Skip to main content
NCBI home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2008 Oct 1;5(4):619–626. doi: 10.1016/j.nurt.2008.08.003

Therapeutic possibilities in the autosomal recessive limb-girdle muscular dystrophies

Volker Straub 1,✉, Kate Bushby 1
PMCID: PMC4514698  PMID: 19019315

Summary

Fourteen years ago, the first disease-causing mutation in a form of autosomal recessive limb-girdle muscular dystrophy was reported. Since then the number of genes has been extended to at least 14 and the phenotypic spectrum has been broadened. The generation of mouse models helped to improve our understanding of the pathogenesis of the disease and also served to study therapeutic possibilities. All autosomal recessive limb-girdle muscular dystrophies are rare diseases, which is one reason why there have been so very few controlled clinical trials. Other reasons are insufficient natural history data and the lack of standardized assessment criteria and validated outcome measures. Currently, therapeutic possibilities are mainly restricted to symptomatic treatment and the treatment of disease complications. On the other hand, new efforts in translational research and the development of molecular therapeutic approaches suggest that more promising clinical trials will be carried out in autosomal recessive limb-girdle muscular dystrophy in the next several years.

Key Words: Limb-girdle muscular dystrophy, sarcoglycan, calpain 3, dysferlin, dystroglycan

Contributor Information

Volker Straub, Email: volker.straub@ncl.ac.uk.

Kate Bushby, Email: kate.bushby@ncl.ac.uk.

References

  • 1.Vainzof M, Ayub-Guerrieri D, Onofre PC, et al. Animal models for genetic neuromuscular diseases. J Mol Neurosci. 2008;34:241–248. doi: 10.1007/s12031-007-9023-9. [DOI] [PubMed] [Google Scholar]
  • 2.Bassett DI, Currie PD. The zebrafish as a model for muscular dystrophy and congenital myopathy. Hum Mol Genet. 2003;12:R265–R270. doi: 10.1093/hmg/ddg279. [DOI] [PubMed] [Google Scholar]
  • 3.Guyon JR, Steffen LS, Howell MH, Pusack TJ, Lawrence C, Kunkel LM. Modeling human muscle disease in zebrafish. Biochim Biophys Acta. 2007;1772:205–215. doi: 10.1016/j.bbadis.2006.07.003. [DOI] [PubMed] [Google Scholar]
  • 4.Kunkel LM, Bachrach E, Bennett RR, Guyon J, Steffen L. Diagnosis and cell-based therapy for Duchenne muscular dystrophy in humans, mice, and zebrafish. J Hum Genet. 2006;51:397–406. doi: 10.1007/s10038-006-0374-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Sampaolesi M, Torrente Y, Innocenzi A, et al. Cell therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science. 2003;301:487–492. doi: 10.1126/science.1082254. [DOI] [PubMed] [Google Scholar]
  • 6.Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63:543–545. doi: 10.1002/ana.21338. [DOI] [PubMed] [Google Scholar]
  • 7.Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87–91. doi: 10.1038/nature05756. [DOI] [PubMed] [Google Scholar]
  • 8.Bushby K, Straub V. Nonmolecular treatment for muscular dystrophies. Curr Opin Neurol. 2005;18:511–518. doi: 10.1097/01.wco.0000181326.86292.aa. [DOI] [PubMed] [Google Scholar]
  • 9.Cagliani R, Comi GP, Tancredi L, et al. Primary beta-sarcogly-canopathy manifesting as recurrent exercise-induced myoglobinuria. Neuromuscul Disord. 2001;11:389–394. doi: 10.1016/S0960-8966(00)00207-8. [DOI] [PubMed] [Google Scholar]
