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Muscular Dystrophies

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Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both X-linked recessive disorders caused by mutations in the dystrophin gene, the largest protein-coding gene in humans. This gene encodes for a cytoskeletal anchor protein present in skeletal and cardiac myocytes.

DMD is caused by frameshift mutations that results in a total absence of functional dystrophin, while BMD arises from in-frame deletions, producing a partially functional dystrophin protein.

The repercussions of these mutations are profound. Absence or dysfunction of dystrophin makes myocytes vulnerable to mechanical injury. Over time, in both DMD & BMD, the ensuing mechanical myocyte injury triggers a cascade of events: myocyte necrosis, compensatory hypertrophy, and eventually replacement of muscle by adipose tissue and fibrosis. Histologically, DMD & BMD present with myocytes of varying sizes, reflecting muscle regeneration in different phases. Another distinguishing feature is the central positioning of nuclei in myocytes, a deviation from their usual peripheral location. As the diseases progress, fibrosis and adipose tissue increasingly replace muscle tissue.

Dystrophin's presence or absence can be detected using immunoblotting. If present, even in trace amounts (as seen in BMD), a brown halo is visible at the myocyte cell membrane. Conversely, its absence in DMD results in no such halo. Both conditions also present with increased creatinine kinase (CK), indicative of muscle breakdown.

Clinically, DMD is more aggressive than BMD, with symptoms typically manifesting early in life ~2-3 yrs old. DMD initially presents with muscle weakness, especially in the proximal lower extremities like the muscles of the pelvic girdle and quadriceps, resulting in a waddling gait. A characteristic feature in DMD, and later in BMD, is pseudohypertrophy of the gastrocnemius to counteract proximal muscle weakness. In order to compensate for this proximal lower extremity weakness, patients with DMD (and late onset in BMD) often adopt the ‘Gower maneuver’ when trying to stand, using their arms them to push their legs into a standing position.

BMD typically presents with manifests in late childhood or adolescence. Both DMD and BMD can lead to cardiac complications. The same mechanism of dystrophin absence or dysfunction that affects skeletal myocytes also affects cardiac myocytes. Consequently, patients can develop dilated cardiomyopathy, heart failure, and cardiac arrhythmias due to progressive myocyte death and fibrosis.

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How is Duchenne muscular dystrophy (DMD) different from Becker muscular dystrophy (BMD) in genetics and clinical presentation?

Duchenne (DMD) and Becker (BMD) muscular dystrophies both arise from mutations in the dystrophin gene and are X-linked recessive disorders. DMD is caused by frameshift mutations that results in a total absence of functional dystrophin, while BMD arises from in-frame deletions, producing a partially functional dystrophin protein. This genetic distinction results in differing clinical severities: DMD manifests earlier in life (~ 2-3 years) with more severe symptoms, whereas BMD typically appears later in childhood or adolescence with milder symptoms. Both conditions, however, lead to muscle weakness starting in the proximal lower extremities and can also present with cardiac complications due to dystrophin dysfunction in cardiac myocytes.

What role does dystrophin play in muscle cells what happens in its absence in DMD & BMD?

Dystrophin plays a pivotal role in skeletal and cardiac myocytes by anchoring the cell membrane to the actin cytoskeleton. Without dystrophin, as seen in DMD & BMD, myocytes become vulnerable to mechanical damage. The lack or dysfunction of dystrophin leads to muscle cell necrosis, followed by compensatory hypertrophy. Over time, muscle tissue is replaced by adipose tissue and fibrosis, culminating in muscle weakness and degeneration.

What symptoms are common to both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)?

Both DMD and BMD present with muscle weakness, initially evident in the proximal lower extremities, resulting in a characteristic waddling gait. As the disease progresses, pseudohypertrophy of the calf muscle is also observed. In DMD (and at a later stage in BMD), the Gower maneuver becomes noticeable, where patients use their arms to assist in standing up. Both disorders can also manifest with dilated cardiomyopathy, leading to heart failure or cardiac arrhythmias due to ongoing myocyte death and fibrosis.

How does Myotonic Dystrophy differ from Duchenne and Becker muscular dystrophies in its genetic cause and clinical presentation?

Myotonic dystrophy is caused by a CTG trinucleotide repeat expansion in the DMPK gene, leading to increasing severity with each generation. Unlike DMD and BMD, myotonic dystrophy is autosomal dominant and presents with muscle weakness and wasting, especially in the distal forearms, hands, and facial muscles. Patients may exhibit a long narrow face, ptosis, mouth drooping, and an abnormal gait with foot drop. Slow muscle relaxation (myotonia), cataracts, testicular atrophy, frontal balding, and cardiac issues similar to DMD and BMD can also occur.

How is dystrophin visualized in DMD, BMD, and myotonic dystrophy using histological and immunoblotting techniques?

In DMD & BMD, histological examinations reveal myocytes of varying sizes due to different regeneration phases, with nuclei centrally located in the cells. As the disease advances, muscle is gradually replaced by fibrosis and adipose tissue. Immunoblotting for dystrophin in BMD shows a brown halo at the myocyte cell membrane, indicating the presence of dystrophin, albeit in reduced amounts or lower molecular weight. In contrast, DMD lacks this halo, signifying the absence of dystrophin. Myotonic dystrophy also exhibits myocytes of diverse sizes in histology, but the immunoblotting effects may differ based on the CTG repeat length and the resulting protein synthesis.