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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Dystrophinopathies

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

, MD, , MD, PhD, FACMG, and , MD.

Author Information
, MD
Director, Neuromuscular Program
Department of Neurology
Children's Hospital Boston
Harvard Medical School
Boston, Massachusetts
, MD, PhD, FACMG
Division of Genetics and Department of Laboratory Medicine
Children’s Hospital Boston, Harvard Medical School
Boston, Massachusetts
, MD
Department of Neurology
Children's Hospital Boston
Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: November 23, 2011.

Summary

Disease characteristics. The dystrophinopathies include a spectrum of muscle disease caused by mutations in DMD, which encodes the protein dystrophin. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria and isolated quadriceps myopathy. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected.

Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed milestones, including delays in sitting and standing independently. Proximal weakness causes a waddling gait and difficulty climbing. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and cardiomyopathy being common causes of death.

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 DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD mutation are at increased risk for DCM.

Diagnosis/testing. DMD is the only gene in which mutations cause the dystrophinopathies. Molecular genetic testing of DMD can establish the diagnosis of a dystrophinopathy without muscle biopsy in most individuals with DMD and BMD. Virtually all males with DMD/BMD have identifiable DMD mutations. The number of individuals with DMD-associated DCM and identifiable DMD mutations is unknown. In the remaining cases, a combination of clinical findings, family history, serum CK concentration, and muscle biopsy with dystrophin studies confirms the diagnosis.

Management. Treatment of manifestations: Aggressive management of DCM with anti-congestive medications in all persons and cardiac transplantation in severe cases; prednisone to improve the strength and motor function in children with DMD unless side effects are severe; deflazacort, a synthetic derivative of prednisolone used in Europe, may have fewer side effects than prednisone; physical therapy to promote mobility and prevent contractures.

Prevention of secondary complications: Evaluation by a pulmonologist and cardiologist before surgeries; pneumococcal and influenza immunizations annually; sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures; weight control to avoid obesity.

Surveillance: For males with DMD or BMD: annual or biannual evaluation by a cardiologist beginning around age ten years; monitoring for scoliosis; baseline pulmonary function testing before wheelchair dependence; frequent evaluations by a pediatric pulmonologist. For heterozygous females: cardiac evaluation at least once after the teenage years.

Agents/circumstances to avoid: Botulinum toxin injections.

Evaluation of relatives at risk: Early identification of heterozygous females who are at increased risk for cardiomyopathy and, thus, need routine cardiac surveillance and prompt treatment.

Genetic counseling. The dystrophinopathies are inherited in an X-linked manner. The risk to the sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the DMD mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers and may or may not develop cardiomyopathy. Males with DMD do not reproduce. Males with BMD or DMD-associated DCM may reproduce: all of their daughters are carriers; none of their sons inherit their father's DMD mutation. Carrier testing for at-risk females and prenatal testing for pregnancies at increased risk are possible if the DMD disease-causing mutation in the family is known or if informative linked markers have been identified.

Diagnosis

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 symmetric 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 symmetric 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–dependent 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)

Table 1. Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies

Phenotype% of Affected Individuals Serum CK Concentration
Males DMD 100% 1 >10X normal
BMD 100% 1 >5X normal
DMD-associated DCM Most individuals 2 "Increased"
Female Carriers DMD ~50% 3,4 2-10X normal
BMD ~30% 3,4 2-10X normal

1. Serum CK concentration gradually decreases with advancing age as a result of the progressive elimination of dystrophic muscle fibers that are the source of the elevated serum CK concentration [Hoffman et al 1988, Zatz et al 1991].

2. Serum CK concentrations are usually increased, but normal concentrations have been reported in DMD-associated DCM [Mestroni et al 1999].

3. Hoogerwaard et al [1999b]

4. Other investigations have confirmed a wide variability in serum CK concentration among DMD/BMD carriers with the mean serum CK concentration significantly increased in carriers younger than age 20 years compared with those older than age 20 years [Sumita et al 1998].

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

  • 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.

Table 2. Findings in the Dystrophin Protein from Skeletal Muscle Biopsy

Phenotype Western Blot Immunohistochemistry 1
Dystrophin Molecular Weight 2 Dystrophin Quantity 3
Males DMD Nondetectable 0%-5% Complete / almost complete absence
Intermediate Normal / abnormal 5%-20%
BMD Normal
Abnormal
20%-50%
20%-100%
Normal appearing or reduced intensity ± patchy staining
Female CarriersDMD random XCI 4 Normal / abnormal >60% 5 (70%±9%) [Pegoraro et al 1995] Normal or minor changes or mosaic pattern
Dystrophin-negative fibers (9%±2%) [Pegoraro et al 1995]
DMD skewed XCI 6Normal / abnormal <30% on average (29%±25%) [Pegoraro et al 1995]Mosaic pattern
Dystrophin-negative fibers (44%±33%) [Pegoraro et al 1995]

1. Uses monoclonal antibodies to the C terminus, N terminus, and rod domain of dystrophin [Hoffman et al 1988]

2. Normal molecular mass is 427 kb.

3. The quantity of dystrophin is expressed in percent of control values. The reference ranges shown in this table are the ones currently used by clinical laboratories and reflect approximate and reconciled data from the literature.

