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. 2008 Oct 1;5(4):613–618. doi: 10.1016/j.nurt.2008.08.004

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

Luciano Merlini 1,2,✉, Paolo Bernardi 3
PMCID: PMC4514708  PMID: 19019314

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.

Key Words: Bethlem myopathy, Ullrich congenital muscular dystrophy, collagen VI, outcome measures, therapy

References

  • 1.Bethlem J, Wijngaarden GK. Benign myopathy, with autosomal dominant inheritance: a report on three pedigrees. Brain. 1976;99:91–100. doi: 10.1093/brain/99.1.91. [DOI] [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. doi: 10.1073/pnas.121027598. [DOI] [PMC free article] [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. doi: 10.1212/WNL.58.4.593. [DOI] [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). [DOI] [PubMed]
  • 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. doi: 10.1016/0960-8966(94)90091-4. [DOI] [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. doi: 10.1006/bbrc.1999.0680. [DOI] [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. doi: 10.1001/archneur.63.11.1617. [DOI] [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. doi: 10.1016/S0960-8966(02)00139-6. [DOI] [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. doi: 10.1086/377107. [DOI] [PMC free article] [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. doi: 10.1093/hmg/ddi025. [DOI] [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. doi: 10.1086/340608. [DOI] [PMC free article] [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. doi: 10.1136/jmg.2004.023754. [DOI] [PMC free article] [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. doi: 10.1212/01.WNL.0000163990.00057.66. [DOI] [PubMed] [Google Scholar]
  • 14.Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet. 2005;42:673–685. doi: 10.1136/jmg.2002.002311. [DOI] [PMC free article] [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. doi: 10.1074/jbc.M709540200. [DOI] [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. doi: 10.1016/S0960-8966(99)00022-X. [DOI] [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. doi: 10.1016/S0960-8966(02)00282-1. [DOI] [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. doi: 10.1016/j.nmd.2006.07.015. [DOI] [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. [DOI] [PubMed]
  • 20.Hicks D, Lampe AK, Barresi R, et al. A refined diagnostic algorithm for Bethlem myopathy. Neurology. 2008;70:1192–1199. doi: 10.1212/01.wnl.0000307749.66438.6d. [DOI] [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. doi: 10.1111/j.1469-8749.1989.tb04029.x. [DOI] [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, Atkins TA, Gunneson EE, Urbaniak JR. Anterior release of the elbow for extension loss. J Bone Joint Surg Am. 2004;86A:1955–1960. doi: 10.2106/00004623-200409000-00014. [DOI] [PubMed] [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. doi: 10.1016/j.arthro.2006.04.100. [DOI] [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. doi: 10.1016/j.nmd.2003.09.003. [DOI] [PubMed] [Google Scholar]
  • 26.Hohenester BR. A therapy for myopathy caused by collagen VI mutations? Matrix Biol. 2007;26:145–145. doi: 10.1016/j.matbio.2007.02.004. [DOI] [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. doi: 10.1038/ng1270. [DOI] [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. doi: 10.1016/S0968-0004(00)01745-X. [DOI] [PubMed] [Google Scholar]
  • 29.Halestrap A. Biochemistry: a pore way to die. Nature. 2005;434:578–579. doi: 10.1038/434578a. [DOI] [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. doi: 10.1093/hmg/7.13.2135. [DOI] [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. doi: 10.1073/pnas.0610270104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Rizzuto R. The collagen—mitochondria connection. Nat Genet. 2003;35:300–301. doi: 10.1038/ng1203-300. [DOI] [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. doi: 10.1073/pnas.0800962105. [DOI] [PMC free article] [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. doi: 10.1016/j.ymthe.2006.04.011. [DOI] [PubMed] [Google Scholar]
  • 35.Moxley RT, 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. doi: 10.1212/01.WNL.0000148485.00049.B7. [DOI] [PubMed] [Google Scholar]
  • 36.Merlini L, Estournet-Mathiaud B, Iannaccone S, ENMC et al. 90th ENMC international workshop: European Spinal Muscular Atrophy Randomised Trial (EuroSMART) 9–10 February 2001, Naarden, The Netherlands. Neuromuscul Disord. 2002;12:201–210. doi: 10.1016/S0960-8966(01)00272-3. [DOI] [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. doi: 10.1056/NEJMoa073108. [DOI] [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. doi: 10.1177/107327480701400209. [DOI] [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. doi: 10.1136/bmj.311.7020.1621. [DOI] [PMC free article] [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. doi: 10.1002/pmic.200500098. [DOI] [PubMed] [Google Scholar]

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