Dystrophinopathies

Clinical characteristics.

The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. 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 DCM when the heart is primarily affected.

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

Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. 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. 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 dilatation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.

Diagnosis/testing.

The diagnosis of a dystrophinopathy is established in a proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic variant in DMD on molecular genetic testing in a male and of a heterozygous pathogenic variant in DMD on molecular genetic testing in a female. Females may present with a classic dystrophinopathy or may be asymptomatic carriers.

Management.

Treatment of manifestations: ACE inhibitors are used with or without beta blockers for cardiomyopathy in both DMD and BMD phenotypes. Congestive heart failure is treated with diuretics and oxygen 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 is treated with bracing and surgery. Corticosteroid therapy improves muscle strength and function for individuals with DMD between ages five and 15 years; the same treatment is used in BMD, although the efficacy is less clear. Dystrophin restoration therapies have been developed by using synthetic antisense oligonucleotides to restore the reading frame by exon skipping for individuals with specific pathogenic variants in DMD.

Prevention of secondary complications: Evaluation by a pulmonologist and cardiologist before surgeries; pneumococcal and influenza immunizations annually; nutrition assessment; physical therapy to promote mobility and prevent contractures; 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 at the time of diagnosis; 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; succinylcholine and inhalational anesthetics because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions.

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 genetic status of the mother. Heterozygous females have a 50% chance of transmitting the DMD pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are heterozygous and may have a range of clinical manifestations. Males with DMD usually do not reproduce. Males with BMD or DMD-associated DCM may reproduce: all of their daughters are heterozygotes; none of their sons inherit their father's DMD pathogenic variant. Carrier testing for at-risk females, prenatal testing, and preimplantation genetic testing are possible if the DMD pathogenic variant in the family is known.

Suggestive Findings

A dystrophinopathy should be suspected in an individual with the following clinical and laboratory test findings that support the diagnosis of DMD, BMD, or DMD-associated DCM – especially when they occur in addition to a positive family history compatible with X-linked inheritance. Findings are most commonly noted in males, but females may also be affected.

Establishing the Diagnosis

Male proband. The diagnosis of a dystrophinopathy is established in a male proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic (or likely pathogenic) variant in DMD on molecular genetic testing (see Table 1).

Female proband. The diagnosis of a dystrophinopathy is usually established in a female proband with characteristic clinical findings and elevated CK concentration and/or by identification of a heterozygous pathogenic (or likely pathogenic) variant in DMD on molecular genetic testing (see Table 1).

Females may present with a classic dystrophinopathy or may be asymptomatic carriers.

• Females with a classic dystrophinopathy. The genetic mechanisms that can explain this rare occurrence (and testing to identify the cause) include the following:
  • A deletion involving Xp21.2 (microarray [CMA] studies)
  • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies)
  • Uniparental disomy (UPD) of the X chromosome (UPD studies)
  • Compound heterozygosity for two DMD pathogenic variants [Soltanzadeh et al 2010] (deletion/duplication analysis and/or sequence analysis)
  • Nonrandom X-chromosome inactivation (XCI). See Genotype-Phenotype Correlations.
• Carrier testing for at-risk female relatives. Note: Carriers are heterozygotes for this X-linked disorder and may later develop clinical findings related to the disorder (see Clinical Characteristics and Management, Evaluation of Relatives at Risk for testing recommendations).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a hemizygous or heterozygous DMD variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Because the majority of pathogenic variants involve deletions of one or more exons, gene-targeted deletion/duplication analysis of DMD is performed first and followed by sequence analysis if no pathogenic variant is found.
• A multigene panel that includes DMD and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  Note: (1) A multigene panel may be most appropriate for individuals with less severe clinical presentations. Men with the BMD phenotype and most women may not have findings clinically distinct enough to suggest single-gene testing of DMD as the initial test. (2) Chromosomal microarray analysis (CMA) may:
  • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including DMD);
  • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as 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] to suggest a contiguous gene disorder;
  • Detect an unexpected or incidental DMD deletion/duplication in an asymptomatic individual.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered, particularly if the presentation is atypical. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
  Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy.

Note: If no DMD pathogenic variant is identified, skeletal muscle biopsy of individuals with suspected DMD or BMD is warranted for western blot and immunohistochemistry studies of dystrophin. Skeletal muscle biopsy continues to be used only rarely in the diagnosis of dystrophinopathies.

