A Comprehensive Report on Muscular Dystrophy

Introduction

Since its discovery in 1860 by Guillaume Duchenne, Muscular Dystrophy (abbreviated MD) has become recognized as one of the most dangerous muscular disorders in the world (Duchenne Muscular Dystrophy, 1) Muscular Dystrophy is a serious muscular condition where the tissue weakens in the extremities and works its way to the midsection of the body. There, it can reach the heart and lung muscles causing severe circulatory and respiratory problems, ultimately leading to death (Lite, 1, 2008). The condition is so severe that by age ten to fifteen, most children are forced into a wheelchair and end up passing away some time into their twenties due to the failure and degradation of the circulatory and respiratory muscles. (Lite, 1, 2008).There are different varieties of Muscular Dystrophy, but they all have the same consequence: muscle degradation and death. The population that suffers from this disease must undergo a series of serious lifestyle changes that may include surgery, dietary restrictions, and extra attention to the very basic aspects of life.

History

The first noted case of muscular dystrophy was recorded in 1836 by Conte and Gioja, who examined two brothers whose muscles began deteriorating at age 10. Later, they began experiencing hypertrophy and weakness in various muscle groups. Modern scientists who have studied this account believe that the two boys had Becker’s Muscular Dystrophy. At the time of the discovery, however, many people credited the observations to tuberculosis, a common disease at the time. Sixteen years later in 1852, a scientist named Meryonstudied a family of four boys, all of whom had similar muscle problems to the boys studied by Conte and Gioja. Meryon then decided to study the central nervous system of the boys and found absolutely nothing wrong with it. He hypothesized that muscles themselves were the problem and even claimed that the sarcolemma was what caused the disease. The man who made the biggest leap in research of Muscular Dystrophy was French Scientist Guillaume Duchenne. Duchenne was famous for his love of faradism. Faradism is the act of shocking muscle fibers with electricity to stimulate them and study neuromuscular diseases. At the time Duchenne was studying a group of thirteen patients who experienced Muscular Dystrophy. He gave the first written account of the unique disease, which he called “paralysiemusculaire pseudo-hypertrophique”. Because of his great achievements in research and understanding of the disease, the most common (and most deadly) form of the disease is named after him: Duchenne Muscular Dystrophy (Do, 1, 2014).

Types of Muscular Dystrophy

In total, there are somewhere around forty types of Muscular Dystrophy. They are then further subdivided into nine subgroups, which are classified by onset age, extent of muscle damage, rate of progression, symptoms, and hereditary pattern (NIH, 1, 2015). This paper will focus on Duchenne’s, which is the most common form of the disease, but it is important to be familiar with some of the others, as they are just as dangerous as Duchenne’s although less prevalent. Before delving into the details of the genetic differences of the diseases, it is crucial to understand what certain terms mean. Autosomes are simply chromosomes 1-22. All healthy humans have two sets of autosomes: one inherited from the mother and the other from the father. The X and Y chromosomes are sex chromosomes; they determine gender. These are called the 23rd chromosomes. An XX is a female, and an XY is a male. Recessive alleles must be in both sets of genes in order to be expressed, while its counterpart, the Dominant allele only needs to be in one set. The Duchenne’s variety of Muscular Dystrophy affects the muscle encasing fibers and causes the muscle tissue to become leaky and eventually die. (NIH, 1, 2015).Duchenne’s Disease is so prevalent that it accounts for 50% of all neuromuscular diseases (NIH, 1, 2015) and affects every one in 3,500 children (Lite, 2008, 1). Becker Muscular Dystrophy is very similar to Duchenne’s, except it works much slower and is much more rare, affecting only 1 in every 5,000 children (Muscular Dystrophy Canada). It was discovered in 1986 that both of these diseases are X linked recessive genes, meaning they are located on the X chromosome (Duchenne Muscular Dystrophy, 1). This is why they are much more common in males than females, since males only have one X chromosome and females have two. This means that it will only take one recessive allele to have the disease expressed in males when it takes two recessive alleles for females. Congential Muscular Dystrophy is another neuromuscular disease that causes a defect in the merosin gene, which results in the absence of connective tissue and connective proteins around muscles (NIH, 2015, 1). Facioscapulohumeral Muscular Dystrophy is the third most common form. It affects the face, neck, and shoulders and is usually noticed in the teenage years, but symptoms can be postponed until age 40 (NIH, 1, 2015). Distal Muscular Dystrophy causes muscular degradation in distal muscles (hand, fingers, toes etc.). It has an onset age of forty to sixty years and can cause difficulty with precise motor functions of those muscles. This gene is autosomal Dominant (it will show no matter what the other allele is), but its late onset age does not affect reproduction and is therefore passed on to the child more frequently (NIH, 1, 2015). Emery – Driefuss is another type of Muscular Dystrophy that targets muscles in the back, spine, upper shoulders, and much of the dorsal thoracic region. Most patients require a pacemaker by age 30. The disease is found in two different genes, an X linked recessive and an autosomaldominant (NIH, 2015, 1).

How Duchenne Muscular Dystrophy Impacts the Body

The way muscular dystrophy attacks the body, is actually not that complicated at all. Muscles are complex tissues in the body that consist of various components that must work in coordination with each other to move. Because there are so many different types of the disease, each one targets different parts of the muscles, yet the result of all of them is the same. In the most general sense Muscular Dystrophy causes muscle death and weakness. Because there are so many this paper will only focus on Duchenne’s. It was realized in 1987 thatDuchenne’s disease targets a specific gene known as the dystrophin-glycoprotein complex (Duchenne Muscular Dystrophy, 1). When translated and transcripted, this gene becomes the dystrophin protein that encases muscle fibers. When dysfunctional with or non-existent, the muscles become leaky, excreting a substance known as CreatineKinase and absorbing Calcium ions, damaging the muscle and hampering its effectiveness. When the muscles become so weak, due to the excess Calcium ions, they end up dying. This gene subjected to mutations extremely frequently because of its enormous length (NIH, 2015, 1). The disease begins its attack on the body at around age 3 when it affects primarily the limbs. By the teenage years, the condition worsens as it moves into the thoracic region and takes the heart and respiratory muscles (Duchenne Muscular Dystrophy, 1). When it reaches the heart it causes cardiomyopathy, or weakening of the heart muscle (Duchenne Muscular Dystrophy, 2). In adults, this is a common cause of heart attacks, but at such a young age heart attacks are uncommon. If there is one silver lining to this horrible disease, it is that it is virtually pain-free. Since Duchenne Muscular Dystrophy only affects muscle development, it has no direct involvement in any other bodily functions, including the nervous system, meaning that it will never cause pain. Its symptoms, however, can become painful if ignored or improperly treated (Duchenne Muscular Dystrophy, 2). One interesting correlation that has not been proved, however, is the large percentage of Muscular Dystrophy patients that suffer from learning disabilities. About one third of the population suffering from Duchenne’s also has some sort of cognitive disability. Some have serious mental retardation as well. This high percentage leads some researchers to believe that the dystrophin protein has some sort of cognitive function in the brain (Duchenne Muscular Dystrophy, 2). Although there is no strong evidence to support this, the high frequency of the disabilities is intriguing.

Symptoms

Muscular Dystrophy, depending on the type of the disease, can have various symptoms, which could present themselves at different times in one’s life. As mentioned in the second paragraph, many forms of the disease do not affect the individual until they have matured completely and have reached a reproductive age, so the disease is frequently passed on to the subsequent generations. For most versions however, the symptoms seem to settle in at an early age. Muscular Dystrophy is a unique disease in that it does not have an immune response. That means, the symptoms that are visible are a direct cause of the gene failure. What this means is that the body will never try to fight Muscular Dystrophy. When someone gets the flu, for example, their body will overheat and inflame in an effort to kill the virus. These symptoms are not a direct cause of the virus, but rather the body’s response. In Muscular Dystrophy, the body never fights the condition. All the symptoms are the inherent results of the disorder. One of the biggest indicators of Duchenne’s Muscular Dystrophy at an early age is the development of pseudohypertrophy, or the false enlargement of muscles due to disease. A child will often display enormous calves at a young age (around 3 years old) (Duchenne Muscular Dystrophy, 2).