4. Asymptomatic to mild disability, XCI = X-chromosome inactivation

5. Quantitative analysis of dystrophin in female carriers is not useful in clinical practice because of the wide range of values and the significant overlap with normal values.

6. Mild, intermediate, severe symptoms. Carriers with mild disease were young (age 5-10 years) [Pegoraro et al 1995].

Molecular Genetic Testing

Gene. DMD is the only gene in which mutations are known to cause DMD, BMD, and DMD-associated DCM.

The frequencies for types of mutations given in this section are for individuals with DMD or BMD. Data are insufficient to estimate the percentage of individuals with DMD-associated dilated cardiomyopathy with detectable DMD mutations.

Deletions of one or more exons account for approximately 60%-70% of mutations in individuals with DMD and BMD [Yan et al 2004, Dent et al 2005, Prior & Bridgeman 2005, Takeshima et al 2010].

Duplications may lead to in-frame or out-of-frame transcripts and account for the disease-causing mutations in approximately 5%-10% of males with DMD and BMD [White et al 2002, White et al 2006, Flanigan et al 2009, Takeshima et al 2010]. Duplications may be slightly more common in BMD: one small series found duplications in 14/75 (19%) males with BMD [Kesari et al 2008]; however, most studies, including those using newer techniques such as MLPA, have not found rates higher than 10% in BMD [Takeshima et al 2010].

White et al [2006] detected duplications in 87% of individuals who did not have a mutation identified by methods to detect a deletion or a point mutation.

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 [Bennett et al 2001, Mendell et al 2001, Dolinsky et al 2002, Flanigan et al 2003, Hofstra et al 2004, Takeshima et al 2010].

  • Nonsense mutations occur more commonly in DMD – in the range of 20%-25% of cases – as compared to fewer than 5% in BMD [Flanigan et al 2009, Takeshima et al 2010].
  • Splice site mutations and small insertion/deletion mutations (indels) are a substantial proportion of sequence changes in both DMD and BMD.
  • Missense mutations are not a common cause of either Duchenne or Becker dystrophy.

Evidence for locus heterogeneity. Although the rate of individuals with a dystrophinopathy for whom no molecular diagnosis can be established may appear slightly higher in BMD than in DMD, this is likely attributable to inclusion of phenotypes similar to the dystrophinopathies that are not caused by mutations in DMD [Kesari et al 2008]. (See Differential Diagnosis.)

Clinical testing

Deletion/duplication analysis can detect either deletions or duplications of DMD in probands and carrier females:

  • Multiplex ligation probe amplification (MLPA) [Gatta et al 2005]
  • Array genomic hybridization (aGH) (also called chromosome microarray (CMA) [Bovolenta et al 2008, del Gaudio et al 2008, Hegde et al 2008]

    Note: (1) This technology offers an advantage over MLPA because it can detect intronic rearrangements. (2) Up to 7% of persons with a dystrophinopathy do not have coding region mutations [Dent et al 2005]; the fraction of these that have intronic rearrangements of clinical significance is unknown. (3) This type of array does not detect intronic point mutations.
  • Note: MLPA and aGH have largely supplanted the following methods used in the past to detect deletions or duplications:

Sequence analysis or mutation scanning detects point mutations (i.e., small deletions or insertions, single-base changes, and splicing mutations):

  • Sequencing of the entire DMD gene can be performed by traditional PCR and Sanger sequencing, or by more automated methods such as universal long PCR combined with massive pyrosequencing [Bonnal et al 2010]. Sequencing of the entire gene is often necessary to detect rare or private mutations.
  • Mutation scanning methods such as denaturing high performance liquid chromatography (dHPLC) or newer methods such as single-condition amplification internal primer sequencing (SCAIP) [Flanigan et al 2003, Flanigan et al 2009] and high-resolution melting curve analysis [Almomani et al 2009] can detect single-base changes at reasonable cost, especially compared to the previously high costs of sequencing.

    Note: Because the costs of direct sequencing have decreased, only a few clinical laboratories perform mutation scanning for individuals in whom a deletion or duplication has not been identified.

Table 3. Summary of Molecular Genetic Testing Used in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

Gene SymbolTest MethodMutations DetectedMutation Detection Rate by Test Method 1
DMDBMD
Affected MalesHeterozygous Females 2Affected MalesHeterozygous Females 2
DMDDeletion / duplication analysis 3Deletion of one or more exons or the whole gene ~50%-65%~50%-65%~65%-70%Unknown
Duplication of one or more exons ~5%-10%~5%-10%~10%-20%Unknown
Sequence analysis / mutation scanning 4Sequence variants 5~20%-35% 6
(Note:~90%-95%) 7
~25%-35% 8~10%-20% 6
(Note:~90%-95%) 7
Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. The mutation spectrum for females heterozygous for a DMD mutation resulting in BMD has not been well documented, but is presumed to be similar to the spectrum for males with BMD. Similarly, there are fewer data about females heterozygous for a DMD mutation resulting in DMD, but it is also presumed to be similar to that seen in males with DMD.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

6. Assuming that all deletions can be detected by lack of amplification (see footnote 7), the theoretic mutation detection frequency using sequence analysis is the sum of the mutation detection frequencies of both methods. Estimate for sequence changes includes small insertion/deletion (indel) mutations.

7. Lack of amplification by PCR prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

8. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

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

Testing Strategy

To establish the diagnosis in a proband with DMD or BMD. For males with clinical findings suggesting a dystrophinopathy and an elevated serum CK concentration:

Reading frame rule. This “rule” states that mutations that do not alter the reading frame (in-frame deletions/duplications) generally correlate with the milder BMD phenotype, whereas those that alter the reading frame (out-of-frame) generally correlate with the more serve DMD phenotype [Monaco et al 1988]. Therefore, the type of deletion/duplication mutation can distinguish between the DMD and BMD phenotypes with 91%-92% accuracy in young children who represent simplex cases (i.e., a single occurrence in a family) [Aartsma-Rus et al 2006b]. (See Genotype-Phenotype Correlations for more information.) Thus, in many cases, a muscle biopsy is not needed to address the issue of BMD vs DMD.

To establish the diagnosis in a boy with DMD and one or more other X-linked disorders. The other X-linked disorders in these contiguous gene deletions can include 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]. The diagnosis of a contiguous gene deletion can be confirmed by chromosome microarray (CMA) studies to look for deletions involving Xp21.2 or FISH analysis with probes (covering GK and NR0B1 in addition to exons in DMD) to look for rearrangements involving Xp21.2.

To establish the diagnosis in a girl with classic DMD. The genetic mechanisms that can explain this rare occurrence (and testing to identify the cause) include:

Carrier testing for at-risk female relatives. Note: Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder (see Clinical Description and Management, Evaluation of Relatives at Risk).

  • When the proband's DMD mutation is known
  • If an affected male is not available for testing, perform molecular genetic testing of the at-risk female:
  • When the proband's DMD mutation is not known and no DMD mutation is identified a carrier female. 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.
    • Because the markers used for linkage in DMD/BMD/DMD-associated DCM are highly informative and lie both within and flanking the DMD locus, they can be used in most families with DMD/BMD/DMD-associated DCM [Kim et al 2002].

      Note: The large size of DMD 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. Testing by linkage analysis is not possible for families in which there is a single affected male.

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 for genetic counseling purposes 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].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) 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.

Clinical Description

Natural History

Males

The dystrophinopathies cover a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of CK, muscle cramps with myoglobinuria, and isolated quadriceps myopathy. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected [Beggs 1997, Cox & Kunkel 1997, Muntoni et al 2003].

The distinction between DMD and BMD is based on the age of wheelchair dependency: before age 13 years in DMD and after age 16 years in BMD. An intermediate group of individuals who become wheelchair bound between ages 13 and 16 years is also recognized. Additionally, some investigators have extended the mild end of the BMD spectrum to include individuals with elevated serum CK concentration and abnormal dystrophin on muscle biopsy, but with "subclinical" skeletal muscle involvement [Melacini et al 1996]. When these individuals with atypical disease develop severe cardiomyopathy, it is not possible to distinguish between BMD and DMD-associated DCM [Cox & Kunkel 1997].

Cardiac involvement is usually asymptomatic in the early stages of the disease, although sinus tachycardia and various ECG abnormalities may be noted. Echocardiography is normal or shows only regional abnormalities.

Subclinical or clinical cardiac involvement is present in approximately 90% of individuals with DMD/BMD; however, cardiac involvement is the cause of death in only 20% of individuals with DMD and 50% of those with BMD [Hermans et al 2010]. DCM generally presents with congestive heart failure secondary to an increase in ventricular size and impairment of ventricular function. In males, DCM is rapidly progressive with onset in teenage years, leading to death from heart failure within one to two years after the diagnosis [Finsterer & Stollberger 2003]. Pericardial effusion with cardiac tamponade and myocardial inflammation precipitating heart failure has been described in people with DMD [Lin et al 2009, Mavrogeni et al 2010]. Individuals with DCM may or may not have clinical evidence of skeletal muscle disease [Neri et al 2007].

DMD usually presents in early childhood with delayed milestones, including delays in sitting and standing independently. The mean age of walking is approximately 18 months (range 12-24 months). The first symptoms of DMD as identified by parents are typically: general motor delays (42%); gait problems, including persistent toe-walking and flat-footedness (30%); delay in walking (20%); learning difficulties (5%); and speech problems (3%). The mean age of diagnosis of boys with DMD without a family history of DMD is approximately four years ten months (range: 16 months - 8 years) [Bushby 1999, Zalaudek et al 1999]. Proximal weakness causes a waddling gait and difficulty climbing. Boys use the Gower maneuver to rise from a supine position, using the arms to supplement weak pelvic girdle muscles. The calf muscles are hypertrophic and firm to palpation. Occasionally there is calf pain. DMD is rapidly progressive, with affected children being wheelchair bound by age 12 years.

Among children with DMD, the incidence of cardiomyopathy increases steadily in the teenage years, with approximately one-third of individuals being affected by age 14 years, one-half by age 18 years, and all individuals after age 18 years [Nigro et al 1990].

Some degree of non-progressive cognitive impairment in boys with DMD has long been known. This was initially described as a general leftward shift in the spectrum of IQ scores in the population with DMD. Earlier reports suggested that verbal IQ was more affected than performance IQ on instruments such as the Wechsler Intelligence Scales.

Hinton et al [2001] demonstrated that the verbal difficulties seen in boys with DMD were mostly the result of troubles with short-term verbal memory. Wicksell et al [2004] noted particular deficits in memory (especially active working memory) and executive function and observed that these deficits in memory occurred in visuospatial as well as verbal-auditory settings. This suggested that the verbal-performance discrepancy observed by Hinton et al [2001] was an artifact of the larger impact of active working memory on the verbal tests of the instruments used in earlier studies.

Cyrulnik et al [2008] later demonstrated that younger boys with DMD had more generalized deficits in cognition and adaptive functioning using standard instruments. This is likely explained by the motor impairments seen in young boys with DMD “masking” the memory deficits because of the more global influence of motor deficits on the performance of younger children as measured by standardized instruments.

Thus, a specific cognitive profile of boys with DMD has emerged, demonstrating deficits in working memory and executive function which take some time to emerge. These deficits in executive function are often confused with attention deficit /hyperactivity disorder (ADHD), particularly if questionnaires or other historic means of evaluation are the only investigations used. To distinguish between ADHD and more broadly defined executive function disorders, neuropsychologic investigation is warranted.

DMD has also been associated with autism spectrum disorders in a rate greater than expected by chance alone [Wu et al 2005, Hendriksen & Vles 2008].

DMD is associated with reduced mobility. Thus, boys with DMD have decreased bone density and an increased risk of fractures. Corticosteroids further increase the risk of vertebral compression fractures, many of which are asymptomatic.

Few affected individuals survive beyond the third decade. Respiratory complications and cardiomyopathy are common causes of death. Because death frequently occurs outside the hospital setting, the cause of death is often difficult to determine [Parker et al 2005].

BMD is characterized by later-onset skeletal muscle weakness; individuals remain ambulatory into their 20s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death [Cox & Kunkel 1997]. Mean age at cardiomyopathy diagnosis is 14.6 years, similar to that in DMD (14.4 years) [Connuck et al 2008]. Heart transplantation rate in BMD is high within five years after the diagnosis of cardiomyopathy [Connuck et al 2008]. Mean age of death is in the mid-40s [Bushby 1999]. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s [Yazaki et al 1999].

Mildly affected individuals with confirmatory DMD molecular genetic studies and/or dystrophin studies on muscle biopsy have been classified as having either of the following [Melacini et al 1996]:

  • BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria; OR
  • "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle

Cognitive impairment is not as common or as severe as in DMD.

DMD-associated DCM. In 1987, a five-generation, 63-member family with DCM but no evidence of skeletal myopathy was reported. Males present in their teens and twenties; the disease course is rapidly progressive and associated ventricular arrhythmias are common. Female carriers develop mild dilated cardiomyopathy in the fourth or fifth decade, with slow progression. The only biochemical abnormality is elevation in serum CK concentration. Towbin et al [1993] demonstrated linkage to the dystrophin locus in this family and one other.

Subsequent study demonstrated that in individuals with the most severe cardiac phenotype the cardiac muscle is usually unable to produce functional dystrophin in the heart, while in skeletal muscle reduced levels of virtually normal dystrophin transcript and protein are present [Ferlini et al 1999, Neri et al 2007]; see Molecular Genetics.

DMD-associated DCM may be the presenting finding in individuals with BMD who have little or no clinical evidence of skeletal muscle disease. Some investigators classify such individuals as having subclinical or benign BMD, whereas others may classify such individuals having DCM with increased serum CK concentration [Towbin 1998]. In one study of 28 individuals with subclinical and benign BMD between ages six and 48 years, 19 (68%) had myocardial involvement, although only two were symptomatic [Melacini et al 1996]. In another study of 21 individuals ranging from age three to 63 years (mean age 40 years), 33% had cardiac failure despite relatively mild skeletal muscle findings [Saito et al 1996].

Females

In some instances girls can have classic DMD. See Testing Strategy.

Signs and symptoms of DMD and BMD were studied among confirmed heterozygous females [Hoogerwaard et al 1999a, Hoogerwaard et al 1999b] (Table 4). In contrast, Nolan et al [2003] found no cardiac abnormalities in 23 proven carriers age 6.2 to 15.9 years. (See Penetrance.)

Table 4. Signs and Symptoms in Females Heterozygous for a DMD Mutation

Signs/Symptoms In Families with DMD In Families with BMD
None 76% 81%
Muscle weakness 1 19% 14%
Myalgia/cramps 5% 5%
Left ventricle dilation19% 16%
Dilated cardiomyopathy8% 0

From Hoogerwaard et al [1999b]

1. Mild to moderate weakness

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 when 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]. More recent studies suggest that duplications, which occur more commonly in BMD, may result in exceptions to the reading frame rule in a higher proportion of cases, perhaps up to 30% [Kesari et al 2008, Takeshima et al 2010]. Correlation of clinical features with molecular test results is thus very important.

    Wingeier et al [2011] showed that there was no clear relationship between mutations seen in males with DMD and specific aspects of cognitive function, or overall performance on standard measures of cognitive abilities. They did note, however, that the lack of the dystrophin isoform Dp140 was associated with greater impairments overall; this observation confirms the findings of a previous study that suggested that dystrophin deletions involving the brain distal isoform Dp140 are associated with intellectual impairment [Felisari et al 2000]. Mild intellectual disability is significantly more common in males with mutations affecting Dp140; also, most males with mutations involving the Dp71 isoform are cognitively disabled [Daoud et al 2009, Taylor et al 2010].

    Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the mutation seems to correlate with full-scale IQ (FSIQ) values (e.g., mutations affecting the Dp140 isoform 5’ UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [Taylor et al 2010]. Further, the cumulative loss of isoforms expressed in the central nervous system increases the risk of cognitive deficit [Taylor et al 2010].
  • 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].

    Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [Takeshima et al 2010]. Another study also reported exceptions to the reading frame rule in 30% of males with BMD with a duplication [Kesari et al 2008]. Correlation of clinical features with molecular test results is crucial; affected males and their families should be informed that using this rule, phenotype prediction may be less accurate.

    In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [Kaspar et al 2009].

DMD-associated DCM is caused by mutations in DMD that affect the muscle promoter (PM) 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 (PB) and Purkinje cells (PP) 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 hypothetic 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, and may depend in part on patterns of X-chromosome inactivation.

  • Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in X-chromosome inactivation (XCI) studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [Sumita et al 1998].
  • In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with nonsense mutations [Soltanzadeh et al 2010].
  • In contrast, Pegoraro et al [1995] showed that more than 90% of heterozygous females with skewed XCI (defined as ≥75% of nuclei harboring the DMD mutation on the active X-chromosome) as demonstrated from a blood sample develop mild, moderate, or severe muscular dystrophy. Heterozygous females with a mild phenotype were young (i.e., age 5-10 years).

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

Prevalence data are not available.

The overall incidence of DMD in Canada (Nova Scotia) is one in 4,700 live male births and has remained stable from 1969 to 2008 [Dooley et al 2010a].

The incidence of BMD is one in 18,450 live male births in northern England [Bushby et al 1991].

During the years 1968 to 1978, the incidence of DMD in southeast Norway was one in 3,917 live male births [Tangsrud & Halvorsen 1989].

Differential Diagnosis

Limb-girdle muscular dystrophy (LGMD) is a group of disorders that are clinically similar to DMD but occur in both sexes as a result of autosomal recessive and autosomal dominant inheritance. Limb-girdle dystrophies are caused by mutations in genes that encode sarcoglycans and other proteins associated with the muscle cell membrane which interact with dystrophin [Bushby 1999]. Testing for deficiency of proteins from the transmembrane sarcoglycan complex and of other proteins is indicated in individuals with dystrophin-positive dystrophies. LGMD type 2I phenotypically resembles DMD/BMD and is caused by mutations in FKRP, the gene encoding fukutin-related protein [Schwartz et al 2005].

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may include palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of the muscle and cardiac involvement show intra- and interfamilial variation. Clinical variability ranges from early and severe presentation in childhood to a late onset and slowly progressive course. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade. The three genes in which mutation is most commonly associated with EDMD are EMD, encoding emerin (X-linked EDMD), LMNA, encoding lamins A and C, and FHL1 (autosomal dominant EDMD and autosomal recessive EDMD).

Spinal muscular atrophy (SMA) is suspected in individuals with poor muscle tone, symmetric muscle weakness that spares the face and ocular muscles, and evidence of anterior horn cell involvement, including fasciculations of the tongue and absence of deep tendon reflexes. SMA is caused by mutations in SMN. Inheritance is autosomal recessive.

Dilated cardiomyopathy (DCM) can be familial or nonfamilial. In a large series in which family studies were performed, one third of individuals had nonfamilial DCM and two thirds had familial DCM. Subtypes of familial DCM included autosomal dominant (56%), autosomal recessive (16%), X-linked with DMD mutation (10%), autosomal dominant with subclinical muscle disease (7.7%), DCM with conduction defects (2.6%), and unclassified (7.7%) [Mestroni et al 1999, Watkins et al 2011].

The spectrum of X-linked infantile DCM (TAZ-related DCM), caused by mutations in TAZ, includes Barth syndrome, X-linked endocardial fibroelastosis, left ventricular non-compaction, and severe X-linked DCM [D'Adamo et al 1997, Yen et al 2008].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [Towbin 2003, Bushby et al 2010b]

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; click Image guidelines.jpg for full text].

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 had 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 and reduced mortality [Colan 2005, Duboc et al 2007]. Further studies are needed to create evidence-based recommendations for the prevention and treatment of cardiomyopathy in men with DMD/BMD.

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.

Scoliosis treatment as needed is appropriate.

Corticosteroid Therapy

Studies have shown that corticosteroids improve the strength and function of individuals with DMD.

