Current Neurology and Neuroscience Reports

, Volume 10, Issue 2, pp 83–91 | Cite as

Congenital Muscular Dystrophies: Toward Molecular Therapeutic Interventions



Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders that typically present at birth or in early infancy with hypotonia, weakness, and histologic evidence of a dystrophic myopathy. CMD biochemical types include various abnormalities of α-dystroglycan O-mannosyl glycosylation as well as defects in integrin matrix receptors, the extracellular matrix proteins laminin-α2 and collagen VI, nuclear proteins such as lamin A/C, and a protein of the endoplasmic reticulum, selenoprotein N. Current therapies are directed mostly at supportive care; however, recent advances in biotechnology and increased knowledge of the pathophysiology underlying the various CMD types have helped identify potential therapeutic strategies directed at genetic, molecular, and biochemical pathways involved in these disorders. In this article, we review our current understanding of the molecular pathogenesis of several CMD types and how these mechanisms may be therapeutically targeted.


Congenital muscular dystrophies Alpha dystroglycan Integrin alpha7 Laminin alpha2 Merosin Collagen VI Selenoprotein N 



The authors thank Dr. A. Reghan Foley and Dr. Anne Rutkowski for their helpful comments regarding the manuscript. Dr. Bönnemann is supported by grants from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR051999) and from MDA USA (MDA3896).


Dr. Collins receives research funding from Cure CMD (not-for-profit patient advocacy). Dr. Bönnemann is an investigator on PTC124 trials (2a and 2b) in patients with Duchenne muscular dystrophy (PTC Therapeutics).


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Bönnemann CG: Congenital muscular dystrophy. In Encyclopedia of Neuroscience. Edited by Squire LR. London, Oxford, Boston, New York, and San Diego: Academic Press; 2008:67–74.Google Scholar
  2. 2.
    Schara U, Kress W, Bönnemann CG, et al.: The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy. Eur J Paediatr Neurol 2008, 12:224–230.CrossRefPubMedGoogle Scholar
  3. 3.
    Nadeau A, Kinali M, Main M, et al.: Natural history of Ullrich congenital muscular dystrophy. Neurology 2009, 73:25–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Capell BC, Collins FS: Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 2006, 7:940–952.CrossRefPubMedGoogle Scholar
  5. 5.
    Barresi R, Campbell KP: Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 2006, 119:199–207.CrossRefPubMedGoogle Scholar
  6. 6.
    Muntoni F, Brockington M, Godfrey C, et al.: Muscular dystrophies due to defective glycosylation of dystroglycan. Acta Myol 2007, 26:129–135.PubMedGoogle Scholar
  7. 7.
    Godfrey C, Clement E, Mein R, et al.: Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 2007, 130:2725–2735.CrossRefPubMedGoogle Scholar
  8. 8.
    Han R, Kanagawa M, Yoshida-Moriguchi T, et al. Basal lamina strengthens cell membrane integrity via the laminin G domain-binding motif of alpha-dystroglycan. Proc Natl Acad Sci U S A 2009,106:12573–12579.CrossRefPubMedGoogle Scholar
  9. 9.
    Moore SA, Saito F, Chen J, et al.: Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 2002, 418:422–425.CrossRefPubMedGoogle Scholar
  10. 10.
    Jimenez-Mallebrera C, Torelli S, Feng L, et al.: A comparative study of alpha-dystroglycan glycosylation in dystroglycanopathies suggests that the hypoglycosylation of alpha-dystroglycan does not consistently correlate with clinical severity. Brain Pathol 2009, 19:596–611.CrossRefPubMedGoogle Scholar
  11. 11.
    Barresi R, Michele DE, Kanagawa M, et al.: LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 2004, 10:696–703.CrossRefPubMedGoogle Scholar
  12. 12.
    Kanagawa M, Saito F, Kunz S, et al.: Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell 2004, 117:953–964.CrossRefPubMedGoogle Scholar
  13. 13.
    Smith PL, Lowe JB: Molecular cloning of a murine N-acetylgalactosamine transferase cDNA that determines expression of the T lymphocyte-specific CT oligosaccharide differentiation antigen. J Biol Chem 1994, 269:15162–15171.PubMedGoogle Scholar
  14. 14.
    Xia B, Martin PT: Modulation of agrin binding and activity by the CT and related carbohydrate antigens. Mol Cell Neurosci 2002, 19:539–551.CrossRefPubMedGoogle Scholar
  15. 15.
    • Welch EM, Barton ER, Zhuo J, et al.: PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007, 447:87–91. Ataluren (PTC124) is now completing phase 2b clinical trials in Duchenne muscular dystrophy. As a drug designed to cause readthough through premature termination codons, ataluren is one of the first mutation-specific treatment approaches that also might be relevant to other neuromuscular disorders with premature termination codons.CrossRefPubMedGoogle Scholar
  16. 16.
    Fan JQ: A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity. Biol Chem 2008, 389:1–11.CrossRefPubMedGoogle Scholar
  17. 17.
    Blankinship MJ, Gregorevic P, Chamberlain JS: Gene therapy strategies for Duchenne muscular dystrophy utilizing recombinant adeno-associated virus vectors. Mol Ther 2006, 13:241–249.CrossRefPubMedGoogle Scholar
  18. 18.
    Qiao C, Li J, Zhu T, et al.: Amelioration of laminin-{alpha}2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin. Proc Natl Acad Sci U S A 2005, 102:11999–12004.CrossRefPubMedGoogle Scholar
  19. 19.
    Hayashi YK, Chou F-L, Engvall E, et al.: Mutations in the integrin α7 gene cause congenital myopathy. Nature Genet 1998, 19:94–97.CrossRefPubMedGoogle Scholar
  20. 20.
    Burkin DJ, Kaufman SJ: The alpha7beta1 integrin in muscle development and disease. Cell Tissue Res 1999, 296:183–190.CrossRefPubMedGoogle Scholar
  21. 21.
    Rooney JE, Gurpur PB, Yablonka-Reuveni Z, et al.: Laminin-111 restores regenerative capacity in a mouse model for alpha7 integrin congenital myopathy. Am J Pathol 2009, 174:256–264.CrossRefPubMedGoogle Scholar
  22. 22.
    Pegoraro E, Cepollaro F, Prandini P, et al.: Integrin alpha 7 beta 1 in muscular dystrophy/myopathy of unknown etiology. Am J Pathol 2002, 160:2135–2143.PubMedGoogle Scholar
  23. 23.
    Rooney JE, Welser JV, Dechert MA, et al.: Severe muscular dystrophy in mice that lack dystrophin and alpha7 integrin. J Cell Sci 2006, 119:2185–2195.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu J, Burkin DJ, Kaufman SJ: Increasing alpha 7 beta 1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. Am J Physiol Cell Physiol 2008, 294:C627–C640.CrossRefPubMedGoogle Scholar
  25. 25.
    Hodges BL, Hayashi YK, Nonaka I, et al.: Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies. J Cell Sci 1997, 110:2873–2881.PubMedGoogle Scholar
  26. 26.
    • Rooney JE, Gurpur PB, Burkin DJ: Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 2009, 106:7991–7996. This study suggests the possibility of protein therapy, that is, the concept that a systemically delivered protein may improve pathology.CrossRefPubMedGoogle Scholar
  27. 27.
    Lisi MT, Cohn RD: Congenital muscular dystrophies: new aspects of an expanding group of disorders. Biochim Biophys Acta 2007, 1772:159–172.PubMedGoogle Scholar
  28. 28.
    Straub V, Rafael JA, Chamberlain JS, et al.: Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. J Cell Biol 1997, 139:375–385.CrossRefPubMedGoogle Scholar
  29. 29.
    Hall TE, Bryson-Richardson RJ, Berger S, et al.: The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin alpha2-deficient congenital muscular dystrophy. Proc Natl Acad Sci U S A 2007, 104:7092–7097.CrossRefPubMedGoogle Scholar
  30. 30.
    Vachon PH, Loechel F, Xu H, et al.: Merosin and laminin in myogenesis; specific requirement for merosin in myotube stability and survival. J Cell Biol 1996, 134:1483–1497.CrossRefPubMedGoogle Scholar
  31. 31.
    Girgenrath M, Dominov JA, Kostek CA, et al.: Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy. J Clin Invest 2004, 114:1635–1639.PubMedGoogle Scholar
  32. 32.
    Dominov JA, Kravetz AJ, Ardelt M, et al.: Muscle-specific BCL2 expression ameliorates muscle disease in laminin {alpha}2-deficient, but not in dystrophin-deficient, mice. Hum Mol Genet 2005, 14:1029–1040.CrossRefPubMedGoogle Scholar
  33. 33.
    Hayashi YK, Tezak Z, Momoi T, et al.: Massive muscle cell degeneration in the early stage of merosin-deficient congenital muscular dystrophy. Neuromuscul Disord 2001, 11:350–359.CrossRefPubMedGoogle Scholar
  34. 34.
    • Erb M, Meinen S, Barzaghi P, et al.: Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-{alpha}2 deficiency. J Pharmacol Exp Ther 2009, 331:787–795. This study provides evidence that a small molecule pharmaceutic with antiapoptotic properties may ameliorate CMDs in which apoptosis appears to play a significant component in the pathogenesis (including MDC1A and collagen VI–deficient CMD) and therefore is a candidate for further clinical studies in these conditions. Omigapil already has been in clinical trials in patients with amyotrophic lateral sclerosis. CrossRefPubMedGoogle Scholar
  35. 35.
    Miller R, Bradley W, Cudkowicz M, et al.: Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007, 69:776–784.CrossRefPubMedGoogle Scholar
  36. 36.
    • Girgenrath M, Beermann ML, Vishnudas VK, et al.: Pathology is alleviated by doxycycline in a laminin-alpha2-null model of congenital muscular dystrophy. Ann Neurol 2009, 65:47–56. This study used already-approved drugs (minocycline and doxycycline) to target a recognized pathophysiologic pathway (apoptosis and inflammation) in a mouse model of merosin-deficient MDC1A. Using approved drugs for novel indications in neuromuscular disorders may accelerate the translational process significantly (but obviously also must take into account each drug's toxic profile).CrossRefPubMedGoogle Scholar
  37. 37.
    Bernasconi P, Di Blasi C, Mora M, et al.: Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies. Neuromuscul Disord 1999, 9:28–33.CrossRefPubMedGoogle Scholar
  38. 38.
    Cohn RD, van Erp C, Habashi JP, et al.: Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 2007, 13:204–210.CrossRefPubMedGoogle Scholar
  39. 39.
    Meinen S, Lin S, Ruegg MA: Treatment approaches in laminin-α2-deficient congenital muscular dystrophy (MDC1A). Neuromuscul Disord 2009, 19:543 EM.P.541.504.Google Scholar
  40. 40.
    Moll J, Barzaghi P, Lin S, et al.: An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 2001, 413:302–307.CrossRefPubMedGoogle Scholar
  41. 41.
    Gawlik K, Miyagoe-Suzuki Y, Ekblom P, et al.: Laminin alpha1 chain reduces muscular dystrophy in laminin alpha2 chain deficient mice. Hum Mol Genet 2004, 13:1775–1784.CrossRefPubMedGoogle Scholar
  42. 42.
    Hagiwara H, Ohsawa Y, Asakura S, et al.: Bone marrow transplantation improves outcome in a mouse model of congenital muscular dystrophy. FEBS Lett 2006, 580:4463–4468.CrossRefPubMedGoogle Scholar
  43. 43.
    Fukada S, Yamamoto Y, Segawa M, et al.: CD90-positive cells, an additional cell population, produce laminin alpha2 upon transplantation to dy(3k)/dy(3k) mice. Exper Cell Res 2008, 314:193–203.CrossRefGoogle Scholar
  44. 44.
    Lampe AK, Bushby KM: Collagen VI related muscle disorders. J Med Genet 2005, 42:673–685.CrossRefPubMedGoogle Scholar
  45. 45.
    Petrini S, D'Amico A, Sale P, et al.: Ullrich myopathy phenotype with secondary ColVI defect identified by confocal imaging and electron microscopy analysis. Neuromuscul Disord 2007, 17:587–596.CrossRefPubMedGoogle Scholar
  46. 46.
    Gara SK, Grumati P, Urciuolo A, et al.: Three novel collagen VI chains with high homology to the alpha3 chain. J Biol Chem 2008, 283:10658–10670.CrossRefPubMedGoogle Scholar
  47. 47.
    Fitzgerald J, Rich C, Zhou FH, Hansen U: Three novel collagen VI chains, alpha4(VI), alpha5(VI), and alpha6(VI). J Biol Chem 2008, 283:20170–20180.CrossRefPubMedGoogle Scholar
  48. 48.
    Kawahara G, Okada M, Morone N, et al.: Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease. Neurology 2007, 69:1043–1049.CrossRefPubMedGoogle Scholar
  49. 49.
    Kawahara G, Ogawa M, Okada M, et al.: Diminished binding of mutated collagen VI to the extracellular matrix surrounding myocytes. Muscle Nerve 2008, 38:1192–1195.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefPubMedGoogle Scholar
  51. 51.
    • 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. This study demonstrated that mitochondrial PTP dysfunction also occurs in human cells derived from patients with collagen VI–deficient CMD and that this dysfunction can be blocked successfully pharmaceutically.CrossRefPubMedGoogle Scholar
  52. 52.
    Hicks D, Lampe AK, Laval SH, et al.: Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue. Brain 2009, 132:147–155.CrossRefPubMedGoogle Scholar
  53. 53.
    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.CrossRefPubMedGoogle Scholar
  54. 54.
    Hansson MJ, Mattiasson G, Mansson R, et al.: The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr 2004, 36:407–413.CrossRefPubMedGoogle Scholar
  55. 55.
    • Tiepolo T, Angelin A, Palma E, et al.: The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1(−/−) myopathic mice. Br J Pharmacol 2009, 157:1045–1052. This study in collagen VI–deficient mice provided evidence that the cyclophilin D inhibitor Debio 025 counteracts the mitochondrially mediated apoptosis seen in these animals and therefore is a candidate for clinical studies in collagen VI–deficient CMDs. Debio 025 already is in clinical trials in patients with hepatitis C.CrossRefPubMedGoogle Scholar
  56. 56.
    Palma E, Tiepolo T, Angelin A, et al.: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Hum Mol Genet 2009, 18:2024–2031.CrossRefPubMedGoogle Scholar
  57. 57.
    Flisiak R, Horban A, Gallay P, et al.: The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 2008, 47:817–826.CrossRefPubMedGoogle Scholar
  58. 58.
    Zou Y, Zhang RZ, Sabatelli P, et al.: 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, 67:144–154.CrossRefPubMedGoogle Scholar
  59. 59.
    Lescure A, Rederstorff M, Krol A, et al.: Selenoprotein function and muscle disease. Biochim Biophys Acta 2009, 1790:1569–1574.PubMedGoogle Scholar
  60. 60.
    Deniziak M, Thisse C, Rederstorff M, et al.: Loss of selenoprotein N function causes disruption of muscle architecture in the zebrafish embryo. Exper Cell Res 2007, 313:156–167.CrossRefGoogle Scholar
  61. 61.
    • Arbogast S, Beuvin M, Fraysse B, et al.: Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment. Ann Neurol 2009, 65:677–686. This study demonstrated that the SEPN1 mutations lead to abnormal redox pathways as well as to abnormal RYR1-mediated calcium modulation in patient-derived cultures and that these abnormalities improve with application of the approved drug NAC, thus opening the perspective of a clinical trial of NAC in this myopathy, as the toxic profile of this drug is favorable.CrossRefPubMedGoogle Scholar
  62. 62.
    Zissimopoulos S, Lai FA: Redox regulation of the ryanodine receptor/calcium release channel. Biochem Soc Trans 2006, 34:919–921.CrossRefPubMedGoogle Scholar
  63. 63.
    Ferreiro A, Monnier N, Romero NB, et al.: A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 2002, 51:750–759.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of NeurologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.The Children’s Hospital of Philadelphia, Division of NeurologyAbramson Research CenterPhiladelphiaUSA

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