Archive for the ‘Duchenne Muscular Dystrophy’ Category

Genetics Of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy:

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.

Symptoms usually appear in male children before age 5 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas. Early signs may include pseudohypertrophy (enlargement of calf and deltoid muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aid in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine. Due to progressive deterioration of muscle, loss of movement occurs, eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worsen as the child ages. The average life expectancy for patients afflicted with DMD is around 25, but this varies from individual to individual.

First Symptoms:

Many kids with muscular dystrophy follow a normal pattern of development during their first few years of life. But in time common symptoms begin to appear. A child who has MD may start to stumble, waddle, have difficulty going up stairs, and toe walk (walk on the toes without the heels hitting the floor). A child may start to struggle to get up from a sitting position or have a hard time pushing things, like a wagon or a tricycle.

Kids with MD often develop enlarged calf muscles (called calf pseudohypertrophy) as muscle tissue is destroyed and replaced by fat.

Background:

Duchenne muscular dystrophy (DMD), which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion “hot spot” is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD) model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD “hot spot”.

What is Duchenne and Becker muscular dystrophy?

Muscular dystrophies are a group of genetic conditions characterized by progressive muscle weakness and wasting (atrophy). The Duchenne and Becker types of muscular dystrophy primarily affect the skeletal muscles, which are used for movement, and the muscles of the heart. These conditions occur much more frequently in males than in females.

Duchenne and Becker muscular dystrophies have similar signs and symptoms and are caused by different mutations in the same gene. The two conditions differ in their severity, age of onset, and rate of progression. In people with Duchenne muscular dystrophy, muscle weakness tends to appear in early childhood and progress rapidly. Affected children may have delayed motor skills, such as sitting, standing, and walking. They are usually wheelchair-dependent by adolescence. The signs and symptoms of Becker muscular dystrophy are usually milder and exhibit a large range of variation. In most cases, muscle weakness becomes apparent later in childhood or adolescence and progresses at a much slower rate.

Both the Duchenne and Becker forms of muscular dystrophy are associated with a heart condition called dilated cardiomyopathy. This form of heart disease enlarges and weakens the heart (cardiac) muscle, preventing it from pumping blood efficiently. Dilated cardiomyopathy progresses rapidly and is life-threatening in many cases. In people with Duchenne muscular dystrophy, the signs and symptoms of cardiomyopathy typically appear in adolescence. The onset of cardiomyopathy in people with Becker muscular dystrophy is later, usually in early to mid-adulthood.

How common is Duchenne and Becker muscular dystrophy?

Duchenne and Becker muscular dystrophies together affect 1 in 3,500 to 5,000 newborn males. Between 400 and 600 boys in the United States are born with these conditions each year. Females are rarely affected by these forms of muscular dystrophy.

What genes are related to Duchenne and Becker muscular dystrophy?

Mutations in the DMD gene cause Duchenne and Becker muscular dystrophy.

The DMD gene provides instructions for making a protein called dystrophin. This protein helps stabilize and protect muscle fibers and may play a role in chemical signaling within cells. Mutations in the DMD gene alter the structure or function of dystrophin, or prevent any functional dystrophin from being produced. Muscle cells without this protein become damaged as muscles repeatedly contract and relax with use. The damaged fibers weaken and die over time, leading to the muscle weakness and heart problems characteristic of Duchenne and Becker muscular dystrophies.

How do people inherit Duchenne and Becker muscular dystrophy?

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In about two thirds of cases, an affected male inherits the mutation from a mother who carries an altered copy of the DMD gene. The other one third of cases probably result from new mutations in the gene.

In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene, but usually does not experience signs and symptoms of the disorder. Occasionally, however, females who carry a DMD gene mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males. Females who carry a DMD gene mutation also have an increased risk of developing heart abnormalities including dilated cardiomyopathy.

Symptoms:

The main symptom of Duchenne muscular dystrophy, a progressive neuromuscular disorder, is muscle weakness associated with muscle wasting with the voluntary muscles[citation needed] 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
•     Fatigue
•     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)

How is Duchenne muscular dystrophy diagnosed?

Duchenne muscular dystrophy is diagnosed in several ways. A clinical diagnosis may be made when a boy has progressive symmetrical muscle weakness. The symptoms present before age 5 years, and they often have extremely elevated creatine kinase blood levels (which are described below) . If untreated, the affected boys become wheelchair dependent before age 13 years.

