What is Duchenne Muscular Dystrophy?

Duchenne Muscular Dystrophy is the most common form of muscular dystrophy. It is a genetic disease, caused by a mutation in the gene needed to make the protein called dystrophin.

Genes also contain smaller sections called introns and exons. The protein gene consist of 79 exons and is the largest gene in the body. There are more than 2000 mutations within the 79 exons that make up the dystrophin gene.

What is Dystrophin?

Dystrophin is a protein that protects and stabilizes muscles during use. It is critical for preserving muscle function and structure. In the skeletal and cardiac muscles, dystrophin forms part of a group of proteins (a protein complex) that work together to strengthen muscle fibres and protect them from injury as the muscles contract and relax.

Even ordinary movement necessary for daily activity produces enough force to damage the muscle cell membrane without the protection provided by dystrophin. Once the membrane becomes damaged, calcium rushes in and destroys the cell. Over time, the once healthy muscle fibres get converted into fat and scar tissue, which leads to progressive loss of strength and function.

The role of Genetics

Genetic information is contained in chromosomes. Women have two X chromosomes (XX), and men have one X and one Y chromosome (XY). The DMD gene is located on one of the X chromosomes (given by the mother). Duchenne occurs in males when the DMD gene on their X chromosome contains a mutation that prevents dystrophin production.

Since females have two X chromosomes, if the DMD gene on one X chromosome contains a mutation that would cause Duchenne, in most cases, they can rely on a second copy of the DMD gene on the other X chromosome to provide the instructions needed to produce dystrophin. However, some women who carry a mutation in one DMD gene, known as manifesting carriers, can show some symptoms of Duchenne.

Mutations in the DMD gene can be inherited from the mother who is a carrier, though Duchenne can occur without a family history as well. A new mutation can come about spontaneously in a single egg cell that was fertilized, also known as a denovo change. Duchenne can also develop if a germ cell carrying the mutation culminates into a pregnancy, known as gonadal mosaicism.

About 33% of Duchenne cases are due to a denovo change, while about 10% of cases are thought to be due to gonadal mosaicism. Genetic testing of the Dystrophin gene for mothers of affected sons can help to distinguish between these possibilities.

In-Frame vs Out-of-Frame

Mutations that maintain the reading frame (in-frame), generally result in abnormal but partly functional dystrophin and are associated with Becker Muscular Dystrophy. In patients with Duchenne, the mutation disrupts the reading frame (out-of-frame) and leads to the production of nearly undetectable concentrations of truncated non-functional proteins. Exceptions do exist, but the reading-frame hypothesis holds for over 90% of cases.

Mutation Types

Different types of genetic mutations can cause Duchenne – including deletions, duplications, and point mutations. The most common mutations are deletions. Deletions occur when one or more of the 79 exons that make up the DMD gene are removed. Large deletions are present in approximately 70% of Duchenne cases. Large duplications are present in approximately 10% of cases. Duplications occur when one or more exons are doubled. A point mutation is when a single base pair is altered, rather than an entire exon. Nonsense mutations – a type of point mutation – occurs when the substitution of a single base pair leads to the appearance of a stop codon. The presence of a premature stop codon results in the production of a shortened, and likely non-functional, protein. Point mutations are involved in approximately 20% of Duchenne cases.