Duchenne Muscular Dystrophy (DMD)
Duchenne Muscular Dystrophy (DMD)
Pseudohypertrophic muscular dystrophy; Muscular dystrophy – Duchenne type
Duchenne muscular dystrophy is an inherited disorder that involves rapidly worsening muscle weakness.
Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is around 1 in 3,600 boys.Females and males are affected, though females are rarely affected and are more often carriers. The disorder is caused by a mutation in the dystrophin gene, located in humans on the X chromosome (Xp21). The dystrophin gene codes for the protein dystrophin, an important structural component within muscle tissue. Dystrophin provides structural stability to the dystroglycan complex (DGC), located on the cell membrane.
Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21. Dystrophin is responsible for connecting the cytoskeleton of each muscle fiber to the underlying basal lamina (extracellular matrix) through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane). Alterations in these signalling pathways cause water to enter into the mitochondria which then burst. In skeletal muscle dystrophy, mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species (ROS) production. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.
Due to the way in which this disease is inherited (in an X-linked recessive pattern) males are much more likely than females to develop the symptoms. The son of females who is a carrier of the disease (who has a defective gene but no symptoms) has a 50% chance of developing the disease. A daughter of such a female has a 50% chance of being a carrier. It is sometimes possible for a female carrier to develop symptoms, but this happens only in a minority of cases and the symptoms are not as severe as with males. Males (XY) have the X chromosome from their mother and the Y chromosome from their father. If their X chromosome has a DMD gene mutation, they will develop DMD. Females (XX) have two copies of the X chromosomes, and if one copy does not work, they have a second back up copy to produce the dystrophin protein.
The main symptom of Duchenne muscular dystrophy, a progressive neuromuscular disorder, is muscle weakness associated with muscle wasting with the voluntary muscles being first affected, especially affecting the muscles of the hips, pelvic area, thighs, shoulders, and calf muscles. Muscle weakness also occurs in the arms, neck, and other areas, but not as early as in the lower half of the body. Calves are often enlarged. Symptoms usually appear before age 6 and may appear as early as infancy. The other physical symptoms are:
Awkward manner of walking, stepping, or running. (patients tend to walk on their forefeet, because of an increased calf tonus. Also, toe walking is a compensatory adaptation to knee extensor weakness.)
- Frequent falls
- Difficulty with motor skills (running, hopping, jumping)
- Increased Lumbar lordosis, leading to shortening of the hip-flexor muscles. This has an effect on overall posture and a manner of walking, stepping, or running.
- Muscle contractures of achilles tendon and hamstrings impair functionality because the muscle fibers shorten and fibrosis occurs in connective tissue
- Progressive difficulty walking
- Muscle fiber deformities
- Pseudohypertrophy (enlarging) of tongue and calf muscles. The muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy.
- Higher risk of neurobehavioral disorders (e.g., ADHD), learning disorders (dyslexia), and non-progressive weaknesses in specific cognitive skills (in particular short-term verbal memory), which are believed to be the result of absent or dysfunctional dystrophin in the brain.
- Eventual loss of ability to walk (usually by the age of 12)
- Skeletal deformities (including scoliosis in some cases)
Signs and tests
A complete nervous system (neurological), heart, lung, and muscle exam may show:
- Abnormal heart muscle (cardiomyopathy)
- Congestive heart failure or irregular heart rhythm (arrhythmias) — rare
- Deformities of the chest and back (scoliosis)
- Enlarged calf muscles, which are eventually replaced by fat and connective tissue (pseudohypertrophy)
- Loss of muscle mass (wasting)
- Muscle contractures in the heels, legs
- Muscle deformities
- Respiratory disorders, including pneumonia and aspiration of food or fluid into the lungs (in late stages of the disease)
- Tests may include:
- Electromyography (EMG)
- Genetic tests
- Muscle biopsy
- Serum CPK
There is no known cure for Duchenne muscular dystrophy. Treatment aims to control symptoms to maximize quality of life. Gene therapy may become available in the future.
Activity is encouraged. Inactivity (such as bedrest) can worsen the muscle disease. Physical therapy may be helpful to maintain muscle strength and function. Orthopedic appliances (such as braces and wheelchairs) may improve mobility and the ability to care for yourself.
- Congestive heart failure (rare)
- Heart arrhythmias (rare)
- Mental impairment (varies, usually minimal)
- Permanent, progressive disability
- Decreased mobility
- Decreased ability to care for self
- Pneumonia or other respiratory infections
- Respiratory failure
Genetic counseling is advised if there is a family history of the disorder. Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy.