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

Journal of Neurology volume 258, pages 1610–1623 (2011)Cite this article

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.

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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.

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Affiliations

  1. Department of Neurological Sciences, Dino Ferrari Centre, University of Milan, I.R.C.C.S. Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Padiglione Ponti, Via Francesco Sforza 35, 20122, Milan, Italy

    Francesca Magri, Alessandra Govoni, Roberto Del Bo, Serena Ghezzi, Monica Sciacco, Patrizia Ciscato, Andreina Bordoni, Francesco Fortunato, Valeria Lucchini, Costanza Lamperti, Yvan Torrente, Stefania Corti, Maurizio Moggio, Nereo Bresolin & Giacomo Pietro Comi

  2. Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy

    Maria Grazia D’Angelo, Gandossini Sandra, Anna Carla Turconi, Sara Bonato & Nereo Bresolin

  3. Laboratory of Medical Genetics, I.R.C.C.S. Foundation Ca’ Granda, Ospedale Maggiore, Policlinico, Milan, Italy

    Silvana Tedeschi & Domenico Coviello

Authors
  1. Francesca Magri
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  2. Alessandra Govoni
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  3. Maria Grazia D’Angelo
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  19. Maurizio Moggio
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  21. Giacomo Pietro Comi
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Correspondence to Giacomo Pietro Comi.

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Magri, F., Govoni, A., D’Angelo, M.G. et al. Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up. J Neurol 258, 1610–1623 (2011). https://doi.org/10.1007/s00415-011-5979-z

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  • DOI: https://doi.org/10.1007/s00415-011-5979-z

Keywords

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