DMD remains an incurable and life shortening genetic disease that directly degenerates human musculature. It is inherited in an X-linked recessive manner therefore affects mainly males however female carriers can generate symptoms of the disease. Future studies are looking at genetic treatments for the disease. Applications such as exon skipping in dystrophin pre-mRNA allows the reading frame to be restored and the internally deleted but functional dystrophin protein to be produced (Kole and Krieg, 2015).
Duchenne Muscular Dystrophy is one of the more common forms of the muscular dystrophy disorders. DMD is illustrated by a loss of dystrophin protein whilst an intermediate loss of the protein causes a milder condition called Becker’s Muscular Dystrophy (Yiu and Kornberg, 2008). DMD is a genetic condition that is inherited in a X-linked recessive manner and remains an incurable disease (Sussman, 2002). In this essay, there will be a discussion on DMD, alongside its diagnosis, pattern of inheritance and a final summary.
Degeneration of muscle tissue begins at birth for those affected and the life expectancy is usually around the early twenties before the sufferer usually dies due to compromised respiratory musculature (Eagle et al. 2002). The initial muscle tissue deficit is prone to replacement by fibrous fatty tissue. DMD patients tend to become wheelchair bound by 12 years of age (Nowak and Davies, 2004).
The main tissue types affected by DMD are voluntary muscle in the upper and lower limbs leading to a characteristic loss of mobility. Respiratory and cardiac muscle are also affected leading to respiratory complications and cardiomyopathies (Emery et al. 2015). Central nervous system impairment can also occur due to a loss of dystrophin protein leading to cognitive impairments and the loss of neurones (Anderson et al 2002).
The loss of dystrophin reduces the structural stability of the muscle fibre plasma membrane. Furthermore during muscle contraction, the force causes perforations in the plasma membrane, which in turn allows Creatine kinase and other intracellular enzymes to exit the cell while also allowing large amounts of extracellular Ca2+ to enter (Deconinck and Dan, 2007). This influx of Ca2+ is the likely cause of necrosis of the dystrophin deficient muscle fibres (Anderson et al. 2002).
DMD remains incurable. However there are clinical approaches available to improve the patient’s quality of life and relieve symptoms (Emery et al. 2015). Wheelchairs, canes and braces can aid mobility if required. Physical therapy and regular exercise is encouraged to aid muscle strength and function.
Also the use of glucocorticoids has shown to slow down muscle wasting and improve muscle strength for up to 2 years (Annexstad et al. 2014). Treatment with prednisolone is highly recommended around the point at which motor development begins to worsen (Annexstad et al. 2014). Mechanical ventilators are utilised when the patient exhibits respiratory symptoms however it has shown increased dependence as the disease progresses (Eagle et al. 2002).
DMD is X linked recessive. The condition is due to a mutation in the gene coding for the dystrophin protein. Dystrophin is a large structural protein with an amino and a carboxyl terminus (Sussman, 2002). Loss of dystrophin disrupts the stability of the glycoprotein structure of the muscle sarcolemma (Deconinck and Dan, 2007). The mutation exists at the locus Xp21 on the short arm of the X chromosome (Towbin et al, 1993). The large size of the DMD gene makes it susceptible to mutations. The gene consists of 2.6 million base pairs with approximately 79 exons (Nowak and Davies, 2004). Most mutations in the DMD gene are intragenic mutations that abrogate the reading frame resulting in a faulty dystrophin protein (Annexstad et al. 2014).
Diagnosis of DMD involves a series of genetic testing made at birth. It usually affects around one in 3300 male births (Biggar, 2006). DMD can go undiagnosed until the age of 3 to 6 in a boy unless a parent is aware of their family history. Early symptoms include a waddled gait, difficulty standing up and hypertrophied calves. Basic diagnosis of DMD can be revealed when a physician carries out a family history and a physical examination. Creatine Kinase is an enzyme that seeps out of damaged muscle tissue possibly due to muscular dystrophy or inflammation and is revealed with a blood test (Rall and Grimm, 2012).
Genetic Testing can analyse the DNA of blood cells to reveal any for changes in the DMD gene. Female relatives of males with DMD can undergo DNA testing to see if they are carriers. Women who are DMD carriers can pass on the disease to their sons and their carrier status to their daughters (Emery et al. 2015).
Physicians may order a biopsy, which is the surgical removal of a small sample of muscle from the patient that eludes a lot of information about any underlying condition. The quantity of functional dystrophin protein found in the biopsy sample uncovers whether the disease course is likely to be DMD (with no dystrophin present) or the milder Becker Muscular Dystrophy (with only some functional dystrophin present)(Biggar, 2006).
Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50% chance of inheriting DMD (Nord, 2016). Each of the diseased mother’s daughters has a 50% chance of inheriting the mutation and being a carrier. This means usually males are more capable of contracting the disease (Nord, 2016). As females have two X chromosomes, a mutation would have to occur in both copies of the gene to cause the disorder (Purushottam et al. 2008). It remains highly unlikely that females will have two altered copies of this gene, which means males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (Purushottam et al. 2008).
As females have two X chromosomes, the second one can compensate for the mutated DMD gene by producing enough functional dystrophin protein to either prevent the symptoms of DMD or cause only mild symptoms such as muscle weakness and cramping (Rall and Grimm, 2012). Female DMD carriers are also at risk of developing cardiomyopathies. The incidence in females remains extremely rare, as males do not live to a reproductive age to pass it on the gene (Nord, 2016)). If a male with DMD lives to reproduce he will pass on the faulty dystrophin gene to all of his daughters who will become carriers. A father cannot pass an X-linked gene to his sons as he can only pass on a Y chromosome to them. Figure 1 helps illustrate the patterns of inheritance for DMD.