• Muscle histology early in the disease shows nonspecific dystrophic changes, including variation in fiber size, foci of necrosis and regeneration, hyalinization, increased internal nuclei, fiber splitting, inflammatory changes, and, later in the disease, deposition of fat and connective tissue.
• Western blot and immunohistochemistry are summarized in Table 3.

Clinical Description

Genotype-Phenotype Correlations

If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and BMD can be difficult in some cases. For example, deletion of exons 3-7, the most extensively investigated deletion associated with both phenotypes, has been found in males with DMD and also with BMD [Aartsma-Rus et al 2006].

Reading frame rule. This "rule" states that pathogenic variants 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 severe DMD phenotype [Monaco et al 1988]. Therefore, the type of deletion/duplication 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 2006], and in many cases a muscle biopsy is not needed to address the issue of BMD vs DMD.

Although exceptions to the "reading frame rule" have been documented to occur at a rate below 10% [Aartsma-Rus et al 2006], more recent studies suggest that this may only hold true for the DMD phenotype, and that the rate of exception may be higher with the BMD phenotype for both deletions and duplications [Kesari et al 2008, Takeshima et al 2010]. Correlation of clinical features with molecular test results is thus very important.

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. Pathogenic variants that disrupt the reading frame include stop variants, some splicing variants, 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": 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 2006]. 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 pathogenic variants 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 pathogenic variants affecting Dp140; also, most males with pathogenic variants involving the Dp71 isoform are cognitively disabled [Daoud et al 2009, Taylor et al 2010]. Recent work from the French Neuromuscular Network suggests that pathogenic variants in the distal parts of the dystrophin gene are more likely to be associated with cognitive impairment [Mercier et al 2013].
  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 pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants 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 variants, and most nontruncating 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 pathogenic variants 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]. Other types of pathogenic variants including a novel rod domain duplication of exons 13-16 [Chamberlain et al 2015], missense variants, and deletions in the exon 45-53 region of DMD [Shimizu et al 2005] have been reported in DMD-associated DCM.

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 pathogenic variants 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. The occurrence of either cardiomyopathy or BMD in the same family raises the possibility of modification of the phenotypic expression of a specific pathogenic variant by epigenetic factors [Palmucci et al 2000].

Penetrance

Penetrance of dystrophinopathies is complete in males.

Penetrance in heterozygous females varies, and may depend in part on patterns of X-chromosome inactivation (XCI).

• Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in 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 pathogenic nonsense variants [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 containing the DMD pathogenic variant 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).
• Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [Giliberto et al 2014, Viggiano et al 2016, Viggiano et al 2017]. However, because the methylation status of the androgen receptor (AR) gene in white blood cells or muscle may not always reflect the methylation status of DMD, the use of the AR methylation assay has limited prognostic value in clinical practice [Juan-Mateu et al 2012].

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 in northern England is 1:18,450 live male births [Bushby et al 1991].

During the years 1968 to 1978, the incidence of DMD in southeast Norway was 1:3,917 live male births [Tangsrud & Halvorsen 1989].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended if they have not already been completed:

• 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]
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life.

Prevention of Secondary Complications

Cardiorespiratory

• Evaluation by pulmonary and cardiac specialists before surgeries [Finder et al 2004]
• Administration of pneumococcal vaccine and annual influenza vaccination [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 2018]:

• Blood
  • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase
  • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually
  • Consideration of magnesium and parathyroid hormone levels
• Urine (calcium, sodium, creatinine)
• Dual-energy x-ray absorptiometry (DXA) 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 DXA 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 and in accordance with country-specific pediatric guidelines.
• Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted.
• Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial.

Surveillance

Agents/Circumstances to Avoid

Individuals with dystrophinopathy should avoid botulinum toxin injections.

Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with dystrophinopathy 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 for malignant hyperthermia susceptibility in individuals with dystrophinopathy when compared with the general population [Gurnaney et al 2009]. However, individuals with DMD have been reported to have severe reactions to anesthesia (malignant hyperthermia-like) that did not meet the criteria for true malignant hyperthermia [Bamaga et al 2016].