Prednisone. It is hypothesized that prednisone has a stabilizing effect on membranes and perhaps an anti-inflammatory 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].
  • In two successive six-month trials of prednisone therapy, improvement began within ten days of starting the treatment, required a single dose of 0.75 mg/kg/day of prednisone for maximal improvement, reached a plateau after three months, and was 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) (in 40%), hypertension, behavioral changes, growth retardation, cushingoid appearance (in 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]. However, a subsequent study proved the effectiveness of lower doses of prednisolone (0.35 mg/kg/day) in both DMD and BMD. One of the authors noted sustained effectiveness with doses initiated at 0.75 mg/kg/day (maximum daily dose: 40 mg) and gradually reduced (usually because of advancing age and weight gain) to as low as 0.3 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 or 20 days “off”) are also used.

  • A 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, Manzur et al 2008] and also by the 124th European Neuromuscular Centre workshop on the treatment of DMD [Bushby et al 2004].
  • High-dose weekly prednisone, 5 mg/kg, given each Friday and Saturday can be considered as an alternative to daily treatment in males on a daily regimen with excessive weight gain and behavioral issues [Bushby et al 2010a].

Whether the improvement seen in individuals with DMD treated with prednisone is the result of an immunosuppressive effect remains unclear, as individuals treated with azathioprine did not have a beneficial effect.

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 improved strength and motor function more than placebo; whether it has a benefit over prednisone on similar outcomes remains unclear [Campbell & Jacob 2003]. Despite the lack of conclusive evidence for superiority of deflazacort over prednisone in the area of effectiveness [Moxley et al 2005], some experts believe that the more favorable side-effect profile (particularly with regard to weight gain) associated with deflazacort makes it a better choice than daily treatment with prednisone.

Initiation and length of treatment. Data regarding the optimal age to begin treatment with corticosteroids or the optimal duration of such treatment are insufficient. 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]; however, large-scale controlled trials to study the efficacy and safety of corticosteroid therapy in early DMD have yet to be conducted. Thus, at this point corticosteroid therapy remains the treatment of choice for affected individuals between ages five and 15 years. Corticosteroid therapy is not recommended in children under age two years [Bushby et al 2010a].

Published guidelines. The following recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [Moxley et al 2005; click Image guidelines.jpg for full text].

  • Boys with DMD who are older than age five years should be offered treatment with prednisone (0.75/mg/kg/day, maximum daily dose: 40 mg) as soon as plateauing or decline in motor skills is noted. 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 also 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, maximum daily dose: 36-39 mg) can also be used to treat DMD. Side effects of asymptomatic cataracts and weight gain should be monitored.

BMD. Information about the efficacy of prednisone in treating individuals with BMD is limited. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [King et al 2007]. Men on steroid therapy were less likely to require spinal surgery [Dooley et al 2010b].

Prevention of Secondary Complications

Cardiorespiratory

  • Evaluation by pulmonary and cardiac specialists before surgeries [Finder et al 2004]
  • Administration of pneumococcal vaccine and influenza vaccination annually [Finder et al 2004]

Nutritional. Assessment if:

  • Planning to commence steroids [Davidson & Truby 2009]
  • Dysphagia is present
  • Patient is chronically constipated
  • Major surgery has been planned
  • Patient is malnourished

Muscular

  • Physical therapy to promote mobility and prevent contractures
  • Exercise
    • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy
    • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe
    • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis.

Bone health

Assessments [Bushby et al 2010b, Darras 2011]:

  • Blood
    • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase
    • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually
    • Magnesium and parathyroid hormone levels may be considered
  • Urine (calcium, sodium, creatinine)
  • Dual energy x-ray absorptiometry (DEXA) scanning
    • At baseline (age ≥3 years) or at start of corticosteroid therapy
    • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DEXA Z score <-2
  • Spine radiograph
    • If back pain is present
    • To exclude vertebral compression fracture
    • To assess degree of kyphoscoliosis if present on physical examination
  • Bone age if growth failure occurs (height for age < 5th percentile or if linear growth is faltering) in persons on or off corticosteroids

Interventions:

  • Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician.
  • 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] and should be considered in all children if levels cannot be maintained [Bushby et al 2010b]. Supplementation should be carried out in consultation with an endocrinologist.
  • Intravenous bisphosphonates; recommended in persons with vertebral fracture(s), but a bone health expert should be consulted.
  • Use of oral biphosphonates for prophylaxis or treatment remains controversial.

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; click Image guidelines.jpg for full text] and consensus guidelines published in 2010 [Bushby et al 2010b; click Image guidelines.jpg for full text (registration or institutional access required)] include the following:

  • For people with DMD, complete cardiac evaluation at least every two years, beginning at the time of diagnosis or by the age of six until the age of ten years or at the onset of cardiac symptoms if they occur earlier
  • Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI.
  • For people with DMD, at approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation

    Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course.
  • If DMD patient’s evaluation reveals ventricular dysfunction, the 2010 consensus guidelines recommend initiation of pharmacologic therapy and surveillance at least every 6 months
  • 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 of female carriers for 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 of the following [Finder et al 2004]:
    • Confinement to a wheelchair
    • Reduction in vital capacity below 80% predicted
    • Age 12 years

The 2010 consensus guidelines [Bushby et al 2010b; click Image guidelines.jpg for full text (registration or institutional access required)] make detailed recommendations regarding pulmonary care, including:

  • Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device;
  • Manual and mechanically assisted cough techniques;
  • Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy.

