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 dilated cardiomyopathy (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 dilation 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.

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 and prenatal testing or preimplantation genetic diagnosis for pregnancies at increased risk 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 Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or DMD-associated dilated cardiomyopathy (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 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 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).

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 at the most reasonable cost 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