  • 10.Mongini T, Doriguzzi C, Bosone I, Chiado-Piat L, Hoffman EP, Palmucci L. Alpha-sarcoglycan deficiency featuring exercise intolerance and myoglobinuria. Neuropediatrics. 2002;33:109–111. doi: 10.1055/s-2002-32374. [DOI] [PubMed] [Google Scholar]
  • 11.Walter MC, Petersen JA, Stucka R, et al. FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet. 2004;41:e50–e50. doi: 10.1136/jmg.2003.013953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2–4 April 2004, Naarden, The Netherlands. Neuromuscul Disord. 2004;14:526–534. doi: 10.1016/j.nmd.2004.05.006. [DOI] [PubMed] [Google Scholar]
  • 13.Groen EJ, Charlton R, Barresi R, et al. Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. Brain. 2007;130:3237–3249. doi: 10.1093/brain/awm259. [DOI] [PubMed] [Google Scholar]
  • 14.Fardeau M, Eymard B, Mgnard C, Tome FM, Richard I, Beckmann JS. Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Reunion Island and French metropolitan communities. Neuromuscul Disord. 1996;6:447–453. doi: 10.1016/S0960-8966(96)00387-2. [DOI] [PubMed] [Google Scholar]
  • 15.Passos-Bueno MR, Moreira ES, Marie SK, et al. Main clinical features of the three mapped autosomal recessive limb-girdle muscular dystrophies and estimated proportion of each form in 13 Brazilian families. J Med Genet. 1996;33:97–102. doi: 10.1136/jmg.33.2.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Kawai H, Akaike M, Kunishige M, et al. Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families. Muscle Nerve. 1998;21:1493–501. doi: 10.1002/(SICI)1097-4598(199811)21:11<1493::AID-MUS19>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  • 17.Passos-Bueno MR, Vainzof M, Moreira ES, Zatz M. Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G. Am J Med Genet. 1999;82:392–398. doi: 10.1002/(SICI)1096-8628(19990219)82:5<392::AID-AJMG7>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  • 18.Pollitt C, Anderson LV, Pogue R, Davison K, Pyle A, Bushby KM. The phenotype of calpainopathy: diagnosis based on a multidisciplinary approach. Neuromuscul Disord. 2001;11:287–296. doi: 10.1016/S0960-8966(00)00197-8. [DOI] [PubMed] [Google Scholar]
  • 19.de Paula F, Vainzof M, Passos-Bueno MR, et al. Clinical variability in calpainopathy: what makes the difference? Eur J Hum Genet. 2002;10:825–832. doi: 10.1038/sj.ejhg.5200888. [DOI] [PubMed] [Google Scholar]
  • 20.Sáenz A, Leturcq F, Cobo AM, et al. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain. 2005;128:732–742. doi: 10.1093/brain/awh408. [DOI] [PubMed] [Google Scholar]
  • 21.Balci B, Aurino S, Haliloglu G, et al. Calpain-3 mutations in Turkey. Eur J Pediatr. 2006;165:293–298. doi: 10.1007/s00431-005-0046-3. [DOI] [PubMed] [Google Scholar]
  • 22.Guglieri M, Magri F, D’Angelo MG, et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat 2007. [DOI] [PubMed]
  • 23.Bartoli M, Roudaut C, Martin S, et al. Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A. Mol Ther. 2006;13:250–259. doi: 10.1016/j.ymthe.2005.09.017. [DOI] [PubMed] [Google Scholar]
  • 24.Fougerousse F, Gonin P, Durand M, Richard I, Raymackers JM. Force impairment in calpain 3-deficient mice is not correlated with mechanical disruption. Muscle Nerve. 2003;27:616–623. doi: 10.1002/mus.10368. [DOI] [PubMed] [Google Scholar]
  • 25.Kramerova I, Kudryashova E, Tidball JG, Spencer MJ. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum Mol Genet. 2004;13:1373–1388. doi: 10.1093/hmg/ddh153. [DOI] [PubMed] [Google Scholar]
