At a glance......
- 1 Causes of Duchenne Muscular Dystrophy
- 2 Symptoms of Duchenne Muscular Dystrophy
- 3 Diagnosis of Duchenne Muscular Dystrophy
- 4 Treatment of Duchenne Muscular Dystrophy
- 4.1 Cyclosporine
- 4.2 Management Guidelines
- 4.3 Physical therapy
- 4.4 Splinting
- 4.5 Manual muscle testing (MMT) and range of motion (ROM)
- 4.6 Seating and positioning
- 4.7 Adaptive equipment and devices
- 4.8 Social skills development
- 4.9 Sexual health
- 4.10 Employment
- 4.11 Home modifications
- 4.12 Leisure
- 4.13 FDA-Approved Treatments
- 4.14 Furthers Treatment
- 4.15 Where to Start
- 4.16 In-Depth Information
- 4.17 Resources for Kids
- 5 References
Duchenne muscular dystrophy (DMD) is a rapidly progressive form of muscular dystrophy that occurs primarily in boys. It is caused by an alteration (mutation) in a gene, called the DMD gene that can be inherited in families in an X-linked recessive fashion, but it often occurs in people from families without a known family history of the condition. It is caused by a mutation in a gene, called the DMD gene, which encodes the muscle proteindystrophin. Boys with Duchenne muscular dystrophy do not make the dystrophin protein in their muscles. Duchenne mucular dystrophy is inherited in an X-linked recessive disease that confined in wheel chair at the age of 12 & died in at the age of 18 in severs case.
Duchenne muscular dystrophy (DMD) one of the most severe forms of inherited muscular dystrophies. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. Mutations in the dystrophin gene lead to progressive muscle fiber degeneration and weakness. This weakness may present initially with difficulty in ambulation but progressively advances to such an extent that affected patients are unable to carry out activities of daily living and become wheelchair bound. Cardiac and orthopedic complications are common, and death usually occurs in the twenties due to respiratory muscle weakness or cardiomyopathy. Current therapy is centered on treatment with glucocorticoids and physiotherapy to prevent orthopedic complications.
Causes of Duchenne Muscular Dystrophy
DMD is caused by a mutation of the dystrophin gene at locus Xp21, located on the short arm of the X chromosome. 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 (the cell membrane).Alterations in calcium and 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 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.
DMD is inherited in an X-linked recessive pattern. Females typically are carriers for the disease, while males are affected. A female carrier will be unaware she carries a mutation until she has an affected son. The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier and a 50% chance of having two normal copies of the gene. In all cases, an unaffected father either passes a normal Y to his son or a normal X to his daughter. Female carriers of an X-linked recessive condition, such as DMD, can show symptoms depending on their pattern of X-inactivation.
How is Duchenne muscular dystrophy (DMD) inherited?
Each person inherits a set of genes from their father and another set from their mother. The genes have been copied from the parents’ cells into the child’s cells.
Genes are found on ‘chromosomes’, rather like houses on a street. The DMD gene is located on a chromosome called the X chromosome. Boys have one X chromosome and one Y chromosome; girls have two X chromosomes.
DMD is inherited in a pattern called ‘X-linked inheritance’. The DMD gene is ‘carried’ by women but does not usually cause problems in girls or women (with rare exceptions, below). This is because of there being two X chromosomes in women: one X chromosome has the ‘faulty’ DMD gene; the other X chromosome has a normal gene, which compensates for the faulty one.
In contrast, boys with the DMD gene do not have a second X chromosome and so they cannot compensate for the faulty gene. Therefore, boys with the DMD gene always have symptoms of the disease.
The DMD gene can be passed on from parent to child. For a woman who carries the DMD gene, there is a 1 in 2 chance that her sons will have DMD, and a 1 in 2 chance that her daughters will carry the gene.
Symptoms of Duchenne Muscular Dystrophy
The main symptom of DMD, a progressive neuromuscular disorder, is muscle weakness associated with muscle wasting with the voluntary muscles being first affected, especially those of the hips, pelvic area, thighs, shoulders, and calves. Muscle weakness also occurs later, in the arms, neck, and other areas. Calves are often enlarged. Symptoms usually appear before age six and may appear in early infancy. Other physical symptoms are
- Awkward manner of walking, stepping, or running – (patients tend to walk on their forefeet, because of an increased calf muscle tone. Also, toe walking is a compensatory adaptation to knee extensor weakness.)
