Muscular dystrophy is one of the most difficult disorders to treat. Although, its pathogenesis is well understood there is no known cure available for any of the 9 types of muscular dystrophy. Conventional methods of coping with the disease include exercise and drugs that slow down or eliminate muscle wasting like anabolic steroids and supplementation. Skeletal muscle is the most abundant tissue of the body and is composed of large multinucleated fibers, whose nuclei cannot divide. Consequently, any cell or gene replacement method must restore proper gene expression in hundreds of post-mitotic nuclei, which are embedded in a highly structured cytoplasm and surrounded by a thick basal lamina. Similarly, most pharmacological approaches must invade the complex and partly unknown biochemical mechanism of fiber degeneration.
Historical aspect of treatment
Demonstration of the mechanics of facial expression. Duchenne and an assistant faradize (Faradic shock) the mimetic muscles of "The Old Man.
The treatment of muscular dystrophy has evolved from electrical simulation to Gene Therapy and Cell Therapy.
Goals of treatment:
1. To correct the genetic defect,
Major therapeutic strategies for Muscular Dystrophy:
1. Gene Therapy:
A. Gene replacement therapy -by
B. Gene modification therapy (DNA/RNA Manipulation): changing or
2. Cell Therapy:
Delivery of cells that make new muscle to diseased areas:
A. Muscle precursor cells (Myoblasts)
B. Stem cells that have the ability to differentiate into muscle cells.
3. Pharmacological Therapy:
A. Drugs to turn on the utrophin gene expression
B. Drugs to cause read-through of a premature stop codon
C. Growth factors/Drugs
D. Protease inhibitors to slow muscle breakdown
E. Anti-inflammatory agents
G. Drugs to increase muscle strength
H. Drugs maintaining calcium Homeostasis
1. DRUG TREATMENT
Steroids have been demonstrated to be efficacious in slowing the progression of muscular dystrophy especially DMD and in delaying the loss of independent ambulation, stabilize muscle strength and preserve pulmonary functions. (1, 2)
Corticosteroids may enhance myoblast proliferation and promote muscle
Unfortunately, in these studies prednisone had a great deal of side effects including weight gain, cushingoid features, hypertension, hyperactivity, growth retardation, and cataracts. A methyloxazoline derivative of prednisolone, deflazacort (DFZ), has shown some promise in providing similar effects to prednisone with a less concerning side
Reduction in the total amount of steroids with different treatment schedules, such as alternate-day, pulsed, high-dose intermittent or daily low-dose administration, may decrease side effects.
Therapeutic molecules such as ACE-031 are also being developed for the treatment of DMD patients with the goal of improving strength and preserving physical functions.
Due to the side effects of the above steroids and therapeutic molecules, many studies have been carried out to study the use of creatine as an effective treatment formuscular dystrophy especially DMD. A study by Tarnopolsky reported the benefits of creatine supplements in patients with DMD. Creatine is a guanidino compound that may confer therapeutic benefit in muscular dystrophy by increasing strength and fatfree
Drugs that have been used to treat myotonia include sodium channel blockers such as procainamide, phenytoin and mexiletine, tricyclic antidepressant drugs such as clomipramine or imipramine, benzodiazepines, calcium antagonists and taurine.
Few drugs such as Heregulin, L-arginine, TAT-utrophin, okadaic acid and SMT C1100 have shown to turn on the utrophin gene expression.
Heregulin, acts via the N-box motif of the utrophin A promoter (11) and L-arginine, results in an increase in utrophin expression as a result of increased production of nNOS. (12) TAT-utrophin is a recombinant utrophin protein modified with the HIVderived TAT protein transduction domain, improves delivery across the cell membrane. (13) Okadaic acid have also been identified to upregulate utrophin expression in mdx
Nutritional support is often overlooked but is important especially in order to improve quality of life. Antioxidants and anti-inflammatories have known to offer some benefit. Animal studies have shown that diet rich in omega-3-fatty acids prevent skeletal muscle lesions and improves muscle appearance on histological examination. (16)
Management of muscle extensibility and joint contractures is a key part of
Genetic counseling is advised for people with a family history of the inherited disorder. It helps to identify families at risk, investigate the problem present, interpret information about the disorder, analyze inheritance patterns and risks of recurrence and review available options with the family. For families living with Duchenne or Becker muscular dystrophy, it can offer several benefits. Genetic counseling plays a
Each time a DMD carrier mother has a child; there are four possible outcomes, each with an equal probability of happening. Thus, the chance of producing an affected son is one in four, or 25 %. Further breakdown of the risk according to the sex of the child, follows that there is a 50% chance that each son will be affected. All daughters will be unaffected, but each has a 50% chance of being a carrier like her mother.
