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Muscular Dystrophy: Hope Through Research states, Muscular Dystrophy was first seen in 1850, by Sir Charles Bell. He wrote about an illness that caused weakness in boys. Six years later, another scientist wrote about two brothers who were ailed with generalized weakness, muscle damage and replacement of damaged tissue with fat and connective tissue. At that time, those symptoms were diagnosed as tuberculosis. In the 1860’s a French neurologist named Guillaume Duchenne wrote about boys exhibiting symptoms of this severe dystrophinopathy (NIDS, n.d.).
That disease is now named after him as Duchenne Muscular Dystrophy. Eventually, it was noted that the disease could present in many ways and didn’t discriminate on sex or age.
The words muscular and dystrophy can be broken down into muscular meaning “relating to muscle” and dystrophy meaning “bad or difficult nourish”. This would roughly translate to the muscle is poorly nourished. This is due to its progressive degeneration. Unlike some other muscular degenerative diseases, that have problems at the neuromuscular junction, the problem in muscular dystrophy is in the muscle itself.
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The muscle will often appear atrophied. In the group of muscular dystrophy disorders, dystrophinopathies are the most common. Dystrophinopathies are variety of diseases that can cause muscle weakness and are X-linked (Daras, 2000). There is more than one type of Muscular Dystrophy. Together, they are a group of genetic diseases in which patients show symptoms of musculoskeletal weakness and progressive degeneration (Dystrophinapathy, n.d.). Ever since the first muscular dystrophy gene encoding dystrophin has been discovered, multiple other genes have been identified as involved in other muscle-wasting and neuromuscular disorders (Rahimov, 2013).
Dystrophin is a protein that plays a very important role in keeping the muscle intact (MDA, n.d.). According to the Human Genome Project, a genome is an organism’s complete set of DNA and humans have about 30,000 genes in our genomes. A mutation in just one of those genes could prove deadly as shown by Muscular Dystrophy.
Within that group the two most common are Duchenne Muscular Dystrophy or DMD and Becker Muscular Dystrophy. These disorders are a result of gene mutation in the DMD gene. (“DMD Gene,” n.d., para 1). Duchenne Muscular Dystrophy is caused by a lack of dsytrophin. Also known as a nonsense or frameshift mutation. Becker Muscular Dystrophy is due to misshapen dystrophin or a missense mutation (Rahimov, 2013). DMD is usually the more severe out of the two because in Becker Muscualr Dystrophy, the dystrophin protein is still partially functional.
The dystrophin chain is located on the X chromosome. It has seventy-nine exons and is over two million base pairs in length. This is a rather large gene since most genes only have about ten exons and fifty thousand base pairs in length. With this gene having so many exons and base pairs, this means that there is a greater chance for a mutation to take place. The mutations would take place during meiosis. Khan Academy’s tutorial on meiosis says meiosis is a division process that takes us from a diploid cell (with two sets of chromosomes) to a haploid cells (with a single set of chromosomes). The haploid cells in humans are a sperm and an egg. When a sperm and egg join in fertilization, the two haploid sets chromosomes form a complete diploid set: a new genome. Genetics Home Reference tells us that most of the gene mutations that take place are deletions of one or more exons. Small amounts are point mutations that would only affect a single nucleotide of a singe nucleic acid.
Centers for Disease Control and Prevention state as of 2013, approximately 1 in every 3,500 to 6,000 male births each year in the United States are affected by Duchenne Muscular Dystropy. Males have one X chromosome and one Y chromosome. Females have two X chromosomes. Muscular Dystrophy is more common in males because it is inherited in an X-linked recessive fashion. This means the mutation occurs on the X chromosome. The DMD gene is located between positions 21.2 and 21.1 on the X chromosome (GeneCards, n.d.). Males only have one copy of the X chromosome. If that copy is defective, that is the only one to produce the dystrophin protein. In females, only one X chromosome gets expressed and the other is inactivated or lyonization (Hiratani and Gilbert, 2010). This means that those females would asymptomatic. If more cells were damaged, they would be considered manifesting carriers and show some symptoms.
Duchenne Muscular Dystrophy is caused by a mutation of the DMD gene. The DMD gene is the largest known human gene and codes for the protein dystrophin (Genetic Home Reference, 2017). Dystrophin is mostly in the skeletal and in the cardiac muscles with a small amount being found in the neurons of the brain. The dystrophin protein is extremely long, rod-shaped and is made up of 3865 amino acid residues (The DMD Mutations Database, n.d.). In its primary structure, the protein can be divided into four domains: (1) the N terminal actin-binding domain, (2) the large triple helical spectrin-like domain, (3) the cysteine-rich domain and (4) the C-terminal domain (The DMD Mutations Database, n.d.). Contracting the different muscles in our body controls the movements we make. The muscles are made of myocytes. Myocytes are long tubular cells and when they contract, the muscles flex. The dystrophin protein links intracellular actin with the Dystrophin-associated Glycoprotein Complex (DGC) (Ervasati, n.d.). This complex is a group of cytoplasmic and cell membrane proteins that are held down to the extracellular matrix, which is a mesh-like structure outside of the myocyte (Ervasati, n.d.). The link between the cytoskeletal actin and extracellular matrix stabilizes the sarcolemma and prevents membrane damage when the muscle contracts. The sarcolemma is a muscle cell membrane. This is comparable to a rafter, a large wooden beam that supports a roof (Macmillan Dictionary, n.d.).
Doing this, it transfers the force of the muscle contraction from inside the muscle cell outward to the cell membrane and stabilizes it. Without dystrophin, the muscle cell membrane (sarcolemma) is unstable. Because of this, every time the muscle contracts, small rips appear in the membrane. Overt time, cellular proteins can escape the damaged cell and calcium ions can enter the cell. Calcium entering through the small openings will then activate calcium dependent cellular enzymes that breakdown proteins. In a normal cell, the cellular calcium levels would be regulated and the proteases would only breakdown old and damaged proteins. In DMD, calcium levels are extremely high leading to the activation of too many proteases, which begin to breakdown important functional proteins. . This can eventually lead to cell death and muscle damage.
As the calcium ions are entering the damaged cell, some important molecules can escape into the blood. One of these molecules is creatine kinase. Creatine kinase is an enzyme that stores energy for myocytes to use during contraction. As the creatine kinase levels drop in the cell, there is less energy storage causing weakened muscles. An elevated level of serum creatine kinase is often used to help diagnose DMD. The older the person is, the harder it is for the muscles to regenerate. As patients get older, muscles no longer regenerate fast enough to keep up with the rapid death rate of myocytes. As the muscle regeneration occurs, this results in muscle fibers of different sizes. Eventually, the muscles are infiltrated by fat and scar tissue.
There are various ways symptoms could present with DMD. Since the muscles are unable to contract properly, they get atrophied over time. A classic (but not exclusive to) Duchenne Muscular Dystrophy symptom called Gower’s sign is where a person is laying down, but needs to the help of their arms to get up. They do this because of the weakness in their hip and leg muscles. DMD is generally spotted in adolescence. A child with DMD can also be seen starting to walk later in childhood with a waddling gait (EPO Medicine, 2016). They also tend to develop calf pseudohypertrophy when their calves appear larger because of fat and fibrosis taking the place of muscle (EPO Medicine, 2016). They may also present with a curved posture because of weak back and their belly may stick out due to weak abdominal muscles. The arms can also be seen held back for balance. As stated, high creatine kinase levels can be tested for as well as dystrophin mutations via DNA testing and Western Blot (Forcina & Miano, 2017). A muscle biopsy with staining for dystrophin may also be done.
As they age, they will get progressively worse. Later on needing a wheelchair because of severe atrophy and weakness. The weakness can affect muscles all over the body including the heart and diaphragm. This can lead to respiratory failure, dilated cardiomyopathy and arrhythmias. All of these complications can lead to a shortened lifespan. There is no official cure for DMD or Becker Dystrophy (CureDuchenne, n.d.). So, it is the patient’s symptoms that are treated to help prolong their lifespan and improve quality of life. None of these measures reverse the underlying process of DMD. Glucocorticoids may be prescribed in an attempt to slow degeneration, but they can result in side effects such as excessive weight gain. Extra weight would make it even harder for the patient to be mobile. Other treatment options include physical therapy and conditioning to help with muscle weakening.
Statistics show Duschenne Muscular Dystrophy affects approximately one out of every five hundred male births (CureDuchenne, n.d.). About fifteen thousand boys are currently living with DMD in the United States alone with over three hundred thousand cases being reported internationally (CureDuchenne, n.d.). Although there is no official cure yet, there are a few exciting prospects in the research phase. Exon skipping is a treatment upon in the clinical stage of development for possibly correcting and restoring the production of dystropin (NCBI, 2017). Genes are divided into two parts exons and introns. Exons are the part of DNA that codes for proteins and are spread out with introns that are often called “junk DNA.” In the process of protein production, introns and cut and discarded leaving just the exons (Muscular Dystrophy UK, n.d.). In Becker Muscular Dystophy, an exon is deleted (Muscular Dystrophy UK, n.d.). This would still be some functional sections in the gene and the two ends of the protein can rejoin. Hence, the milder form of Muscular Dystrophy. In Duchenne Muscular Dystrophy an exon or exons are deleted which can cause problems for the rest of the gene to be put back together (Muscular Dystophy UK, n.d.). In gene skipping, the point is to skip over or the faulty exon leading to a still functional protein (NCBI, 2017).
In 2017, Parent Project Muscular Dystrophy (PPMD), a non-profit organization, awarded Jerry Mendell, MD, PhD; co-PI Louise Rodino-Klapac, PhD; and Nationwide Children's Hospital a 2.2 million dollars grant (CISION, 2017). This team is working on gene therapy as a potential cure for Duchenne Muscular Dystrophy. A gene editing method called consists of studying the CRISPR-Cas9 system. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats and is part of the bacterial immune system (Broad Institue, n.d.) Cas9 is an enzyme made by the CRISPR system that binds to DNA and cuts a specific portion (Broad Institute, n.d.). CRISPR-Cas9 can be used to cleave multiple genes at the same time specifically targeting the mutation site, which sets it apart from other gene editing methods (Broad Institute, n.d.). The hope is that once the faulty DNA is cleaved out, the two ends will join to make a continuous DNA sequence (CureDuchenne, n.d.).
The list of Muscular Dystrophies is long, but Duchenne Muscular Dystrophy is the most severe and limiting. With the absence of dystophin having so many devastating effects, a cure or a more advanced treatment regimen is imperative.
Danger And Features Of Muscular Dystrophies. (2024, Feb 15). Retrieved from https://studymoose.com/danger-and-features-of-muscular-dystrophies-essay
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