Duchenne Muscular Dystrophy (DMD), is a disease that affects children and is one of the nine forms of Muscular Dystrophy (MD). Duchenne usually presents in early childhood between the ages of three and five, and although girls can be affected, it is more prevalent in boys. The disease affects 1 in 3,500 worldwide and most patients are in wheelchairs by the age of fifteen. Because of the way that the lack of dystrophin is believed to affect the neuron connection and message transmittal, those affected are likely to have neurological deficiencies that are wide ranging and include speech, memory, intelligence, attention, mental health and seizures.
The prognosis for children diagnosed with the disorder until recently did not extend beyond the teenage years, but recent improvements in cardiac and respiratory care have seen life expectancy extend for some patients into their thirties, with a few living well into their forties. This expanded adult population prompts the need for implementation of new care and treatment protocols.
Exon chains on the dystrophin gene in patients with DMD contain errors or mutations that manifest as large deletions in chain resulting in missing exons, duplication of the same exons in the chain or minor deletions and duplications, so the exons don’t fit together well. Consequently it lacks the proper instructions to create the dystrophin protein that helps muscles work the way that they should. Over eighteen hundred different mutations of the exon chains have been identified but the only way of knowing which mutations affect a patient is through genetic testing, knowing the specific mutations and deletions on individual dystrophin genes helps in tailoring treatment plans and makes managing care easier.
Approximately two thirds of people that are affected by DMD have deletions and duplications of the exons on the dystrophin gene, the rest of the population are likely the result of not easily identifiable point mutations. Another recently identified issue researchers have identified as a secondary cause of DMD are significantly shortened telomeres in DMD patients.
What are Telomeres?
Telomeres for lack of a better term, are caps at the end of all DNA strands that protect them. The job of telomeres is vital to the health of the body because every cell in the body contains them. The cells in the body replenish themselves by creating copies; this happens more when people are young, and slows down as they get older. This happens because the longer that cells replenish themselves, the shorter the telomeres become and eventually they become too short to continue working well, this is when cell aging will begin and their functionality begins to fail. Telomeres also help with organizing the chromosomes in the nucleus of the cell and allow the cells to be replicated properly.
The replicating and anti-aging of cells is aided by an enzyme, Telomerase, that is responsible for adding the TTAGGG telomere sequence to end of DNA. Telomerase is found in all somatic cells at very low levels, as they don’t use telomerase regularly in these sorts of cells the telomeres shorten faster leading to faster cell aging. It’s is however found in very high concentration in germline and stem cells and as such telomere length is maintained after replication and cell aging slowed.
One of the counterproductive acts of telomerase is that it’s found in exceedingly high concentrations in cancer cells, much higher than is typically found in any other cell of the body including germline cells. Telomerase is the reason that cancer cells replicate themselves as quickly as they do, it gives cancer cells something of an immortality. However, if telomerase were to be switched off in cancer cells, they would divide only as much as a normal cell and eventually reaching a critical length which would stop them from dividing fast enough to form tumors.
How Telomeres Affect DMD
Telomeres are so small that they can’t be measured with tools that would normally be used in this setting, so the researchers had to create their own new set of tools from existing fluorescence in situ hybridisation (FISH) technology. The new methodology uses fluorescent probes that are specifically designed to stick to only the telomeres of a cell. The longer the telomere the more the number of probes that adhere and glow more brightly to be seen under a microscope or electronic magnifying equipment so that their lengths can be measured.
With the aid of the newly created tools, researchers have found in patients with DMD that the telomeres are prematurely shortened in the young muscle stem cells which affect their ability to build new muscle. In patients with DMD and other forms of MD gene mutations usually cause the degeneration of muscles and typically telomeres would be able to help this problem, but the cells are trying so frantically to replicate and repair themselves in an effort to compensate for the gene mutation that in less time than would happen in a healthy cell. They’ve exhausted themselves and the telomeres have become too short to continue working in any effective capacity.
Shortened telomeres have also been linked to the heart problems that are also experienced in DMD patients. When an experiment was conducted on mice bred to model the disease, researchers found that of the muscles most affected by shortened telomeres, the cardiomyocytes of the heart were specifically targeted. The shortening of the telomeres caused DNA damage response in the mitochondria and the cardiomyocytes were unable to pump blood throughout the body efficiently. The effect was a surprise to researchers because cardiomyocytes rarely replicate and telomeres on these cells are usually some of the most stable of the somatic cells.
The study also reported that when newborn mice lacking the dystrophin protein gene were examined in weeks one, four, eight and thirty-two even though the cardiomyocytes had stopped dividing the telomeres continued to shorten. By week thirty-two the telomeres had lost almost forty percent of their length. Upon further inspection a protein, p53, known for being at higher concentration levels in the presence of DNA damage was causing the telomeres to shorten even with no cell division happening. P53, beyond signaling DNA damage is complicit in the inhibition of expression by two other proteins that are essential for mitochondrial replication and function.
The reduction in these two proteins led to malfunction and a reduction in the overall number of mitochondria in the cell robbing the cell of energy necessary to complete tasks. The mitochondria were only able to manufacture small amounts of ATP and had higher levels of damaging reactive oxygen species commonly referred to as oxidative stress, which causes even greater damage to the cells, this eventually leads to cardiomyopathy and possible death. The researchers treated the mice with a mitochondrial specific antioxidant at four weeks old and found that any further damage to mitochondrial cells although not eliminated, was significantly reduced. The next step they plan is research into artificially lengthening the telomeres of dystrophin deficient mice.
What the Future Looks Like
Although researchers admit that it will be years before they would be able to start human trials, based on recent discoveries they do believe that they will be able to get there one day. The capacity for new treatments protocols that not only aim to manage DMD and other forms of MD and their accompanying symptoms such as cardiomyopathy and the chance that perhaps eliminate it altogether through the use of artificially lengthened telomeres is something that the medical community and DMD patients can get excited about.