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Therapy of collagen VI-related myopathies (Bethlem and Ullrich)

  • Review Article
  • Published:
Neurotherapeutics

Summary

The collagen VI-related myopathies comprise two major forms, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. Specific diagnosis requires molecular genetic testing showing mutation in one of the three genes involved. This review summarizes current treatments, in particular indication for physiotherapy, orthopedic treatment for correction of foot deformity, scoliosis, and flexion contractures of elbows, and treatment of respiratory failure. The turning point in basic research on collagen VI myopathies was the discovery of an unexpected mitochondrial dysfunction as a pathogenetic mechanism underlying the myopathic syndrome seen in Col6a1 null mice. Treatment of Col6a1 −/− mice with cyclosporin A (CsA) rescued the mitochondrial dysfunction and decreased apoptosis. Similar mitochondrial defects were revealed in cultures of UCMD patients. The results of an open pilot trial with CsA in five patients with collagen VI-related myopathies are summarized and discussed. With the availability of new potential effective treatments, several challenges must be addressed in conducting trials in orphan diseases and in neuromuscular disorders in particular. Outcome measures are discussed in the context of the expected effect of the cure. Randomized clinical trials often are not feasible for rare diseases, and sometimes would be ethically inappropriate. The need to develop alternative outcome measures or biomarkers using platforms such as genomics and proteomics is stressed in this context.

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References

  1. Bethlem J, Wijngaarden GK. Benign myopathy, with autosomal dominant inheritance: a report on three pedigrees. Brain 1976;99: 91–100.

    Article  CAS  PubMed  Google Scholar 

  2. Camacho Vanegas O, Bertini E, Zhang RZ, et al. Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci USA 2001;98: 7516–7521.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Scacheri PC, Gillanders EM, Subramony SH, et al. Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 2002;58: 593–602.

    Article  CAS  PubMed  Google Scholar 

  4. Merlini L, Martoni E, Grumati BS, et al. Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 2008 (in press).

  5. Merlini L, Morandi L, Granata C, Ballestrazzi A. Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures: description of two new families. Neuromuscul Disord 1994;4: 503–511.

    Article  CAS  PubMed  Google Scholar 

  6. Pepe G, Giusti B, Bertini E, et al. A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the α1(VI) collagen chain in an Italian family affected by Bethlem myopathy. Biochem Biophys Res Commun 1999;258: 802–807.

    Article  CAS  PubMed  Google Scholar 

  7. an der Kooi AJ, de Voogt WG, Bertini E, et al. Cardiac and pulmonary investigations in Bethlem myopathy. Arch Neurol 2006;63: 1617–1621.

    Article  PubMed  Google Scholar 

  8. Pepe G, Bertini E, Bonaldo P, et al. Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 23–24 November 2001, Naarden, The Netherlands. Neuromuscul Disord 2002;12: 984–993.

    Article  PubMed  Google Scholar 

  9. Pan TC, Zhang RZ, Sudano DG, Marie SK, Bonnemann CG, Chu ML. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet 2003;73: 355–369.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Baker NL, Morgelin M, Peat R, et al. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 2005;14: 279–293.

    Article  CAS  PubMed  Google Scholar 

  11. Demir E, Sabatelli P, Allamand V, et al. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet 2002;70: 1446–1458.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Lampe AK, Dunn DM, von Niederhausern AC, et al. Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet 2005;42: 108–120.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lucioli S, Giusti B, Mercuri E, et al. Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 2005;64: 1931–1937.

    Article  CAS  PubMed  Google Scholar 

  14. Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet 2005;42: 673–685.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Gara SK, Grumati P, Urciuolo A, et al. Three novel collagen VI chains with high homology to the α3 chain. J Biol Chem 2008;283: 10658–10670.

    Article  CAS  PubMed  Google Scholar 

  16. Merlini L, Villanova M, Sabatelli P, Malandrini A, Maraldi NM. Decreased expression of laminin β1 in chromosome 21-linked Bethlem myopathy. Neuromuscul Disord 1999;9: 326–329.

    Article  CAS  PubMed  Google Scholar 

  17. Higuchi I, Horikiri T, Niiyama T, et al. Pathological characteristics of skeletal muscle in Ullrich’s disease with collagen VI deficiency. Neuromuscul Disord 2003;13: 310–316.

    Article  PubMed  Google Scholar 

  18. Jimenez-Mallebrera C, Maioli MA, Kim J, et al. A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations. Neuromuscul Disord 2006;16: 571–582.

    Article  CAS  PubMed  Google Scholar 

  19. Zou Y, Zhang RZ, Sabatelli P, Chu ML, Bonnemann CG. Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle: implications for congenital muscular dystrophy types Ullrich and Bethlem. J Neuropathol Exp Neurol 2008.

  20. Hicks D, Lampe AK, Barresi R, et al. A refined diagnostic algorithm for Bethlem myopathy. Neurology 2008;70: 1192–1199.

    Article  CAS  PubMed  Google Scholar 

  21. Merlini L, Granata C, Bonfiglioli S, Marini ML, Cervellati S, Savini R. Scoliosis in spinal muscular atrophy: natural history and management. Dev Med Child Neurol 1989;31: 501–508.