To compensate for this, the child will then walk on the balls of his feet or his heels. They will also stand up in an odd way (Duchenne Muscular Dystrophy, 2). The Disease will first affect the limbs and then move towards the trunk of the body, where its most serious symptoms are displayed (Lite, 2008, 1). The patient will be able to walk until age 10-15, when the muscles in the legs become so weak, they will no longer be able to support the weight of a maturing human. While still in the limbic regions of the body, contractures of muscles and tendons around joints are very common (Mayo Clinic Staff, 2014, 1). Contractures are simply the stiffening of the tissue so much that it will restrict normal movement. Some other common symptoms are spinal curvature problems such as kyphosis (curvature of the cervical vertebrae), lordosis (curvature of the lumbar vertebrae), and scoliosis (horizontal curvature of the spinal column). These curvatures are a result of the weakness of the muscles that would normally support the spinal column and keep it upright (Duchenne Muscular Dystrophy, 5). The disease will have already spread to the heart and respiratory muscles by this time. Once it reaches this point, it will cause cardiomyopathy (weakness of the heart muscle), shortness of breath, tiredness and exhaustion, and nightmares during sleep (Duchenne Muscular Dystrophy, 2). Most people affected by Duchenne’s Muscular Dystrophy will die around 20 years old due to complications with breathing and blood circulation (Lite, 2008, 1). It is important to note that Muscular Dystrophy will never cause any pain since it does not affect the nervous system at all. Children will never complain about aching muscles for reasons other than excessive use, something that all people will suffer from (Duchenne Muscular Dystrophy, 2). Instead, they will have odd movement patterns, such as the way they walk or the way they stand up from a sitting or reclined position. Another important note is that other diseases and conditions can also cause all of the symptoms listed above. If someone develops any of these symptoms, they do not necessarily have Muscular Dystrophy, so it is very important that they are tested immediately and correctly.

Testing

There are various methods of testing for Muscular Dystrophy, many of which are more accurate than others. Some, are much simpler processes, but may not produce the best results. On the contrary, the most beneficial tests often are the most invasive as well. A very basic, preliminary test is called electromyography. This does not test for the specific Duchenne Muscular Dystrophy condition, but rather the presence of a muscular disease in general. In this test, a needle with an electrical node is stuck into the muscle. The node reads electrical signals passed through the muscles and the doctor assigned to reading the graph will look for irregular or changes in pattern (Mayo Clinic Staff, 2014, 1). One of the most effective ways to test for Duchenne’s Muscular Dystrophy is to draw blood and test for the presence of a specific enzyme: CreatineKinase (CK) (Mayo Clinic Staff, 2014, 1). Similar preliminary tests include heart and lung monitoring, both of which would detect irregularities in patterns of circulation and respiration respectively. Again, they do not point to a specific cause of these oddities, but will at least alert the doctor and patient of a possible disease in the body (Mayo Clinic Staff, 2014, 1). As mentioned in previous paragraphs, when Duchenne Muscular Dystrophy is present, muscle cells secrete large amounts of this enzyme into the blood stream (Muscular Dystrophy, 3). If testing discovers CreatineKinase in the blood, it is often an indicator of the possible presence of Muscular Dystrophy in the patient. Of course, like any sort of enzyme test, there could be other factors that lead to the enzyme in the blood, so the presence of CreatineKinase does not necessarily stem from Muscular Dystrophy, however, it usually does. The two most effective ways of testing for the disease are muscle biopsies and genetic testing (Mayo Clinic Staff, 2014, 1). Muscle biopsy is simply the extraction of a small portion of muscle tissue and examination of that tissue for any damage. If a researcher can look closely at the muscle and identify the extent and cause of the damage, they can conclude what the causing agent would be. Since Duchenne’s Muscular Dystrophy is a genetic disorder, genetic testing is by far the most accurate way of determining the presence of the condition. The researcher simply compares the DNA strand of the patient to a normal DNA strand and looks for discrepancies. If there are changes in the patient’s genome then it is clear that Duchenne’s Muscular Dystrophy is present. If, however, there are no genetic mutations, but symptoms are present, then it is another condition that is causing them. Since many of these tests can produce ambiguous results, it is important to be 100% certain that the disease is in fact Muscular Dystrophy. The only way to be 100% sure is do either a biopsy or a genetic test. After the diagnosis, the next step is to find and begin the proper treatment to control the effects of the incurable disease.

