INTRODUCTION — The Duchenne and Becker muscular dystrophies (as well as a third intermediate form) are caused by pathogenic variants of the dystrophin gene and are therefore named dystrophinopathies. Weakness is the principal symptom as muscle fiber degeneration is the primary pathologic process.
The genetics and pathogenesis of Duchenne and Becker muscular dystrophy are reviewed here. Other clinical aspects of these conditions are discussed elsewhere. (See "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Duchenne and Becker muscular dystrophy: Management and prognosis".)
TERMINOLOGY — The dystrophinopathies are inherited as X-linked recessive traits and have varying clinical characteristics:
●Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis", section on 'Duchenne muscular dystrophy')
●Becker muscular dystrophy (BMD) has a similar presentation to DMD, but typically has a later onset and a milder clinical course (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis", section on 'Becker muscular dystrophy')
●Patients with an intermediate phenotype (outliers) may be classified clinically as having either mild DMD or severe BMD (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis", section on 'Intermediate phenotype')
GENETICS AND PATHOGENESIS — DMD and BMD are caused by a defective gene located on the X chromosome that is responsible for the production of dystrophin [1-3]. The dystrophin (DMD) gene is the largest gene yet identified in humans, spanning approximately 2.3 megabases at chromosome Xp21.2. The protein product is also extremely large, weighing 427 kilodaltons (kD) [4].
Pathogenic variants in the DMD gene — The majority of pathogenic variants of the DMD gene are deletions of one or more exons, which are found in approximately 68 to 77 and 65 to 70 percent of patients with DMD and BMD, respectively [5-9]. Partial gene duplications have also been reported in approximately 11 to 13 percent of affected individuals [7,10]; duplication of DMD exon 2 is the most common, accounting for approximately 6 to 10 percent of all DMD duplications [11,12].
The DMD pathogenic variants in the remaining patients (ie, without detectable deletions or duplications) are single nucleotide variants, small deletions or insertions in the coding sequence, or splice site variants. Patients with clinical phenotypes suggestive of DMD or BMD, but without a clear X-linked pattern of inheritance, may have defects in other genes, including those encoding the dystrophin-associated glycoproteins.
Dystrophin — The phenotype of dystrophinopathy is primarily dependent upon the quantity of residual dystrophin in muscle, with absent or minimal dystrophin (eg, 0 to 5 percent of normal) correlating with a more severe phenotype (DMD) and higher levels of dystrophin (5 to 50 percent of normal) correlating with less severe phenotypes (intermediate or BMD) [10]; other reports suggest that very low dystrophin levels (<5 percent) may be associated with a milder phenotype in a subset of patients [13]. However, these correlations are imprecise and confounded primarily by variations in Western blot quantification methods and the effect of genetic modifiers on disease course.
Dystrophin is located on the cytoplasmic face of the plasma membrane of muscle fibers, functioning as a component of a large, tightly associated glycoprotein complex (figure 1) [3]. Dystrophin normally provides mechanical reinforcement to the sarcolemma and stabilizes the glycoprotein complex, thereby shielding it from degradation. In its absence, the glycoprotein complex is digested by proteases. Loss of these membrane proteins may initiate the degeneration of muscle fibers, resulting in muscle weakness.
The loss of dystrophin in mdx mice leads to myofibril membrane instability [14]. However, genetic disruption of the dystrophin gene in mdx mice is associated with only a mild dystrophy [15]. Although the reduced disease severity in mdx mice compared with human DMD is not fully understood, several possible explanations are postulated. As an example, a homolog of dystrophin called utrophin is present in mice and humans. Its expression in muscle can compensate physiologically for the absence of dystrophin in mice, but this compensation does not occur in humans. This hypothesis is supported by the finding that mice lacking both dystrophin and utrophin have a severe dystrophy that phenotypically resembles DMD [15]. Further, the selective expression in skeletal muscle of utrophin via the use of a transgene completely rescues these double-knockout mice from early death and the DMD phenotype [16].
As part of the glycoprotein complex, dystrophin secures a number of dystrophin-associated proteins (figure 2), including neuronal nitric oxide synthase (nNOS), to the sarcolemma [17]. Sarcolemmal nNOS is necessary for the production of nitric oxide, which regulates vasodilation and increased blood flow into muscle, and is important for the prevention of early muscle fatigue with exercise [18-20]. The absence of dystrophin in humans with DMD or mdx mice is associated with a loss of muscle nNOS [17,21], resulting in exercise-induced muscle fatigue [18-20,22].
Disruption of calcium regulation may also play a role in the pathogenesis of DMD [23-26]. Muscle cell membrane damage related to the loss of dystrophin may permit the pathologic entry of extracellular calcium into muscle fibers. In addition, inflammatory mediators in dystrophic muscle may increase the expression of inducible nitric oxide synthase (iNOS), which binds to and destabilizes ryanodine receptors of the sarcoplasmic reticulum that regulate calcium ion flow [27,28]. The result is calcium leakage from the sarcoplasmic reticulum into the cytosol. The excess cytosolic calcium can activate calpains, which promote muscle proteolysis [29,30].
Genotype-phenotype correlations — There is no clear correlation between the size of DMD gene deletions and the severity and progression of the DMD/BMD phenotype [31,32]. The molecular basis of Duchenne (more severe) versus Becker (less severe) muscular dystrophy is related, at least in part, to whether the amino acid translational reading frame is disrupted or preserved by the deletion [5,10,33]. This "reading frame rule," and important exceptions to it, are reviewed in the sections that follow.
Reading frame rule — During the synthesis of mature mRNA, the joining ends of the exons (after splicing of introns) must be in phase to maintain the correct translational open reading frame.
●Out-of-frame deletions – A deletion that juxtaposes exons and shifts the translational reading frame (ie, an out-of-frame deletion) most often leads to unstable messenger RNA (mRNA) and the production of a severely truncated dystrophin molecule (figure 3). Truncated protein is rapidly degraded in the cell by nonsense-mediated mRNA decay and results in a DMD (severe) phenotype [33].
●In-frame deletions – A deletion that juxtaposes exons but preserves the translational reading frame (eg, an in-frame deletion) usually results in an internally deleted but semifunctional dystrophin protein with intact amino-terminal and carboxy-terminal domains (figure 3). Semi-functional dystrophin protein can persist in some quantity in the cell, and results in a BMD (mild) phenotype.
Exceptions to the reading frame rule — Exceptions to the reading frame rule as a predictor phenotype occur in approximately 8 percent of DMD cases [34-40] and up to 34 percent of BMD cases [7,41]. These exceptions may occur because of variants in critical domains, exon skipping events, post-translational mechanisms, and other factors. Thus, affected males and their families and caregivers should be informed that phenotype prediction may not be accurate when based on the reading frame rule [10].
Some regions of the dystrophin protein are more critical to function than others. Deletions in the regions coding for the amino-terminal or carboxy-terminal domains of dystrophin often result in more severe phenotypes than pathogenic variants affecting the rod domain [32,36]. However, exceptions occur [40]. Very large deletions or deletions in protein-binding domains (eg, cysteine-rich domain), even if in-frame, can result in a severe phenotype [37,38].
Out-of-frame deletions of exons 3 to 7 or exon 45 can result in BMD, DMD, or an intermediate phenotype [39,42]. Exon-skipping events or activation of new cryptic translational start sites may create situations in which apparently out-of-frame deletions behave as in-frame deletions or vice versa [43]. Alternatively, post-transcriptional mechanisms (eg, ribosomal frame shifting or reinitiation) may help restore the mRNA reading frame in patients with BMD who have out-of-frame deletions involving exons 3 to 7 [39,44]. Variations in the severity of the phenotype among patients with similar pathogenic variants (eg, deletion of exon 45) have been reported, supporting the contribution of other factors in the phenotypic expression of these variants [36,45].
