Please note! This essay has been submitted by a student.
The average lifespan of the world is 72 years. However, cancer and certain disorders can cut that number down drastically. One of those disorders is the Duchenne Muscular Dystrophy (DMD). DMD is a sex-linked disorder that arises from a mutation in the gene that codes for the protein dystrophin. This protein serves to strengthen muscles and connects the cytoskeleton within muscle cells (NIH, 2017). However, because of the mutation caused by DMD, dystrophin is no longer produced and sufferers of this disorder have weakened muscles and will continue to have muscle degradation called atrophy. This can lead to multiple life threatening symptoms such as the muscles losing the ability to support the lungs or heart. Moreover, weakened muscles are more susceptible to damage. The severity of the disease varies with the difference in mutation. The symptoms of this disorder usually develop at ages 2 to 3, and most patients do not live past 20 or 30 years old. In rare cases, some people can live full lives with mild DMD. Currently, there is no cure for this disease, but there are clinical trials that hope to change this. The mutations, inheritance, cure in development, current research, and ethics are essential to gaining a deeper understanding of DMD.
The cause of DMD is from the lack of dystrophin is from a mutation in the gametes. The mutation can be a frameshift mutation from a deletion of a base that shifts the nucleotide sequence (Aartsma-Rus, 2006). Usually, this mutations causes the production of a nonfunctional protein as one of the exons needed to produce dystrophin no longer exists. To elaborate, when snRNPs join with other proteins to produce spliceosomes to cut out introns and join exons, the resulting mRNA that goes through translation no longer have the codons that code for dystrophin. The anticodon of the tRNA will not match what’s not there. This makes the protein lack the amino acid essential for dystrophin. Other possibilities that give rise to DMD include a duplication error during crossing over in meiosis, or a point mutation (specifically a missense or a nonsense mutation) where a base is substituted for another. All of these mutations cause the production of a nonfunctional protein or a protein that does not do the desired function that dystrophin usually does. To date, it is known that around 2000 different mutations can cause DMD (Sarepta, 2017). Moreover, DMD is a X-linked disorder. Therefore, males only need one copy of this gene to inherit the disease as males have one X and one Y chromosome. Females need both copies of the DMD mutation as they have two X chromosomes. This makes DMD a recessive trait. If females have only one copy of DMD, then she is considered a carrier and she does not usually show signs of having DMD. However, in the case of X-inactivation, females can experience a whole spectrum from mild to severe DMD. This is because X-inactivation turns off one of the X chromosomes during development and can cause the X chromosome with the DMD mutation to give gene expression. To help better understand the inheritance of DMD, The National Center for Advancing Translational Sciences gives an example that in a monohybrid cross between a DMD male and a normal female, all male children will not have DMD due to the inheritance of the X chromosome from the mother, while all female children will become carriers of DMD. In the case of a cross between a normal male and a carrier female, all male offsprings will have a 50% chance of inheriting DMD, while 50% of female offsprings will be carriers.
Dystrophin is known for its role in maintaining and stabilize muscles. However, it is also involved with the function of the brain. While current research have yet to reveal much about its precise role within the brain, around 80% to 99% of children with DMD also have cognitive impairment (Rae, 2016). There are also conditions such as ADHD and OCD that accompanies DMD. The current study suggests that perhaps the cognitive impairment comes from its effect on neurons as some of the dystrophin protein is also produced in the hippocampus. The lack of the protein production may disrupt the hippocampus’ role in processing explicit memory, spatial memory, and associating names with faces to name a few.
There are several diagnosis for DMD. The CK test, or creatine kinase test, shows that the more CK present in the blood, the greater the muscle damage. While this does not directly indicate DMD, it does suggest DMD if there are high CK levels (Aartsma-Rus, 2006). There is also molecular genetic testing done usually through a blood test that can show if there is a DMD mutation. Muscle biopsies are also an option. It shows the amount and location of dystrophin in muscle tissues. However, with the rise of genetic testing, this method is not used often anymore (MDA, 2019). After diagnosis, there are a wide range of options for treatment. The use of corticosteroids to slow muscle loss is common to slow the progression of DMD. However, there are side effects such as weight gain and behavior changes to be aware of. Light exercise may also be beneficial in maintaining muscle strength, whereas overextension or inactivity may speed up muscle degradation (Torgan, 2018). Other treatments will vary with each patient as their needs differ. For example, there may be patients that require a heart transplants or spinal fusion surgery in severe cases.
Current research proposes a new method of treatment called gene therapy. This process is replacing the mutated DMD gene with a unmutated gene (MDA, 2019). However, this treatment still faces many major challenges. The large size of the dystrophin gene poses a problem for the method of insertion. Moreover, targeting the delivery of the gene to only the muscle cells require much more research since the DMD replacement gene in other tissues should remain unread during transcription to prevent potential undesirable effects. If the healthy gene can be inserted, there is the problem of a possibility of a unwanted immune responses from the protein that the replacement gene makes. In response to these challenges, there have been trials to make an alternate version of dystrophin that is smaller. This microdystrophin contains just enough genetic information to construct the gene. The most recent model, rAAVrh74.MCK.Micro-Dystrophin, is in the first phase of clinical trial at Nationwide Children’s Hospital for young male children (MDA, 2019). Another research is exploring methods to deliver healthy genes to the muscle cells without them affecting other tissues. Researchers have created a promoter, the region in which RNA polymerase II attaches to for transcription, called the muscle creatine kinase (MCK) that is only specific to muscle cells. This allows for transcription of dystrophin only in muscle cells. There is currently a first phase clinical trial utilizing MCK (MDA, 2019). Finally, there is also exon skipping in development that does not cure DMD but lessens muscle weakness. This is where researchers hope to make proteins with certain exons of dystrophin left unread that results in a partially functional dystrophin. This process is done with the help of antisense oligonucleotides (AONs). On September 19, 2016, Exondys 51 is approved and it targets exon 51 with AONs (Lim, 2017). Other exons skips are still being researched. There are still many methods to alleviate or cure DMD in research that are in clinical trial not discussed.
Numerous ethical challenges are to be considered with the treatment of DMD. One of the greatest ethical considerations is when the patient wishes to stop treatment while their guardians wish to continue treatment (Geller, 2003). The problem lies with how certain countries like the US do not allow minors to take part in the decision making of continuation of treatment whereas other countries like Canada do. Personally, if there is even with a slight chance of temporary alleviation of symptoms from DMD, patients should take the treatment if financial situations allow for it. This is because it may extend one’s lifespan while they wait for a better treatment to be developed. Another ethical concern regards the current research of exon skipping on personalized medicine that questions equity and minimum entitlement. By exon skipping and helping specific patients with mutations at a specific exon, this will help slow muscle degradation. However, not all exons can be skipped with the current knowledge and having to invest more for specific needs of individual cases may not be cost effective which can lead to harm by omission (McCormack, 2010). I believe that even if only exon 51 is the only available treatment, it should to be applied to cater to those that can be helped. Despite this being harm by omission, other patients should be understanding and accept that their treatment is not developed yet. Economic barriers also exist as an ethical concern. Treatment for certain therapies can reach up to $300,000 per year, leaving health resources and minimum entitlements as an ethical challenge (McCormack, 2010). Knowing that 1 in 3500 people are diagnosed with DMD, a large sum should be devoted to research and medical resources to help those that need it. Patients don’t choose to have DMD, it was a mutation that led to their situations.
DMD is a X-linked disorder that can be caused by a duplication error in meiosis, a deletion error, or a point mutation in transcription. This disorder affects mostly young male children and most do not live past 20. While there is no cure for DMD currently, many potential treatments are under development with exon skipping, insertion of a replacement gene, and gene therapy among many others. Ethical considerations concerning DMD is whether or not young patients should take part in the decision making of medical treatment, whether or not to continue to invest large sums to these patients, and whether or not exon skipping is ethical.