Duchenne Muscular Dystrophy: Symptom & Treatment - Health 365 day

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Saturday, June 26, 2021

 Duchenne Muscular Dystrophy: Symptom & Treatment

Muscular dystrophy


What is Muscular dystrophy?

Muscular dystrophy is a disease that causes the degeneration and necrosis of skeletal, muscle fibers which results in muscles weakness. By the way, Necrosis means cell death. After the date of the cell eventually, pseudo hypertrophy sets in which is the replacement of muscle with fat and connective tissue. Pseudo hypertrophy is very common in the calf of someone with muscular dystrophy.

All movement is controlled by contracting various muscles in our body. Muscles are made up of many long, tubular cells called myocytes that can contract to cause flexing.

An important structural protein called dystrophic is located near the membrane of myositis. Dystrophic 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 acting-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.

Introducing Duchenne muscular dystrophy

In Duchenne muscular dystrophy a genetic mutation causes dystrophin to the 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 the diffusion of various molecules into and out of the myocyte.  The most important substance involved in damaging muscles 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.


Duchenne muscular dystrophy symptoms:

However, in Duchenne muscular dystrophy, 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 the blood is often used to diagnose Duchenne muscular dystrophy.  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 an order through, 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.


Why Duchenne muscular dystrophy happened?

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 ad 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. 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 makes up proteins, and the final codon is a stop codon that 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 the causes DMD is known as the "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 that code for different amino acids, usually resulting in a non-functional protein, much like how if a letter is deleted, the sentence makes no chance. 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.

 

Treatment of Duchenne muscular dystrophy:

Currently, there is no cure for Duchenne muscular dystrophy, but there are many ways to control its symptoms to prolong lifespan.

Physical therapy, steroids, and surgery can all help slow down muscles weakening. 

What is most interesting is current research being done to cure Duchenne muscular dystrophy by directly manipulating the dysfunctional dystrophin gene.

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.

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 no other cells.

Gene therapy is still in its early stage with mixed success in human patients. However, with further research on these treatments, a cure to DMD seems to be near in the future.

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