We move around all our life to get things done. Unfortunately, there exist some conditions that prevent this typical movement in the lives of DMD victims. DMD or Duchenne muscular dystrophy is a condition characterized by weak muscles. They exhibit poor balance and an irregular body posture due to weak back and stomach muscles. The prime reason behind this condition is a mutation in the dystrophin gene. There is no cure, but there are several treatments for Duchenne muscular dystrophy. So what is the dystrophin gene mutation that interrupts the life of DMD patients?
What is the role of dystrophin protein?
Muscle contraction is a vital activity for mobility. The intracellular and extracellular proteins of the muscle should interact to maintain cell integrity. One such linker protein is the dystrophin, located near the muscular membrane.
Dystrophin protein consists of three segments. One links the muscle interiors, the other links to various extracellular proteins. The third is the central rod (spectrin proteins repeats), which holds these ends together. Since it connects the center of the muscle to the edge of the cell, it is extremely long. The exact number of this spectrin is critical for optimal function.
A genetic mutation can lead to reduced production of this protein, resulting in a short-chain. This short-chain can no longer link the extracellular and intracellular components leading to instability. As a result, whenever the muscle contracts, the muscle membrane rips open.
Creatine kinase can move to the extracellular space via these rips and serves as one of the diagnostic measures. It also stores energy for the muscle cells. Hence, with more creatine moving out of the cell, the muscle weakens over time.
The calcium ions, which are present in bulk outside the muscle, start entering into the cells. They activate calcium-dependent proteases, which typically kill damaged proteins. But, due to the high number, they start killing the healthy ones as well. As you get older, the muscles will not regenerate fast enough for compensation. Fat and other stores slowly start filling in the gaps in DMD, further weakening the muscles.
What is the mutation?
Due to random factors, DNA can undergo mutation. However, mutations can also be inherited. One such mutation responsible for DMD is frameshift mutation. Three nucleotides on the mRNA code for one amino acid — codon. The stop codon stops the synthesis of the protein (a polymer of amino acids).
In a frameshift mutation, one single nucleotide is added or deleted. This changes the reading frame, and stop codon can appear in the early stages, resulting in a shortened non-functional protein, i.e., the short dystrophin in DMD.
Symptoms of muscular dystrophy
- Gower’s sign: The person uses hands to get up because the muscles are too weak.
- Curved spine due to weak back muscles
- Belly sticks out due to weak back and abdominal muscles
- Calves are swollen with fat, and thighs are thin and weak.
- Arms are held up for balance
- Weak butt muscles
All these symptoms exhibit poor balance in the individual. As the disease progresses, it can turn to be life-threatening. Once the chest muscles weaken, patients start facing breathing difficulty and may need all-time assistance. The added pressure on the lungs contributes to this heaviness.
Women with muscular dystrophy can have healthy pregnancies. But since DMD is inherited, you might want to talk to a genetic counselor. During pregnancy, your healthcare provider will closely monitor your health to help you avoid complications like muscle weakness and limited mobility due to weight gain.
Treatments for Duchenne muscular dystrophy
There is no cure, but there are several treatments for Duchenne muscular dystrophy. These can range from over-the-counter drugs to gene therapies
1. Creatine and corticosteroid treatment
Creatine is a substance typically found in the body that helps supply energy to muscle and nerve cells. Recent research has shown that a creatine supplement can improve muscle strength in some people with MD, although it causes a few side effects.
Corticosteroids are the gold standard for the treatment of DMD. Studies suggest that they preserve motion and can delay the need for surgery and respiratory aids. However, a few side-effects include weight gain, delayed puberty, behavioral disorders and more. These symptoms can be reduced by finding an optimal regimen. Prednisone and prednisolone exhibit anti-inflammatory effects and deflazacort acts on muscle regeneration and differentiation.
2. Nanoparticle gene transfer
Dystrophin is a relatively short protein to qualify for a typical gene transfer. Hence, they tried to insert dystrophin genes into the cell via viral vectors — nanoparticle gene transfer method. These are not virulent but can induce an immunologic response. As a result, the recipient cells can interact with this gene, strengthening the muscles upto a considerable level. However, this method is still under debate for not producing the expected result in the human body.
3. Exon skipping
We know that frameshift mutation changes the reading frame. As a result, the stop codon appears early. In exon skipping, the specific molecules can override the translation to skip the stop codon and proceed to the next amino acid, resulting in a functional protein. Besides, myostatin is also a protein that regulates muscle size can be a reason for reduced size. Hence, destructive exon-skipping of myostatin is also a potential treatment.
4. Mutation suppression
Premature stop codon read-throughs like aminoglycosides and ataluren can also help skip premature stop codons. Aminoglycosides exhibit limitations since high doses can lead to renal toxicity. In comparison, ataluren is the alternate agent with the same activity and high safety.
5. Utrophin modulation
Utrophin is a dystrophin homolog, expressing the same activity. When the cell matures, dystrophin replaces the utrophin, which is typically present in unmatured cells’ sarcolemma. In DMD patients, the utrophin localizes to the mature muscles to compensate for the lost dystrophin. Hence, upregulating utrophin production can delay disorder progression.
Supportive care treatments for Duchenne muscular dystrophy
Treatments are available based explicitly on the individuals’ progression into the disorder. As MD progresses, it weakens their muscles and patients tend to lose stability while walking and while doing other routine chores.
Low impact exercise (such as swimming) and physiotherapy can maintain muscle strength, preserving flexibility, and loosening the stiff joints. Corticosteroids may slow disease progression. Surgery relieves tension on contracted muscles and corrects spine curvature (scoliosis).
Medical devices, like walker sticks and wheelchairs, can improve mobility and prevent falls. Respiratory care, such as cough-assist devices, respirators and breathing aids are necessary for individuals with breathing difficulty, especially during night. They may require heart assist devices, such as pacemakers, for heart-related complications.
Also, DMD increases the risk of fractures of long bones due to low bone density. DMD also increases the risk of osteoporosis and the side effects of prolonged steroid treatment. Hence, therapists recommend vitamin D supplements when in DMD treatment regime.
Inheritance pattern — are males more susceptible for DMD?
Every egg has an X chromosome, which fuses with a sperm (consisting of an X or Y chromosome) to form the zygote. If the fused sperm carries an X, the baby will be female (XX), and if it carries a Y, the baby will be male (XY).
The gene responsible for dystrophin protein synthesis is present on the X chromosome. The inheritance pattern is X-linked recessive, meaning the individual should have two mutated chromosomes to show the symptoms of the disorder. If a female has only one mutated X chromosome, it makes them carriers of the disease. They are unlikely to show any symptoms since they have another X as a backup.
Since every male inherits only one X from the mother, the risk of acquiring the disease is more if the mother is a DMD sufferer. Fortunately, they cannot acquire the father’s disease as they only inherit Y from the father. But since females inherit two X chromosomes from each parent and acquire a mutated X from one DMD parent, they will still have another normally functioning X for compensation. This makes them carriers, and they are unlikely to show any symptoms.
You can never be sure about what chromosome your child inherited unless you go through the process of genetic counseling and prenatal diagnosis.
What is genetic counseling? How can they help you?
If you are concerned that your child may inherit the disorder, you should always consult genetic counselors who can diagnose the condition before the child’s birth. They also help you understand
- Causes and types of the disorder
- Typical symptoms
- Chances of the disorder to occur again in the family and other family planning options
- Understanding the result and guiding through necessary treatments and follow-ups.
Prenatal diagnosis is a must to identify the problem during pregnancy and is the best time to take-up preventive measures.
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