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.
Alright so the dystrophin protein links intracellular actin with the “dystrophin-associated protein
complex,” which is a cluster of cytoplasmic and cell membrane proteins that are anchored
to the extracellular matrix around the muscle cell, making that link between cytoskeletal
actin and the extracellular matrix stabilizes the sarcolemma, or muscle cell membrane, in
the same way that a large wooden support beam running along the roof keeps a house sturdy.
Without the support of dystrophin in place, the sarcolemma essentially wilts and becomes
unstable.
Over time, cellular proteins like creatine kinase, or CK, start escaping the damaged
cell and calcium starts to enter the cell, and this ultimately leads to cell death.
In the short term, there is muscle regeneration resulting in muscle fibers of different sizes,
but in the long term, the muscles atrophy and are infiltrated by fat and fibrotic tissue,
which leaves them really weak.
This process is particularly noticeable in the legs, and children with Duchenne muscular
dystrophy begin to walk later in childhood, and they have they have a “waddling” gait,
and they tend to develop calf pseudohypertrophy, where they have visibly enlarged calves which
are large because of fat and fibrotic tissue rather than muscle tissue.
Another classic sign of Duchenne muscular dystrophy is Gowers’ sign, where if a child
is lying down flat on their stomach, they will slowly stand up with the help of their
arms, because of weak muscles around the hips and upper legs.
Later symptoms include needing a wheelchair because of severe weakness, developing respiratory
failure because of a weak diaphragm, scoliosis, and developing dilated cardiomyopathy and
arrhythmias since the dystrophin protein is also expressed in heart muscle.
Unfortunately, these complications often lead to a shortened lifespan.
For diagnosis, people with Duchenne or Becker muscular dystrophy often have a high creatine
kinase level, and the diagnosis can be confirmed by looking for mutations in dystrophin (by
either DNA tests or Western blot), as well as having a muscle biopsy with staining for
dystrophin.
Unfortunately, there are no great treatments for Duchenne or Becker muscular dystrophy.
Glucocorticoids can sometimes slow degeneration, but can also result in side effects like excessive
weight gain.
Other treatments like physical therapy and conditioning can improve quality of life,
but they don’t reverse the underlying process.
Given the possibility of genetic inheritance, counseling parents of the person and understanding
the risk of having another child with these conditions is important.
About 2/3 of the time the person’s mother is a carrier and the the other 1/3 of the
time the disease is sporadic, which means it’s caused by a new mutation.
If the mother is a carrier, and we look at her future sons, half or 50% will end up having
the mutation, and if we look at her future daughters, half or 50% of them will be carriers
for the mutation.
Okay so as a quick recap: the protein dystrophin is super important for stabilizing the muscle
cell membrane.
Mutations in the dystrophin gene that lead to a loss of dystrophin leads to duchenne
muscular dystrophy, whereas mutations in the dystrophin gene that leads to misshapen dystrophin
leads to Becker muscular dystrophy.
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