Evaluation of Relatives at Risk

It is appropriate to evaluate at-risk female family members (i.e., the sisters or maternal female relatives of an affected male and first-degree relatives of a known or possible heterozygous female) in order to identify as early as possible heterozygous females who would benefit from cardiac surveillance (see Surveillance). Evaluations can include the following:

• Molecular genetic testing if the DMD pathogenic variant in the family is known
• Serum creatine phosphokinase (CK) testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative.
• Molecular genetic testing of the at-risk female if an affected male is not available for testing:
• By deletion/duplication analysis first
• If no pathogenic variant is identified, by sequence analysis
• Linkage analysis to determine carrier status in at-risk females if (1) the DMD pathogenic variant in the proband is not known, (2) no DMD pathogenic variant or serum CK elevation is identified in a carrier female, and (3) the family has 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: (1) 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. (2)Testing by linkage analysis is not possible for families in which there is a single affected male. (3) Testing by linkage analysis may not be widely available on a clinical basis.

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

Pregnancy Management for Heterozygous Females

Symptomatic heterozygous women should undergo an evaluation for dilated cardiomyopathy ideally prior to conceiving a pregnancy or as soon as the pregnancy is recognized. Asymptomatic heterozygous women should consider undergoing a cardiac evaluation prior to conception or when a pregnancy is recognized. Those with evidence of dilated cardiomyopathy should be treated and/or monitored by a cardiologist and a high-risk obstetrician.

Therapies Under Investigation

See also Table 5.

Gene therapy. Clinical studies in gene therapy currently focus on restoring dystrophin expression by administering recombinant adeno-associated virus vectors that deliver either functional dystrophin transgene (micro- or minidystrophin genes) [Mendell et al 2010, Konieczny et al 2013, Bengtsson et al 2016] or gene-editing components [Calos 2016, Long et al 2016, Nelson et al 2016, Tabebordbar et al 2016].

Gene repair. CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (CRISPR/Cas9)-mediated genome editing in mdx mice has been shown to partially restore dystrophin protein expression in cardiac and skeletal muscle by cutting the noncoding introns that flank the mutated sequence-containing exon 23 [Long et al 2016, Nelson et al 2016, Tabebordbar et al 2016].

Ataluren. Ten to 15 percent of individuals with DMD have nonsense (stop) pathogenic variants, which the investigational drug ataluren may treat by promoting ribosomal read-through, allowing bypass of the pathogenic variant and continuation of the translation process to production of a functioning protein [Finkel 2010].

Preclinical efficacy studies showed production of dystrophin in primary muscle cells from humans and mdx mice [Welch et al 2007]. Studies in humans have shown increased full-length dystrophin expression in vitro and in vivo, and decreased serum muscle enzyme levels within 28 days of treatment [Bönnemann et al 2007]. Affected individuals on low doses of ataluren had a 30-meter lower decline in the six-minute walk distance than those on high doses or placebo [Bushby et al 2014]. Based on these results, the drug Translarna^TM was granted conditional approval from the European Medicines Agency in August 2014 to treat DMD caused by a nonsense variant; Translarna^TM is not approved for treating DMD in the US.

A Phase III multicenter 48-week double-blind placebo-controlled trial (ACT DMD) showed no significant benefit of ataluren for the primary endpoint (i.e., change from baseline in the 6-minute walk test), though there was benefit for some secondary endpoints [McDonald et al 2017].

Myostatin inactivation. The protein myostatin has an inhibitory effect on muscle growth; without it, mice that would otherwise express the DMD phenotype have increased muscle mass compared with those with a wild type myostatin gene [Wagner et al 2002]. Animals treated with antibodies to myostatin have increased muscle mass and strength, lower serum creatine kinase, and less histologic evidence of muscle damage [Bogdanovich et al 2002], suggesting a potential therapeutic target to increase muscle bulk and strength in humans with DMD [McNally 2004].

Wagner et al [2008] conducted a double-blind placebo-controlled multinational randomized study of 116 subjects to test the safety of a neutralizing antibody to myostatin, MYO-029. Campbell et al [2017] found that ACE-031, a fusion protein that binds myostatin and related ligands, noted a trend toward maintenance of the six-minute walk test compared with a decline in the placebo group (not statistically significant), as well as a trend toward increased lean body mass and bone mineral density and reduced fat mass; however, the study was stopped due to non-muscle-related adverse effects.

Cell therapy. Skeletal muscle progenitors continue to be investigated in the treatment of DMD. A promising technique in mice isolates and transplants muscle satellite cells, a natural source of cells for muscle regeneration [Blau 2008, Cerletti et al 2008].

Idebenone. A randomized controlled trial of the antioxidant idebenone showed significantly reduced decline in respiratory function as measured by peak expiratory flow and other pulmonary function tests [Buyse et al 2015]. Nearly all of the 64 individuals with DMD (age 10-18 years) were nonambulatory at baseline. Further study is needed to determine if idebenone treatment improves outcomes such as the time to assisted ventilation or to death.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 disorder nor will he be hemizygous for the DMD pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote.
• If a woman has more than one affected child and no other affected relatives and if the DMD pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. The likelihood of germline mosaicism for a DMD pathogenic variant in this instance is 15%-20% (empiric risk). Consequently, each of her offspring is at increased risk of inheriting the DMD pathogenic variant [van Essen et al 1992, van Essen et al 2003, Wang et al 2017].
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo DMD pathogenic variant, in which case the mother is not a heterozygote. Approximately two thirds of mothers of males with Duchenne muscular dystrophy (DMD) and no family history of DMD are heterozygotes.
• Recommendations for the mother of a proband include molecular genetic testing; heterozygous females need to be identified for the purpose of cardiac surveillance (see Surveillance).
• Molecular genetic testing can be used to determine the point of origin of a de novo pathogenic variant. This information is important for determining which branches of the family are at risk for the dystrophinopathies.
• Rarely, a female may be the only affected family member. A female proband may have inherited the DMD pathogenic variant from either her mother or her father or the pathogenic variant may be de novo. Molecular genetic testing of the mother (and possibly – or subsequently – the father) is recommended.

Sibs of a proband

• The risk to sibs of a male proband depends on the genetic status of the mother; if the proband is female, the risk to sibs depends the genetic status of the mother and the father.
• If the mother of a proband is heterozygous for a DMD pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations (see Clinical Description).
• If the DMD pathogenic variant identified in a male proband is not detectable in maternal leukocyte DNA, it is possible that the proband has a de novo pathogenic variant. However, because the likelihood of maternal germline mosaicism in this instance is 15%-20%, the sibs of a proband are at increased risk of inheriting the family-specific DMD pathogenic variant.
• If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific DMD pathogenic variant may be higher than if the mother has germline mosaicism only [van Essen et al 2003].
• If the father of an affected female has a DMD pathogenic variant, he will transmit it to all of his daughters and none of his sons.

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 heterozygotes and could have a range of clinical manifestations (see Clinical Description).
• Males with Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM) may reproduce. All of the daughters will be heterozygotes. None of the sons will inherit their father's DMD pathogenic variant.
• Women with a DMD pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

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

Heterozygote Detection

Carrier testing is possible for at-risk females. See Management, Evaluation of Relatives at Risk.

Females who are identified as heterozygous for a DMD pathogenic variant need to be informed of their risk for DMD-associated cardiomyopathy, as well as the recommended surveillance.

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.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the DMD pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Fetal muscle biopsy. In utero fetal muscle biopsy has been used in the prenatal diagnosis of DMD in families with DMD in which the DMD pathogenic variant is not known [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 various publications [Raymond et al 2010, Xu et al 2015, Parks et al 2016].

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)
Partha S Ghosh, MD (2018-present)
Bruce R Korf, MD, PhD, FACMG; University of Alabama-Birmingham (1999-2011)
David T Miller, MD, PhD, FACMG; Boston Children’s Hospital (2011-2018)
David K Urion, MD (1999-present)

Revision History

• 20 January 2022 (aa) Revision: dystrophin restoration therapies (See Treatment of Manifestations; Table 5.)
• 26 April 2018 (ha) Comprehensive update posted live
• 26 November 2014 (me) Comprehensive update posted live
• 23 November 2011 (me) Comprehensive update posted live
• 21 March 2008 (me) Comprehensive update posted live
• 25 August 2005 (me) Comprehensive update posted live
• 1 October 2004 (cd) Revision
• 3 August 2004 (cd) Revision: Management
• 24 March 2004 (cd) Revision: Diagnosis
• 23 June 2003 (me) Comprehensive update posted live
• 5 September 2000 (me) Review posted live
• December 1999 (bk) Original submission

Published Guidelines / Consensus Statements

• 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 5-23-23.
• 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, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available online. 2010. Accessed 5-23-23.
• Moxley RT III, 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 5-23-23.

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