,450 live male births.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended:

• Physical therapy assessment

• Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary

• If the individual is older than age ten years at diagnosis, evaluation for cardiomyopathy by electrocardiography, chest radiography, cardiac echocardiography, pulmonary function studies, and/or MRI [Towbin 2003]

Treatment of Manifestations

Appropriate management of males with DMD/BMD can prolong survival and improve quality of life.

Dilated cardiomyopathy. Recommendations are based on an American Academy of Pediatrics policy statement [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005].

A retrospective observational study found that ventricular remodeling may occur in males with DMD and BMD with early diagnosis and treatment of cardiomyopathy [Jefferies et al 2005]. Among 69 affected boys with a first echocardiogram indicating dilated cardiomyopathy (e.g., LVEP <55% or left ventricular dilation), 27 with DMD and four with BMD were started on an ACE inhibitor at a mean age of 15 years. If echocardiography at three months showed no improvement, a beta blocker (carvedilol or metoprolol) was added. When these 31 individuals had repeat echocardiography at a mean of 3.3 years later, left ventricular size and function normalized in 19 (66%), improved in eight (26%), and stabilized in two (8%). Mean LVEF increased from 36% to 53%. Measurement of reduced sphericity indicated improved ventricular geometry. Whether this therapy reverses the cardiomyopathy or only masks the manifestations of a progressive process is not clear; however, a more recent study [Duboc et al 2005] lends support to the hypothesis that early introduction of afterload reduction therapy may lead to improved preservation of myocardial function [Colan 2005].

The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease.

• Treatment with anti-congestive medications as needed

• Therapeutic intervention using angiotensin-converting enzyme inhibitors and beta-blockers at the earliest signs of cardiomyopathy [Towbin 2003]
  
  Note: In most cases, this approach leads to normalization of left ventricular size and systolic function early on.

• Cardiac transplantation in severe cases

Medications

Prednisone. Studies have shown that prednisone improves the strength and function of individuals with DMD. It is hypothesized that prednisone has a stabilizing effect on membranes and perhaps an anti-inflammatory effect. Whether the improvement is the result of an immunosuppressive effect remains unclear, as individuals treated with azathioprine did not have a beneficial effect.

In a randomized double-blind six-month trial, prednisone administered at a dose of either 0.75 mg/kg/day or 1.5 mg/kg/day increased strength and reduced the rate of decline in males with DMD [Mendell et al 1989]. The improvement begins within ten days of starting the treatment, requires a single dose of 0.75 mg/kg/day of prednisone for maximal improvement, reaches a plateau after three months, and can be sustained for as long as three years in those children maintained on doses of 0.5 and 0.6 mg/kg/day [Fenichel et al 1991]. One open-label study suggested that therapy with prednisone could prolong ambulation by two years. Side effects include weight gain (>20% of baseline) (40%), hypertension, behavioral changes, growth retardation, cushingoid appearance (50%), and cataracts [Mendell et al 1989, Griggs et al 1993].

Follow-up studies showed that a dose of 0.75 mg/kg/day was more beneficial than a dose of 0.3 mg/kg/day [Fenichel et al 1991]. Nevertheless, a subsequent study proved the effectiveness of lower doses (0.35 mg/kg/day) of prednisolone in both DMD and BMD. One of the authors has noted sustained effectiveness with doses initiated at 0.75 mg/kg/day (maximum daily dose: 40 mg) and gradually reduced (usually not deliberately but because of advancing age and weight gain) to as low as 0.4 mg/kg/day. At lower doses, the improvement is less robust [Darras, personal communication].

Alternate-day dosing and intermittent dosing (e.g., 10 days on, 10 days off) are also used; the optimal dosage and schedule have not been adequately studied [Dubowitz 1997]. Another study showed reduced incidence of side effects by high-dose (5 mg/kg), twice-weekly dosing [Connolly et al 2002]. A randomized, cross-over, controlled trial of intermittent prednisone (0.75 mg/kg/day) therapy (prednisone or placebo) during the first ten days of each month for six months showed that prednisone slowed deterioration of muscle function in individuals with DMD [Beenakker et al 2005]; side effects did not negatively affect quality of life. Similar conclusions regarding the effect and side-effect profile of prednisone treatment for DMD were reached by a Cochrane systematic review [Manzur et al 2004] and also by the 124th European Neuromuscular Centre workshop on the treatment of DMD [Bushby et al 2004].

