USMLE® Step 1 style questions USMLE
A study is carried out to evaluate X-linked recessive disorders in female carriers. The clinical features of eight female gene carriers of Duchenne muscular dystrophy were noted, and a relationship was established between the genotype and phenotype. Five of the eight cases were symptomatic and showed mild muscle weakness, difficulty walking, mild to moderate elevations of the serum creatinine kinase level, or myopathic changes on an electromyogram. Upon immunofluorescence, a mosaic pattern of dystrophin deficiency was found. Only two carriers were clinically asymptomatic. Which of the following genetic terms best describes the underlying cause for the difference in these patients’ symptoms?
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.
More base pairs and more exons mean that there are more chances for mistakes during meiosis, which is when the egg or sperm are being created.
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.
Since this is linked to the X chromosome, both Duchenne and Becker muscular dystrophy are called X-linked recessive.
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.
Muscular dystrophy is a group of inherited diseases that cause progressive weakness and degeneration of the skeletal muscles that control movement (e.g. Duchenne and Becker muscular dystrophy). Muscular dystrophy is caused by genetic defects that interfere with the production of proteins needed to form healthy muscle. There is currently no cure for muscular dystrophy, physical and occupational therapy, and medications can help manage the symptoms and slow the progression of the disease.