Treatment/Lifestyle

As one could imagine, living with Duchenne Muscular Dystrophy can lead to many lifestyle changes, in areas such as diet, activity, and even medication. The disease limits much of the daily freedoms that people possesses, especially as it progresses into its terminal stages and leaves the patient in a wheelchair with assistive devices allowing them to breath and survive. Since muscular dystrophy compromises the distal muscles first, it is very difficult to maintain a healthy lifestyle filled with exercise. One of the biggest problems caused by Muscular Dystrophy is joint contractures, which is the shortening of joints. In order to maintain healthy joints and alleviate some of the stress on tendons, proper exercise, usage of braces, and maybe even surgery are crucial (Duchenne Muscular Dystrophy, 5). However, it is crucial that the muscles get as much activity as possible so they do not become complacent and nonfunctional as this state causes further damage to them. There are many different forms of exercise that a patient with Duchenne’s Muscular Dystrophy can do to avoid the stiffening of joints, which is a result of poor muscle movement. Swimming is perhaps the most beneficial exercise as it allows the patient to use many different muscle groups at the same time. In addition, it is a non-contact activity, which reduces the risk of injury or further damage to the muscle fibers. Similarly, there are other non-impact activities that a person affected by the disease should attempt such as yoga and mobility exercises that will keep the muscles strong for a longer period of time (Mayo Clinic Staff, 1, 2014). There are many forms of exercise that can actually be detrimental to a patient’s health. Overuse of the muscle can cause extra damage, so patients should try to avoid heavy weight lifting. One of the major side effects of the disease is that the lack of activity for a patient can lead to obesity. Patients with Duchenne’s Muscular Dystrophy must pay extra attention to their diet and make sure they are receiving the proper nutrition so as to avoid illnesses that are caused by obesity and malnutrition (Mayo Clinic Staff, 1, 2014). Due to muscle problems in the trunk of the body, much of the gastrointestinal system can be disrupted. The gastrointestinal system is more commonly known as the digestive system, or the system that is in charge if eating, digesting, and absorbing food. Much of the gastrointestinal system relies on muscles to push food down.

Also, much of the sphincters (small muscle rings that close openings such as the stomach and anus) are affected. The weakness and death of these muscles leads to the sphincters opening at unfortunate times, usually unexpectedly. Conversely, the weakening of abdominal muscles can cause constipation for people with Duchenne Muscular Dystrophy. To counter this, the person affected should maintain a diet with high fiber (vegetables, fruits, oats etc.) since fibers can help clear the stomach (Duchenne Muscular Dystrophy). When a person is diagnosed with Muscular Dystrophy, and the disease has spread to the respiratory muscles, they become much more susceptible to viral and bacterial infections in the area such as pneumonia. As a result, these patients must be vaccinated much more regularly and extensively to prevent infection. Similarly, they are often required to take various medications to control infectious diseases (Mayo Clinic Staff, 1, 2014). In dealing with respiratory problems, treatment usually starts with a non-invasive technique. Non-invasive just means that surgery is not required. A simple solution would be to wear a pressurized mask to aid the respiratory muscles. However, as the disease progresses, surgery and automatic breathing systems may be required (Duchenne Muscular Dystrophy, 5). Another one of the biggest disadvantages of having Duchenne Muscular Dystrophy is the risk of anesthesia. Almost all surgeries are performed under general or local anesthesia, which prevents the patient from feeling anything, which is a good thing when a surgeon is cutting open your skin with a scalpel. However, patients with Duchenne Muscular Dystrophy often react negatively to anesthesia (Mayo Clinic Staff, 1, 2014). This is because many anesthetics have a chemical called succinylocholine, which is a muscle-relaxing agent. This chemical has also been found to cause rhabdomyolisis, or rapid and completely uncontrollable muscle death. This is extremely dangerous to Duchenne Muscular Dystrophy patients, since they already suffer from a condition that causes rhabdomyolisis (Hayes, 1, 2007). Anesthesiologists must be very aware of their patients’ medical history. In terms of medication, there is a specific type of medicine that has been shown to help control Muscular Dystrophy. This type of medication is called corticosteroids. Corticosteroids are drugs such as cortisone, hydrocortisone, and prednisone that help control inflammation. The drugs create hormones that are usually produced by the adrenal glands of the kidneys (Mayo Clinic Staff, 2015). It has been shown that Corticosteroids delay the effects of Duchenne Muscular Dystrophy of patients that take them regularly, but not completely prevent them (Duchenne Muscular Dystrophy, 5). In fact, a recent study shows that patients who were placed on a short term corticosteroid treatment plan, lost ambulation (walking), .08 years faster than those who were without any sort of medication. However, when the boys were put on long term medication plans, they retained the ability to walk for two extra years (Kim, 1, 2015). In addition to these, there are many other cure for Duchenne Muscular Dystrophy that have not been proven, but are very promising. One of these is called “exon skipping”. Exons are nucleotides in nucleic acids that are skipped when they are being read. Scientists have attempted to use this method to produce a partially functional dystrophin protein that could work normally (Duchenne Muscular Dystrophy, 7). Another method is to replace the faulty dystrophin gene with a smaller version of itself (since the original is so large) that can produce the same dystrophin protein. This however, has run into some obstacles during testing as the host often experiences unwanted immune responses (Duchenne Muscular Dystrophy, 7). One of the more promising tests has been the use of a protein called myostatin. Myostatin, when present, limits muscle growth. Since patients with Duchenne Muscular Dystrophy experience rapid muscle death, a lot of research has been trying to find a way to limit the presence of myostatin. This would allow the muscles to grow much larger than normal, so that when the disease kicks in, the muscles die, but return to a normal size (Duchenne Muscular Dystrophy, 7). The Gersbach lab at Duke University has been focusing on a process called gene therapy. Basically, they are attempting to delete a massive portion of the dystrophin gene (the part that has the highest frequency of mutations), so that the gene will not mutate as much. This could lead to a permanent cure for 60% of the population suffering from Duchenne Muscular Dystrophy (Wahl, 1, 2015). With all the new technology and research going into Muscular Dystrophy, both the quality of life and the life expectancy of patients with the disease has improved tremendously. When the disease was still new to scientists and doctors, patients were expected to die in their teens or at the very latest, their twenties. Now, most patients with Duchenne Muscular Dystrophy are living into their thirties, and many patients with less severe forms of the disease are living much longer and having normal lives (Duchenne Muscular Dystrophy, 1).