- Frequent falls
- Difficulty with motor skills (running, hopping, jumping)
- Lumbar hyperlordosis, possibly 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 fibrose 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)
- Trouble getting up from lying or sitting position
- A positive Gowers’ sign reflects the more severe impairment of the lower extremities muscles. The child helps himself to get up with upper extremities: first by rising to stand on his arms and knees, and then “walking” his hands up his legs to stand upright.
- Affected children usually tire more easily and have less overall strength than their peers.
- Creatine kinase (CPK-MM) levels in the bloodstream are extremely high.
- An electromyography (EMG) shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.
- Genetic testing can reveal genetic errors in the Xp21 gene.
- A muscle biopsy (immunohistochemistry or immunoblotting) or genetic test (blood test) confirms the absence of dystrophin, although improvements in genetic testing often make this unnecessary.
- Abnormal heart muscle (cardiomyopathy)
- Congestive heart failure or irregular heart rhythm (arrhythmia)
- Deformities of the chest and back (scoliosis)
- Enlarged muscles of the calves, buttocks, and shoulders (around age 4 or 5). These muscles are eventually replaced by fat and connective tissue (pseudohypertrophy).
- Loss of muscle mass (atrophy)
- Muscle contractures in the heels, legs
- Muscle deformities
- Respiratory disorders, including pneumonia and swallowing with food or fluid passing into the lungs (in late stages of the disease)
Diagnosis of Duchenne Muscular Dystrophy
Duchenne is typically diagnosed in boys between the ages of 3 and 7.
The most commonly reported initial symptoms of Duchenne are:
- delayed motor development
- waddling gait (walk)
- trouble getting up off the floor (they walk their hands up their legs to help them get up)
- the difficulty with steps and falling often
- enlarged calves
- speech and language delay
- behavioral problems/learning difficulties
- Genetic tests are done using a blood sample. The DNA in the blood is tested to look at the dystrophin gene. This test can diagnose most cases of DMD.
- An electromyogram (EMG) – this is a recording of the electrical activity in a muscle.
- Muscle ultrasound is used to look for suspected CMD.
Once Duchenne is suspected from the symptoms, there is a range of tests that can be done by a doctor to reach a diagnosis, which is listed below.
Laboratory testing involves creatinine kinase measurements, muscle biopsies, gene testing, and ECG findings for cardiomyopathy.
Serum Creatinine Kinase (CK)
- Serum CK measurements are elevated before the development of clinical symptoms and signs and may also be elevated in newborns. Levels peak by age 2 and can be more than 10 to 20 times above the upper limit of normal. As age and disease progress, serum CK levels decrease as fibrosis and fat progressively replace muscle. Other muscle enzymes such as aldolase levels and AST levels may also elevate. Asymptomatic carriers may also have elevated CK levels. This is seen in about 80% of cases, and the highest levels are noted between ages 8 and 12.
- A muscle biopsy will demonstrate endomysial connective tissue proliferation, scattered degeneration, and regeneration of myofibers, muscle fiber necrosis with a mononuclear cell infiltrate and replacement of muscle with adipose tissue and fat. The common muscles biopsies are the quadriceps femoris and the gastrocnemius.
- Characteristic myopathic features can be seen; however, this is nonspecific. Motor and sensory nerve conduction velocities are normal, and denervation is not present.
- Patients with DMD demonstrate the complete or near complete absence of dystrophin gene. Dystrophin immunoblotting can be used to predict the severity of the disease. In DMD, patients are found to have less than 5% of the normal quantity of dystrophin.
- Polymerase chain reactions (PCR) can also be used and detect up to 98% of mutations. Multiplex ligation-dependent probe amplification (MPLA) is also used to identify duplications and deletions. Duplications can lead to in-frame or out of frame transcription products. Fluorescence in situ hybridization (FISH) is used less frequently but is useful to identify small point mutations. Dystrophin immunocytochemistry can also be sued to detect cases not identifies by PCR.
