Duchenne & Becker muscular dystrophy – causes, symptoms, treatment & pathology
With muscular dystrophy, “dys” means bad or difficult, and “troph” means nourish; so muscular dystrophy basically refers tothe 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.
A 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, thereforeend up causing a lot of the same symptoms as the dystrophinopathies.
Now, the fact that both Duchenne and Beckermuscular 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 enoughto result in no protein at all, for example a nonsense or a frameshift mutation, the resultis 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 fora misshapen protein to form, like missense mutations, lead to Becker muscular dystrophywhich 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 geneon the X-chromosome, that has 79 exons and is over 2 million base pairs in length. By comparison, most genes have only about10 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 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, its 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 withthe 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 beamrunning 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 atrophyand are infiltrated by fat and fibrotic tissue, which leaves them really weak. This process is particularly noticeable inthe 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 tissuerather than muscle tissue.