  • 26.Tagawa K, Taya C, Hayashi Y, et al. Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A. Hum Mol Genet. 2000;9:1393–1402. doi: 10.1093/hmg/9.9.1393. [DOI] [PubMed] [Google Scholar]
  • 27.Wenzel K, Geier C, Qadri F, et al. Dysfunction of dysferlin-deficient hearts. J Mol Med. 2007;85:1203–1214. doi: 10.1007/s00109-007-0253-7. [DOI] [PubMed] [Google Scholar]
  • 28.Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, et al. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology. 2000;55:1931–1933. doi: 10.1212/WNL.55.12.1931. [DOI] [PubMed] [Google Scholar]
  • 29.Weiler T, Bashir R, Anderson LV, et al. Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s) Hum Mol Genet. 1999;8:871–877. doi: 10.1093/hmg/8.5.871. [DOI] [PubMed] [Google Scholar]
  • 30.Argov Z, Sadeh M, Mazor K, et al. Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features. Brain. 2000;123:1229–1237. doi: 10.1093/brain/123.6.1229. [DOI] [PubMed] [Google Scholar]
  • 31.Illa I, Serrano-Munuera C, Gallardo E, et al. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol. 2001;49:130–134. doi: 10.1002/1531-8249(200101)49:1<130::AID-ANA22>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  • 32.Mahjneh I, Marconi G, Bushby K, Anderson LV, Tolvanen-Mahjneh H, Somer H. Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin mutations. Neuromuscul Disord. 2001;11:20–26. doi: 10.1016/S0960-8966(00)00157-7. [DOI] [PubMed] [Google Scholar]
  • 33.Zatz M, de Paula F, Starling A, Vainzof M. The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromuscul Disord. 2003;13:532–544. doi: 10.1016/S0960-8966(03)00100-7. [DOI] [PubMed] [Google Scholar]
  • 34.Diers A, Carl M, Stoltenburg-Didinger G, Vorgerd M, Spuler S. Painful enlargement of the calf muscles in limb girdle muscular dystrophy type 2B (LGMD2B) with a novel compound heterozygous mutation in DYSF. Neuromuscul Disord. 2007;17:157–162. doi: 10.1016/j.nmd.2006.09.015. [DOI] [PubMed] [Google Scholar]
  • 35.Bittner RE, Anderson LV, Burkhardt E, et al. Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B. Nature genetics. 1999;23:141–142. doi: 10.1038/13770. [DOI] [PubMed] [Google Scholar]
  • 36.Luft FC. Dysferlin, dystrophy, and dilatative cardiomyopathy. J Mol Med. 2007;85:1157–1159. doi: 10.1007/s00109-007-0252-8. [DOI] [PubMed] [Google Scholar]
  • 37.Ho M, Post CM, Donahue LR, et al. Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency. Hum Mol Genet. 2004;13:1999–2010. doi: 10.1093/hmg/ddh212. [DOI] [PubMed] [Google Scholar]
  • 38.Straub V, Bushby K. The childhood limb-girdle muscular dystrophies. Semin Pediatr Neurol. 2006;13:104–114. doi: 10.1016/j.spen.2006.06.006. [DOI] [PubMed] [Google Scholar]
  • 39.Meena AK, Sreenivas D, Sundaram C, et al. Sarcoglycanopathies: a clinico-pathological study. Neurol India. 2007;55:117–121. doi: 10.4103/0028-3886.32781. [DOI] [PubMed] [Google Scholar]
  • 40.White SJ, de Willige SU, Verbove D, et al. Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis. Hum Mutat. 2005;26:59–59. doi: 10.1002/humu.9347. [DOI] [PubMed] [Google Scholar]
  • 41.Walter MC, Dekomien G, Schlotter-Weigel B, et al. Respiratory insufficiency as a presenting symptom of LGMD2D in adulthood. Acta Myol. 2004;23:1–5. [PubMed] [Google Scholar]
  • 42.Politano L, Nigro V, Passamano L, et al. Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord. 2001;11:178–185. doi: 10.1016/S0960-8966(00)00174-7. [DOI] [PubMed] [Google Scholar]
