Duchenne muscular dystrophy

DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne (1806-1875), who first described the disease in the 1860s. It is due to mutations in the dystrophin gene, which encodes a cell membrane protein in myocytes (muscle cells). One third of the cases are known to be caused by development of spontaneous mutations in the gene, while the remainder are inherited. Boys with DMD develop weak muscles because the muscle fibers that were present at birth are destroyed. Some people with Duchenne Muscular Dystrophy die by age 30 but it depends on how the disease affects them. The main cause of death is respiratory failure. There are a good amount of people that go on to live into their 40's and 50 also. Duchenne dystrophy is a type of dystrophinopathy which includes a spectrum of muscle disease caused by mutations in the DMD gene, which encodes the protein dystrophin. Becker's muscular dystrophy is a milder type of dystrophinopathy. Although it is caused by a defective gene, it often occurs in people from families without a known family history of the condition.

Duchenne muscular dystrophy is inherited in an X-linked recessive pattern. Because of random X inactivation, some female carriers can actually be partially affected by this disease, despite its recessive nature. X inactivation leads to women being in a state of X0, not XX as is usually thought (see below). Women who carry the defective gene can pass an abnormal X on to their sons. Since boys have an X from their mother and a Y from father, there is no second X to make up for the defective gene from the carrier mother. The sons of carrier females each have a 50% chance of having the disease, and the daughters each have a 50% chance of being carriers. Daughters of men with Duchenne will always be carriers, since they will inherit an affected X chromosome from their father (note that the diagram only shows the results from an unnaffected father) but since affected males are infertile they do not have children. Also, affected males 2/3 of the time inherited the mutation from the mother while 1/3 of the time the mutation is de novo, or new. Some females will also have very mild degrees of muscular dystrophy, and this is known as being a manifesting carrier.

Prenatal testing, such as amniocentesis, for pregnancies at risk is possible if the DMD disease-causing mutation has been identified in a family member or if informative linked markers have been identified.

In 1/3 of the cases, the disease is a result of a spontaneous or new mutation [1].

In some female cases, DMD is caused by skewed x inactivation. In these cases, two copies of the x chromosome exist, but for reasons currently unknown, the flawed x chromosome manifests instead of the unflawed copy. In these cases, a mosaic form of DMD is seen, in which some muscle cells are completely normal while others exhibit classic DMD findings. The effects of a mosaic form of DMD on long-term outlook is not known. There is no known cure for Duchenne muscular dystrophy, though recently, stem-cell reasearch has shown some ways to replace the damaged muscle tissue. Treatment is aimed at control of symptoms to maximize the quality of life. Physical activity is encouraged. Inactivity (such as bed rest) can worsen the muscle disease. Physical and occupational therapy may be helpful to maintain muscle strength and function. Orthopaedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care. Promising research is being conducted around the globe to find a cure, or at the least a therapy that is able to mitigate some of the devastating effects of the disease.

The research group of Kay Davies work on the upregulation of utrophin as a substitute for dystrophin.

At the Généthon Institute in Evry near Paris under Olivier Danos and Luis García the U7 gene transfer technique is under development. This new technique is a combination of exon skipping and the transfer of a gene that instructs the muscle cells to continuously produce the antisense oligonucleotides (AONs) themselves so that they do not have to be injected repeatedly. The AONs are potential drugs which are able to modify the genetic information in such a way that the fast progressing Duchenne muscular dystrophy is converted into the much slower developing Becker muscular dystrophy. Early research into the effects of U7 Gene Transfer[3] have been very promising. Treated mice have gone on to show very little muscle weakness even after being stressed. Treated monkeys have retained the active AONs 6 years after injection, and treated dogs have developed 80% of the normal muscle mass within 2 months of treatment. First round tests in humans are due to begin soon, but given the need for multiple rounds of testing before a treatment can be released to the public, it will be at least a few years before this cure is widely available (if indeed these results are possible in humans). Genetic counseling is advised if there is a family history of the disorder. Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy.