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).
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).
can analyse the DNA of blood cells to reveal any for changes in the DMD gene. Female
relatives of males with DMD can seek out DNA tests to reveal if there is a
carrier status. Female carriers can pass on their carrier status to their
daughters and the disease itself to their sons (Emery et al. 2015).
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
amount of functional dystrophin protein originating within the biopsy specimen
uncovers whether the condition is likely to be DMD (no dystrophin present) of
the milder Becker Muscular dystrophy (some functional dystrophin present)
Each son born to a
mother with a faulty dystrophin gene on one of her two X chromosomes has a 50%
chance of inheriting the condition. Each daughter born to the carrier mother
has a 50% chance of inheriting the dystrophin mutation and becoming 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).
Females have two X
chromosomes, one of which can compensate for the faulty DMD gene by producing enough
functional dystrophin to either prevent DMD symptoms or cause only mild
symptoms such as muscle cramping and weakness. (Rall and Grimm, 2012).
Cardiomyopathies are a major risk for female DMD carriers. The incidence of DMD
in females remains extremely rare, as males do not live to a reproductive age
to pass on the mutated 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.
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).