A 9-year-old boy with a history of Duchenne muscular dystrophy (DMD) is being seen by his pediatrician for a routine maintenance exam. He initially presented at 3 years of age for evaluation of toe walking and excessive falling, and was diagnosed with DMD. He started walking independently between 12 to 14 months of age. He had always been slower than his peers and has difficulty keeping up with them. At the time of diagnosis, the family reported increasing difficulty going up steps which he can only do one step at a time. He also had difficulty getting up from the floor, needing to push on his knee or use furniture for assistance (Gower sign), which has continued and is pronounced at the current visit (Figure 208-1). He also tends to be clumsy with excessive falling and has an awkward appearing waddling gait, exacerbated by running.
FIGURE 208-1
Gower sign. In order to stand up, the child gets into a prone crawl position with hands on the floor (A-D), extends and locks the legs in a widened stance (E-F), then using extended arms they shift their weight backwards and use their hands on their knees and thighs until they can achieve an upright position (G-H). (Used with permission from Neil Friedman, MD.) (continued )
Most common form of muscular dystrophy.
Presents between 2 to 5 years of with progressive, symmetric proximal weakness manifesting as difficulty getting up from the floor, difficulty climbing stairs, a waddling gait, and excessive tripping and falling.
Loss of ambulation typically between 7 to 13 years of age.
Early demise in 2nd or 3rd decade secondary to cardiomyopathy and progressive respiratory failure due to weakness.
Results from mutation of the DMD gene; dystrophin is the gene product.
X-linked recessive inheritance—Primarily affects males but female carriers may manifest disease characteristics due to skewed inactivation of the X-chromosome (Lyon hypothesis).
Variable phenotype depending on the nature of the gene mutation.
Absence of dystrophin results in the severe Duchenne muscular dystrophy (DMD) phenotype.
Preservation of some dystrophin results in the allelic, milder Becker muscular dystrophy (BMD) phenotype or a dilated cardiomyopathy (DCM) in which the heart is primarily affected with little or no skeletal muscle involvement (Table 208-1).
1851—Edward Meryon reported first clinical cases of DMD in the medical literature.
1868—The French neurologist Duchenne de Boulogne describes a series of children with the disease that would later bear his name.
1954—Walton and Nattrass developed first classification of muscular dystrophies based on clinical and inheritance factors.
1986—DMD gene identified by Luis Kunkel (positional cloning or “reverse genetics”).
| Duchenne | Becker | |
| Age of presentation | 3–5 years | 5–10 years, sometimes adolescence |
| Loss of ambulation | Before 13th birthday | Beyond 16th birthday |
| Death | Early 20’s—from cardiopulmonary failure | Variable—long-term survival possible |
| CK | Massively elevated >10-100 × normal | Massively elevated >10–100 × normal |
| Cardiomyopathy | Late—end stage | Early, disproportionate to muscle weakness May be presenting feature |
| Dystrophin | Absent (<5%) | Reduced in quantity or quality (>10%) |
| Gene deletion | Large Deletions: about 2/3 of cases Small deletions, point mutations and duplications: about 1/3 of cases | Large Deletions: about 2/3 of cases Small deletions, point mutations and duplications: about 1/3 of cases |
DMD is caused by an out-of-frame deletion, point mutation or duplication in the DMD gene leading to a complete absence of protein; whereas BMD results from an in-frame deletion or duplication in the DMD gene resulting in the expression of an altered size, but partially functional dystrophin protein.2
Deletions account for approximately 65 percent of cases of DMD and 85 percent of cases of BMD; the remainder due to point mutations or rarely duplications.
De novo mutations occur in approximately 1/3 of cases, while 2/3 of cases are inherited from the mother.
The DMD gene is the largest in the human genome (0.1% of the entire genome), encompassing 2.6 million base pairs of DNA and containing 79 exons.
Dystrophin is a large, subsarcolemmal structural protein that has a major structural role in muscle as it links the internal actin cytoskeleton to the dystrophin-associated glycoproteins (DAG) in the sarcolemmal membrane (Figure 208-2).3
Absence of dystrophin disrupts the muscle ultra structure resulting in muscle injury, inflammatory changes and ultimately degeneration of the muscle fibers with resultant replacement of muscle fibers by connective tissue and fatty infiltration, which is irreversible.4
FIGURE 208-2
Dystrophin-associated glycoprotein complex. (Reprinted by permission from Macmillan Publishers Ltd: Molecular Therapy (Mol Ther.2012 Feb;20(2):462-7), Copyright 2012.)
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