Conclusion

Muscular Dystrophy is a group of progressive (never stopping) muscle diseases that causes rapid deterioration of muscles in the body. The quickness in which some forms of the disease are able to destroy the body is so intense that there is no cure and no prevention of the disease. Some forms, however, are extremely slow and only affect muscles in the extremities of the body, such as the face muscles. These forms usually appear later in life and will not kill the person. However, forms such as Duchenne are so dangerous that patients die at a very early age. The disease starts its assault on the body at a young age and is unrelenting in its advance into the trunk of the body, where the significant damage begins to occur. While still in the extremities of the body, it creates many difficulties in movement, as the muscles are not strong enough to allow the person to move normally. For example, many children affected by the disease have an odd method of rising up from the ground due to the weakness of leg muscles. The deterioration of muscles also results in joint contractures and other joint problems. It is crucial to weak brace and stretch regularly to maintain a decent level of functionality in the limbs. It is here in the torso of the body, where the disease begins to attack respiratory and cardiovascular muscles, wreaking havoc on the person’s ability to absorb oxygen and fight diseases. Also at this point, it spreads to the gastrointestinal system; the system that digests food. When it reaches this area, the disease impedes the ability to digest food and excrete toxins, resulting in many stomach problems. Duchenne Muscular Dystrophy is caused by a defect in the dystrophin gene, which produces the dystrophin protein. The protein is crucial in maintaining membranes of the muscle and when the protein is nonexistent or mutated, it causes muscle development to go haywire and not work. The gene is subject to such frequent mutations due to its enormous length and difficulty to regulate. Thus, the gene itself is the target of many research groups and labs that are attempting to cure and prevent Muscular Dystrophy. Some of these experiments deal with the insertion of a completely new gene that will replace the fault ones. Others include just modifying the gene (exon skipping) and in order to make a semi functional version of the protein. Other treatments include surgery and corticosteroids, which have been proven to delay the disastrous effects of Duchenne Muscular Dystrophy, specifically delaying the loss of ambulation (walking). When the whole scope of the disease is taken into account, it is extremely dangerous and is one that both doctors and scientists hope to find a cure for in the near future.