Note: Long-term benefit of twice-weekly oral prednisolone (5 mg/kg) beginning at three or four weeks has also been documented in the mdx mouse model of DMD [Keeling et al 2007].

Data regarding the optimal age to begin treatment with corticosteroids or the optimal duration of such treatment are insufficient. During the past few years, it has been proposed that individuals with DMD begin treatment with low-dose prednisone as soon as the diagnosis is made (age 2-5 years) [Merlini et al 2003]. Nonetheless, the efficacy and safety of early treatment have not been studied adequately. Thus, at this point corticosteroid therapy remains the treatment of choice for affected individuals between ages five and 15 years. It should be noted that studies have suggested that an optimal window for treatment may be before age five years, but large-scale controlled trials of corticosteroid therapy in early DMD have yet to be conducted.

Immunosuppressive therapy. The following recommendations for immunosuppressive therapy are in accordance with the national practice parameters regarding corticosteroid therapy developed by the American Academy of Neurology and the Child Neurology Society [Moxley et al 2005].

• Boys with DMD who are older than age five years should be offered treatment with prednisone (0.75/mg/kg/day). Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual.

• To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes).

• There is an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [King et al 2007].

• The optimal maintenance dose of prednisone (0.75 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day.

• If excessive weight gain occurs (>20% over estimated normal weight for height over a 12-month period), the prednisone dose should be decreased to 0.5 mg/kg/day. If excessive weight gain continues, the dose should be further decreased to 0.3 mg/kg/day after three to four months.

• Deflazacort (0.9 mg/kg/day) can also be used to treat DMD. Side effects of asymptomatic cataracts and weight gain should be monitored.

Information about the efficacy of prednisone in treating individuals with BMD is limited.

Deflazacort. Deflazacort, a synthetic derivative of prednisolone used in Europe but not currently available in the US, is thought to have fewer side effects than prednisone, particularly with regard to weight gain [Angelini 2007]. A larger study comparing deflazacort to prednisone, carried out in Europe, showed that the two medications were similarly or equally effective in slowing the decline of muscle strength in DMD. Another European multicenter, double-blind, randomized trial of deflazacort versus prednisone in DMD showed equal efficacy in improving motor function and functional performance [Bonifati et al 2000]. A more recent study of deflazacort treatment showed efficacy in preserving pulmonary function as well as gross motor function [Biggar et al 2006].

In a comparison of two different protocols of deflazacort treatment in DMD, a 0.9-mg/kg/day dose was more effective than a dose of 0.6 mg/kg/day for the first 20 days of the month and no deflazacort for the remainder of the month [Biggar et al 2004]; 30% of children on the highest dose developed asymptomatic cataracts that required no treatment. A systematic review and meta-analysis of 15 studies showed that deflazacort improves strength and motor function more than placebo; whether it has a benefit over prednisone on similar outcomes remains unclear [Campbell & Jacob 2003].

Scoliosis treatment as needed is appropriate.

Prevention of Secondary Complications

The following measures are appropriate:

• Evaluation by pulmonary and cardiac specialists before surgeries [Finder et al 2004]

• Administration of pneumococcal vaccine and influenza vaccination annually [Finder et al 2004]

• Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures
  
  Note: Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [Bachrach 2005, Biggar et al 2005, Quinlivan et al 2005].

• Physical therapy to promote mobility and prevent contractures

• Weight control to avoid obesity
  
  Note: Routine evaluation by a nutritionist is recommended.

Surveillance

Cardiac. The American Academy of Pediatrics (AAP) recommendations for optimal cardiac care in persons with DMD or BMD [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005] include the following:

• For DMD, complete cardiac evaluation at least every two years, beginning in early childhood

• For DMD, at approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation
  
  Note: Individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course.

• For BMD, complete cardiac evaluations beginning at approximately age ten years or at the onset of signs and symptoms. Evaluations should continue at least every two years.

The AAP recommendations for optimal cardiac care for female carriers of DMD or BMD [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005] include the following:

• Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure

• Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms

• Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years

• Treatment of cardiac disease similar to that for boys with DMD or BMD

Pulmonary

• Baseline pulmonary function testing before confinement to a wheelchair (usually age ~9-10 years)

• Evaluation by a pediatric pulmonologist twice yearly after any one of the following: confinement to a wheelchair, reduction in vital capacity below 80% predicted, and/or age 12 years [Finder et al 2004]

Orthopedic. Monitoring for orthopedic complications, especially scoliosis in those with DMD and BMD

Agents/Circumstances to Avoid

Individuals with DMD/BMD should avoid botulinum toxin injections.

