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A 17-year-old teenage boy comes to the office because of generalized leg weakness. His medical history is relevant to a recently diagnosed idiopathic heart failure. Upon medical interrogation, the patient claims that lately, he stumbles easily when he walks. Physical exam shows a "duck-like" walk and bilaterally enlarged calf muscles. His temperature is 36.4°C (97.5°F), pulse is 90/min, respirations are 17/min, blood pressure is 120/80 mmHg. Laboratory findings show increased serum creatine kinase. Which of the following mutations is the most likely cause of this patient's current condition?
Content Reviewers:Rishi Desai, MD, MPH
Contributors:Tanner Marshall, MS
With muscular dystrophy, “dys” means bad or difficult, and “troph” means nourish; so muscular dystrophy basically refers to the muscle appearing poorly nourished because of degeneration, which leads to muscle weakness.
Under a microscope, a biopsy of the tissue shows changes in the muscle itself but not in the nerve or neuromuscular junction; this distinguishes muscular dystrophy from other problems that cause muscle weakness as a result of nerve damage, like neuropathies.
Muscular dystrophy is actually a group of disorders, all of which are caused by genetic mutations.
Within that group, dystrophinopathies are the most common, which includes Duchenne muscular dystrophy, or DMD, and Becker muscular dystrophy, both of which result from mutations in the dystrophin gene.
In addition to those two, genetic mutations in other genes are responsible for several dozen other muscular dystrophies, some of which code for proteins that form a protein complex with dystrophin protein.
These other muscular dystrophies, therefore end up causing a lot of the same symptoms as the dystrophinopathies.
Now, the fact that both Duchenne and Becker muscular dystrophy result from mutations in the same dystrophin gene means that they are “allelic disorders,” and when a mutation occurs in dystrophin that’s severe enough to result in no protein at all, for example a nonsense or a frameshift mutation, the result is Duchenne muscular dystrophy, which ends up being the more severe of the two, with symptoms usually presenting by age 5.
On the other hand, mutations that allow for a misshapen protein to form, like missense mutations, lead to Becker muscular dystrophy which is basically a milder form of Duchenne muscular dystrophy that presents later on, usually between age 10 to 20.
Alright so the dystrophin gene is a huge gene on the X-chromosome, that has 79 exons and is over 2 million base pairs in length.
By comparison, most genes have only about 10 exons and are 50 thousand base pairs in length.
Most of these gene mutations are deletions or duplications of one or more exons, and a small amount are point mutations.
Now males males have one X and one Y chromosome, and females have two X chromosomes.
This means it’s way more common in boys, because they only have one copy of the dystrophin gene, and if that copy’s defective, it’s the only one available to muscle cells, whereas girls with a defective dystrophin gene might have another functional one.
In females, though, only one X chromosome gets expressed, and the other is inactivated, called X-inactivation or lyonization.
Now if this inactivation’s random, you’d expect about half of the female’s cells to have a functional dystrophin gene and the other half to have a defective dystrophin gene, and these people are typically asymptomatic.
Having said that, if more cells end up with the defective dystrophin gene, and less with the functional one, they can end up being “manifesting carriers,” meaning that they manifest or show some symptoms.