What is Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy (DMD) is a serious type of inherited muscle disorder. It’s the most common inherited muscular disease, and it isn’t more common in one race or ethnic group over another. This condition is caused by changes in a particular gene, the dystrophin gene, which leads to a gradual breakdown and weakening of the muscle fibers. Initially, these changes can cause problems with walking, but as it progresses, it can become so severe that those affected can no longer perform daily activities and often have to use wheelchairs. Heart and bone problems are common, and it often leads to death in a patient’s twenties due to the weakening of the respiratory muscles or severe heart disease. Currently, treatment focuses on controlling symptoms with steroid medications and physical therapy to prevent problems with the bones.
What Causes Duchenne Muscular Dystrophy?
DMD, or Duchenne Muscular Dystrophy, is a genetic disease caused by a mutation, or change, in a gene called dystrophin, located on the X chromosome. This disease is usually passed down from parents to their children. But, in about 30% of cases, the mutation happens for the first time in the affected person.
This gene mutation causes diseases known as dystrophinopathies, which include Duchenne muscular dystrophy, Becker muscular dystrophy, and a form that lies in the middle of these two. These mutations prevent the production of enough dystrophin protein, resulting in the muscle fibers continually breaking down and regenerating. Over time, the muscle gets replaced by fibrous tissue and fat, which lead to the symptoms of the disease.
Most of the time, female carriers of this gene do not have any muscle weakness, but there have been some cases where female carriers have shown symptoms. Around 2.5% to 20% of female carriers can get affected. This can be because of a phenomenon called the Lyon hypothesis, where the normal X chromosome gets inactivated and the mutated X chromosome gets expressed.
If a female carrier has another condition like Turner syndrome, or if she has a chromosomal rearrangement affecting the dystrophin gene, she can show symptoms. Also, females with a normal set of chromosomes can show symptoms if the X chromosome carrying the normal dystrophin gene gets inactivated.
The dystrophin gene is one of the largest in the human genome. It consists of 79 coding sequences known as exons, and it makes up 2.5 million bases of DNA. This gene codes for the protein dystrophin which weighs 427 kDa.
The majority of mutations (around 70% to 80%) are deletions or duplications of part of the gene. 20% to 30% of patients have point mutations, which is a change in a single base pair.
Dystrophin is present in muscles, heart, brain, and the retina of the eye. There is less of it in the brain than in the muscle, but it can still have effects on the brain and cause symptoms of the disease.
Risk Factors and Frequency for Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is a genetic condition. It’s more common in boys because it’s passed down through what’s called ‘X-linked recessive’ inheritance. Essentially, this means the faulty gene that causes DMD is located on the X chromosome, which boys only have one of. The condition is quite common – for every 3,600 boys born, one will have DMD. In the United States, out of every 10,000 people, about 2 have this disease. DMD is one of the most frequent and most serious inherited muscle diseases.
Signs and Symptoms of Duchenne Muscular Dystrophy
Children with this condition usually develop normally in the first few years, although they may hit milestones at a slightly delayed rate. They grow slower than typical kids and are shorter. They may have a condition called hypotonia, where their muscles are too loose when they are babies. They may also have weak neck control as babies. It’s common for them to show signs of muscle weakness on the face in later childhood. Children often start having difficulty in walking or running between the ages of 2 and 3. They may walk on their toes, have trouble running or climbing stairs, and fall down often. They are weaker in their proximal muscles (the ones closer to the center of the body) than the distal muscles (the ones further away from the center of the body), and their lower body is weaker than their upper body.
Children who can walk may fall and fracture bones more frequently. They may develop abnormal curves in their spine, leading to impaired lung function. Infants can also develop stiffness and lack of movement in their ankles, knees, hips and elbows. Some patients may have bigger calves and thinner thighs, which give the illusion of the calves being enlarged – this is known as pseudohypertrophy. This feature may also appear in the tongue and forearm muscles, but it’s not as common. The majority of the children will need to use a wheelchair by the age of 12.
Weakness in the throat muscles can cause trouble in swallowing, nasal regurgitation of liquids, and a nasal voice quality. Urinary and faecal incontinence due to weakness in the urethral and anal muscles can occur but are less common and usually arise late in the disease. There are also rare cases where the first symptom of the disease is a severe reaction to anesthesia known as malignant hyperthermia. Females who carry the gene for this disease may develop an early onset and progressive muscular dystrophy.
- Nearly all patients have some degree of intellectual impairment, but only 20% to 30% have an IQ less than 70.
- The degree of impairment does not correlate with the severity of the disease.
- Most patients just have a mild learning disability and can function in a regular classroom.
- Epilepsy is more common in these patients than in the general population.
- In some rare cases, patients may show behavior similar to autism.
Signs of cardiomyopathy, a condition that makes it harder for the heart to pump blood to the rest of the body, can start to develop in the early teens and are almost always present in patients in their twenties. Symptoms such as persistent fast heart rate and heart failure can be initial signs of this disease. As the disease progresses, fibrosis can spread to different parts of the heart, leading to significant mitral regurgitation, a condition when the heart’s mitral valve doesn’t close tightly enough and allows blood to flow back into the heart. Abnormalities in heart conduction and arrhythmia, particularly supraventricular arrhythmias, are also associated with the developing cardiomyopathy.
Physical exams typically show the pseudohypertrophy in the calf muscles and occasionally the quadriceps muscles. Shortening of the Achilles tendon may be noted, and the patient may have hyporeflexia or areflexia. Ankle reflexes often continue to function until the later stages of the disease. Deep tendon reflexes (DTRs) in the knee are usually gone by age 6. When asked to stand up from a sitting position, children often need to leverage their arms off their knees to help them stand up. This is known as Gower’s sign.
Testing for Duchenne Muscular Dystrophy
If you’re experiencing symptoms of weakness, have physical examination results that suggest a muscle disorder, or have family members with a similar disease, your doctor might suspect dystrophinopathy. To get to the bottom of this, they will likely conduct several tests. These might include measuring creatinine kinase levels in your blood, taking a muscle biopsy, conducting gene testing, or checking for heart muscle problems with an ECG.
Creatinine kinase, or CK, is a muscle enzyme seen in higher quantities when muscles are damaged. This level in your blood might rise before you start to show symptoms. It may peak significantly above normal when you’re around two and start to drop off as you age or as the disease progresses. It’s worth noting that other muscle enzymes such as aldolase and AST might also be higher. Even if you’re just a carrier of dystrophinopathy and not displaying symptoms, your CK levels might be elevated. This is the case for about 80% of carriers, primarily between the ages of 8 and 12.
A muscle biopsy, which is a sample of your muscle tissue, might be taken as well. This could show a variety of changes that align with muscle damage and replacement of muscle by fat and fibrous tissue. The muscles typically sampled are the quadriceps femoris and gastrocnemius, located in the thigh and calf, respectively.
Another method, electromyography, can identify certain features associated with muscle disease, but it’s not specific to dystrophinopathy. This test would reveal that the speed at which your nerves transmit signals is normal.
To be thorough, your doctor might also look at your genes. In dystrophinopathy, the dystrophin gene is often completely or almost entirely absent. Low levels can help predict how severe the disease might be. Other tests, like PCR and MPLA, can identify up to 98% of gene modifications. These, along with dystrophin immunocytochemistry, can detect abnormal genes undetected by PCR.
Regarding heart health, an ECG could show peculiar patterns typical in dystrophinopathies, such as tall R waves, deep Q waves, or irregular rhythms. Dilated cardiomyopathy, a condition where the heart’s main pumping chamber is enlarged and doesn’t pump efficiently, is seen in almost all patients by the time they’re in their late teens or early 20s.
Treatment Options for Duchenne Muscular Dystrophy
There’s no medical cure for this certain kind of muscle disorder present from birth, and unfortunately, the outlook for this condition is not good. The focus of treatment involves a type of medication referred to as glucocorticoids, methods to prevent tightening of the muscles and joints, and medical attention to heart and breathing problems.
Glucocorticoid treatment, which includes medications like prednisone, can slow down muscle damage and deterioration. This therapy works by decreasing the speed at which muscle cells die. Generally, prednisone is used for patients above four years of age, when their muscle function isn’t improving or is starting to worsen. This medication is given daily or weekly depending on the patient’s condition.
A different version of prednisone, called deflazacort, sometimes might be a better choice because it may cause fewer side effects. Studies have shown that glucocorticoid therapy can improve breathing, slow the development of abnormalities in the spine, reduce heart issues, and overall improve survival rates.
For heart disease issues, medication to control blood pressure such as angiotensin-converting enzyme inhibitors and beta-blockers are recommended. Early research indicates that starting these medicines early may delay worsening of the disease and prevent heart failure. More severe heart failure is treated similarly to other patients with heart issues. Regular heart health check-ups, including tests such as ECG and echocardiogram, are important, starting from the time of diagnosis or by the time the patient is 6 years old.
It’s also important to monitor breathing function, especially before a patient becomes reliant on a wheelchair. This should be repeated twice a year once the patient reaches the age of 12, or wheelchair-bound or when their lung function drops below 80% of what is expected.
Physical therapy is key to prevent muscle and joint tightening or contractures. Depending on the patient’s needs, passive stretching exercises, plastic leg-braces during sleep, and long leg braces may be used. In severe cases or advanced disease, surgery may be required to release contractures or to correct abnormal spinal curves, which can also help improve breathing function.
It’s important to keep an eye on patient’s diet as they are at risk for undernutrition, and, paradoxically, obesity. They should take calcium and vitamin D supplements to prevent weak and brittle bones caused by long-term steroid use. Bone density should be checked at age three and then every year after that.
Everyone with this condition is advised to take part in gentle exercise to prevent muscles from wasting due to lack of use. A mix of swimming and recreational exercises is recommended. However, if visible blood appears in the urine or if severe muscle pain occurs, activity should be reduced.
New treatments are constantly being explored, including gene therapies. This involves drugs that can attach to RNA particles and skip over the faulty genetic codes. This results in a shorter but possibly functional protein produced. One such medication is Eteplirsen, which the FDA has approved for this purpose.
What else can Duchenne Muscular Dystrophy be?
Beckers Muscular Dystrophy (or BMD for short) typically starts later in life and most patients live longer with this condition. Also, these patients typically have higher levels of a protein called dystrophin.
There’s also an intermediate type of muscular dystrophy. Patients diagnosed with this type have dystrophin levels that fall somewhere in between those with DMD and BMD.
Myotonic Muscular Dystrophy is passed down through families and typically affects the muscles that are farthest away from the center of the body, like those in your legs and arms. But, this condition often doesn’t affect a person’s ability to walk.
Limb-Girdle Muscular Dystrophy is another inherited disorder, and it usually affects the muscles in the hips and shoulders.
Congenital Myotonic Dystrophies are a group of muscular dystrophy diseases that someone can be born with. These conditions can be severe at birth, but they often don’t get worse over time. People with these conditions are also more likely to have brain malformations. This group includes diseases like Ullrich type of muscular dystrophy, Fukuyama type of congenital muscular dystrophy, and muscular dystrophy associated with Walker-Warburg syndrome, among others.
What to expect with Duchenne Muscular Dystrophy
The usual outcome for patients suffering from this condition is not positive. Often, by the time they reach 12 years old, they end up needing a wheelchair for mobility. Tragically, these patients may pass away due to heart or breathing complications typically in their teenage years or early twenties. Other potential causes of death can include pneumonia, choking hazards, or blockages in their airway.
