About DMD

DMD – Our focus now!!!


Duchenne Muscular Dystrophy was originally described by Edward Meryon, an English doctor at a meeting of the Royal Medical and Chirurgical Society in 1851. He showed that the disease was familial and only affected boys; most importantly, he demonstrated that the spinal cord at necropsy was normal. Therefore, this was a disease of muscle (myogenic) and was not secondary to anterior-horn cell degeneration. Furthermore, his detailed histological studies led him to conclude that the muscle membrane or sarcolemma was broken down and destroyed. However, Meryon's observations were neglected for many years for various reasons, and the disorder became eponymously associated with Duchenne in Paris, who detailed the clinical and muscle histology some years later.

The disease is named for the pioneering 19th century French neurologist Guillaume Benjamin Amand Duchenne. Becker muscular dystrophy (BMD) is named after the German doctor Peter Emil Becker, who first described this variant of DMD in the 1950s. Duchenne described a boy with the form of muscular dystrophy in the 1861 edition of his book. In 1868 he gave an account of 13 affected children under the designation "paralysie musculaire pseudohypertrophique." The term "pseudohypertrophic" stuck to this form of muscular dystrophy. Duchenne was the first to do a biopsy to obtain tissue from a living patient for microscopic examination. Duchenne used his biopsy needle on boys with DMD and concluded correctly that the disease was one of muscle.

Overview: Duchenne muscular dystrophy (DMD) is lethal neuromuscular disorder that is characterized by proximal muscle weakness and wasting. The X-linked disease affects boys of all ethnic origins. DMD has a worldwide estimated prevalence of 1 in 3500 live male births (fig 1), with a world-wide prevalence of an estimated 63 people per million. Females are typically carriers of the DMD gene mutation and are not clinically affected.
Symptoms: There are two key symptoms that alert medical professionals to the presence of Duchenne Muscular Dystrophy. Enlarged calves (fig 3) and progressive muscle weakness and failure are the hallmark signs.
Specific early clinical symptoms can include:
Delayed onset of walking
Difficulty in performing a standing jump
A waddled walk
Difficulty in getting up from the floor (fig 2).
{mosimage} {mosimage}Specific late clinical symptoms can include:
Difficulty in getting up from a chair
The loss of ability to normally climb stairs
A very wide gaited walk with balance problems
As the disease progresses, immobility is inevitable, organ systems start to malfunction, the child eventually has to be placed on a ventilator to retain the ability to breathe (Table 1). Ultimately, failure of the heart muscles is what kills boys affected with this disease.

Both Duchenne muscular dystrophy (DMD) and Becker muscular dystophy (BMD) are allelic diseases caused by mutations in the dystrophin gene. Dystrophin is the largest human gene located in chromosome Xp21 and spans up to 2.4 mega base pairs of DNA in length. The gene is comprised of 79 exons, and the fully processed transcript is 14 kb. The dystrophin gene is expressed in a cell-specific and developmentally regulated manner controlled by seven independent promoters.In around 30% of cases the mutation arises spontaneously, and the remaining cases are inherited in an X-linked recessive manner (fig 4).

Therefore the disease affects the male gender, though in rare instances females may also show a similar phenotype if they carry X-autosomal translocations that disrupt the dystrophin gene.Deletions of single or multiple exons are responsible for about 65% to 70% of DMD cases; the remaining have point mutations resulting from nonsense or frame-shift mutations (30%) or duplications (6%).Generally, a precise correlation exists between a patient's clinical state and the dystrophin gene defect. Mutations which cause a translational frameshift, and therefore give rise to a protein missing its C-terminal region, are tightly correlated with a severe DMD phenotype. On the other hand mutations conserving the frame of translation and, consequently, resulting in a protein with internal deletions or duplications, are usually correlated with a milder BMD phenotype.


Dystrophin is a muscle cell structural protein that resides beneath the sarcolemma, the plasma membrane that covers the outer surface of a muscle fiber (fig 5). The dystrophin protein stabilizes the muscle during muscle contraction by anchoring muscle filaments to the sarcolemma. In DMD, mutations to the DMD gene result in the production of non-functioning dystrophin proteins or no dystrophin production at all.

The lack of functioning dystrophin proteins prevents the normal contraction of muscle. When the muscles contract abnormally, the muscle cells become damaged. As the body attempts to repair the damage, it replaces the damaged muscle tissue with scar tissue. Affected individuals typically exhibit hypertrophy, in which muscles appear much larger than normal.

DMD affects the skeletal (voluntary) muscles, but also affects smooth (involuntary) muscles, such as the heart and diaphragm. Approximately 95% of DMD-affected individuals have cardiac involvement by the time of death. Cardiac problems include ECG abnormalities, arrhythmias, myocardial dilatation and myocardial thickening.

Dystrophin-related abnormalities in the brain may cause subtle cognitive and behavioral deficits which are not progressive.

Fig 5: The dystrophin-associated protein complex in muscle linking the internal cytoskeleton to the extracellular matrix. NOS, nitric oxide synthase.

Laboratory Testing:

Laboratory investigations of muscle are performed primarily via four methods: biochemical analysis, electromyography, DNA analysis, and histologic examination. CK is the most useful marker of muscle disease and is measured most commonly. The most spectacular elevation of serum CK (50 to 100 times normal) occurs in DMD. It is elevated at birth before there is clinical evidence of muscle weakness. Other muscle enzymes whose concentrations are elevated in the blood include aspartate aminotransferase,alanine aminotransferase, and lactic dehydrogenase, which also are found in hepatocytes.

Electromyography is the recording of muscle electrical activity by an electrode, both surface and needle. Electromyographic changes in DMD are nonspecific and of little use in establishing the diagnosis.

The molecular techniques for complimenting the diagnosis of muscular disorders have advanced significantly in the past few years. Identification of mutations in the dystrophin gene is a difficult task due to its large size. However, several techniques have been identified and standardized to screen mutations in this gene. Moreover, the fact that 98% of the gene deletions occur in specific hot spots identified in the gene has also made genetic screeing simple

A muscle biopsy is a very useful diagnostic tool but less so if the CK concentration and electromyography results are normal. The histologic changes in DMD depend somewhat on the muscle selected and the age of the boy. When the boys are very young, the histologic changes are minimal and include some focal areas of inflammation and muscle degeneration or regeneration. With time, muscle fibers are replaced with fibrous and fatty tissue along with inflammatory cells. Dystrophin, as assessed by immunohistochemical staining, is absent or nearly absent.

Treatment and management:

Management must be multidisciplinary accommodating each patient's complex and changing needs over time. Initially genetic counseling and psychosocial support for the boy and family members are important. Early rehabilitation goals should focus on promoting mobility and maintaining good ankle positioning through physical therapy and orthotic devices. Moderate activities such as swimming and biking are encouraged. Excessively strenuous activities and fatigue should be avoided.

Obesity is common and can have a major impact on such areas as quality of life, life expectancy, and burden of care. Nutritional management is most important and frequently requires alterations in the eating habits of all family members.

Despite recent advances in our understanding of the molecular and genetic aspects of DMD, very few treatments exist. Corticosteroids delay the very predictable and relentless progression of muscle weakness; their mechanism of action is unknown. Two corticosteroids, prednisone and deflazacort, seem to be equally effective and the most effective when administered daily but have certain adverse effects.

Many boys who have DMD have significant learning issues. Their schools must accommodate both physical and learning needs. The family, the school, and the rehabilitation team need to communicate with each other and work together. Some suggestions for the school environment include seating the child near the door and allowing "free" bathroom privileges. The desk may need to accommodate a wheelchair. Computer skills should be encouraged early. Enjoyable activities should be found for the child and emphasized. These children may need assistance with classroom and bathroom activities. The teacher should be encouraged to learn about DMD and approaches that might facilitate and strengthen school experiences.

Opportunities for treatment:

Increased knowledge of the function of dystrophin and its role in muscle has led to a greater understanding of the pathogenesis of DMD. This, together with advances in the genetic toolkit of the molecular biologist, are leading to many different approaches to treatment. Gene therapy can be achieved using plasmids or viruses, mutations can be corrected using chimaeraplasts and short DNA fragments, exon skipping of mutations can be induced using oligonucleotides and readthrough of nonsense mutations can be achieved using aminoglycoside antibiotics. Blocking the proteasome degradation pathway can stabilize any truncated dystrophin protein, and upregulation of other proteins can also prevent the dystrophic process. Muscle can be repopulated with myoblasts or stem cells. All, or a combination, of these approaches hold great promise for the treatment of this devastating disease.


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