A muscle biopsy (taking a sample of muscle) for dystrophin studies can be done to look for abnormal levels of dystrophin in the muscle. The dystrophin protein can be visualized by staining the muscle sample with a special dye that allows you to see the dystrophin protein. A muscle which has average amounts of dystrophin will appear with the staining technique as though there is caulking around the individual muscles cells and it is holding them together like window panes. A boy with Duchenne, on the other hand, will have an absence of dystrophin and appear to have an absence of the caulking around the muscle cells. Some individuals can be found to have an intermediate amount of the dystrophin protein. Often these boys are classified as having Becker muscular dystrophy.

Genetic testing (looking at the body’s genetic instructions) on a blood sample for changes in the DMD gene can help establish the diagnosis of Duchenne muscular dystrophy without performing a muscle biopsy. Genetic testing is constantly changing, but the methods currently being used look for large changes in the gene (deletion/duplication) and another method, which looks at the letters that spell out the instructions found within the DMD gene (sequencing). Together these two methods can detect the disease causing changes in about 95% of patients. Those individuals who are not found to have a detected change in the DMD gene using this method, and who are diagnosed with DMD by biopsy, still have a change in their gene but it is in areas of the gene that are not examined using these methods. However, the results of genetic testing may not be conclusive of a diagnosis of DMD, and only the muscle biopsy can tell the level of dystrophin protein for sure.

For the remaining individuals, a combination of clinical findings, family history, blood creatine kinase concentration and muscle biopsy with dystrophin studies confirms the diagnosis. Creatine kinase is an enzyme that is present normally in high concentrations in the muscle cells of our body. During the process of muscle degeneration or breakdown, the muscle cells are broken open and their contents find their way to the bloodstream. Therefore elevated levels of creatine kinase can be detected from a blood test and it is a measure of muscle damage. Elevated levels can be the result of multiple reasons including acute muscle injury, or chronic condition such as Duchenne muscular dystrophy.

Duchenne muscular dystrophy:

Duchenne muscular dystrophy (DMD) is one of a group of muscular dystrophies characterized by the enlargement of muscles. DMD is one of the most prevalent types of muscular dystrophy and is characterized by rapid progression of muscle degeneration that occurs early in life. All are X-linked and affect mainly males an estimated 1 in 3500 boys worldwide.

The gene for DMD, found on the X chromosome, encodes a large protein dystrophin. Dystrophin is required inside muscle cells for structural support; it is thought to strengthen muscle cells by anchoring elements of the internal cytoskeleton to the surface membrane. Without it, the cell membrane becomes permeable, so that extracellular components enter the cell, increasing the internal pressure until the muscle cell “explodes” and dies. The subsequent immune response can add to the damage.

A mouse model for DMD exists and is proving useful for furthering our understanding on both the normal function of dystrophin and the pathology of the disease. In particular, initial experiments that increase the production of utrophin, a dystrophin relative, in order to compensate for the loss of dystrophin in the mouse are promising and may lead to the development of effective therapies for this devastating disease.
What is the official name of the DMD gene?

The official name of this gene is “dystrophin.”

DMD is the gene’s official symbol. The DMD gene is also known by other names, listed below.

What is the normal function of the DMD gene?

DMD, the largest known human gene, provides instructions for making a protein called dystrophin. There are many different versions of dystrophin, some of which are specific to certain cell types. Dystrophin is located chiefly in muscles used for movement (skeletal muscles) and the muscles of the heart (cardiac muscles). Small amounts of the protein are present in nerve cells in the brain.

In skeletal and cardiac muscles, dystrophin is part of a group of proteins that work together (a protein complex) that strengthens muscle fibers and protects them from injury as muscles contract and relax. The dystrophin complex acts as an anchor, connecting each muscle cell’s structural framework (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix). The dystrophin complex may also play a role in cell signaling by interacting with proteins that send and receive chemical signals.

Little is known about the function of dystrophin in nerve cells. Research suggests that the protein is important for the normal structure and function of synapses, which are specialized connections between nerve cells where cell-to-cell communication occurs.
How are changes in the DMD gene related to health conditions?

Duchenne and Becker muscular dystrophy – caused by mutations in the DMD gene

•     Hundreds of mutations in the DMD gene have been identified in people with the Duchenne and Becker forms of muscular dystrophy. Most of these mutations delete part of the DMD gene. Other mutations abnormally duplicate part of the gene or change a small number of DNA building blocks (nucleotides) in the gene.
•     Mutations that cause Becker muscular dystrophy, which typically has milder features and a later age of onset than Duchenne muscular dystrophy, usually lead to an abnormal version of dystrophin that retains some function. Mutations that cause the more severe Duchenne muscular dystrophy typically prevent any functional dystrophin from being produced.
•     Skeletal and cardiac muscle cells without enough functional dystrophin become damaged as the muscles repeatedly contract and relax with use. The damaged cells weaken and die over time, causing the characteristic muscle weakness and heart problems seen in Duchenne and Becker muscular dystrophy.
• other disorders – caused by mutations in the DMD gene
•     Mutations in the DMD gene also cause a form of heart disease called X-linked dilated cardiomyopathy. This condition enlarges and weakens the cardiac muscle, preventing it from pumping blood efficiently. Although dilated cardiomyopathy is a sign of Duchenne and Becker muscular dystrophy, the isolated X-linked form of this heart condition is not associated with weakness and wasting of skeletal muscles. Researchers are not certain why some mutations in the DMD gene cause X-linked cardiomyopathy instead of muscular dystrophy. They believe that some DMD mutations affect a version of dystrophin that is specific to heart muscle.

Treatment:

• There is no current cure for DMD, although phase 1-2a trials with exon-skipping treatment for certain mutations have halted decline and produced small clinical improvements in walking.
• Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life, and include the following:
•     Corticosteroids such as prednisolone and deflazacort increase energy and strength and defer severity of some symptoms.
•     Randomised control trials have shown that beta2-agonists increase muscle strength but do not modify disease progression. Follow-up time for most RCTs on beta2-agonists is only around 12 months and hence results cannot be extrapolated beyond that time frame.[citation needed]
•     Mild, non-jarring physical activity such as swimming is encouraged. Inactivity (such as bed rest) can worsen the muscle disease.
•     Physical therapy is helpful to maintain muscle strength, flexibility, and function.
•     Orthopedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care. Form-fitting removable leg braces that hold the ankle in place during sleep can defer the onset of contractures.
•     Appropriate respiratory support as the disease progresses is important
• Comprehensive multi-disciplinary care standards/guidelines for DMD have been developed by the Centers for Disease

 Prognosis:

Duchenne muscular dystrophy is a progressive disease which eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. The life expectancy is currently estimated to be around 25,[1] but this varies from patient to patient. Recent advancements in medicine are extending the lives of those afflicted. The Muscular Dystrophy Campaign, which is a leading UK charity focusing on all muscle disease, states that “with high standards of medical care young men with Duchenne muscular dystrophy are often living well into their 30s”.

• In rare cases, persons with DMD have been seen to survive into the forties or early fifties, with the use of proper positioning in wheelchairs and beds, ventilator support (via tracheostomy or mouthpiece), airway clearance, and heart medications, if required. Early planning of the required supports for later-life care has shown greater longevity in people living with DMD.

Physical therapy:

• Physical therapists are concerned with enabling children to reach their maximum physical potential. Their aim is to:
•     minimize the development of contractures and deformity by developing a programme of stretches and exercises where appropriate
•     anticipate and minimize other secondary complications of a physical nature
•     monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions
•     Schedule weekly to monthly sessions at a massage therapist to alleviate pain present.

Mechanical ventilatory/respiration assistance:

Modern “volume ventilators/respirators,” which deliver an adjustable volume (amount) of air to the person with each breath, are valuable in the treatment of people with muscular dystrophy related respiratory problems. The ventilator may require an invasive endotracheal or tracheotomy tube through which air is directly delivered, but, for some people non-invasive delivery through a face mask or mouthpiece is sufficient. Positive airway pressure machines, particularly bi-level ones, are sometimes used in this latter way. The respiratory equipment may easily fit on a ventilator tray on the bottom or back of a power wheelchair with an external battery for portability.

Ventilator treatment may start in the mid to late teens when the respiratory muscles can begin to collapse. If the vital capacity has dropped below 40 percent of normal, a volume ventilator/respirator may be used during sleeping hours, a time when the person is most likely to be under ventilating (“hypoventilating”). Hypoventilation during sleep is determined by a thorough history of sleep disorder with an oximetry study and a capillary blood gas (See Pulmonary Function Testing).

If the vital capacity continues to decline to less than 30 percent of normal, a volume ventilator/respirator may also be needed during the day for more assistance. The person gradually will increase the amount of time using the ventilator/respirator during the day as needed.

However, there are also people with the disease in their 20′s who have no need for a ventilator.