Duchenne muscular dystrophy (DMD) is a rare, severe and progressive genetic disorder.It is caused by a genetic mutation that prevents the body from producing dystrophin, a protein that enables muscles to work properly. It is one of the most common types of muscular dystrophy, primarily affecting boys; however, it can rarely affect girls also. The prevalence of DMD is approximately 1 in 3500 to 5000 male births worldwide. There are currently no curative therapies for DMD, but gene therapy is a promising experimental method.
Symptoms and Traits
DMD symptom onset occurs in early childhood, usually between ages 3 and 5 years . Over time, children with Duchenne will have difficulty walking and breathing. These hardships will eventually lead to disability, dependence, and premature death .
Muscle weakness is the principal symptom of DMD and worsens over time, targeting the proximal muscles first and later affecting the distal limb muscles. Patients with DMD progressively lose the ability to perform activities independently and often require a wheelchair by their early teens. As the disease advances, life-threatening heart and respiratory conditions can occur. Generally, patients succumb to the disease in their 20s or 30s . However, disease severity and life expectancy may vary.
DMD is caused by mutations in the DMD gene, which encodes the protein product called dystrophin. The DMD gene is one of the largest identified human genes, spanning 2.4 Mb of a genomic sequence and corresponding to about 0.1% of the total human genome . The gene consists of 79 exons encoding a 14,000 bp messenger RNA transcript . The most common mutation responsible for DMD is a deletion spanning one or multiple exons accounting for 60–70% of all DMD cases. While point mutations are responsible for around 26% of DMD cases, exonic duplications account for 10 to 15% of all DMD cases . Mutations in the DMD gene disrupt the protein’s reading frame, which causes premature stop codons, leaving little or no functional dystrophin protein produced in cells.
Figure 1. Schematic depiction of dystrophin transcripts in an individual living with DMD vs. a control 
(A) In the normal situation, the dystrophin mRNA(Messenger Ribonucleic acid) consists of 79 exons that are translated into the dystrophin protein. (B) In patients with DMD, protein translation is stopped prematurely. This can be due to frame-shifting mutations (in this example, a deletion of exons 47–50, top panel) that lead to the inclusion of aberrant amino acids and generally premature truncation of translation. Alternatively, a point mutation can change an amino acid codon into a stop codon (bottom panel, nonsense mutation). This premature stop codon will be used instead of the natural stop codon at the end of the transcript .
Dystrophin protein, which consists of 3,685 amino acids with a molecular weight of 427 kDa, is located in the cytoplasmic face of the sarcolemma . Based on sequence homology, dystrophin is divided into four distinct structural domains: (i) amino-terminal actin-binding domain that contains two calponin homology domain which directly interacts with cellular actin cytoskeleton , (ii) a long central rod-shaped domain is composed of 24 structurally similar spectrin-type repeats , (iii) cysteine-rich domain binds to the intrinsic membrane protein β-dystroglycan, and (iv) the carboxy-terminal domain binds to dystrobrevin and syntrophins . Dystrophin is a cytoskeletal protein that binds to actin and associates with the dystrophin–glycoprotein complex (DGC) to link the cytoskeleton to the extracellular matrix (ECM) [12, 13]. The DGC consists of integral and peripheral proteins: dystroglycans, sarcoglycans, and syntrophins [12, 13]. Defects in dystrophin and/or other components of the DGC are responsible for several phenotypes of muscular dystrophy, including DMD.
Diagnosis and Treatment
Recent advances in molecular therapies for DMD require a precise genetic diagnosis since a large number of therapeutic approaches are mutation-specific. Genetic tests involve the examination of deoxyribonucleic acid (DNA) to identify specific genetic mutations: deletions, duplications, and single point mutations. If the genetic tests are not informative, a surgical removal and microscopic examination (biopsy) of affected muscle tissue may reveal characteristic changes of the muscle fibers. Specialized blood tests (e.g. creatine kinase) that evaluate the presence and levels of certain proteins in muscle (immunohistochemistry) are also used.
There are currently no curative therapies for DMD. Different therapies are currently being investigated to treat muscular dystrophy.
Figure 2. Dystrophin and dystrophin-associated glycoprotein complex 
Exon skipping is the “patching” of that gene part with missing or mutated exons using short stretches of DNA. This can lead to the production of a truncated, albeit functional, protein to ease some of the symptoms of muscular dystrophy.
Several kinds of vector-mediated gene therapies are also being developed to treat DMD. For example, vector-mediated gene therapy delivers functioning genes directly into specific tissues. Currently, Adeno-associated viruses (AAV) vectors are the most widely used vector in vector-mediated gene therapy. Four main categories of AAV-delivered gene therapy (gene replacement, modiﬁer gene expression, gene editing, and gene lockdown) are emerging as a potential treatment for DMD.
CRISPR/Cas9 is a powerful gene-editing method that is being investigated for potential applications in treating DMD. Delivery of CRISPR genome editing tools by AAVs can reframe the mutated DMD gene and restore dystrophin expression.
DMD is a rare, severe, and progressive genetic disorder that gives rise to disability and premature death. DMD is caused by mutations in the dystrophin-encoding DMD gene, which is one of the largest identified human genes. There is currently no curative treatment for DMD, but gene therapy may open up new possibilities for treating patients with this disorder in the future.
Education 2018.7~Present West Windsor-Plainsboro High School South, New Jersey, US 2015.9~2018.6 Thomas R. Grover Middle School, New Jersey, US