What causes Ullrich congenital muscular dystrophy (CMD)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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This is an autosomal recessive (or more rarely dominant) disorder caused by a mutation in 1 of the 3 collagen type VI genes (COL6A1, COL6A2, COL6A3).

Collagen VI is manufactured primarily in interstitial fibroblasts and not in myogenic cells, but it is deposited in the extracellular matrix around nearly all cell types. [29]

Collagen VI is composed of equal amounts of α1, α2, and α3 chains, which intracellularly form a triple helix heterotrimeric monomer. Two of the triple helix monomers associate in an antiparallel arrangement to form six-chain dimers, and then 2 dimers associate in parallel to form a 12-chain tetramers all stabilized by disulfide bonds. The tetramers are excreted into the extracellular space.

Tetramers aggregate into beaded collagen microfibrils, which require the presence of all 3 α chains.

Mutations in all 3 α chains have been associated with Ullrich congenital muscular dystrophy (and Bethlem myopathy).

Collagen type VI has cell adhesion properties and binds to numerous extracellular matrix proteins, including decorin, biglycan, perlecan, fibronectin, proteoglycans, and other collagens.

The major role of collagen type VI is likely to assist in anchoring the basement membrane to the underlying connective tissue and to act as a scaffold for the formation of the collagen fibrillar network. It also plays a role in cell-cycle signaling during cellular proliferation and differentiation. Lastly, it likely has a role in tissue homeostasis by assisting in interactions between cells and the extracellular matrix and by its role in the development of the extracellular matrix supramolecular structure.

How mutations cause disease and why some mutations cause Ullrich congenital muscular dystrophy and others causeBethlem myopathy is not entirely clear. However, Ullrich congenital muscular dystrophy and Bethlem myopathy are likely 2 ends of a spectrum of collagen type VI diseases. This is based on the finding of severe Bethlem myopathy patients and mild Ullrich congenital muscular dystrophy patients with a great deal of clinical similarity. Furthermore, some mutations in collagen type VI can cause both diseases.

About 50% of patients with Ullrich CMD have been shown to have de novo dominant negative mutations, and not the previously thought autosomal recessive mutations

Bethlem myopathy is most often an autosomal dominant disease although rare autosomal recessive cases have been described.

Genotype-phenotype correlations were found in a study of early onset collagen VI myopathies. [30] Early-severe patients (never walked) had complete absence or strongly reduced secretion of collagen VI and most had homozygous premature termination codon mutations in the triple helical region. Moderate-progressive patients (initially able to walk, but loss of ambulation at 4-25 years) most often (83%) had complete absence or strongly reduced secretion of collagen VI and had mutations that where either dominant de novo exon skipping or missense mutations affecting the triple helical domain. Mild patients (remained ambulatory into third decade) in only 50% of cases had absent or reduced secretion of collagen VI.

In contrast to the above study where the most severe cases had absent collagen VI secretion, other reports suggest that the severity of dominantly acting mutations appears to depend on the ability of the mutant protein to be incorporated into the secreted tetramer. The farther the process can proceed, the more severe the dominant negative effect will be. [31] Patients with Bethlem myopathy secrete very little mutant protein, while patients with Ullrich congenital muscular dystrophy have more mutant protein secreted and incorporated into collagen tetramers and subsequent microfibrils.

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