Duchenne and Becker muscular dystrophy 9/3/05. By Richard Twyman Duchenne and Becker muscular dystrophy are two inherited muscle-wasting diseases caused by mutations in the same gene on the X-chromosome.

Overview

The term muscular dystrophy encompasses a number of diseases characterised by progressive muscle wasting. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and is also the most severe, with symptoms presenting in infancy and most affected individuals wheelchair-bound by the age of 11.

Becker muscular dystrophy (BMD) is a similar but much less aggressive form of the disease with a later age of onset and milder symptoms. Both diseases are caused by mutations in the same gene on the X chromosome.

Genetics

DMD and BMD are single gene disorders caused by a malfunctioning gene on the X chromosome. They are both recessive diseases , and therefore occur much more commonly in males than females. This is because two defective chromosomes must be present for the disease to occur in females, whereas only one is required in males. The occurrence of DMD is about one in 3500 males, while BMD is much less common, with an occurrence of one in 20 000 males.

The disease gene is named DMD and is the largest known gene in the human genome (2.2 million base pairs of DNA). The protein is called dystrophin, and is located under the membranes of muscle cells. The function of the protein is to join the muscle cell's internal framework to proteins in the extracellular matrix, a sort of glue that binds cells together.

In DMD, very little dystrophin is produced and the muscle cells become more permeable, causing them to swell and burst. As they die, they are replaced by fat cells and connective tissue. In BMD, near normal amounts of dystrophin are produced, but there are subtle differences in the structure of the protein which adversely affects its function. These two outcomes are caused by different types of mutation in the DMD gene.

Symptoms

DMD affects boys from about three years of age with gradually worsening muscle weakness. The first symptoms include difficulties with walking normally and getting up off the floor. Progressive deterioration leaves the patient relying on a wheelchair by the age of 11 and the disease is generally fatal by the age of 18 due to heart and breathing problems. Although the disease is characterised by the loss of muscle cells, the overall size of certain muscles, such as the calves, appears to increase as the muscle fibres are replaced by fat and connective tissue.

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 the case with DMD, and BMD patients can expect a near normal lifespan.

Diagnosis

The increased permeability of muscle cells in boys with DMD leads to the release of muscle-specific proteins into the bloodstream. One of these proteins, the enzyme creatine kinase, was once used widely for the diagnosis of DMD in boys displaying the characteristic hallmarks of the disease. There is also a slightly elevated creatine kinase level in females carrying a DMD disease allele. However, the creatine kinase test has a low sensitivity, meaning that it is not particularly accurate and does not identify all cases of the disease.

This biochemical test has been largely superseded by direct analysis of the DMD gene for mutations, a method which is useful for both diagnosis and the detection of carriers.

Treatment

Although regular physiotherapy can help to prolong mobility, no curative treatment is available for DMD or BMD. However, these diseases are prime targets for gene therapy because they represent defects in a single gene affecting an easily accessible tissue. Possible approaches 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 approaches have produced encouraging results when tried in mice.