Orthopedic

  • Monitoring for orthopedic complications, especially contractures and scoliosis in those with DMD and BMD
  • Evaluation for surgical interventions as needed

Agents/Circumstances to Avoid

Individuals with DMD/BMD should avoid botulinum toxin injections.

Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with DMD or BMD because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions (rhabdomyolysis, cardiac complications, hyperkalemia), it should be noted that an extensive literature search did not find an increased risk of malignant hyperthermia susceptibility in people with DMD or BMD when compared with the general population [Gurnaney et al 2009].

Evaluation of Relatives at Risk

Heterozygous females need to be identified for the purpose of cardiac surveillance (see Surveillance). Therefore, genetic counseling and molecular genetic testing (if the family-specific mutation is known) should be offered to females who are the sisters or maternal female relatives of an affected male and to females who are a first-degree relative of a known or possible carrier female.

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 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; however, it is applicable only for 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 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 [Kimura et al 2005].
  • In a clinical study of 12 people with DMD whose mutations resulted in premature stop codons, no statistically significant benefit on clinical outcome measures of efficacy was shown after weekly or biweekly gentamicin infusions for six months [Malik et al 2010].

Ataluren (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].
  • In a phase IIb, multicenter, double-blind, placebo-controlled trial, 174 ambulatory males with DMD/BMD were given placebo or low- or high-dose ataluren for 48 weeks. The high-dose ataluren and placebo groups failed to show statistically significant change in the six-minute walk distance [Finkel et al 2010]. Patients treated with low-dose ataluren (10-10-20 mg/kg/day) had an approximately 29-meter change in the six-minute walk distance, close to the 30-meter change deemed clinically significant and higher than that for the placebo group.

Additional studies are in progress but the clinical efficacy of ataluren for the treatment of DMD and BMD remains unproven at this time.

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, Wilton & Fletcher 2010].

  • In preliminary human studies, the intramuscular injection of antisense oligonucleotides that bind to exon 51 and induce its skipping during messenger RNA splicing proved to be safe and led to local dystrophin synthesis within the injected muscles [van Deutekom et al 2007, Kinali et al 2009].
  • Systemic weekly subcutaneous administration of an oligonucleotide targeting exon 51 (PRO051) induced dystrophin expression in ten of 12 patients with DMD. Furthermore, a 12-week extension study showed improvement in the six-minute walk test in eight of 12 patients [Goemans et al 2011].

Additional exon skipping studies are in progress.

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 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] and Gregorevic et al [2006] 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), which led to preservation of muscle function and extension of life span.

Despite progress in the field, cellular immunity issues may be an obstacle to successful dystrophin gene therapy for DMD. One study showed evidence of dystrophin-specific T cells in four of six treated patients, with two of them harboring immunity to dystrophin even before vector treatment [Mendell et al 2010]. It is plausible that truncated dystrophin protein from revertant dystrophin fibers primes the cellular immune system [Arechavala-Gomeza et al 2010, Moore & Flotte 2010].

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]. Isolation and transplantation of muscle satellite cells yielded promising results in mouse experiments [Blau 2008, Cerletti et al 2008]. Mesenchymal stem cell therapy also seems promising for muscle regeneration in DMD [Markert et al 2009].

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 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. In another controlled study, no statistically significant benefit over placebo was found in 50 boys randomized to receive either creatine 5 g/day, glutamine 0.6 g/kg per day, or placebo [Escolar et al 2005]. The primary outcome measure was the modified manual muscle testing score. Given the lack of significant benefit, treatment with creatine monohydrate cannot be recommended routinely for treatment of DMD. It should be noted that creatine was well tolerated in these studies with no evidence of renal dysfunction; despite that, good hydration is recommended in patients taking creatine.

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 (trichostatin A, valproic acid, phenylbutyrate) have improved the mdx mouse by inducing the expression of the myostatin inhibitor follistatin [Minetti et al 2006]. Human trials are needed to determine the efficacy of these agents.

Myostatin inhibitors or blockers result in increased muscle mass and strength, decreased serum creatine kinase concentration, and improved muscle histology in the mdx mouse [Bogdanovich et al 2002]. However, a phase I/II trial of MYO-029, an antibody against myostatin, in adults with muscular dystrophy failed to show any improvements in muscle strength or function [Wagner et al 2008]. The study was not powered to look for efficacy. Additional studies are in progress.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The dystrophinopathies are inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

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 the family-specific DMD mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers.
  • If the mother does not have the family-specific DMD mutation detectable in her DNA, it is possible that the proband has a de novo mutation. However, because the incidence of germline mosaicism in mothers is 15%-20%, the sibs of a proband are at increased risk of inheriting the family-specific DMD mutation.
  • If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific 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. If they were to reproduce, all male offspring would be unaffected and all female offspring would be carriers.
  • Males with BMD and DMD-associated DCM may reproduce. All of the daughters will be carriers. None of the sons will inherit their father's DMD mutation.

Other family members of the proband. The proband's maternal grandmother, 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 possible for at-risk females. See Testing Strategy.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Females who are identified as carriers of a DMD 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 the 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) 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.

Prenatal Testing

Molecular genetic 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 to 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.

Fetal muscle biopsy. In utero fetal muscle biopsy has been used in the prenatal diagnosis of DMD in families with DMD in which the causative DMD mutation is not known or in which genetic linkage has not been established [Ladwig et al 2002].

The history of molecular diagnostic testing in DMD and the impact of new techniques including chromosome microarray (CMA) analysis and noninvasive prenatal diagnosis methods are reviewed in detail by Raymond et al [2010].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Parent Project Muscular Dystrophy
    158 Linwood Plaza
    Suite 220
    Fort Lee NJ 07024
    Phone: 800-714-5437 (toll-free); 201-944-9985
    Fax: 201-944-9987
    Email: info@parentprojectmd.org
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Medline Plus
  • Muscular Dystrophy Association - Canada
    2345 Yonge Street
    Suite 900
    Toronto Ontario M4P 2E5
    Canada
    Phone: 866-687-2538 (toll-free); 416-488-0030
    Fax: 416-488-7523
    Email: info@muscle.ca
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • DuchenneConnect Patient Registry
    DuchenneConnect has been created to serve as a central hub linking the resources and needs of the Duchenne/Becker MD community. One goal of their Registry is to develop new and improved treatments and learn more about the impact of Duchenne/Becker muscular dystrophy on individuals and families.
    c/o The Parent Project for Muscular Dystrophy Research, Inc.
    401 Hackensack Avenue
    9th Floor
    Hackensack NJ 07601
    Phone: 404-778-0553
    Fax: 404-935-0636
    Email: coordinator@duchenneconnect.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Dystrophinopathies: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
DMDXp21​.2-p21.1DystrophinDMD homepage - Leiden Muscular Dystrophy pagesDMD

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Dystrophinopathies (View All in OMIM)

300376MUSCULAR DYSTROPHY, BECKER TYPE; BMD
300377DYSTROPHIN; DMD
302045CARDIOMYOPATHY, DILATED, 3B; CMD3B
310200MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD

Normal allelic variants. DMD spans 2.2 Mb of DNA and comprises 79 exons. It has at least four promoters. It is the largest known human gene. Innumerable intragenic variants have been described, many of which are useful as markers for genetic linkage analysis.

Pathologic allelic variants. More than 5,000 mutations have been identified in persons with DMD or BMD [Aartsma-Rus et al 2006b, Flanigan et al 2009]. Disease-causing alleles are highly variable, including deletion of the entire gene, deletion or duplication of one or more exons, and small deletions, insertions, or single-base changes. In both DMD and BMD, partial deletions and duplications cluster in two recombination hot spots, one proximal at the 5' end of the gene, comprising exons 2-20 (30%), and one more distal, comprising exons 44-53 (70%) [Den Dunnen et al 1989]. Duplications cluster near the 5' end of the gene, with duplication of exon 2 being the single most common duplication identified [White et al 2006].

Normal gene product. Dystrophin is a membrane-associated protein present in muscle cells and some neurons. The N-terminal domain binds to actin. A large rod domain includes 24 homologous repeats forming an α-helical structure, a cysteine-rich calcium-binding region near the C terminus, and a C-terminal domain that binds with other membrane proteins. Dystrophin is therefore part of a protein complex that links the cytoskeleton with membrane proteins that in turn bind with proteins in the extracellular matrix.

Abnormal gene product. Mutations that lead to lack of dystrophin expression tend to cause DMD, whereas those that lead to abnormal quality or quantity of dystrophin lead to BMD. In DMD-associated DCM, functional dystrophin is absent in the myocardium but may be normal or mildly abnormal in skeletal muscle [Ferlini et al 1999, Neri et al 2007] because DMD-associated DCM is associated with specific types of DMD mutations that have a differential response to tissue-specific transcription or alternative splicing in cardiac vs skeletal muscle.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Available online. 2005. Accessed 9-7-12. [PubMed: 16322188]
  2. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available online (registration or institutional access required). 2010. Accessed 9-7-12.
  3. Moxley RT 3rd, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, Baumbach L, McDonald C, Sussman M, Wade C. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Available online. 2005. Accessed 9-7-12. [PubMed: 15642897]

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Suggested Reading

  1. Hu X, Ray PN, Murphy EG, Thompson MW, Worton RG. Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin and phenotype/genotype correlation. Am J Hum Genet. 1990;46:682–95. [PMC free article: PMC1683676] [PubMed: 2316519]
  2. Kang PB, Kunkel LM. The muscular dystrophies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 216. Available online. Accessed 9-7-12.

Chapter Notes

Acknowledgments

The authors would like to thank Elizabeth DeChene, MS, CGC, and Elicia Estrella, MS, CGC, of the Program in Genomics/Harvard Neuromuscular Disease Project, Children’s Hospital Boston, for their assistance in reviewing and editing the Genetic Counseling Section.

Author History

Basil T Darras, MD (1999-present)
Bruce R Korf, MD, PhD, FACMG; University of Alabama-Birmingham (1999-2011)
David T Miller, MD, PhD, FACMG (2011-present)
David K Urion, MD (1999-present)

Revision History

  • 23 November 2011 (me) Comprehensive update posted live
  • 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
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    Konkle BA, Josephson NC, Nakaya Fletcher SM, Thompson AR. GeneReviews<sup>®</sup>. 1993
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