What is the pathophysiology of muscular dystrophy?

Updated: Aug 17, 2020
  • Author: Twee T Do, MD; Chief Editor: Jeffrey D Thomson, MD  more...
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Answer

Multiple proteins are involved in the complex interactions of the muscle membrane and extracellular environment. For sarcolemmal stability, dystrophin and the dystrophin-associated glycoproteins (DAGs) are important elements. [6, 7]

The dystrophin gene is located on the short arm of chromosome X near the p21 locus and codes for the large protein Dp427, which contains 3685 amino acids. Dystrophin accounts for only approximately 0.002% of the proteins in striated muscle, but it has obvious importance in the maintenance of the muscle's membrane integrity. [5]

Dystrophin aggregates as a homotetramer at the costomeres in skeletal muscles, as well as associates with actin at its N-terminus and the DAG complex at the C-terminus, forming a stable complex that interacts with laminin in the extracellular matrix. Lack of dystrophin leads to cellular instability at these links, with progressive leakage of intracellular components; this results in the high levels of creatine phosphokinase (CPK) noted on routine blood workup of patients with Duchenne MD.

Less-active forms of dystrophin may still function as a sarcolemmal anchor, but they may not be as effective a gateway regulator because they allow some leakage of intracellular substance. This is the classic Becker dystrophy. In both Duchenne and Becker MD, the muscle-cell unit gradually dies, and macrophages invade. Although the damage in MD is not reported to be immunologically mediated, class I human leukocyte antigens (HLAs) are found on the membrane of dystrophic muscles; this feature makes these muscles more susceptible to T-cell mediated attacks.

Selective monoclonal antibody hybridization was used to identify cytotoxic T cells as the invading macrophages; complement-activated membrane attack complexes have been identified in dystrophic muscles as well. Over time, the dead muscle shell is replaced by a fibrofatty infiltrate, which clinically appears as pseudohypertrophy of the muscle. The lack of functioning muscle units causes weakness and, eventually, contractures.

Other types of MDs are caused by alterations in the coding of one of the DAG complex proteins. The gene loci coding for each of the DAG complex proteins is located outside the X chromosomes. Gene defects in these protein products also lead to alterations in cellular permeability; however, because of the slightly different mechanism of action and because of the locations of these gene products within the body, there are other associated effects, such as those in ocular and limb-girdle type dystrophies (see the image below).

Schematic of the sarcomere with labeled molecular Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.

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