    Article  CAS  PubMed  Google Scholar 

  22. Fujak A, Ingenhorst A, Heuser K, Forst R, Forst J. Treatment of scoliosis in intermediate spinal muscular atrophy (SMA type II) in childhood. Ortop Traumatol Rehabil 2005;7: 175–179.

    PubMed  Google Scholar 

  23. Aldridge JM 3rd, Atkins TA, Gunneson EE, Urbaniak JR. Anterior release of the elbow for extension loss. J Bone Joint Surg Am 2004;86A: 1955–1960.

    Google Scholar 

  24. Nguyen D, Proper SI, MacDermid JC, King GJ, Faber KJ. Functional outcomes of arthroscopic capsular release of the elbow. Arthroscopy 2006;22: 842–849.

    Article  PubMed  Google Scholar 

  25. Wallgren-Pettersson C, Bushby K, Mellies U, Simonds A; ENMC. 117th ENMC workshop: ventilatory support in congenital neuro-muscular disorders: congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II) 4–6 April 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14: 56–69.

    Article  PubMed  Google Scholar 

  26. Hohenester BR. A therapy for myopathy caused by collagen VI mutations? Matrix Biol 2007;26: 145.

    Article  CAS  PubMed  Google Scholar 

  27. Irwin WA, Bergamin N, Sabatelli P, et al. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 2003;35: 367–371.

    Article  CAS  PubMed  Google Scholar 

  28. Bernardi P, Petronilli V, Di Lisa F, Forte M. A mitochondrial perspective on cell death. Trends Biochem Sci 2001;26: 112–117.

    Article  CAS  PubMed  Google Scholar 

  29. Halestrap A. Biochemistry: a pore way to die. Nature 2005;434: 578–579.

    Article  CAS  PubMed  Google Scholar 

  30. Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 1998;7: 2135–2140.

    Article  CAS  PubMed  Google Scholar 

  31. Angelin A, Tiepolo T, Sabatelli P, et al. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proc Natl Acad Sci U S A 2007;104: 991–996.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Rizzuto R. The collagen—mitochondria connection. Nat Genet 2003;35: 300–301.

    Article  CAS  PubMed  Google Scholar 

  33. Merlini L, Angelin A, Tiepolo T, et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc Natl Acad Sci U S A 2008;105: 5225–5229.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Usuki F, Yamashita A, Kashima I, Higuchi I, Osame M, Ohno S. Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. Mol Ther 2006;14: 351–360.

    Article  CAS  PubMed  Google Scholar 

  35. Moxley RT 3rd, Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64: 13–20.

    Article  CAS  PubMed  Google Scholar 

  36. Merlini L, Estournet-Mathiaud B, Iannaccone S, et al.; ENMC. 90th ENMC international workshop: European Spinal Muscular Atrophy Randomised Trial (EuroSMART) 9–10 February 2001, Naarden, The Netherlands. Neuromuscul Disord 2002;12: 201–210.

    Article  PubMed  Google Scholar 

  37. van der Beek NA, Hagemans ML, van der Ploeg AT, Reuser AJ, van Doorn PA. Pompe disease (glycogen storage disease type II): clinical features and enzyme replacement therapy. Acta Neurol Belg 2006;106: 82–86.

    PubMed  Google Scholar 

  38. van Deutekom JC, Janson AA, Ginjaar IB, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 2007;357: 2677–2686.

    Article  PubMed  Google Scholar 

  39. Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer Control 2007;14: 160–166.

    PubMed  Google Scholar 

  40. Lilford RJ, Thornton JG, Braunholtz D. Clinical trials and rare diseases: a way out of a conundrum. BMJ 1995;311: 1621–1625.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Committee for Medicinal Products for Human Use, European Medicines Agency (CHMP—EMEA). Guideline on clinical trials in small populations. Adopted 27 July 2006. Available at: http://www.emea.europa.eu/pdfs/human/ewp/8356105en.pdf.

  42. De Palma S, Morandi L, Mariani E, et al. Proteomic investigation of the molecular pathophysiology of dysferlinopathy. Proteomics 2006;6: 379–385.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Myology, Department of Medical Genetics, S. Anna Hospital, University of Ferrara, Via Fossato di Mortara 74, 44100, Ferrara, Italy

    Luciano Merlini

  2. Laboratory of Cell Biology, Istituto Ortopedico Rizzoli, 40136, Bologna, Italy

    Luciano Merlini

  3. Department of Biomedical Sciences, University of Padova, 35121, Padova, Italy

    Paolo Bernardi

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  1. Luciano Merlini
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  2. Paolo Bernardi
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Correspondence to Luciano Merlini.

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Merlini, L., Bernardi, P. Therapy of collagen VI-related myopathies (Bethlem and Ullrich). Neurotherapeutics 5, 613–618 (2008). https://doi.org/10.1016/j.nurt.2008.08.004

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  • DOI: https://doi.org/10.1016/j.nurt.2008.08.004

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