It is important to know that unaffected son of carrier mothers do not have the DMD gene, and therefore, cannot transmit DMD to their offspring. The same is true for those daughters of carriers who have not inherited the DMD gene. If circumstances should allow a male affected with DMD to reproduce, and if his wife was not a carrier of DMD, then all of his sons would be unaffected and free of the gene but all of his daughters would be carriers.
Genetic testing can help tell whether a woman is definitely a carrier or whether she is very unlikely to be a carrier. Carriers have an increased chance of having boys with Duchenne or Becker muscular dystrophy. All women who could be carriers, based on their family history with sons or brothers with DMD/BMD, uncles or cousins on their mother's side of the family who have DMD/BMD, mothers or sisters who are carriers for DMD/BMD, and aunts or cousins in their mother's side of the family who
The method for carrier testing should be determined by the woman's family history, including whether the mutation in the family is known .If the mutation is known; only that mutation needs to be tested. If the mutation in the family is not known because the affected person was not tested, it is best to test him first. If genetic testing was done in the past and no mutation was found, it might be appropriate to test the affected individual again using new and improved tests, which can identify more mutations.
The types of tests that have been used for carrier testing include creatine
If a woman has a child with DMD or BMD and also has other affected male family members, for example an affected brother or nephew, it is extremely likely that she is a carrier. If there are no other affected family members, there is a 66% (or 2 in 3) chance of being a carrier. Approximately 33% (or 1 in 3) of cases of Duchenne muscular dystrophy are caused by what are called new mutations. These are random changes tothe genetic code in the dystrophin gene that happen in only one egg or sperm, that one egg or sperm could create an affected male; rarely, a carrier female child who could later have affected children. The possibility for new mutations is one of the reasons why 1/3 or more of individuals with Duchenne muscular dystrophy will have no family history. Another possibility is that some families have several generations with mostly
There are many different reproductive options for carrier families with a higher chance of having a child with Duchenne or Becker muscular dystrophy. There is a 25% chance of having an affected child (25% affected son; 25% unaffected son; 25% carrier daughter; 25% non-carrier daughter). If the child is known to be male, the chance of having an affected son is thus 50%; if it is female, the chance of a carrier daughter is 50%.
1. Mutation in the family is known: Have a natural pregnancy and pursue testing for sex, followed by testing for the gene mutation in the family.
Chorionic villus sampling (CVS) is generally offered between the 10th and 13th weeks of pregnancy. A small piece of the placenta is tested to determine the sex of the baby. If male, those same cells can be tested for the known mutation in the dystrophin gene in the family. Amniocentesis is generally performed starting at 15 weeks, and can be performed through the end of the pregnancy. Cells from amniotic fluid are tested to determine the sex of the baby. If male, those same cells can be tested for the known
2. Mutation in the family is not known: Have a natural pregnancy and pursue
For families with a confirmed diagnosis of Duchenne or Becker muscular
When linkage analysis is not possible, some hospitals offer fetal muscle biopsy (taking a small sample of muscle from the developing baby). This procedure is not offered in very many hospitals and has a higher risk for complications, including death of the fetus, than amniocentesis or CVS. Counseling about the risk and benefits of fetal muscle biopsy is absolutely necessary.
3. Preimplantation Genetic Diagnosis (PGD)
PGD combines in-vitro fertilization (IVF) with genetic testing, with the goal of implanting only unaffected embryos into the uterus. Different women will have different numbers of embryos without the dystrophin gene mutation. IVF and PGD are expensive and invasive technologies that are not available in all medical centers.
4. Egg and sperm donation
Carrier females may consider pregnancy with a donor egg. Egg donation from a non-carrier reduces the chance of having a child with muscular dystrophy to the chance in the general population. Males with DMD or BMD may consider using a donor sperm. Sperm donation from an un-affected male reduces the chance of having carrier daughters to the chance in the general population.
Adoption is another option that may be explored.
4. GENE THERAPY
Development of gene therapy for muscular dystrophy represents a challenge which requires significant advances in the knowledge of defective genes, muscle promoters, viral vectors, immune system surveillance and methods for systemic delivery of vectors. However, tremendous progress has been made in developing improved viral vectors and avoiding immune reactions against gene transfer. There is a gene therapy method known as targeting repairing or chimeraplast, using a synthetic blend of DNA and the related RNA, which tricks the patient's own cells to repair the mutation. The chimeraplasts match the patients' own DNA except for where the mutation occurs, attach to the DNA, and then activate DNA repair mechanisms. Although this approach initially appeared promising, the repair rate is generally found to be too low to cure. U7, a non spliceosome small nuclear RNA (snRNA), normally involved in the processing of the histone mRNA 3' end, to enhance the delivery of antisense sequences (17). By slightly modifying the binding site for Sm/Lsm proteins, U7 can be converted into a versatile tool for splicing modulation. Delivery of the appropriately modified U7 snRNA using an adeno-associated virus has demonstrated widespread dystrophin restoration in both the mdx mouse and the GRMD (18) models of DMD following only a single dose.
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