DMD/BMD (Duchenne and Becker Muscular Dystrophies)

Duchenne and Becker Muscular Dystrophies (DMD/BMD)

 DMD and BMD are X-linked recessive muscular dystrophies caused by mutations in the dystrophin gene resulting in deficiency of dystrophin, a muscle membrane protein.  Prior to the discovery of the dystrophin gene in 1987, the distinction between DMD and BMD was based on onset of symptoms and clinical features including the age at which ambulation is lost. 

Mutation that result in complete absence of dystrophin result in the more severe phenotype of DMD, while mutations that result in a truncated but partially functioning dystrophin result in milder phenotype of BMD.

Epidemiology

DMD is the most common form of muscular dystrophy in children.  The worldwide birth prevalence of DMD is 1.3 – 2.6 per 10,000 population.   In the U.S the incidence is 1:3.500 male births and prevalence is 1.8 per 18,000 (males 5-24 years).  

New born screening is proposed to add DMD to the panel of diseases for which newborns are routinely screened.  A 2 tier analysis is proposed involving checking CK levels on dried blood spot in a new born and if elevated further testing using genetic testing is advised. 

 Genetics and DMD and BMD

The dystrophinopathies are X-linked recessive mutations in dystrophin gene at locus Xp21.2.  Approximately 30% of cases are de novo mutations. Dystrophin is the largest known gene, spanning 2.4 million base pairs and constitutes 1.5% of X chromosome.   It has 70 exons.   The full 14,000 base pairs (bp) mRNA transcribed from dystrophin gene is expressed mostly in skeletal and cardiac muscles, with small amounts also expressed in the brain.   Full length of dystrophin which is 427 kilodalton (kDa) is localized in the inner muscle membrane and is a part of a protein complex that links muscle membrane to the cytoskeleton and extracellular matrix.  The dystrophin-glycoprotein complex offers stability to the sarcolemma and prevents contraction induced damage and necrosis.  Shorter forms of dystrophin are expressed in brain, retina, kidney, liver, heart, lung, and peripheral nerves.  

>3000 mutation are present in DMD patients.  

60-70% are exon deletions,  25-35% are point mutations, and 5% and duplications. 

There is no correlation between the size of mutation and resulting phenotypic severity.  For example, deletion of a single exon such as exon 44 frequently result in classic DMD, while mutations encompassing as much as 50% of the gene have been described in a mild BMD.  Frameshift that caused a complete lack of dystrophin expression are responsible for the severe phenotype of DMD, while in-frame mutations that result in an abnormal but partially functional dystrophin account for the milder phenotype of BMD.  

An out of frame mutation, means it is DMD and it must be put back 'in frame' to make the body 'read' it.  For example:

Disease penetrance is complete in males.  Carrier females have a 50% chance to transmit the pathogenic mutation in each pregnancy; their daughters have 50% chance of being carriers and theirs sons will have 50% chance of having DMD.  Female carriers are usually asymptomatic but can rarely manifest a moderate-severe DMD phenotype due to a skewed X chromosome inactivation defined by >75% of nuclei harboring the mutant DMD gene on the active X chromosome (manifesting carrier).  DMD or BMD phenotype is also seen in females with an XO genotype (Turner’s syndrome), with a structurally abnormal X chromosome or with an X-autosome translocation. 

 Carrier Detection and Prenatal Testing

When the proband’s disease causing mutation is known, carrier testing can be performed in at-risk females in the family.  Prenatal testing is possible in pregnant carriers if their specific mutation is known.  Fetal sex is determined by chromosomal analysis from cells obtained from chorionic villus sampling at 10-12 weeks gestation or by amniocentesis at approximately 15-18 weeks gestation; if the phenotype is XY, the known disease-causing mutation can be analyzed in DNA extracted from fetal cells to establish disease status. 

 Clinical Features: DMD

Although DMD is diagnosed at birth based on family history and elevated CK, clinical abnormalities at birth are uncommon.  Parents and school teachers recognize  the signs and symptoms first when the child is between ages of 2 and 5 years.  

Clinical features of BMD

Outliers 

 Differential Diagnosis

 Diagnosis and Tests

Serum CK is the most useful screening test for the diagnosis of DMD.  Whole-blood DNA analysis for dystrophin gene mutations has largely replaced the clinical need for muscle biopsy to confirm the diagnosis. 

Treatment

 

Differential diagnosis of toe walking:

Parent Project for DMD

Vitolarsen

Eteplirsen (Exondys 51)

Ataluren (Translarna)Enabling the ribosome to read through a premature stop codon (nonsense mutations) is the mechanism of ataluren, another treatment for Duchenne muscular dystrophy.  “Nonsense mutations” in the dystrophin gene prematurely stops the production of a normal dystrophin protein and lead to a shortened and nonfunctional dystrophin protein.  Ataluren works in these patients by enabling the protein-making apparatus in cells to move past the nonsense mutation, allowing the cells to produce a functional dystrophin protein.

Viondys 53 (golodirsen)

ELEVIDYS (delandistrogene moxeparvovec-rokl) suspension, for intravenous infusion 

https://www.parentprojectmd.org/wp-content/uploads/2020/04/Transitions-Checklist.pdf