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Journal of Neurology

, Volume 258, Issue 9, pp 1610–1623 | Cite as

Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up

  • Francesca Magri
  • Alessandra Govoni
  • Maria Grazia D’Angelo
  • Roberto Del Bo
  • Serena Ghezzi
  • Gandossini Sandra
  • Anna Carla Turconi
  • Monica Sciacco
  • Patrizia Ciscato
  • Andreina Bordoni
  • Silvana Tedeschi
  • Francesco Fortunato
  • Valeria Lucchini
  • Sara Bonato
  • Costanza Lamperti
  • Domenico Coviello
  • Yvan Torrente
  • Stefania Corti
  • Maurizio Moggio
  • Nereo Bresolin
  • Giacomo Pietro Comi
Original Communication

Abstract

Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype–phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype–genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.

Keywords

Duchenne muscular dystrophy Becker muscular dystrophy Dystrophin gene sequencing Protein analysis Cardiac involvement in DMD and BMD Respiratory involvement in DMD and BMD 

Notes

Acknowledgments

We wish to thank the patients and their families for their support and collaboration. This research received funding support from Telethon—UILDM Grant GUP07009 (GPC). Telethon Genetic Biobanks Network GTB07001E was the source of the DNA used in this study. Eurobiobank project QLTR-2001-02769 is also gratefully acknowledged. Telethon North Star.

Conflict of interest

The authors have no conflicts of interest to declare.

References

  1. 1.
    Davies KE, Smith TJ, Bundey S, Read AP, Flint T, Bell M, Speer A (1988) Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome. J Med Genet 25:9–13PubMedCrossRefGoogle Scholar
  2. 2.
    Comi GP, Prelle A, Bresolin N, Moggio M, Bardoni A, Gallanti A, Vita G, Toscano A, Ferrò MT, Bordoni A et al (1994) Clinical variability in Becker muscular dystrophy. Genetic, biochemical and immunohistochemical correlates. Brain 117:1–14PubMedCrossRefGoogle Scholar
  3. 3.
    Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, Angelini C, Sugita H, Kunkel LM (1991) Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 49:54–67PubMedGoogle Scholar
  4. 4.
    Béroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N, Moizard MP, Voelckel MA, Calemard LM, Boisseau P, Blayau M, Philippe C, Cossée M, Pagès M, Rivier F, Danos O, Garcia L, Claustres M (2007) Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat 28:196–202PubMedCrossRefGoogle Scholar
  5. 5.
    Emery AE (1994) Some unanswered questions in Duchenne muscular dystrophy. Neuromuscul Disord 4:301–303PubMedCrossRefGoogle Scholar
  6. 6.
    Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Müller CR, Lindlöf M, Kaariainen H et al (1989) The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45:498–506PubMedGoogle Scholar
  7. 7.
    Todorova A, Todorov T, Georgieva B, Lukova M, Guergueltcheva V, Kremensky I, Mitev V (2008) MLPA analysis/complete sequencing of the DMD gene in a group of Bulgarian Duchenne/Becker muscular dystrophy patients. Neuromuscul Disord 18:667–670PubMedCrossRefGoogle Scholar
  8. 8.
    Desguerre I, Christov C, Mayer M, Zeller R, Becane HM, Bastuji-Garin S, Leturcq F, Chiron C, Chelly J, Gherardi RK (2009) Clinical heterogeneity of duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive criteria by long-term follow-up. PLoS One 4:e4347PubMedCrossRefGoogle Scholar
  9. 9.
    Deburgrave N, Daoud F, Llense S, Barbot JC, Récan D, Peccate C, Burghes AH, Béroud C, Garcia L, Kaplan JC, Chelly J, Leturcq F (2007) Protein- and mRNA-based phenotype–genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene. Hum Mutat 28:183–195PubMedCrossRefGoogle Scholar
  10. 10.
    Manzur AY, Kuntzer T, Pike M, Swan A (2008). Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 23(1):CD003725Google Scholar
  11. 11.
    Kaspar RW, Allen HD, Montanaro F (2009) Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract 21:241–249PubMedCrossRefGoogle Scholar
  12. 12.
    Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K (2002) Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 12:926–929PubMedCrossRefGoogle Scholar
  13. 13.
    Nelson SF, Crosbie RH, Miceli MC, Spencer MJ (2009) Emerging genetic therapies to treat Duchenne muscular dystrophy. Curr Opin Neurol 22:532–538PubMedCrossRefGoogle Scholar
  14. 14.
    Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87–91PubMedCrossRefGoogle Scholar
  15. 15.
    Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (2007) Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. Clin Pharmacol 47:430–444CrossRefGoogle Scholar
  16. 16.
    Hammond SM, Wood MJ (2010) PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy. Curr Opin Mol Ther 12:478–486PubMedGoogle Scholar
  17. 17.
    Heemskerk HA, de Winter CL, de Kimpe SJ, van Kuik-Romeijn P, Heuvelmans N, Platenburg GJ, van Ommen GJ, van Deutekom JC, Aartsma-Rus A (2009) In vivo comparison of 2′-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J Gene Med 11:257–266PubMedCrossRefGoogle Scholar
  18. 18.
    Muntoni F, Bushby KD, van Ommen G (2008) 149th ENMC International Workshop and 1st TREAT-NMD Workshop on: “planning phase i/ii clinical trials using systemically delivered antisense oligonucleotides in duchenne muscular dystrophy”. Neuromuscul Disord 18:268–275PubMedCrossRefGoogle Scholar
  19. 19.
    Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Muntoni F (2009) Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol 8:918–928PubMedCrossRefGoogle Scholar
  20. 20.
    Tuffery-Giraud S, Béroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L, Moizard MP, Bernard R, Cossée M, Boisseau P, Blayau M, Creveaux I, Guiochon-Mantel A, de Martinville B, Philippe C, Monnier N, Bieth E, Khau Van Kien P, Desmet FO, Humbertclaude V, Kaplan JC, Chelly J, Claustres M (2009) Genotype–phenotype analysis in 2, 405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase. Hum Mutat 30:934–945PubMedCrossRefGoogle Scholar
  21. 21.
    Brabec P, Vondrácek P, Klimes D, Baumeister S, Lochmüller H, Pavlík T, Gregor J (2009) Characterization of the DMD/BMD patient population in Czech Republic and Slovakia using an innovative registry approach. Neuromuscul Disord 19:250–254PubMedCrossRefGoogle Scholar
  22. 22.
    American Academy of Orthopedic Surgeons (1965) Joint motion: method of measuring and recording. London, Churchill LivingstonGoogle Scholar
  23. 23.
    Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J (2005) Interpretative strategies for lung function tests. Eur Respir J 26:948–968PubMedCrossRefGoogle Scholar
  24. 24.
    Nicholson LV, Davison K, Johnson MA, Slater CR, Young C, Bhattacharya S, Gardner-Medwin D, Harris JB (1989) Dystrophin in skeletal muscle. II. Immunoreactivity in patients with Xp21 muscular dystrophy. J Neurol Sci 94:137–146PubMedCrossRefGoogle Scholar