  • 43.Merlini L, Kaplan JC, Navarro C, et al. Homogeneous phenotype of the gypsy limb-girdle MD with the gamma-sarcoglycan C283Y mutation. Neurology. 2000;54:1075–1079. doi: 10.1212/WNL.54.5.1075. [DOI] [PubMed] [Google Scholar]
  • 44.Calvo F, Teijeira S, Fernandez JM, et al. Evaluation of heart involvement in gamma-sarcoglycanopathy (LGMD2C). A study of ten patients. Neuromuscul Disord. 2000;10:560–566. doi: 10.1016/S0960-8966(00)00147-4. [DOI] [PubMed] [Google Scholar]
  • 45.Bonnemann CG. Disorders of the sarcoglycan complex (sarco-glycanopathies) In: Deymeer F, editor. Neuromuscular diseases: from basic mechanisms to clinical management. Basel: Karger; 2000. pp. 26–43. [Google Scholar]
  • 46.Angelini C, Fanin M, Freda MP, Duggan DJ, Siciliano G, Hoffman EP. The clinical spectrum of sarcoglycanopathies. Neurology. 1999;52:176–179. doi: 10.1212/WNL.52.1.176. [DOI] [PubMed] [Google Scholar]
  • 47.van der Kooi AJ, de Voogt WG, Barth PG, et al. The heart in limb girdle muscular dystrophy. Heart. 1998;79:73–77. doi: 10.1136/hrt.79.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Prelle A, Comi GP, Tancredi L, et al. Sarcoglycan deficiency in a large Italian population of myopathic patients. Acta Neuropathol (Berl) 1998;96:509–514. doi: 10.1007/s004010050926. [DOI] [PubMed] [Google Scholar]
  • 49.Duggan DJ, Gorospe JR, Fanin M, Hoffman EP, Angelini C. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med. 1997;336:618–624. doi: 10.1056/NEJM199702273360904. [DOI] [PubMed] [Google Scholar]
  • 50.Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands. Neuromuscul Disord. 2003;13:166–172. doi: 10.1016/S0960-8966(02)00213-4. [DOI] [PubMed] [Google Scholar]
  • 51.Bushby K, Griggs R, MSG/ENMC FOR DMD Trial Study Group 145th ENMC International Workshop: planning for an International Trial of Steroid Dosage Regimes in DMD (FOR DMD), 22–24th October 2006, Naarden, The Netherlands. Neuromuscul Disord. 2007;17:423–428. doi: 10.1016/j.nmd.2007.01.006. [DOI] [PubMed] [Google Scholar]
  • 52.Coral-Vazquez R, Cohn RD, Moore SA, et al. Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy. Cell. 1999;98:465–474. doi: 10.1016/S0092-8674(00)81975-3. [DOI] [PubMed] [Google Scholar]
  • 53.Duclos F, Straub V, Moore SA, et al. Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice. J Cell Biol. 1998;142:1461–1471. doi: 10.1083/jcb.142.6.1461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Durbeej M, Cohn RD, Hrstka RF, et al. Disruption of the beta-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol Cell. 2000;5:141–151. doi: 10.1016/S1097-2765(00)80410-4. [DOI] [PubMed] [Google Scholar]
  • 55.Hack AA, Ly CT, Jiang F, et al. Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin. J Cell Biol. 1998;142:1279–1287. doi: 10.1083/jcb.142.5.1279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Kobuke K, Piccolo F, Garringer KW, et al. A common disease-associated missense mutation in alpha-sarcoglycan fails to cause muscular dystrophy in mice. Hum Mol Genet. 2008;17:1201–1213. doi: 10.1093/hmg/ddn009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Bartoli M, Gicquel E, Barrault L, et al. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation. Hum Mol Genet. 2008;17:1214–1221. doi: 10.1093/hmg/ddn029. [DOI] [PubMed] [Google Scholar]
  • 58.Iwata Y, Katanosaka Y, Shijun Z, et al. Protective effects of Ca2+ handling drugs against abnormal Ca2+ homeostasis and cell damage in myopathic skeletal muscle cells. Biochem Pharmacol. 2005;70:740–751. doi: 10.1016/j.bcp.2005.05.034. [DOI] [PubMed] [Google Scholar]