- Characteristic ECG changes are tall R waves in V1-V6 with an increased R/S ratio and deep Q waves in leads I,aVL and V5-6. Conduction abnormalities with arrhythmias may be identified with telemetry. As mentioned previously, supraventricular arrhythmias are more common. Intra-atrial conduction abnormalities are more common than AV or infra-nodal defects in DMD.
- Evidence of dilated cardiomyopathy is present in almost all patients by the end of their teens or in their 20s.
- The muscles contain an enzyme called creatine kinase (CK), and when muscles are damaged, this enzyme spills out into the bloodstream. Measuring CK levels in the blood is a simple, cost-effective, readily available test. A raised CK level verifies that there has been muscle damage, but does not give a definite diagnosis, so further testing (usually by a pediatric neurologist) will be required.
- DNA is obtained from a blood sample and scientists are able to examine the dystrophin gene to find out if there is a change that indicates Duchenne.
- If DNA testing does not give a clear diagnosis a muscle biopsy may be needed (in rare cases). A surgeon removes a small sample of muscle and it is examined under a microscope to see if dystrophin protein is present.
- Beckers Muscular Dystrophy (BMD) – BMD has a later onset, and the length of survival is longer. Patients typically have higher concentrations of dystrophin protein.
- The intermediate form of Muscular Dystrophy – Patients with this form of dystrophy have dystrophin levels between DMD and BMD.
- Myotonic Muscular Dystrophy – Inherited as an autosomal dominant disorder, distal muscles are more commonly affected the ability to walk is often preserved.
- Limb-Girdle Muscular Dystrophy – This inherited dystrophy primarily affects the muscles of the hip and shoulder girdles
- Congenital Myotonic Dystrophies – This encompasses a group of inherited disorders associated with muscular dystrophy. The dystrophy is characterized by an increased severity at birth but has a benign course through life. There is a higher association with brain malformations. This includes diseases such as Ullrich type of muscular dystrophy, Fukuyama type of congenital muscular dystrophy and muscular dystrophy associated with Walker-Warburg syndrome to name a few.
Treatment of Duchenne Muscular Dystrophy
- Prednisone is a steroid that has been shown to extend the ability to walk by 2 to 5 years. However, the possible side effects of prednisone include weight gain, high blood pressure, behavior changes, and delayed growth.
- Deflazacort (another form of prednisone), is used in Europe and believed to have fewer side effects.
- Oxandrolone, a medication used in a research study, also has similar benefits to prednisone, but with fewer side effects.
- Randomized control trials have shown that β2 agonists increase muscle strength, but do not modify disease progression. Follow-up time for most RCTs on β2 agonists is only around 12 months, hence results cannot be extrapolated beyond that time frame.
- Mild, nonjarring 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(Montelukast/ambroxol hydrochloride) support as the disease progresses is important.
- Cardiac problems may require a pacemaker.
- Proton Pump Inhibitor for remove constipation.
- Pheno barbiton /Valproic acid for Jurki movement
- Gabapentin/Pregabalin for inhabiting the pain pathway & regenerator the myoline sheeth in the nervous system
No medical cure exists for this congenital dystrophy, and the disease has a poor prognosis. Treatment is centered on glucocorticoid therapy, prevention of contractures and medical care of cardiomyopathy and respiratory compromise.
- Glucocorticoid therapy decreases the rate of apoptosis of myotubes and can decelerate myofiber necrosis. Prednisone is used in patients four years and older in whom muscle function is declining or plateauing.
- Prednisone is recommended at a dosage of (0.75 mg/kg per day or 10 mg/kg per week is given over 2 weekend days).
- Deflazacort, an oxazoline derivative of prednisone is sometimes preferred over prednisone as it has a better side effect profile and has an estimated dosage equivalency of 1:1.3 compared with prednisone. The recommended dosage is 0.9 mg/kg/day.
- Studies have shown that glucocorticoid treatment is associated with the improved pulmonary function, delayed development of scoliosis reduces incidence and progression of cardiomyopathy and overall improved mortality.
- Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers is recommended. Early studies suggest that early treatment with ACE inhibitors may slow the progression of the disease and prevent the onset of heart failure.
- Overt heart failure is treated with digoxins and diuretics as in other patients with cardiomyopathy.