Testing of Relatives at Risk

Females. Female carriers need to be identified for the purpose of cardiac surveillance (see Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Aminoglycosides. Up to 15% of individuals with DMD exhibit the gene mutation known as a premature stop codon. Suppression of stop codons has been demonstrated with aminoglycoside treatment of cultured cells; the treatment creates misreading of RNA and thereby allows alternative amino acids to be inserted at the site of the mutated stop codon. In the mdx mouse, in vivo gentamicin therapy resulted in dystrophin expression at 10%-20% of that detected in normal muscle [Barton-Davis et al 1999], a level that provided some degree of functional protection against contraction-induced damage.

Aminoglycoside therapy has been suggested as an alternative to gene therapy but could be aimed only at individuals with premature stop codons. In a preliminary study in which gentamicin (7.5 mg/kg/day) was administered to four individuals for two weeks, full-length dystrophin did not appear in the muscles of the treated individuals [Wagner et al 2001]. Some authors, unable to reproduce the results previously published for the mouse model of DMD, have called for more preclinical investigation of this potential therapy [Dunant et al 2003]. In an in vitro study [Kimura et al 2005], dystrophin expression was detected in myotubes of males with DMD using gentamicin; however, the treatment was more effective in persons with the nonsense mutation TGA than TAA or TAG.

PTC124 is a new, orally administered non-antibiotic drug that appears to promote ribosomal read-through of nonsense (stop) mutations. Preclinical efficacy studies in mdx mice have yielded encouraging results [Barton et al 2005, Welch et al 2007]. A Phase I multiple-dose safety trial is ongoing [Hirawat et al 2005].

Morpholino antisense oligonucleotides mediate exon skipping [Aartsma-Rus et al 2006a] and have improved the mdx mouse model of DMD [Wilton & Fletcher 2005, Alter et al 2006].

Oxandrolone, an anabolic (androgenic) steroid with a powerful anabolic effect on skeletal muscle myosin synthesis [Balagopal et al 2006], was shown in a pilot study to have effects similar to prednisone, with fewer side effects [Fenichel et al 1997]. A randomized, prospective, controlled trial showed that oxandrolone did not produce a significant change in the average manual muscle strength score of males with DMD, as compared with placebo; however, the mean change in quantitative muscle strength was significant [Fenichel et al 2001]. The investigators conducting this study felt that oxandrolone may be useful before initiating therapy with corticosteroids because it is safe in the short term, accelerates linear growth, and may be beneficial in slowing the progression of weakness. However, the long-term effects of oxandrolone in the treatment of DMD have not been studied.

Gene therapy. Experimental gene therapies are currently under investigation [Gregorevic & Chamberlain 2003, Tidball & Spencer 2003, van Deutekom & van Ommen 2003, Nowak & Davies 2004].

Gregorevic et al [2004] reported systemic administration of rAAV6 vectors resulting in successful delivery of DMD to affected muscles of dystrophin-deficient mdx mice (a mouse model for DMD).

Stem cell therapy is under investigation but remains experimental [Gussoni et al 1997, Gussoni et al 1999, Gussoni et al 2002, Skuk et al 2004].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Immunosuppression with azathioprine is not beneficial.

Myoblast transfer has been inefficient.

Creatine monohydrate has been studied as potential treatment in muscular dystrophies and neuromuscular disorders [Tarnopolsky & Martin 1999, Walter et al 2000, Louis et al 2003]. In a recent randomized, controlled, cross-over trial, 30 boys with DMD were given creatine (~0.1 g/kg/day) for four months and placebo for four months [Tarnopolsky et al 2004]. Treatment with creatine resulted in improved grip strength of the dominant hand and increased fat-free mass when compared to placebo; however, no functional improvement was noted. Given the limited data and modest benefit, treatment with creatine monohydrate cannot be recommended for treatment of DMD.

Cyclosporin was reported to improve clinical function in children with DMD who received the medication for eight weeks. Nevertheless, because of the rare reports of cyclosporin-induced myopathy in individuals receiving the medication for other reasons, the use of cyclosporin in treating DMD remains controversial.

Histone deacetylase inhibitors have improved the mdx mouse by inducing the expression of the myostatin inhibitor follistatin [Minetti et al 2006].

