As children, they have difficulty walking.
As teenagers, most require wheelchairs.
Their average lifespan is less than 30 years old.
What devastating disease do these people have?
Join me in this episode of Medicurio where we will discuss one of the most debilitating
muscular diseases: Duchenne muscular dystrophy.
All movement is controlled by contracting various muscles in our body.
If we zoom into muscle, we see that it is made up of many long, tubular cells called
myocytes that can contract to cause flexing.
An important structural protein called dystrophin is located near the membrane of myocytes.
Dystrophin acts like a chain that links the skeleton of the myocyte, made of actin, to
the extracellular matrix, which is a mesh-like structure outside the myocyte.
This linkage prevents membrane damage when the muscle contracts.
Dystrophin has three important areas: the actin-binding end, which attaches to the cellular
skeleton, the central rod, and the dystroglycan-binding end which attaches to the dystroglycan complex
within the membrane that is anchored to the extracellular matrix.
In Duchenne muscular dystrophy, a genetic mutation causes dystrophin to be extremely
short, often lacking the dystroglycan-binding end, making it dysfunctional.
Because of this, every time the muscle contracts, small rips appear in the membrane.
These small rips allow diffusion of various molecules into and out of the myocyte.
The most important substance involved in damaging muscle is calcium.
Calcium ions, found plentifully outside of the myocyte, flow in through these small rips
and activate calcium dependent cellular enzymes that break down proteins, called proteases.
Normally, by carefully regulating cellular calcium levels, these proteases only break
down old and damaged proteins.
However, in DMD, extremely high calcium levels activate too many of these proteases, which
begin to break down important, functional proteins as well.
This kills the myocyte.
Another important molecule that diffuses through the rips is creatine kinase, which leaks out
of the cell and eventually into the blood.
This elevated level of creatine kinase in blood is often used to diagnose DMD.
Creatine kinase is an enzyme that stores energy for myocytes to use during contraction.
With less creatine kinase, less energy storage occurs, which also weakens muscles.
Muscle repair and regeneration can occur at younger ages.
As patients get older though, muscles no longer regenerate fast enough to keep up with the
constant death of myocytes.
Instead, fat and scar tissue begin to fill in the gaps.
Since fat and scar tissue are unable to contract, muscles get weaker over time.
This weakening leads to a distinct pattern of symptoms, such as Gower’s sign, where
a child must use his or her arms to stand up because the leg muscles are too weak.
As well, other physical symptoms appear, such as a curved posture to account for weaker
chest and leg muscles, and calves that are swollen due to buildup of fat and scar tissue.
Since the heart and diaphragm are also muscles, they gradually weaken over time as well.
Eventually, they stop working, leading to death often before age 30.
Currently, there is no cure for DMD, but there are many ways
to control its symptoms to prolong lifespan.
Physical therapy, steroids, and surgery can all help slow down muscle weakening.
What is most interesting is current research being done to cure DMD by directly manipulating
the dysfunctional dystrophin gene.
In order to understand how these techniques work, we must first understand the characteristics
of the dystrophin gene.
The dystrophin gene is located on the X-chromosome, making DMD an X-linked recessive disease affecting
mostly males.
This is because females have two X chromosomes, while males only have one X and one Y chromosome.
Therefore, if a female has a mutation in one of her X chromosomes, the other X chromosome
acts as a backup.
This is not the case for males, who only have one X chromosome and no backup, since the Y chromosome
does not have the dystrophin gene, therefore making this disease more common in boys.
Approximately 1/3500 boys have this disease.
Females who have a copy of a defective dystrophin gene are known as carriers, since despite
not being affected by the disease, they have a 50% chance of passing down the defective
gene to their children.
Interestingly, inheritance only explains two-thirds of DMD cases.
The remaining one-third of patients have parents who do not have the disease and are not carriers.
This is because everybody has random, often harmless mutations in their genes.
Unluckily, their random mutation in the dystrophin gene is harmful.
Genes consist of a sequence of nucleotides: adenine, guanine, thymine, and cytosine, which
are abbreviated as letters.
Whenever a cell wants to make a certain protein, cellular machinery “reads” genetic material
three nucleotides at a time.
These triplets are called codons.
Each codon corresponds to a certain amino acid, which make up proteins, and the final
codon is a stop codon which tells the cell that the protein is finished, such as the
codon TGA.
Much like how a sentence is made up of three-letter words ending with a period, a protein is made
up of amino acids corresponding to three-nucleotide codons ending with a stop codon.
The most common mutation in the dystrophin gene that causes DMD
is known as a “frameshift” mutation.
If a nucleotide gets removed due to DNA damage or errors in DNA replication,
the reading frame changes.
Now, cellular machinery reads different codons which code for different amino acids, usually
resulting in a non-functional protein, much like how if a letter is deleted, the sentence
makes no sense.
In this example and in DMD, the frameshift mutation causes a stop codon to appear in
the middle of the protein, which results in an incomplete, non-functional dystrophin protein.
Gene therapy aims at fixing the mutated dystrophin gene.
One way is by making the cell skip a segment of the gene containing an early stop codon,
a technique known as exon-skipping.
This results in a functional dystrophin protein with a slightly shorter central rod.
Going back to the sentence analogy, by skipping part of the sentence, it makes sense again,
although missing some trivial information.
Another fascinating treatment method is by using viral vectors.
Some viruses are known to incorporate their own DNA into human cells.
Scientists have been able to take advantage of this skill to make viruses carry a modified
dystrophin gene instead of viral genes, which gets incorporated into DMD myocytes, allowing
these myocytes to produce the modified functional dystrophin protein.
The main limitation to these two techniques is ensuring that the technique can affect
myocytes but not other cells.
Gene therapy is still in its early stages with mixed success in human patients.
However, with further research on these treatments, a cure to DMD seems to be near in the future.
Check out the links in the description below to learn more about DMD or to support the
ongoing research about this debilitating muscular disease.
Thanks for watching, and see you next time for another explanation of a disease on Medicurio.