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Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients

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Abstract

In the second most common dystrophy associated with predominant pelvic and shoulder girdle muscle weakness termed Limb-Girdle Muscular Dystrophy (LGMD), genetic complexity, large phenotypic variability, and clinical overlap can result in extensive diagnostic delays in certain individuals. In view of the large strides genetics has taken in this day and age, we address the question if muscle biopsies can still provide diagnostic evidence of substance for these patients. We reviewed and reanalyzed muscle biopsy characteristics in a cohort of LGMD patient pairs in which gene variants were picked up in CAPN3, FKRP, TTN, and ANO5, using histochemical–immunohistochemical—and immunofluorescent staining, and western blotting. We found that not the nature and severity of inflammatory changes, but the changed properties of the dystrophin complex were the most valuable assets to differentiate LGMD from myositis. Proteomic evaluation brought both primary and secondary deficiencies to light, which could be equally revealing for diagnosis. Though a muscle biopsy might, at present, not always be strictly necessary anymore, it still represents an irrefutable asset when the genetic diagnosis is complicated.

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The datasets generated in the context of this study are available from the corresponding author upon simple request.

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Acknowledgements

We would like to thank Marco Savarese from the Folkshalsan Institute of Genetics, University of Helsinki, Finland, and Bjarne Udd from the Neuromuscular Research Center, Tampere University, Finland for their help with interpreting TTN variants. Jan De Bleecker is a member of the European Reference Network (ERN) for rare neuromuscular disorders Euro-NMD.

Funding

This study was funded by the International Federation of Medical Students’ Associations (IFMSA) SCORE research exchange program.

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Authors and Affiliations

  1. Department of Neurology, Laboratory for Neuropathology and Neuromuscular Reference Center, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Ghent, Belgium

    Boel De Paepe, Elise Velghe, Linnea Salminen, Balint Toth, Pieter Olivier & Jan L. De Bleecker

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Correspondence to Boel De Paepe.

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All procedures performed in the study of human participants were in accordance with the ethical standards of the institutional research committee, approved by the Ghent University Hospital Ethics Committee under reference B670201836756, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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De Paepe, B., Velghe, E., Salminen, L. et al. Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients. Acta Neurol Belg 121, 1019–1033 (2021). https://doi.org/10.1007/s13760-020-01559-0

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