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

The dystrophinopathies are inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• A woman with an affected son and one other affected relative in the maternal line is an obligate heterozygote.

• A woman with more than one affected son and no other family history of a dystrophinopathy has either:

  • A germline mutation (i.e., a DMD disease-causing mutation present in each of her cells); or

  • Germline mosaicism (i.e., mosaicism for a DMD disease-causing mutation that includes her germline) [Bakker et al 1987, Darras & Francke 1987 Ferreiro et al 2004].

• If pedigree analysis reveals that the proband is the only affected family member, several possibilities regarding his mother's carrier status and carrier risks of extended family members need to be considered. One of the following genetic mechanisms [van Essen et al 1997] is responsible:

  • The proband has a de novo DMD disease-causing mutation as a result of one of the following:

    • The mutation occurred in the egg at the time of the proband's conception and is therefore present in every cell of the proband's body. In this instance, the proband's mother does not have a DMD disease-causing mutation and no other family member is at risk.

    • The mutation occurred after conception and is thus present in some but not all cells of the proband's body (somatic mosaicism). In this instance, the likelihood that the mother is a heterozygote is low.

  • The proband's mother has a de novo DMD disease-causing mutation. Approximately two-thirds of mothers of males with DMD and no family history of DMD are carriers. The mechanisms by which a de novo DMD disease-causing mutation could have occurred in the mother are the following:

    • The mutation occurred in the egg or sperm at the time of her conception (germline mutation) and is thus present in every cell of her body and detectable in DNA extracted from leukocytes.

    • The mutation is present in some but not all cells of her body (somatic mosaicism) and may or may not be detectable in DNA extracted from leukocytes.

    • The mutation is present in her egg cells only (termed "germline mosaicism") and is not detectable in DNA extracted from a blood sample. The likelihood of germline mosaicism in this instance is 15%-20%. Consequently, each of her offspring has an increased risk of inheriting the DMD disease-causing mutation [van Essen et al 1992, van Essen et al 2003].

  • The proband's mother has inherited a DMD mutation from one of the following:

    • Her mother, who is a carrier

    • Her mother or her father, who has somatic mosaicism

    • Her mother or her father, who has germline mosaicism

• Molecular genetic testing combined with linkage analysis can often determine the point of origin of a de novo mutation. This information is important for determining which branches of the family are at risk for the dystrophinopathies.

Sibs of a proband

• The risk to sibs of a proband depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.

• If the mother does not have a DMD mutation detectable in her DNA, it is possible that the proband has a de novo gene mutation. However, because the incidence of germline mosaicism in mothers is 15%-20%, the sibs of a proband are at increased risk of inheriting a DMD mutation.

• If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting a DMD mutation may be higher than if the mother has germline mosaicism only [van Essen et al 2003].

Offspring of a proband

• Males with DMD usually die before reproductive age or are too debilitated to reproduce.

• Males with BMD and DMD-associated DCM may reproduce. All the daughters are carriers. None of the sons will inherit their father's DMD mutation.

Other family members of the proband. The proband's maternal aunts and their offspring may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Carrier Detection

Carrier testing is clinically available for at-risk females. See Molecular genetic testing, Carrier testing.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Females who are identified as carriers of a DMD disease-causing mutation need to be informed of their risk for DCM, as well as the recommended surveillance.

BMD and DMD-associated DCM are sometimes observed in the same family [Palmucci et al 2000]. Thus, the entire spectrum of possible muscle disease should be considered when obtaining a family history and providing genetic counseling.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking. DNA banking is the storage of DNA (typically extracted from leukocytes) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers if the DMD mutation has been identified in a family member or if linkage has been established. The usual procedure is to determine fetal sex by karyotype or specialized studies to identify the sex chromosomes from cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15-18 weeks' gestation. If the karyotype is 46,XY, DNA extracted from fetal cells can be analyzed for the known disease-causing mutation or using the linkage previously established.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Revision History

• 21 March 2008 (me) Comprehensive update posted to live Web site

• 25 August 2005 (me) Comprehensive update posted to live Web site

• 1 October 2004 (cd) Revision

• 3 August 2004 (cd) Revision: Management

• 24 March 2004 (cd) Revision: Diagnosis

• 23 June 2003 (me) Comprehensive update posted to live Web site

• 5 September 2000 (me) Review posted to live Web site

• December 1999 (bk) Original submission