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Research paper
Limb girdle muscular dystrophy due to mutations in POMT2
  1. Sofie Thurø Østergaard1,
  2. Katherine Johnson2,
  3. Tanya Stojkovic3,
  4. Thomas Krag1,
  5. Willem De Ridder4,5,6,
  6. Peter De Jonghe4,5,6,
  7. Jonathan Baets4,5,6,
  8. Kristl G Claeys7,8,
  9. Roberto Fernández-Torrón9,
  10. Lauren Phillips2,
  11. Ana Topf2,
  12. Jaume Colomer10,
  13. Shahriar Nafissi11,
  14. Shirin Jamal-Omidi11,
  15. Celine Bouchet-Seraphin12,
  16. France Leturcq13,
  17. Daniel G MacArthur14,15,
  18. Monkol Lek14,15,
  19. Liwen Xu14,15,
  20. Isabelle Nelson16,
  21. Volker Straub2,
  22. John Vissing1
  1. 1 Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark
  2. 2 John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  3. 3 AP-HP, Institute of Myology, Centre de reference des maladies neuromusculaires Paris Est, G-H Pitié-Salpêtrière, France
  4. 4 Neurogenetics Group, Center for Molecular Neurology, Vlaams Instituut voor Biotechnologie, Antwerp, Belgium
  5. 5 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
  6. 6 Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital, Antwerpen, Belgium
  7. 7 Department of Neurology, Neuromuscular Reference Centre, University Hospitals Leuven, Leuven, Belgium
  8. 8 Department of Neurosciences, Experimental Neurology, Laboratory for Muscle Diseases and Neuropathies, Katholieke Universiteit Leuven, Leuven, Belgium
  9. 9 Department of Neurology, Donostia University Hospital, Biodonostia Health Research Institute, Donostia-San Sebastián, Spain
  10. 10 Servei de Neurologia, Hospital Sant Joan de Déu, Unitatde Patología Neuromuscular, Barcelona, Spain
  11. 11 Department of Neurology, Iranian Center of Neurological Research, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  12. 12 Département de Biochimie et de Génétique, AP-HP, Hôpital Bichat, Paris, France
  13. 13 Laboratoire de Génétique et Biologie Moleculaires Hopital Cochin, Paris, France
  14. 14 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  15. 15 Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  16. 16 Center of Research in Myology, Institutede Myologie, Paris, France
  1. Correspondence to Miss Sofie Thurø Østergaard, Copenhagen Neuromuscular Center, Rigshospitalet, 3342, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; sofie.thuroe.oestergaard.02{at}


Background Mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four cases have been reported so far. ID: NCT02759302

Methods We report 12 new cases of LGMD2N, aged 18–63 years. Muscle involvement was assessed by MRI, muscle strength testing and muscle biopsy analysis. Other clinical features were also recorded.

Results Presenting symptoms were difficulties in walking, pain during exercise, delayed motor milestones and learning disabilities at school. All had some degree of cognitive impairment. Brain MRIs were abnormal in 3 of 10 patients, showing ventricular enlargement in one, periventricular hyperintensities in another and frontal atrophy of the left hemisphere in a third patient. Most affected muscle groups were hip and knee flexors and extensors on strength testing. On MRI, most affected muscles were hamstrings followed by paraspinal and gluteal muscles. The 12 patients in our cohort carried 11 alleles with known mutations, whereas 11 novel mutations accounted for the remaining 13 alleles.

Conclusion We describe the first cohort of patients with LGMD2N and show that unlike other LGMD types, all patients had cognitive impairment. Primary muscle involvement was found in hamstring, paraspinal and gluteal muscles on MRI, which correlated well with reduced muscle strength in hip and knee flexors and extensors. The study expands the mutational spectrum for LGMD2N, with the description of 11 novel POMT2 mutations in the association with LGMD2N.

Clinical trial registration NCT02759302.

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  • Contributors STØ: design of study, analysis, acquisition and interpretation of data, and drafting the manuscript. KJ, TS, PDeJ, JB, KGC, RF-T, LP, AT, JC, WDeR, SN, SJ-O, CB-S, FL, DGMacA, ML, LX, IN and VS: acquisition of data and revision of manuscript. TK: acquisition and interpretation of data, and revision of manuscript. JV: design of study, acquisition and interpretation of data, and revision of manuscript.

  • Funding MYO-SEQ is funded by Sanofi Genzyme, Ultragenyx Pharmaceutical, the LGMD2I Research Fund, the Kurt + Peter Foundation, the LGMD2D Foundation and the Samantha J Brazzo Foundation. Also the Myocapture project, France Génomique National infrastructure, was funded as part of the ‘Investissements d’Avenir’ for performing the whole exome sequencing of our French patients. The study was also supported by the Medical Research Council UK (reference G1002274, grant ID 98482). This work was supported by the Association Belge contre les Maladies Neuromusculaire (ABMM) – Aide à la Recherche ASBL and the EUFP7/2007-2013 under grant agreement number 2012-305121 (NEUROMICS). JB is supported by a Senior Clinical Researcher mandate of the Research Fund – Flanders (FWO).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Danish National Committee on Health Research Ethics (H-3-2012-163 withamendment #41665, #43449 and #50556) and the local Ethical Review Boards of the participating centers.

  • Provenance and peer review Not commissioned; externally peer reviewed.