- Surveillance consists of a cardiology assessment with ECG and ECHO. This should be performed at the time of diagnosis or by the age of 6 years. Routine surveillance should be performed once every 2 years until the age of 10 and then yearly after that. If evidence of cardiomyopathy is present, surveillance every 6 months is indicated.
- The pulmonary function must be tested prior to wheelchair confinement. This should be repeated twice a year once the patient reaches 12 years of age, is wheelchair confined or vital capacity is found to be less than 80% of predicted.
- Physiotherapy to prevent contractures is the mainstay of the orthopedic interventions. Based upon patient requirements, passive stretching exercises, plastic ankle-foot orthosis during sleep, long leg braces to assist in ambulation may be used. Surgery to release contractures may be required for advanced disease. Surgery to correct scoliosis may improve pulmonary function.
- Patients are at risk for malnutrition including obesity. Calcium and Vitamin D should be supplemented to prevent osteoporosis secondary to chronic steroid use. DEXA scanning should be obtained at age 3 and then repeated yearly.
- Guidelines recommend all patients participate in a gentle exercise to avoid disuse atrophy. A combination of a swimming pool and recreation based exercises is recommended. Activity should be reduced if myoglobinuria is noted or significant muscle pain develops.
- Gene therapies include medications that bind RNA and skip over the defective codon. This produces a shorter but potentially functional protein. Eteplirsen and Dispersion are exon 51 skipping antisense oligonucleotides medications used for this purpose. Eteplirsen has been approved by the FDA for this purpose.
- The section on Cardiology and Cardiac Surgery – Cardiovascular health supervision for individuals affected by Duchenne or Becker Muscular Dystrophy. Pediatrics 2006;
- GeneReviews – Provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
- Orphanet Emergency Guidelines – Is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.
- Project Orphan Anesthesia – Is a project whose aim is to create peer-reviewed, readily accessible guidelines for patients with rare diseases and for the anesthesiologists caring for them. The project is a collaborative effort of the German Society of Anesthesiology and Intensive Care, Orphanet, the European Society of Pediatric Anesthesia, anesthetists and rare disease experts with the aim to contribute to patient safety.
- The goal of physical and occupational therapy in Duchenne muscular dystrophy is to obtain a clear understanding of the individual, of their social circumstances and of their environment in order to develop a treatment plan that will improve their quality of life.
- Individuals with DMD often experience difficulties in areas of self-care, productivity and leisure. This is related to the effects of the disorder, such as decreased mobility; decreased strength and postural stability; progressive deterioration of upper-limb function; and contractures.
- Occupational and physical therapists address an individual’s limitations using meaningful occupations and by grading the activity, by using different assessments and resources such as splinting, bracing, manual muscle testing (MMT), ROM, postural intervention and equipment prescription
- minimize the development of contractures and deformity by developing a programme of stretches and exercises where appropriate
- anticipate and minimize other secondary complications of physical nature by recommending bracing and durable medical equipment
- monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions.
- Splints also referred to as orthoses, are designed to maintain or improve ROM, prevent deformity, and improve function. Splints help to support and keep limbs stretched, which delays or prevents the onset of contractures that commonly affect the knees, hips, feet, elbows, wrists, and fingers.
- Ankle-foot orthoses (AFOs) can be used during sleep or during the day. The purpose of this is to keep the foot from pointing downward and sustain the stretch of the Achilles tendon. Maintaining the length of the tendo-Achilles also referred to as the gastrocnemius-soleus complex, is extremely important for walking. Knee ankle foot orthoses (KAFOs) are also used for walking or for standing and can be used to prolong ambulation or help delay the onset of lower limb contractures.
Manual muscle testing (MMT) and range of motion (ROM)
- MMT is used to evaluate muscular strength, whereas goniometry or ROM tests measure movement around a joint. These tests indicate the need for intervention such as passive and active ROM, strengthening and splinting. Passive ROM combined with the use of night splints can significantly improve tendo-Achilles contractures.
Seating and positioning
- Proper seating is essential to prevent spinal curvatures. Severe scoliosis is common in DMD and can interfere with sitting, sleeping, and breathing. A wheelchair that is fitted appropriately accounts for frame size, type of seat, lumbar support and cushioning to avoid pressure ulcers.