  • 59.Iwanaga Y, Gu Y, Dieterle T, et al. A nitric oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure. Faseb J. 2004;18:587–588. doi: 10.1096/fj.03-0872fje. [DOI] [PubMed] [Google Scholar]
  • 60.Li J, Wang D, Qian S, Chen Z, Zhu T, Xiao X. Efficient and long-term intracardiac gene transfer in delta-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors. Gene Ther. 2003;10:1807–1813. doi: 10.1038/sj.gt.3302078. [DOI] [PubMed] [Google Scholar]
  • 61.Toyo-oka T, Kawada T, Xi H, et al. Gene therapy prevents disruption of dystrophin-related proteins in a model of hereditary dilated cardiomyopathy in hamsters. Heart, Lung Circ. 2002;11:174–181. doi: 10.1046/j.1444-2892.2002.00151.x. [DOI] [PubMed] [Google Scholar]
  • 62.Kawada T, Nakazawa M, Nakauchi S, et al. Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters. Proc Natl Acad Sci USA. 2002;99:901–906. doi: 10.1073/pnas.022641799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Kondoh H, Sawa Y, Miyagawa S, et al. Longer preservation of cardiac performance by sheet-shaped myoblast implantation in dilated cardiomyopathic hamsters. Cardiovasc Res. 2006;69:466–475. doi: 10.1016/j.cardiores.2005.11.005. [DOI] [PubMed] [Google Scholar]
  • 64.Pouly J, Hagege AA, Vilquin JT, et al. Does the functional efficacy of skeletal myoblast transplantation extend to nonischemic cardiomyopathy? Circulation. 2004;110:1626–1631. doi: 10.1161/01.CIR.0000142861.55862.15. [DOI] [PubMed] [Google Scholar]
  • 65.Ohno N, Fedak PW, Weisel RD, Mickle DA, Fujii T, Li RK. Transplantation of cryopreserved muscle cells in dilated cardiomyopathy: effects on left ventricular geometry and function. J Thorac Cardiovasc Surg. 2003;126:1537–1548. doi: 10.1016/S0022-5223(03)01021-3. [DOI] [PubMed] [Google Scholar]
  • 66.Serose A, Salmon A, Fiszman MY, Fromes Y. Short-term treatment using insulin-like growth factor-1 (IGF-1) improves life expectancy of the delta-sarcoglycan deficient hamster. J Gene Med. 2006;8:1048–1055. doi: 10.1002/jgm.934. [DOI] [PubMed] [Google Scholar]
  • 67.Serose A, Prudhon B, Salmon A, Doyennette MA, Fiszman MY, Fromes Y. Administration of insulin-like growth factor-1 (IGF-1) improves both structure and function of delta-sarcoglycan deficient cardiac muscle in the hamster. Basic Res Cardiol. 2005;100:161–170. doi: 10.1007/s00395-004-0506-3. [DOI] [PubMed] [Google Scholar]
  • 68.Nakamura T, Matsumoto K, Mizuno S, Sawa Y, Matsuda H. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts. Am J Physiol. 2005;288:H2131–H2139. doi: 10.1152/ajpheart.01239.2003. [DOI] [PubMed] [Google Scholar]
  • 69.Iwase M, Kanazawa H, Kato Y, et al. Growth hormone-releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters. Cardiovasc Res. 2004;61:30–38. doi: 10.1016/j.cardiores.2003.10.012. [DOI] [PubMed] [Google Scholar]
  • 70.Gastaldello S, D’Angelo S, Franzoso S, et al. Inhibition of proteasome activity promotes the correct localization of disease-causing alpha-sarcoglycan mutants in HEK-293 cells constitutively expressing beta-, gamma-, and delta-sarcoglycan. Am J Pathol. 2008;173:170–181. doi: 10.2353/ajpath.2008.071146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Bauer R, Macgowan GA, Blain A, Bushby K, Straub V. Steroid treatment causes deterioration of myocardial function in the lta-sarcoglycan-deficient mouse model for dilated cardiomyopathy. Cardiovasc Res 2008 Jun 30; [Epub ahead of print]. [DOI] [PubMed]
  • 72.Weller B, Massa R, Karpati G, Carpenter S. Glucocorticoids and immunosuppressants do not change the prevalence of necrosis and regeneration in mdx skeletal muscles. Muscle Nerve. 1991;14:771–774. doi: 10.1002/mus.880140812. [DOI] [PubMed] [Google Scholar]
  • 73.Connolly AM, Pestronk A, Mehta S, Al-Lozi M. Primary alpha-sarcoglycan deficiency responsive to immunosuppression over three years. Muscle Nerve. 1998;21:1549–1553. doi: 10.1002/(SICI)1097-4598(199811)21:11<1549::AID-MUS30>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  • 74.Bartoli M, Poupiot J, Vulin A, et al. AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency. Gene Ther. 2007;14:733–740. doi: 10.1038/sj.gt.3302928. [DOI] [PubMed] [Google Scholar]
  • 75.Bogdanovich S, McNally EM, Khurana TS. Myostatin blockade improves function but not histopathology in a murine model of limb-girdle muscular dystrophy 2C. Muscle Nerve. 2008;37:308–316. doi: 10.1002/mus.20920. [DOI] [PubMed] [Google Scholar]
  • 76.Minetti GC, Colussi C, Adami R, et al. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med. 2006;12:1147–1150. doi: 10.1038/nm1479. [DOI] [PubMed] [Google Scholar]
  • 77.Parsons SA, Millay DP, Sargent MA, McNally EM, Molkentin JD. Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy. Am J Pathol. 2006;168:1975–1985. doi: 10.2353/ajpath.2006.051316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Steffen LS, Guyon JR, Vogel ED, et al. Zebrafish orthologs of human muscular dystrophy genes. BMC Genomics. 2007;8:79–79. doi: 10.1186/1471-2164-8-79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Bassett DI, Bryson-Richardson RJ, Daggett DF, Gautier P, Keenan DG, Currie PD. Dystrophin is required for the formation of stable muscle attachments in the zebrafish embryo. Development. 2003;130:5851–5860. doi: 10.1242/dev.00799. [DOI] [PubMed] [Google Scholar]
  • 80.Guyon JR, Mosley AN, Zhou Y, et al. The dystrophin associated protein complex in zebrafish. Hum Mol Genet. 2003;12:601–615. doi: 10.1093/hmg/ddg071. [DOI] [PubMed] [Google Scholar]
  • 81.Nixon SJ, Wegner J, Ferguson C, et al. Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning. Hum Mol Genet. 2005;14:1727–1743. doi: 10.1093/hmg/ddi179. [DOI] [PubMed] [Google Scholar]
  • 82.Parsons MJ, Campos I, Hirst EM, Stemple DL. Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos. Development (Cambridge, England) 2002;129:3505–3512. doi: 10.1242/dev.129.14.3505. [DOI] [PubMed] [Google Scholar]
  • 83.Cheng L, Guo XF, Yang XY, et al. Delta-sarcoglycan is necessary for early heart and muscle development in zebrafish. Biochem Biophys Res Commun. 2006;344:1290–1299. doi: 10.1016/j.bbrc.2006.03.234. [DOI] [PubMed] [Google Scholar]
  • 84.Guyon JR, Mosley AN, Jun SJ, et al. Delta-sarcoglycan is required for early zebrafish muscle organization. Exp Cell Res. 2005;304:105–115. doi: 10.1016/j.yexcr.2004.10.032. [DOI] [PubMed] [Google Scholar]
  • 85.Frosk P, Greenberg CR, Tennese AA, et al. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum Mutat. 2005;25:38–44. doi: 10.1002/humu.20110. [DOI] [PubMed] [Google Scholar]
  • 86.Kang PB, Feener CA, Estrella E, et al. LGMD2I in a North American population. BMC Musculoskelet Disord. 2007;8:115–115. doi: 10.1186/1471-2474-8-115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Poppe M, Bourke J, Eagle M, et al. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol. 2004;56:738–741. doi: 10.1002/ana.20283. [DOI] [PubMed] [Google Scholar]
