The Biochemical basis and pathology of DMD/BMD
Dystrophin is a rod-shaped cytoplasmic protein that is a vital part of a protein complex, which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane – the dystrophin glycoprotein complex. The dystrophin glycoprotein complex may also play a role in cell signaling by interacting with proteins that send and receive chemical signals.
There are many different types of dystrophin, some of which are specific to certain cell types. Dystrophin is located mainly in muscles used for movement (skeletal muscles) and the muscles of the heart (cardiac muscles), though small amounts are present in nerve cells in the brain.
Not much is known about the function of dystrophin in nerve cells. Research suggests that the protein is important for the normal structure and function of synapses, which are specialized connections between nerve cells where cell-to-cell communication occurs.
In skeletal and cardiac muscles, dystrophin localizes to the sarcolemma and is absent in patients with DMD.,
Normal distribution of dystrophin DMD, absence of dystrophin
Taken from: https://biochem.umn.edu/muscle_lectures%5C2009%5CLec08_Ervasti.pdf
Based on its structure, location at the sarcolemma (cell membrane of muscle cells), and disruption of the sarcolemma when absent, dystrophin is thought to mechanically stabilize the sarcolemma against stress during muscle contraction. Dystrophin-deficient muscles show large drops in force after titanic stimulation with simultaneous lengthening. The magnitude of force drop correlates with sarcolemmal disruption. Even though dystrophin is only present at a level of 0.002% in muscle cells, its role as a key part of the dystrophin glycoprotein complex, is very important.
Taken from: https://www.mda.org/publications/Quest/q84pharmacy.html https://biochem.umn.edu/muscle_lectures%5C2009%5CLec08_Ervasti.pdf
The dystrophin-glycoprotein complex is enriched at costameres, which physically couple the myofibrils with the sarcolemma. Dystrophin is necessary for mechanical coupling between the sarcolemma and costameric actin (which plays a role in muscle contraction), and as such, is necessary for the stabilization of the sarcolemma.
Diagnosis
One of the first signs of DMD and BMD is progressive muscle weakness and pseudohypertrophy (enlargement) of the calves, as the muscle fibres are replaced by fat and connective tissue. The sufferer usually has gait difficulty and shows Gower’s sign (a characteristic way of changing from a sitting to a standing position shown in the picture below) from a young age.
Taken from: https://neuromuscular.wustl.edu/musdist/dmd.html
DMD has an earlier and more severe onset than BMD. DMD affects boys from about three years of age. Patients are generally wheelchair-bound by the age of 11 and the disease is usually fatal by the age of 18 due to heart and breathing problems. The symptoms of BMD are very similar but they usually do not appear until the patient is in his teens and may present much later in life. The progression of the disease is much slower than in DMD, and BMD patients can expect a near normal lifespan.
BMD and DMD patients also show elevated levels of creatine kinase in serum. Creatine kinase is a muscle enzyme, which is only present at high concentrations in the blood when muscle cells have been damaged. Individuals with BMD may also have myoglobinuria, which can be detected by the excretion of red-brown myoglobin-rich urine.
Muscle biopsy (analysis of an extracted sample of muscle tissue), genetic testing and family history can be used to confirm the diagnosis. Muscle biopsies of sufferers reveal abnormal levels of dystrophin. In DMD patients, there is no dystrophin surrounding the muscle cells, while individuals with BMD have intermediate levels of dystrophin. Most DMD and BMD sufferers will also show large changes in the DMD gene (deletions and duplications), when this gene is sequenced. Mutations that lead to DMD tend to cause frame shifts, so that the dystrophin produced is non-functional. Mutations that cause BMD are in-frame, so the dystrophin produced is partially functional, though usually shorter that normal dystrophin molecules.
Treatment
The treatment of DMD is mainly aimed at managing symptoms. Anti-congestive drugs can be used to control dilated cardiomyopathy, which results in diminished pumping of blood from the heart due to enlargement (most notably in the left ventricle).
It may also be necessary to provide assisting devices for walking and breathing (if there are respiratory complications).
Physical therapy helps to increase the patient’s range of motion and delay the onset of contractures. The progression of scoliosis (spinal curvature) and severe contractures may be halted by surgical procedures to release of the spina muscles, resection of the tensor fasciae latae muscle, and a lengthening of the tendo calcaneus.
The steroid prednisone can improve muscle strength and function in DMD patients and may prolong their ability to walk by a few years. However, it has strong side effects a few of which are high blood pressure, delayed growth and behavioural changes. A synthetic form of prednisilone, called Deflazacort, is believed to have fewer side effects than prednisone and may be used in its place. Oxandrolone, a medication used in a research study, also has similar effects to prednisone with fewer side effects. The drug cyclosporine has been shown to improve clinical function in children, but causes cyclosporine-induced myopathy. Coenzyme Q10, glutamine, pentoxifylline, and PTC124 are currently being researched as potential therapies for muscular dystrophy.
Research into the use of gene therapy as a potential future treatment for DMD and BMD is currently being conducted. Possible therapies include the infection of muscle cells with viruses carrying a functional dystrophin gene, the direct injection of DNA into muscle cells, and the injection of immature muscle cells carrying a normal DMD gene into the muscle of DMD patients. All these have produced encouraging results in mice.