  25. 25.
    Prelle A, Comi GP, Tancredi L et al (1998) Sarcoglycan deficiency in a large Italian population of myopathic patients. Acta Neuropathol 96:509–514PubMedCrossRefGoogle Scholar
  26. 26.
    Minetti C, Sotgia F, Bruno C et al (1998) Mutations in the caveolin-3 gene cause autosomal dominant limb–girdle muscular dystrophy. Nat Genet 18:365–368PubMedCrossRefGoogle Scholar
  27. 27.
    Valle G, Faulkner G, De Antoni A et al (1997) Telethonin, a novel sarcomeric protein of heart and skeletal muscle. FEBS Lett 415:163–168PubMedCrossRefGoogle Scholar
  28. 28.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57PubMedCrossRefGoogle Scholar
  29. 29.
    Den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12CrossRefGoogle Scholar
  30. 30.
    Consensus conference (1999) Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation—a consensus conference report. Chest 116:521–534CrossRefGoogle Scholar
  31. 31.
    Finsterer J (2006) Cardiopulmonary support in Duchenne muscular dystrophy. Lung 184:205–215PubMedCrossRefGoogle Scholar
  32. 32.
    Felisari G, Martinelli Boneschi F, Bardoni A, Sironi M, Comi GP, Robotti M, Turconi AC, Lai M, Corrao G, Bresolin N (2000) Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy. Neurology 55:559–564PubMedGoogle Scholar
  33. 33.
    D’Angelo MG, Bresolin N (2006) Cognitive impairment in neuromuscular disorders. Muscle Nerve 34:16–33PubMedCrossRefGoogle Scholar
  34. 34.
    Daoud F, Angeard N, Demerre B, Martie I, Benyaou R, Leturcq F, Cossée M, Deburgrave N, Saillour Y, Tuffery S, Urtizberea A, Toutain A, Echenne B, Frischman M, Mayer M, Desguerre I, Estournet B, Réveillère C, Penisson-Besnier, Cuisset JM, Kaplan JC, Héron D, Rivier F, Chelly J (2009) Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression. Hum Mol Genet 18:3779–3794PubMedCrossRefGoogle Scholar
  35. 35.
    Cunniff C, Andrews J, Meaney FJ, Mathews KD, Matthews D, Ciafaloni E, Miller TM, Bodensteiner JB, Miller LA, James KA, Druschel CM, Romitti PA, Pandya S (2009) Mutation analysis in a population-based cohort of boys with Duchenne or Becker muscular dystrophy. J Child Neurol 24:425–430PubMedCrossRefGoogle Scholar
  36. 36.
    Nigro G, Politano L, Nigro V, Petretta VR, Comi LI (1994) Mutation of dystrophin gene and cardiomyopathy. Neuromuscul Disord 4:371–379PubMedCrossRefGoogle Scholar
  37. 37.
    Bullam DE, Murphy EG, Zubrycka-Gaan EE et al (1991) Differentiation of Duchenne and Becker muscular dystrophy with amino- and carboxy terminal antisera specific for dystrophin. Am J Hum Mol Genet 48:295Google Scholar
  38. 38.
    Arahata K, Beggs AH, Honda H, Ito S, Ishiura S, Tsukahara T, Ishiguro T, Eguchi C, Orimo S, Arikawa E et al (1991) Preservation of the C-terminus of dystrophin molecule in the skeletal muscle from Becker muscular dystrophy. J Neurol Sci 101:148–156PubMedCrossRefGoogle Scholar
  39. 39.
    Finsterer J, Stöllberger C (2003) The heart in human dystrophinopathies. Cardiology 99:1–19PubMedCrossRefGoogle Scholar
  40. 40.
    Novaković I, Bojić D, Todorović S, Apostolski S, Luković L, Stefanović D, Milasin J (2005) Proximal dystrophin gene deletions and protein alterations in Becker muscular dystrophy. Ann NY Acad Sci 1048:406–410PubMedCrossRefGoogle Scholar
  41. 41.
    van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, van der Kooi AJ, Goemans NM, de Kimpe SJ, Ekhart PF, Venneker EH, Platenburg GJ, Verschuuren JJ, van Ommen GJ (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357:2677–2686PubMedCrossRefGoogle Scholar
  42. 42.
    Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, den Dunnen JT (2009) Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30:293–299PubMedCrossRefGoogle Scholar
  43. 43.
    Harper SQ, Hauser MA, DelloRusso C, Duan D, Crawford RW, Phelps SF, Harper HA, Robinson AS, Engelhardt JF, Brooks SV, Chamberlain JS (2002) Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat Med 8:253–261PubMedCrossRefGoogle Scholar
  44. 44.
    Phelps SF, Hauser MA, Cole NM, Rafael JA, Hinkle RT, Faulkner JA, Chamberlain JS (1995) Expression of full-length and truncated dystrophin mini-genes in transgenic mdx mice. Hum Mol Genet 4:1251–1258PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Francesca Magri
    • 1
  • Alessandra Govoni
    • 1
  • Maria Grazia D’Angelo
    • 2
  • Roberto Del Bo
    • 1
  • Serena Ghezzi
    • 1
  • Gandossini Sandra
    • 2
  • Anna Carla Turconi
    • 2
  • Monica Sciacco
    • 1
  • Patrizia Ciscato
    • 1
  • Andreina Bordoni
    • 1
  • Silvana Tedeschi
    • 3
  • Francesco Fortunato
    • 1
  • Valeria Lucchini
    • 1
  • Sara Bonato
    • 2
  • Costanza Lamperti
    • 1
  • Domenico Coviello
    • 3
  • Yvan Torrente
    • 1
  • Stefania Corti
    • 1
  • Maurizio Moggio
    • 1
  • Nereo Bresolin
    • 1
    • 2
  • Giacomo Pietro Comi
    • 1
  1. 1.Department of Neurological Sciences, Dino Ferrari CentreUniversity of Milan, I.R.C.C.S. Foundation Ca’ Granda, Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Scientific Institute IRCCS E. MedeaLeccoItaly
  3. 3.Laboratory of Medical GeneticsI.R.C.C.S. Foundation Ca’ GrandaMilanItaly

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