  • 88.Gaul C, Deschauer M, Tempelmann C, et al. Cardiac involvement in limb-girdle muscular dystrophy 2I: conventional cardiac diagnostic and cardiovascular magnetic resonance. J Neurol. 2006;253:1317–1322. doi: 10.1007/s00415-006-0213-0. [DOI] [PubMed] [Google Scholar]
  • 89.Mercuri E, Brockington M, Straub V, et al. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol. 2003;53:537–542. doi: 10.1002/ana.10559. [DOI] [PubMed] [Google Scholar]
  • 90.Poppe M, Cree L, Bourke J, et al. The phenotype of limb-girdle muscular dystrophy type 2I. Neurology. 2003;60:1246–1251. doi: 10.1212/01.WNL.0000058902.88181.3D. [DOI] [PubMed] [Google Scholar]
  • 91.Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol. 2006;59:808–815. doi: 10.1002/ana.20824. [DOI] [PubMed] [Google Scholar]
  • 92.Walter MC, Petersen JA, Stucka R, et al. FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet. 2004;41:e50–e50. doi: 10.1136/jmg.2003.013953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Darin N, Kroksmark AK, Ahlander AC, Moslemi AR, Oldfors A, Tulinius M. Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I. Eur J Paediatr Neurol. 2007;11:353–357. doi: 10.1016/j.ejpn.2007.02.018. [DOI] [PubMed] [Google Scholar]
  • 94.Godfrey C, Escolar D, Brockington M, et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol. 2006;60:603–610. doi: 10.1002/ana.21006. [DOI] [PubMed] [Google Scholar]
  • 95.Sveen ML, Jeppesen TD, Hauerslev S, Krag TO, Vissing J. Endurance training: an effective and safe treatment for patients with LGMD2I. Neurology. 2007;68:59–61. doi: 10.1212/01.wnl.0000250358.32199.24. [DOI] [PubMed] [Google Scholar]
  • 96.Thornhill P, Bassett D, Lochmuller H, Bushby K, Straub V. Developmental defects in a zebrafish model for muscular dystrophies associated with the loss of fukutin-related protein (FKRP) Brain. 2008;131:1551–1561. doi: 10.1093/brain/awn078. [DOI] [PubMed] [Google Scholar]
  • 97.Kurahashi H, Taniguchi M, Meno C, et al. Basement membrane fragility underlies embryonic lethality in fukutin-null mice. Neurobiol Dis. 2005;19:208–217. doi: 10.1016/j.nbd.2004.12.018. [DOI] [PubMed] [Google Scholar]
  • 98.Willer T, Prados B, Falcon-Perez JM, et al. Targeted disruption of the Walker-Warburg syndrome gene Pomt1 in mouse results in embryonic lethality. Proc Natl Acad Sci USA. 2004;101:14126–14131. doi: 10.1073/pnas.0405899101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Chiyonobu T, Sasaki J, Nagai Y, et al. Effects of fukutin deficiency in the developing mouse brain. Neuromuscul Disord. 2005;15:416–426. doi: 10.1016/j.nmd.2005.03.009. [DOI] [PubMed] [Google Scholar]
  • 100.Takeda S, Kondo M, Sasaki J, et al. Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet. 2003;12:1449–1459. doi: 10.1093/hmg/ddg153. [DOI] [PubMed] [Google Scholar]
  • 101.Mchele DE, Barresi R, Kanagawa M, et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature. 2002;418:417–422. doi: 10.1038/nature00837. [DOI] [PubMed] [Google Scholar]
  • 102.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. doi: 10.1038/nm1059. [DOI] [PubMed] [Google Scholar]
  • 103.Roberds SL, Leturcq F, Allamand V, et al. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell. 1994;78:625–633. doi: 10.1016/0092-8674(94)90527-4. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES