Muscular Dystrophy/duchenne Muscular Dystrophy

Case Study #3: Muscular Dystrophy/Duchenne Muscular Dystrophy

Definitions

Muscular Dystrophy refers to a group of diseases in which there is a weakening and breakdown of skeletal muscles over time. In normal, non-dystrophic muscle tissue multipotent myosatellite cells can replace worn or damaged myocytes. However in dystrophic muscle the genetic mutations prevent the replacement of a fully functioning myocyte (see below image).The prognosis of the disorder is based on the type of muscular dystrophy, the muscles affected, and the degree of severity of the symptoms. The nine main categories of MD are due to mutation of genes responsible for muscle protein synthesis and are classified according to phenotype, pathology, and mode of inheritance. Genetic mutations resulting in MD can be inherited via sex-linked (X-linked), autosomal recessive, or autosomal dominant modalities, but may also be acquired early in development. The most common category of MD is Duchenne Muscular Dystrophy (DMD) which is caused by a mutation on the X chromosome and is one of the most severe forms. This category was named after a renowned French neurologist who published the first study to define and characterize the disorder in 1868.

Patients typically experience progressive muscle weakness occurring in a proximal to distal direction. The progressive decrease of muscle strength may compromise the patient’s ambulation potential and eventually their cardiopulmonary function. For this reason most patients diagnosed with DMD or the other severe form of the disorder, Becker Muscular Dystrophy (BMD), die by the age of 30 from cardiopulmonary failure. In 2007, 85% of males with DMD or BMD ages 15-19 were still living, while 58% of males with DMD or BMD ages 20-24 were still living.

Soft tissue and spinal deformities may develop from poor posture due to muscle weakness. Changes in bone density over time can lead to fractures which contribute to further disuse and exacerbation of deformities. As posture worsens, scoliosis may become apparent and can potentially lead to respiratory disorders; on average, for every 10° of thoracic scoliosis curvature, forced vital capacity of the lungs decreases by 4%.

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Pathophysiology

Dystrophin is a 427 kilodalton skeletal muscle protein synthesized from the Dp427 gene located on the short arm of the X chromosome. Defects within this gene produce defected dystrophin proteins which results in the various manifestations of MD such as weakness and pseudohypertrophy. Dystrophin can also be found in cardiac muscle and in the brain accounting for possible cardiovascular or neurological deficits in the patient.

Dystrophin accounts only for 0.0002% of the proteins in striated muscle, but has a crucial role in maintaining cell membrane integrity. Dystrophin aggregates as a homotetramer at the costameres in skeletal muscle (as shown in image A below)); it associates with actin at it’s N-terminus and dystrophin-associated glycoproteins (DAGs) at it’s C-terminus, forming a stable complex that interacts with laminin of the extracellular matrix. Mechanically induced damage through eccentric contractions puts high stress on fragile membranes and provokes microlesions that could eventually lead to loss of calcium homeostasis and cell death. Lack of dystrophin at these links causes cellular instability which leads to progressive leakage of cellular components into the extracellular space; this leakage ultimately leads to cell death. Even though this death is not reported to be immunologically mediated, invasion of cytotoxic T-cells have been shown to invade dystrophic muscles. Gradually the dead muscle is replaced by fibrofatty infiltrate which appears as pseudohypertrophy of the muscle (image B below). The lack of functional muscle units leads to weakness and ultimately loss of contracture. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis are all downstream events that contribute to the symptoms and prognosis of MD.

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