Author: Ruoxi Lin
Editors: Chiara Chen and Rachel Chen
Artist: Jenny Luo
Ever since DNA was identified as the fundamental biological molecule that allows for reproduction, growth, heredity, and even life itself, geneticists have been studying mutations that cause debilitating diseases, conditions, and disorders. However, there is still a lack of information about these genetic diseases, emphasizing the need for greater awareness and further research—especially given that certain deadly mutations, while rare, can affect anyone. Among these diseases are muscular dystrophies, which are genetic conditions causing muscle degeneration. The most common neuromuscular disease is Duchenne muscular dystrophy (DMD), identified in the 1860s by the neurologist Guillaume Benjamin Amand Duchenne. It affects about 1 in every 5000 male births and 1 in every 50,000,000 female births worldwide.
DMD symptoms are usually first noticed between ages two and five, which is when a toddler usually takes their first steps. Children with the disease struggle getting up from a lying or sitting position, often using their hands in the process to compensate for the weakness in their lower limb muscles. This is known as Gowers’ sign, a significant characteristic in DMD patients. They may exhibit a waddling gait and have difficulty with running, walking, jumping, and climbing stairs. One study in particular showed that for a group of boys aged 5 to 12 with the disease, their walking ability declined before they reached adulthood. Signs of pseudohypertrophy, or enlargement of the calves and lower limbs due to excess fat, are often observed. There is also a higher chance of developing cardiomyopathy, a progressive heart muscle disease that hinders the heart’s ability to effectively pump blood, and life expectancy rates are only around 22 to 30 years. Children with DMD are predisposed to learning disabilities such as dyslexia, dysgraphia, and dyscalculia, and also show signs of cognitive impairment and developmental delays.
Typically, individuals diagnosed with Duchenne muscular dystrophy are assigned male at birth. This is in part due to how sex chromosomes are inherited, and how human genes are expressed. The DMD gene, the largest known gene on a human X-chromosome, is responsible for the production of the dystrophin protein. This protein is primarily found in skeletal and cardiac muscles. On a cellular level, dystrophin stabilizes the membrane of muscle cells during contraction and mediates cellular signaling. However, frameshift and nonsense mutations may result in non-functioning dystrophin, as such mutations can cut short the nucleotide sequences created during DNA transcription, the process of copying DNA into single-stranded RNA. Those assigned male at birth inherit only one X chromosome from their mother, while those assigned female at birth have two X chromosomes, one from each parent. As a result, most females are carriers of DMD and can still produce sufficient dystrophin, while males with the gene cannot. The presence of the DMD gene on the X chromosome and the pattern of inheritance from mother to son makes DMD an X-linked recessive disease.
Despite the low risk for females, it’s estimated that 8-22% of female carriers from families with DMD exhibit symptoms. One phenomenon responsible for this could be skewed X activation, where the female’s human body preferentially inactivates one X chromosome for 90% of the time instead of randomly activating or deactivating both. This can lead to amplified disease symptoms if the X chromosome with the mutation is preferred over the other. A homozygous female with two mutant alleles on either X chromosome will also show symptoms; however, this is unlikely, as most male patients die before their 30s and thus have a smaller chance of reproducing with a female who also has the mutated DMD gene. Chromosomal translocation—the process where a chromosome splits into two and reattaches to other chromosomes—involving an autosome and an X-chromosome can cause genes on the X-chromosome to be disrupted and cause the female to show symptoms. Lastly, those who only have one X chromosome, known as Turner Syndrome, do not have the reliability of X-inactivation.
Fortunately, there are now more resources available for DMD patients. People are diagnosed through Serum Creatinine Kinase tests, muscle biopsies, gene analyses, and electrocardiograms. Treatment usually entails using steroids that help improve muscle strength and function, using ACE inhibitors to relax arteries and beta blockers to control irregular heartbeat to prevent heart complications, getting surgical procedures done to treat possible scoliosis, attending physical, behavioral, and occupational therapy sessions, utilizing canes, walkers or wheelchairs to get around, and joining support groups. Recent advancements made in developing gene therapy have led to the creation of Elevidys, a drug that delivers into the body a gene that produces micro-dystrophin, a shorter version of dystrophin. Those with DMD must be surveilled at a young age and have a multidisciplinary care team that helps them with their symptoms. Organizations such as Parent Project Muscular Dystrophy and CureDuchenne have provided resources for patients. Hopefully, in the near future, there will be continued efforts put towards DMD research and genetic disease research as a whole.
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