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  Disease summary:

  
  
  
  
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    The term dystrophinopathy encompasses three interrelated diseases: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy.

    
    
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    DMD has an incidence of approximately 1:4000 live male births and presents in early childhood with progressive proximal muscle weakness leading to loss of ambulation and, cardiomyopathy in the second decade with death in the third decade due to cardiorespiratory compromise. BMD causes later onset of muscle weakness with cardiomyopathy being the most common cause of death in the fourth to fifth decades. DMD-associated dilated cardiomyopathy is common in both phenotypes and may also be present in female carriers of DMD mutations.

    
    
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    Dystrophinopathies result from mutations in the DMD gene on Xp21.2 causing a reduced or deficient amount of dystrophin, a membrane-bound protein expressed in skeletal, cardiac, smooth muscle, and neurons. The type of mutation determines the amount of residual protein and the phenotype.

  
  
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  Hereditary basis:

  
  
  
  
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    Deletions, duplications, insertions, and point mutations in the DMD gene, on Xp21.2, cause the dystrophinopathies.

    
    
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    Inheritance is X-linked and there is complete penetrance in males who inherit the mutation.

    
    
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    Manifestations in female heterozygotes including muscle weakness, myalgias, and cardiomyopathy, are usually due to skewed X-inactivation. In rare circumstances, females can have classic DMD or BMD. In these individuals a structural abnormality of the X chromosome should be ruled out.

    
    
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    One-third of mutations are de novo, and are not inherited.

  
  
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  Differential diagnosis:

  
  
  
  
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    When considering the diagnosis of muscular dystrophy, the differential should include facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, and dilated cardiomyopathy (Table 135-1).

Diagnostic Criteria for Dystrophinopathies

Diagnostic evaluation should include the following

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  Three-generation pedigree to identify affected or at-risk family members

  
  
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  Physical examination with particular attention paid to gait, ability to run and jump, proximal muscle weakness, calf hypertrophy, and Gower sign. Fasciculations are absent.

  
  
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  Creatine kinase level

  
  
  
  
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    Elevated to greater than 10× normal in DMD

    
    
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    Elevated to greater than 5× normal in BMD

    
    
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    Increased in DMD-associated dilated cardiomyopathy

  
  
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  DNA testing for deletion, duplication, or mutation of DMD. If no mutation identified, muscle biopsy with evaluation of histology and immunostaining for dystrophin

Clinical Spectrum of Dystrophinopathies

Duchenne Muscular Dystrophy

Symmetric muscle weakness worse in proximal muscles, calf hypertrophy, symptom onset less than 5 years of age, Gower sign, intellectual disability, loss of ambulation or wheelchair dependence by 13 years of age without treatment, dilated cardiomyopathy by age 18.

Becker Muscular Dystrophy

Symmetric muscle weakness as above but with milder, later onset; can present with muscle cramping with exercise, distal muscle hypertrophy; isolated quadriceps weakness; no cognitive impairment; loss of ambulation or wheelchair dependence after 16 years of age; preservation of neck flexor muscles; variable age of onset of dilated cardiomyopathy from mid-20s to mid-40s.

Intermediate Phenotype

Loss of ambulation or wheelchair dependence between 13 and 16 years of age.

Female Heterozygotes of DMD Mutations

Wide phenotypic variability ranging from asymptomatic to significant muscle disease. Up to 20% are thought to develop dilated cardiomyopathy.

DMD-Associated Dilated Cardiomyopathy

No or subclinical skeletal muscle involvement; dilated cardiomyopathy; may present with congestive heart failure, arrhythmias, or thromboembolic disease; age of onset later in women than men.

Contiguous Gene Deletion Syndromes

Xp21 deletions that include the DMD gene.

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  Proximal deletion: DMD with McLeod syndrome, chronic granulomatous disease, and/or retinitis pigmentosa.

  
  
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  Distal deletion: DMD with adrenal hypoplasia congenita and glycerol kinase deficiency.

Screening

See Fig. 135-1 for diagnostic screening.

Carrier Screening

No population wide carrier or new-born screening is currently recommended. Women who are at risk for being carriers of DMD mutations can be offered targeted mutation analysis if the familial mutation is known. If unknown, DMD deletion/duplication analysis and sequencing may be offered.