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  • Review Article
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Limb-girdle muscular dystrophies — international collaborations for translational research

Nature Reviews Neurology volume 12, pages 294–309 (2016)Cite this article

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Key Points

  • New sequencing technologies, including whole-exome and whole-genome sequencing, combined with increased data sharing and international research collaborations, are resulting in the identification of new limb-girdle muscular dystrophy (LGMD) subtypes and diagnosis of additional patients

  • These technologies are also providing evidence that added complexities, including intronic and regulatory mutations, oligogenic inheritance and modifier gene effects, could have a role in the hardest-to-diagnose forms of LGMD

  • The increased molecular and pathogenetic understanding of LGMD subtypes is now calling into question their original classification by phenotype, and new systems-based and pathway-based classification systems may be required

  • 'Trial readiness', which includes preparation of patient cohorts, care standards, outcome measures, and biomarkers stratified according to genes and/or pathways, is a key concept for translation of basic research to the clinic

  • Collaboration between patients, industry and academia is essential in the translational pathway towards therapy development and clinical trials

Abstract

The limb-girdle muscular dystrophies (LGMDs) are a diverse group of genetic neuromuscular conditions that usually manifest in the proximal muscles of the hip and shoulder girdles. Since the identification of the first gene associated with the phenotype in 1994, an extensive body of research has identified the genetic defects responsible for over 30 LGMD subtypes, revealed an increasingly varied phenotypic spectrum, and exposed the need to move towards a systems-based understanding of the molecular pathways affected. New sequencing technologies, including whole-exome and whole-genome sequencing, are continuing to expand the range of genes and phenotypes associated with the LGMDs, and new computational approaches are helping clinicians to adapt to this new genomic medicine paradigm. However, 60 years on from the first description of LGMD, no curative therapies exist, and systematic exploration of the natural history is still lacking. To enable rapid translation of basic research to the clinic, well-phenotyped and genetically characterized patient cohorts are a necessity, and appropriate outcome measures and biomarkers must be developed through natural history studies. Here, we review the international collaborations that are addressing these translational research issues, and the lessons learned from large-scale LGMD sequencing programmes.

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Figure 1: Clinical aspects of LGMD subtypes.
Figure 2: Pathophysiological mechanisms in LGMD.
Figure 3: Translational research projects in LGMD.
Figure 4
Figure 5: Components of trial readiness in LGMD.
Figure 6: The translational pathway.

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Acknowledgements

The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreements 305444 (RD-Connect) and 305121 (Neuromics). TREAT-NMD was funded under EU FP6 contract no. 036825 (2007–2011) and TREAT-NMD Operating Grant — Second Public Health Programme (contract no. 2012 3307). Funding has also been received from the Jain Foundation, the LGMD2I Research Fund, Genzyme and Ultragenyx Pharmaceutical.

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  1. The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK

    Rachel Thompson & Volker Straub

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Both authors contributed equally to all stages of the preparation of this article.

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Correspondence to Volker Straub.

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Competing interests

V.S. is or has been a principal investigator for trials sponsored by Genzyme, GSK, Prosensa/Biomarin, ISIS Pharmaceuticals, and Sarepta. He has received speaker honoraria from Genzyme and has been a member of the company's international Pompe advisory board. He also is or has been on advisory boards for Acceleron Pharma, Audentes Therapeutics, Bristol-Myers Squibb, Italfarmaco, Nicox, Pfizer, Prosensa, Santhera, Summit Therapeutics and TrophyNOD. He has research collaborations with Ultragenyx pharmaceutical and Genzyme/Sanofi. None of the industry collaborations pose a conflict of interest for this Review article. R.T. declares no competing interests.

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Thompson, R., Straub, V. Limb-girdle muscular dystrophies — international collaborations for translational research. Nat Rev Neurol 12, 294–309 (2016). https://doi.org/10.1038/nrneurol.2016.35

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