- It should be equipped with other mechanical devices, such as tilt ability, in order to provide comfort and to protect the skin. Power wheelchairs are indicated for most clients who can no longer ambulate, as they do not have enough upper extremity strength to propel a manual wheelchair independently.
- DMD affects many people in their adolescence, so it is crucial for rehab therapists to be conscious that significant development may occur during this time. Without proper seating and postural support throughout development, deformation may occur.
- This could then result in dysfunctional positioning. It is important for rehab therapists to re-evaluate the fit of an individual’s wheelchair as often as every year during adolescence.
Adaptive equipment and devices
- There are many alternate mobility options, positioning aids and other equipment that rehab therapists may prescribe. These include walkers or quad-canes, which can be used for individuals who are able to ambulate to reduce the risk of falling.
- In addition, transfer boards, mechanical lifts, and specific transferring education are important because fractures have been seen to occur during transfers as a result of osteoporosis. Handheld shower heads and bath benches are indicated to enable individuals to manage their own self-care needs as much as possible.
- Individuals who are able to bear weight and take a few steps may utilize commode chairs, thus giving them the ability to visit the toilet independently.
- To complement an individualized wheelchair, an occupational therapist may also consider prescribing a hospital bed, pressure-relieving mattresses, and foam wedges for proper positioning to prevent pressure skin ulcers, contractures, and deformitiesSpecialized trays, input devices and software may also be prescribed to facilitate computer use.
Social skills development
- Along with physical difficulties, individuals with DMD may have social issues that an occupational therapist can assist them in overcoming.
- Group sessions or individualized programs that focus on coping mechanisms for depression are examples of what an occupational therapist can facilitate. Self-esteem building for individuals of all ages is an essential part of ensuring that a high quality of life is achieved.
- Occupational therapy intervention can play an essential role in supporting the development of social skills through group interactions and other life experiences.
- Sexuality is a topic that many people feel uncomfortable discussing and thus may be overlooked by health care professionals.
- An occupational therapist will educate individuals with DMD on safe and effective ways to experience their sexual life. Such education can include various forms of sex as well as numerous positions that they would be able to perform.
- Gaining and maintaining employment can be difficult for individuals with DMD. An occupational therapist may collaborate with an individual, employer and case manager to ensure that the individual’s work environment is as enabling and accessible as possible.
- By adapting the physical work environment, the social environment, and the work requirements and guidelines, an individual can maintain meaningful employment as well as be as an asset to his or her employer. This may not only impact the individual’s perceived self-efficacy but also his or her financial well-being.
- If it is a priority of the client, maintaining independence is often the main focus of occupational therapy interventions. Within the home, there are numerous obstacles that may prevent a client from being as independent as possible.
- Home modifications and adaptations are something that an occupational therapist can assist with. Such modifications may include: railings for safe mobility and transfers, lifts, adapted kitchens that are accessible for wheelchairs and bathroom modifications such as raised toilet seats or modified baths.
- Other examples are adaptive equipment for playing computer and video games, supports for biking and adaptations for fishing rods.
- A recreational or occupational therapist can support individuals with DMD to find leisure activities in which it is meaningful for them to take part. Accommodations and adaptations can be made to enhance participation.
- The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for the treatment of this condition. Learn more orphan products.
- Deflazacort (Brand name: Emblaze) – Manufactured by Marathon Pharmaceuticals
FDA-approved indication: Treatment of Duchenne Muscular Dystrophy in patients 5 years of age and older.
National Library of Medicine Drug Information Portal
- Eteplirsen (Brand name: Exondys 51) – Manufactured by Sarepta Therapeutics, Inc.
FDA-approved indication: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.
- These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.
Where to Start
- Genetics Home Reference (GHR) contains information on Duchenne muscular dystrophy. This website is maintained by the National Library of Medicine.
- MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
- The National Human Genome Research Institute’s (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.
- The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
- Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
- The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
- Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
- Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
- PubMed is a searchable database of medical literature and lists journal articles that discuss Duchenne muscular dystrophy. Click on the link to view a sample search on this topic.
Resources for Kids
- BrainPOP presents the topic of Duchenne muscular dystrophy in a short, animated movie that is available on CheckOrphan’s Web site. BrainPOP produced this video in partnership with Parent Project Muscular Dystrophy, this four-minute video strives to provide kids of all ages with a clear understanding of Duchenne.