Duchenne muscular dystrophy pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

It is understood that Duchenne muscular dystrophy is the result of genetic mutation of dystrophin gene located on X-chromosome. Duchenne muscular dystrophy arises from muscle cells, which are involved in muscular contraction. Dystrophin protein is a part of the protein complex named dystrophin-associated protein complex (DAPC) which acts as an anchor that connect the intracellular cytoskeleton proteins such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan to the extracellular matrix. On microscopic histopathological analysis, replacement of muscle by fat and connective tissue, muscle degeneration, muscle regeneration, and opaque hypertrophic fibers are characteristic findings of Duchenne muscular dystrophy.

The normal physiology of dystrophin protein can be understood as follows:^[1][2]

• Dystrophin protein is a part of the protein complex named dystrophin-associated protein complex (DAPC) which acts as an anchor that connect the intracellular cytoskeleton proteins such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan to the extracellular matrix.
• This protein guaranties muscle strength and integrity.
• The absence of this protein or misfolded protein leads to decreased strength, increased instability, and deformity of sarcolemma.

• It is understood that Duchenne muscular dystrophy is the result of genetic mutation of dystrophin gene located on X-chromosome.
• Duchenne muscular dystrophy arises from muscle cells, which are involved in muscular contraction.
• Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene whose protein product is responsible for the connection of muscle fibres to the extracellular matrix through a protein complex containing many subunits.
• The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane).
• In a complex cascading process involving several pathways, the excess calcium causes the creation of more reactive oxygen species than the cell’s oxide-scavenging enzymes can effectively process.
• This creates oxidative stress within the cell which damages the sarcolemma and allows more entry points for calcium, and ultimately resulting in the death of the cell.
• Muscle fibres undergo necrosis and are ultimately replaced with adipose and connective tissue.

• Duchenne muscular dystrophy is transmitted in X-link recessive pattern.^[3][4][5]

• Gene involved in the pathogenesis of Duchenne muscular dystrophy is Xp21 gene, which encodes the protein dystrophin.

• The development of Duchenne muscular dystrophy is the result of multiple genetic mutations such as:
  • Single gene defect
    • 1/3 New mutation
    • 2/3 X-link recessive inheritance
  • Xp21.2 region
  • Absent dystrophin

• In Duchenne muscular dystrophy, the dystrophin protein is absent.

• Male children, who have an XY chromosome pair, receive one of their mother’s two X chromosomes and their father’s Y chromosome.
• Women DMD carriers who have an abnormal X chromosome have a one-in-two chance of passing that abnormality on to their male children.
• Unlike most female children, a male child with an inherited defective Xp21 gene does not have a second X chromosome to provide correct genetic instructions, and the disease manifests.

• The sons of carrier females each have a 50% chance of having the disease, and the daughters each have a 50% chance of being carriers.
• Daughters of men with Duchenne will always be carriers, since they will inherit an affected X chromosome from their father.
• Some females will also have very mild degrees of muscular dystrophy, and this is known as being a manifesting carrier.^[6]
• In one-third of the cases, the disease is a result of an unspontaneous or new mutation.

• Prenatal testing, such as amniocentesis, for pregnancies at risk is possible if the DMD disease-causing mutation has been identified in a family member or if informative linked markers have been identified.^[7]

• The dystrophin gene contains 24 regions of 109 amino acids that are similar but not exact, making it susceptible to misalignment at the meiotic synapse, which can lead to frameshift mutations and an untranslatable gene.
• This can happen with a frequency of about 1 in 10,000.

• In some female cases, DMD is caused by skewed X inactivation.
• In these cases, two copies of the X chromosome exist, but for reasons currently unknown, the flawed X chromosome manifests instead of the unflawed copy.
• In these cases, a mosaic form of DMD is seen, in which some muscle cells are completely normal while others exhibit classic DMD findings.
• The effects of a mosaic form of DMD on long-term outlook is not known.

There is no charactristic findings on gross pathology for Duchenne muscular dystrophy.

On microscopic histopathological analysis, these findings are characteristic of Duchenne muscular dystrophy:^[8][9]

• Replacement of muscle by fat and connective tissue
• Muscle degeneration
• Muscle regeneration
• Opaque hypertrophic fibers

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