Duchenne Muscular Dystrophy (DMD) is an inherited neuromuscular disease characterized by rapidly progressive muscle weakness. Since Duchenne-Becker myodystrophy is associated with the X chromosome, most of the time only boys suffer from that disease. The frequency of occurrence is one in 3,500 newborn boys.
Symptoms usually appear at between two or three years of age. DMD makes it difficult for children to run, jump, climb stairs, or stand up from the floor. Over time, patients will need to use wheelchairs, usually between the ages of 10 and 13.
Becker Muscular Dystrophy (BMD) is a milder form of DMD and is less common: Only one in 12,000 newborn boys are afflicted. The severity of symptoms varies greatly, depending on the patient. For example, the disease can manifest as loss of the ability to move independently after the age of 16, but there are also extremely mild forms, which means patients can remain asymptomatic until midlife - 50’s or even 60’s.
The biology behind Duchenne-Beker Myodystrophy
The human genome contains 21,000 genes that code for different proteins, each of which performs a specific function in our body. Mutations in the gene that encodes the dystrophin, important for muscle function protein, lead to the development of Duchenne-Becker muscular dystrophy.
The dystrophin protein is part of a special complex, which ensures the stability and elasticity of the muscle fiber during subsequent muscle contractions. In the absence of dystrophin, the cell's membrane is being destroyed.
Depending on which part of dystrophin protein is affected, the outcome of the disease can vary. Some protein parts are crucial and even one amino acid (the main structural part of the protein) change to another can affect the functions of dystrophin. On the other hand, there are areas, in which even big changes do not affect protein function.
Genetics behind Duchenne-Beker Myodystrophy
The severity of myodystrophy is affected not only by what part of the protein is changed, but also by the type of mutation that occurs. The DMD gene is one of the largest genes in our genome and therefore the number of different mutations in it increases drastically.
If the mutation affects only one region of the dystrophin gene, and after it the sequence remains unchanged, it leads to a more favorable outcome. However, if the sequence changes drastically, then completely different amino acids are formed starting from that place. Some changes lead to a premature stop in the synthesis of dystrophin. It is resulting in a protein with a completely different structure, which cannot perform its function.
Not all mutations tragically affect the outcome. Since in our genome several different molecules code one amino acid, sometimes changes in a gene do not lead to a change in a protein.
How do mutations appear in the patient's genome?
The gene encoding dystrophin is located on the X chromosome. Since women have two X chromosomes, in the absence of other diseases, even if there is one X chromosome with a mutation in the dystrophin gene, a woman will not manifest this disease. However, since males have only one X chromosome, it is critical whether there are mutations in it or not.
This type of inheritance is called X-linked recessive. The probability that the son of a mother with a mutation in the dystrophin gene will have Duchenne muscular dystrophy is 50%. As well as the probability that the born daughter will be a carrier of this mutation. However, even in the case when both parents do not have a mutation in dystrophin gene, they still can have a child with a new mutation, such cases account for 30%.
Duchenne-Becker Muscular Dystrophy diagnosis
The physician can establish a preliminary diagnosis already during the examination, observing the child's attempts to walk, run, jump, climb stairs, get up from the floor. Once a physician confirms a DBM diagnosis the following tests are carried out:
Activity of creatine kinase in patients’ blood serum. With Duchenne-Becker muscular dystrophy, muscle cells break down and release creatine kinase and other cytolysis products into the blood. Therefore, the level of creatine kinase in the blood is significantly increased (> 100 times).
The indications of such enzymes as lactate dehydrogenase (LDH), and the so-called "liver enzymes" alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are also checked. The activity of the LDH enzyme is increased by 3-5 times. The activity of AST and ALT enzymes, which are of extrahepatic origin, can be increased tenfold.
These tests allow us to determine the presence or absence of dystrophin, as well as its amount. By this test it is possible to distinguish a milder form from a more severe one.
Dystrophin gene tests.
Genetic testing usually begins with a search for deletions/duplications using the MLPA (Multiplex ligation-dependent probe amplification) method. This method reveals whether the dystrophin gene consists of exactly 79 exons (the main parts of the gene) no more and no less.
If the mutation has not been detected by this method, dystrophin gene sequencing is used to detect point mutations. When a mutation is found in a child, his mother, sisters, and preferably female relatives on the maternal side should also do a genetic test to find out if they are carriers of this mutation. Although this will not affect their health, it will help to plan a pregnancy and warn against the birth of a child with Duchenne-Becker muscular dystrophy in the future.
A genetic test also can be performed prenatally (during pregnancy), as well as pre-implantation in the case of in vitro fertilization.
Treatment for Duchenne-Becker muscular dystrophy
Corticosteroids are the main treatment for DMD. They improve motor abilities and allow patients to extend the time of independent movement. Over the past few years, scientists have been developing new methods to prevent the synthesis of dystrophin. One of them is the antisense oligonucleotide approach for gene therapy.
This approach uses short nucleotide sequences that cover the DMD gene sequence with mutation, responsible for stopping protein synthesis. In this case, one part of the gene is skipped but all subsequent parts of the gene continue producing dystrophin. FDA has already validated several drugs for such therapy, for example Amondys 45 (casimersen), Viltepso (viltolarsen), Vyondys 53 (golodirsen), Emflaza (deflazacort), and Emflaza (deflazacort).
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