Duchenne muscular dystrophy (DMD) is a progressive muscle wasting condition that mainly affects skeletal and heart muscles. It is one of many types of muscular dystrophy, an inheritable condition that is more common in boys than girls. Symptoms first appear in young children and become progressively worse with age.
The DMD gene
DMD is caused by a mutation in the DMD gene, which encodes for a protein called dystrophin. There are many different types of mutations associated with DMD, with the majority leading to no, or very little, functional dystrophin being produced. Dystrophin is primarily found in the skeletal muscles, which are responsible for movement, and the in the heart or cardiac muscle.
Dystrophin normally functions to strengthen and protect muscles from damage when they contract and relax. It acts as an anchor, keeping muscle cells together and connecting them with surrounding structures.
With little or no functional dystrophin is being produced in muscle cells, these cells are damaged each time muscles contract. Over time, damaged cells weaken and die and are replaced by scar tissue, leading to muscular weakness.
Types of mutation in the DMD gene
Different types of mutations can be associated with differences in disease severity and may be treated with different types of medication. Some types are discussed here.
Genes are split into sections called exons and introns. To make a protein, the gene is transcribed (or copied) into a molecule similar to DNA, called RNA. The introns are then removed and the exons are joined together. These instructions are sent to the protein-making machinery of the cell, which reads the RNA bases in consecutive groups of three “letters,” called “codons.” Each codon gives an instruction to add a specific amino acid, the building blocks of proteins, or gives a signal to stop making the protein. The three letters making up a codon can sometimes be split between two exons.
The most common DMD-causing mutation is the deletion of a large section of the DMD gene. When a section of the gene is deleted, this can shift what bases make up each codon after the mutation, resulting in a different set of instructions for the protein. The result is a faulty protein being produced that cannot function properly. This type of mutation is called a frameshift mutation, as it causes a shift in the reading frame of the gene. A type of therapy, called “exon-skipping,” aims to realign the codons by forcing the masking of an exon. One example is Exondys 51, a treatment produced by Sarepta Therapeutics and approved by the U.S. Food and Drug Administration (FDA) for Duchenne MD patients amenable to exon 51 skipping.
Another common mutation seen in DMD patients is a “nonsense mutation.” This is a small change that adds a premature stop codon, causing the protein production to stop part-way through. This break results in a shortened, non-functional dystrophin protein being produced, which is usually destroyed by the cell. Translarna (ataluren), produced by PTC Therapeutics, aims to force the protein-making machinery of the cell to continue past the stop signal to produce a full-length, functional dystrophin protein. This should slow disease progression in DMD patients with a nonsense mutation. Translarna has conditional approval in Europe to treat ambulatory patients ages 5 and older, but is not yet authorized in the U.S.
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