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). 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
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).
A man with DMD cannot pass the DMD gene to his sons because
he gives a son a Y chromosome, not an X (Genomics Education Programme, 2014). However
he can pass it to his daughters because each daughter inherits her father’s
only X chromosome. Subsequently they will become carriers and each of their
sons will have a 50 percent chance of developing the disease and so on
(Genomics Education Programme, 2014). Each son born to a woman with a
dystrophin mutation on one of her two X chromosomes has a 50% chance of inheriting
DMD (Purushottam et al. 2008). 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. 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 (Yiu and Kornberg, 2008).
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).