Certain missense or nonsense variants may occur within exonic splicing enhancers (ESEs) and induce exon skipping with variable results on the phenotype [46]. For example, a nonsense variant within exon 27 disrupts an ESE sequence and induces partial skipping of the exon, which results in a BMD phenotype [47]. Nonsense variants within DMD muscle isoform exon 1 have been associated with an extremely mild BMD phenotype with loss of ambulation in the seventh decade. It seems that internal initiation of translation at two AUG codons within exon 6 ameliorates the phenotype [48].
Specific examples follow:
●DMD phenotype with in-frame deletions – Large in-frame deletions in the 5' region that extend into the mid-rod domain (eg, exons 3 to 31, 3 to 25, 4 to 41, or 4 to 18) result in severe phenotype [49]. By contrast, large deletions in the rod domain that do not involve the 5' putative actin binding site of dystrophin result in a mild BMD phenotype [50-53]. However, small in-frame deletions, such as the deletion of exons 3 to 13, which disrupt the 5' actin binding domain, are associated with a DMD phenotype [54]. These exceptions underscore the functional relevance of the 5' actin binding domain.
●BMD phenotype with out-of-frame deletions – Out-of-frame deletions or duplications involving the 5' end of the gene (exons 3 to 7, 5 to 7, 3 to 6) or further downstream (exons 51, 49 to 50, 47 to 52, 44 or 45) have been described in patients with BMD. The carboxy-terminal domain is not disrupted in these patients and some dystrophin is produced because of exon skipping that occurs via alternative splicing. The exon skipping events probably create larger mRNA deletions, which presumably are in-frame and hence functional [55-57]. In patients with BMD and out-of-frame deletions involving exons 3 to 7, it is hypothesized that an alternative translation initiation site within exon 8 becomes activated [58].
The DMD exon 2 duplication is an out-of-frame pathogenic variant and, as such, is expected to result in a frameshift and thus a severe DMD phenotype. However, milder phenotypes (intermediate and BMD) have been described in cohorts of individuals with DMD exon 2 duplications, possibly related to activation of an internal ribosome entry site in DMD exon 5, which can drive production of mildly truncated but functional dystrophin from an AUG codon within exon 6 [11,12].
In men with BMD, deletions involving the amino-terminal domain (5' end) have been correlated with an earlier-onset (third decade) dilated cardiomyopathy, whereas deletions affecting part of the rod domain and hinge 3 have been correlated with a later-onset (fifth decade) dilated cardiomyopathy [10,59].
Other genetic modifiers — Some data suggest that genes other than dystrophin may affect disease severity and response to treatment [60-64]. As an example, variants of the LTBP4 gene may influence the age at loss of ambulation in DMD [61-63]. In addition, a few reports suggested that a variant of the SPP1 gene promoter region (the G allele of the polymorphism rs28357094) was associated with decreased muscle strength and younger age at loss of ambulation in patients with DMD, and appeared to modulate glucocorticoid treatment response [60,62]. However, another study found no significant association of the SPP1 rs28357094 polymorphism with age of ambulation loss [63]. Further studies are needed to clarify these relationships.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)
SUMMARY
●Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by a defective gene located on the X chromosome that is responsible for the production of dystrophin. (See 'Genetics and pathogenesis' above.)
●Dystrophin is located on the cytoplasmic face of the plasma membrane of muscle fibers, functioning as a component of a large, tightly associated glycoprotein complex (figure 1). Dystrophin normally provides mechanical reinforcement to the sarcolemma and stabilizes the glycoprotein complex, thereby shielding it from degradation. In its absence, the glycoprotein complex is digested by proteases. Loss of these membrane proteins may initiate the degeneration of muscle fibers, resulting in muscle weakness. (See 'Dystrophin' above.)
●There is no clear correlation between the size of dystrophin (DMD) gene deletions and the severity and progression of the DMD/BMD phenotype. The molecular basis of DMD (more severe) versus BMD (less severe) is partly related to whether the amino acid translational reading frame is disrupted or preserved by the deletion. However, there are exceptions to this general rule. (See 'Genotype-phenotype correlations' above.)
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