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Research paper
Hereditary myopathy with early respiratory failure: occurrence in various populations
  1. Johanna Palmio1,
  2. Anni Evilä2,
  3. Françoise Chapon3,
  4. Giorgio Tasca4,
  5. Fengqing Xiang5,
  6. Björn Brådvik6,
  7. Bruno Eymard7,
  8. Andoni Echaniz-Laguna8,
  9. Jocelyn Laporte9,
  10. Mikko Kärppä10,
  11. Ibrahim Mahjneh11,
  12. Rosaline Quinlivan12,
  13. Pascal Laforêt7,
  14. Maxwell Damian13,
  15. Andres Berardo14,
  16. Ana Lia Taratuto15,
  17. Jose Antonio Bueri14,
  18. Johanna Tommiska16,
  19. Taneli Raivio16,
  20. Matthias Tuerk17,
  21. Philipp Gölitz18,
  22. Frederic Chevessier19,
  23. Caroline Sewry20,
  24. Fiona Norwood21,
  25. Carola Hedberg22,
  26. Rolf Schröder19,
  27. Lars Edström23,
  28. Anders Oldfors22,
  29. Peter Hackman2,
  30. Bjarne Udd1,2,24
  1. 1Department of Neurology, Neuromuscular Research Unit, Tampere University and University Hospital, Tampere, Finland
  2. 2Department of Medical Genetics, Folkhälsan Institute of Genetics and Haartman Institute, University of Helsinki, Helsinki, Finland
  3. 3CHU de Caen, Neuromuscular Disorders Competence Centre, and University Hospital of Caen, Caen, France
  4. 4Don Carlo Gnocchi Onlus Foundation, Milan, Italy
  5. 5Department of Womeńs and Childreńs Health, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
  6. 6Department of Neurology, Institution of Clinical Sciences, Lund University, Lund, Sweden
  7. 7Institute of Myology, National Reference Center for neuromuscular disorders, University Hospital of Salpêtrière, UPMC, Paris, France
  8. 8Department of Neurology, Hôpitaux Universitaires, Strasbourg, France
  9. 9Department of Translational Medecine and Neurogenetics, IGBMC, University Strasbourg, Illkirch, France
  10. 10Department of Clinical Medicine, Neurology, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland
  11. 11Department of Neurology, University of Oulu and Pietarsaari Hospital, Oulu, Finland
  12. 12MRC Centre for Neuromuscular Disease, Institute of Neurology, National Hospital, London, UK
  13. 13Cambridge University Hospitals, Cambridge, UK
  14. 14Neuromuscular Section, Hospital Universitario Austral (HUA), Buenos Aires, Argentina
  15. 15Department of Neuropathology, Institute for Neurological Diseases, FLENI, Buenos Aires, Argentina
  16. 16Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland
  17. 17Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
  18. 18Department of Neuroradiology, University of Erlangen-Nuremberg, Erlangen, Germany
  19. 19Departments of Neuropathology, University of Erlangen-Nuremberg, Erlangen, Germany
  20. 20Wolfson Centre for Inherited Neuromuscular Diseases, RJAH Orthopaedic Hospital, Oswestry, UK
  21. 21Department of Neurology, King's College Hospital NHS Foundation Trust, London, UK
  22. 22Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
  23. 23Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
  24. 24Department of Neurology, Vaasa Central Hospital, Vaasa, Finland
  1. Correspondence to Dr Johanna Palmio, Department of Neurology, Neuromuscular Research Unit, Tampere University Hospital and University of Tampere, Tampere FIN-33014, Finland; johanna.palmio{at}


Objective Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort.

Methods DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations.

Results All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin.

Conclusions We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.


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