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Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues

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Abstract

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

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Acknowledgements

We thank the patients and their families. Because facial features are part of the clinical picture, patients have kindly consented to the use of their clinical photographs without masking their faces. MRI images of patients F13 and F16 were kindly provided, respectively, by Dr Milja Holstila, Finland, and Dr Florence Caillon, France, and muscle biopsy from patient F3 was managed by Cardiobiotec Biobanck, Lyon, France. We thank Claire FEGER and Nadine KEMPF for technical assistance. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, the France Génomique National infrastructure, funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09), and Fondation Maladies Rares within the frame of the “Myocapture” sequencing project, ANR-10-LABX-0030-INRT under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02, Fondation pour la Recherche Médicale (DBI20131228569) and AFM (AFM-16992) and CREGEMES for the MYOdiagHTS Project.

Author information

Author notes

  1. Sophie Scheidecker and Marguerite Miguet contributed equally to this work.

Authors and Affiliations

  1. Laboratoire Diagnostic Génétique, Faculté de Médecine, CHRU, Nouvel Hôpital Civil, 1 place de l’Hôpital, 67091, Strasbourg, France

    Valérie Biancalana, Sophie Scheidecker, Marguerite Miguet, Nicolas Dondaine, Claire Gasnier & Nadège Calmels

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Valérie Biancalana, Xavière Lornage, Nasim Vasli, Raphael Schneider & Jocelyn Laporte

  3. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France

    Valérie Biancalana, Xavière Lornage, Nasim Vasli, Raphael Schneider & Jocelyn Laporte

  4. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Valérie Biancalana, Xavière Lornage, Nasim Vasli, Raphael Schneider & Jocelyn Laporte

  5. Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Illkirch, France

    Valérie Biancalana, Xavière Lornage, Nasim Vasli, Raphael Schneider & Jocelyn Laporte

  6. Department of Pathology, Normandie Univ, UNIROUEN, INSERM U1245, Rouen University Hospital, F76000, Rouen, France

    Annie Laquerrière

  7. Center for Research in Myology, GH Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Paris, France

    Norma B. Romero & Michel Fardeau

  8. Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France

    Norma B. Romero, Tanya Stojkovic & Michel Fardeau

  9. Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

    Osorio Abath Neto & Edmar Zanoteli

  10. Service de Génétique Médicale, Unité de Génétique Clinique, CHU, Nantes, France

    Sandra Mercier

  11. Atlantic Gene Therapy Institute, University of Nantes, Nantes, France

    Sandra Mercier

  12. Centre de Référence des Maladies Neuromusculaires Nantes-Angers, CHU de Nantes, Nantes, France

    Sandra Mercier, Armelle Magot & Julie Perrier

  13. Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Nicol Voermans

  14. Department Clinical Genetics, University Hospital, Turku, Finland

    Laura Tanner

  15. Greenwood Genetic Center, Greenwood, SC, USA

    Curtis Rogers

  16. Service de Génétique, Neurogénétique et Médecine Prédictive, Hôpital de la Croix Rousse, Lyon, France

    Elisabeth Ollagnon-Roman

  17. Heartlands Hospital, Birmingham, UK

    Helen Roper

  18. Pôle de psychiatrie et neurologie, CHU Grenoble, Grenoble, France

    Célia Boutte

  19. Sourasky Medical Center, Tel Aviv University, Tel-Aviv, Israel

    Shay Ben-Shachar

  20. Service de Génétique Médicale, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France

    Elise Schaefer

  21. Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier-Universitaire Pitié-Salpêtrière, Paris, France

    Pascal Laforet & Bruno Eymard

  22. National center of Expertise for Neuromuscular Disorders, University Hospital La Timone, APHM, Aix-Marseille University, Marseille, France

    Jean Pouget

  23. Service de Génétique Clinique, CHRU de Lille, Hôpital Jeanne de Flandre, Lille, France

    Alexandre Moerman

  24. Service de Génétique Clinique, CHU de Rennes, Hôpital Sud, Rennes, France

    Laurent Pasquier

  25. Service anatomie et cytologie pathologique, Centre de compétence Breton des maladies neuromusculaires, CHRU Brest, Brest, France

    Pascale Marcorelle

  26. EA 4586 LNB, Université de Bretagne Occidentale, Brest, France

    Pascale Marcorelle

  27. Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Benno Küsters

  28. Hospices Civils de Lyon, Université Claude Bernard Lyon1, Institut NeuroMyogène, CNRS, UMR 5310, INSERM U1217, Lyon, France

    Nathalie Streichenberger

  29. Neurologie, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France

    Christine Tranchant

  30. ICube, UMR7357, CSTB Complex Systems and Translational Bioinformatics, Faculté de Médecine, Strasbourg, France

    Raphael Schneider & Julie Thompson

  31. Service cytogénétique constitutionnelle et prénatale, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France

    Valérie Kremer

  32. Department of Medical Genetics, APHM, GMGF, Timone Hospital, Aix Marseille University, Marseille, France

    Karine Nguyen

  33. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands

    Erik Jan Kamsteeg

  34. Institut de Myologie, Laboratoire de résonnance magnétique, Groupe Hospitalier-Universitaire Pitié-Salpêtrière, Paris, France

    Pierre Carlier

  35. Service de radiologie, Hôpital Raymond Poincaré, Garches, France

    Robert-Yves Carlier

  36. CNRGH, Institut de Biologie François Jacobs, CEA, Evry, France

    Anne Boland & Jean-François Deleuze

Authors
  1. Valérie Biancalana
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  2. Sophie Scheidecker
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  3. Marguerite Miguet
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  4. Annie Laquerrière
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  5. Norma B. Romero
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  6. Tanya Stojkovic
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  7. Osorio Abath Neto
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  8. Sandra Mercier
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  9. Nicol Voermans
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  10. Laura Tanner
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  11. Curtis Rogers
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  12. Elisabeth Ollagnon-Roman
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  13. Helen Roper
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  14. Célia Boutte
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  15. Shay Ben-Shachar
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  16. Xavière Lornage
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  17. Nasim Vasli
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  18. Elise Schaefer
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  19. Pascal Laforet
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  20. Jean Pouget
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  21. Alexandre Moerman
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  22. Laurent Pasquier
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  23. Pascale Marcorelle
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  24. Armelle Magot
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  25. Benno Küsters
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  26. Nathalie Streichenberger
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  27. Christine Tranchant
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  28. Nicolas Dondaine
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  29. Raphael Schneider
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  30. Claire Gasnier
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  31. Nadège Calmels
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  32. Valérie Kremer
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  33. Karine Nguyen
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  34. Julie Perrier
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  35. Erik Jan Kamsteeg
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  36. Pierre Carlier
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  37. Robert-Yves Carlier
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  38. Julie Thompson
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  39. Anne Boland
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  40. Jean-François Deleuze
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  41. Michel Fardeau
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  42. Edmar Zanoteli
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  43. Bruno Eymard
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  44. Jocelyn Laporte
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Contributions

VB and JL directed the study; VB, SS and MM performed the study; VB analyzed the data; all the others authors contributed materials; VB and JL wrote the manuscript.

Corresponding author

Correspondence to Valérie Biancalana.

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Conflict of interest

The authors have no conflicts of interest.

Statement of human rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from patients F4, F5, F16 and F17 for whom identifying photographic information is included in this article.

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Biancalana, V., Scheidecker, S., Miguet, M. et al. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta Neuropathol 134, 889–904 (2017). https://doi.org/10.1007/s00401-017-1748-0

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  • DOI: https://doi.org/10.1007/s00401-017-1748-0

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