Skip to main content

Advertisement

SpringerLink
Log in

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation–reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Engel AG, Shen X-M, Selcen D, Sine SM (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:420–434. doi:10.1016/S1474-4422(14)70201-7

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tintignac LA, Brenner H-R, Rüegg MA (2015) Mechanisms regulating neuromuscular junction development and function and causes of muscle wasting. Physiol Rev 95:809–852. doi:10.1152/physrev.00033.2014

    Article  CAS  PubMed  Google Scholar 

  3. Beeson D (2016) Congenital myasthenic syndromes: recent advances. Curr Opin Neurol 29:565–571. doi:10.1097/WCO.0000000000000370

    Article  CAS  PubMed  Google Scholar 

  4. Bauché S, O’Regan S, Azuma Y et al (2016) Impaired presynaptic high-affinity choline transporter causes a congenital myasthenic syndrome with episodic apnea. Am J Hum Genet 99:753–761. doi:10.1016/j.ajhg.2016.06.033

    Article  PubMed  PubMed Central  Google Scholar 

  5. O’Grady GL, Verschuuren C, Yuen M et al (2016) Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology 87:1442–1448

    Article  PubMed  Google Scholar 

  6. O’Connor E, Töpf A, Müller JS et al (2016) Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome. Brain 139:2143–2153. doi:10.1093/brain/aww130

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shen X-M, Scola RH, Lorenzoni PJ et al (2017) Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Ann Clin Transl Neurol 4:130–138. doi:10.1002/acn3.387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lam C-W, Wong K-S, Leung H-W, Law C-Y (2017) Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations. Eur J Hum Genet EJHG 25:192–199. doi:10.1038/ejhg.2016.162

    Article  CAS  PubMed  Google Scholar 

  9. Salpietro V, Lin W, Delle Vedove A et al (2017) Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Ann Neurol. doi:10.1002/ana.24905

    PubMed  PubMed Central  Google Scholar 

  10. Evangelista T, Hanna M, Lochmüller H (2015) Congenital myasthenic syndromes with predominant limb girdle weakness. J Neuromuscul Dis 2:S21–S29. doi:10.3233/JND-150098

    Article  PubMed  PubMed Central  Google Scholar 

  11. Müller JS, Herczegfalvi A, Vilchez JJ et al (2007) Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain J Neurol 130:1497–1506. doi:10.1093/brain/awm068

    Article  Google Scholar 

  12. Beeson D, Higuchi O, Palace J et al (2006) Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313:1975–1978. doi:10.1126/science.1130837

    Article  CAS  PubMed  Google Scholar 

  13. Ben Ammar A, Petit F, Alexandri N et al (2010) Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol 257:754–766. doi:10.1007/s00415-009-5405-y

    Article  CAS  PubMed  Google Scholar 

  14. Palace J (2012) DOK7 congenital myasthenic syndrome: DOK7 congenital myasthenic syndrome. Ann N Y Acad Sci 1275:49–53. doi:10.1111/j.1749-6632.2012.06779.x

    Article  CAS  PubMed  Google Scholar 

  15. Guergueltcheva V, Müller JS, Dusl M et al (2012) Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. J Neurol 259:838–850. doi:10.1007/s00415-011-6262-z

    Article  PubMed  Google Scholar 

  16. Belaya K, Finlayson S, Cossins J et al (2012) Identification of DPAGT1 as a new gene in which mutations cause a congenital myasthenic syndrome. Ann N Y Acad Sci 1275:29–35. doi:10.1111/j.1749-6632.2012.06790.x

    Article  CAS  PubMed  Google Scholar 

  17. Belaya K, Finlayson S, Slater CR et al (2012) Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet 91:193–201. doi:10.1016/j.ajhg.2012.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cossins J, Belaya K, Hicks D et al (2013) Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain 136:944–956. doi:10.1093/brain/awt010

    Article  PubMed  PubMed Central  Google Scholar 

  19. Belaya K, Rodríguez Cruz PM, Liu WW et al (2015) Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain 138:2493–2504. doi:10.1093/brain/awv185

    Article  PubMed  PubMed Central  Google Scholar 

  20. Montagnese F, Klupp E, Karampinos DC et al (2017) Two patients with G MPPB mutation: the overlapping phenotypes of limb-girdle myasthenic syndrome and limb-girdle muscular dystrophy dystroglycanopathy: GMPPB dystroglycanopathy. Muscle Nerve. doi:10.1002/mus.25485

    PubMed  Google Scholar 

  21. Senderek J, Müller JS, Dusl M et al (2011) Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 88:162–172. doi:10.1016/j.ajhg.2011.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Selcen D, Shen X-M, Milone M et al (2013) GFPT1-myasthenia clinical, structural, and electrophysiologic heterogeneity. Neurology 81:370–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dusl M, Senderek J, Muller JS et al (2015) A 3′-UTR mutation creates a microRNA target site in the GFPT1 gene of patients with congenital myasthenic syndrome. Hum Mol Genet 24:3418–3426. doi:10.1093/hmg/ddv090

    Article  CAS  PubMed  Google Scholar 

  24. Willems AP, van Engelen BGM, Lefeber DJ (2016) Genetic defects in the hexosamine and sialic acid biosynthesis pathway. Biochim Biophys Acta BBA Gen Subj 1860:1640–1654. doi:10.1016/j.bbagen.2015.12.017

    Article  CAS  Google Scholar 

  25. Huh S-Y, Kim H-S, Jang H-J et al (2012) Limb-girdle myasthenia with tubular aggregates associated with novel GFPT1 mutations. Muscle Nerve 46:600–604. doi:10.1002/mus.23451

    Article  CAS  PubMed  Google Scholar 

  26. Couteaux R, Taxi J (1952) Distribution of the cholinesterase activity at the level of the myoneural synapse. Comptes Rendus Hebd Seances Acad Sci 235:434–436

    CAS  Google Scholar 

  27. Chevessier F, Bauché-Godard S, Leroy J-P et al (2005) The origin of tubular aggregates in human myopathies. J Pathol 207:313–323. doi:10.1002/path.1832

    Article  CAS  PubMed  Google Scholar 

  28. Zephir H, Stojkovic T, Maurage CA et al (2001) Tubular aggregate congenital myopathy associated with neuromuscular block. Rev Neurol (Paris) 157:1293–1296

    CAS  Google Scholar 

  29. Finlayson S, Palace J, Belaya K et al (2013) Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1. J Neurol Neurosurg Psychiatry 84:1119–1125. doi:10.1136/jnnp-2012-304716

    Article  PubMed  Google Scholar 

  30. Chevessier F, Marty I, Paturneau-Jouas M et al (2004) Tubular aggregates are from whole sarcoplasmic reticulum origin: alterations in calcium binding protein expression in mouse skeletal muscle during aging. Neuromuscul Disord 14:208–216. doi:10.1016/j.nmd.2003.11.007

    Article  CAS  PubMed  Google Scholar 

  31. Chaouch A, Müller JS, Guergueltcheva V et al (2012) A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. J Neurol 259:474–481. doi:10.1007/s00415-011-6204-9

    Article  PubMed  Google Scholar 

  32. Brady S, Healy EG, Gang Q et al (2016) Tubular aggregates and cylindrical spirals have distinct immunohistochemical signatures. J Neuropathol Exp Neurol 75:1171–1178. doi:10.1093/jnen/nlw096

    Article  PubMed  Google Scholar 

  33. Schiaffino S (2012) Tubular aggregates in skeletal muscle: Just a special type of protein aggregates? Neuromuscul Disord 22:199–207. doi:10.1016/j.nmd.2011.10.005

    Article  PubMed  Google Scholar 

  34. Takizawa S, Ishihara T, Shinohara Y (1986) A case of hypokalemic periodic paralysis with tubular aggregates in type 2A fibers and type 2B fibers. Rinsho Shinkeigaku 26:81–86

    CAS  PubMed  Google Scholar 

  35. Böhm J, Bulla M, Urquhart JE et al (2017) ORAI1 mutations with distinct channel gating defects in tubular aggregate myopathy: human mutation. Hum Mutat 38:426–438. doi:10.1002/humu.23172

    Article  PubMed  Google Scholar 

  36. Böhm J, Chevessier F, De Paula AM et al (2013) Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy. Am J Hum Genet 92:271–278. doi:10.1016/j.ajhg.2012.12.007

    Article  PubMed  PubMed Central  Google Scholar 

  37. Noury J-B, Böhm J, Peche GA et al (2017) Tubular aggregate myopathy with features of Stormorken disease due to a new STIM1 mutation. Neuromuscul Disord NMD 27:78–82. doi:10.1016/j.nmd.2016.10.006

    Article  PubMed  Google Scholar 

  38. Nesin V, Wiley G, Kousi M et al (2014) Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci USA 111:4197–4202. doi:10.1073/pnas.1312520111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schartner V, Romero NB, Donkervoort S et al (2017) Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy. Acta Neuropathol (Berl) 133:517–533. doi:10.1007/s00401-016-1656-8

    Article  CAS  Google Scholar 

  40. Zoltowska K, Webster R, Finlayson S et al (2013) Mutations in GFPT1 that underlie limb-girdle congenital myasthenic syndrome result in reduced cell-surface expression of muscle AChR. Hum Mol Genet 22:2905–2913. doi:10.1093/hmg/ddt145

    Article  CAS  PubMed  Google Scholar 

  41. Oki T, Yamazaki K, Kuromitsu J et al (1999) cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amidotransferase (GFAT2) in human and mouse. Genomics 57:227–234. doi:10.1006/geno.1999.5785

    Article  CAS  PubMed  Google Scholar 

  42. Chen Q, Müller J, Pang P-C et al (2015) Global N-linked glycosylation is not significantly impaired in myoblasts in congenital myasthenic syndromes caused by defective glutamine-fructose-6-phosphate transaminase 1 (GFPT1). Biomolecules 5:2758–2781. doi:10.3390/biom5042758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Carss KJ, Stevens E, Foley AR et al (2013) Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. Am J Hum Genet 93:29–41. doi:10.1016/j.ajhg.2013.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tajima Y, Uyama E, Go S et al (2005) Distal myopathy with rimmed vacuoles: impaired O-glycan formation in muscular glycoproteins. Am J Pathol 166:1121–1130. doi:10.1016/S0002-9440(10)62332-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Voermans NC, Guillard M, Doedee R et al (2010) Clinical features, lectin staining, and a novel GNE frameshift mutation in HIBM. Clin Neuropathol 29:71

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Cerino M, Gorokhova S, Béhin A et al (2015) Novel pathogenic variants in a french cohort widen the mutational spectrum of GNE myopathy. J Neuromuscul Dis 2:131–136. doi:10.3233/JND-150074

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the families for their invaluable contribution in this work. This study was supported by AFM-Téléthon (Grant ID 20030) and “Investissements d’avenir”ANR-10-IAIHU-06 programs (IHU-A-ICM). We also thank Prof. Hanns Lochmuller and Yasmin Issop (Institute of Genetic Medicine, Newcastle University, UK) for fruitful discussions. We thank the Plateforme d’Imagerie Cellulaire Pitié Salpêtrière (PICPS) and the Service Commun de Microscopie Université PARIS DESCARTES for confocal microscopy as well as the DNA and Cell Banks of Généthon and CRBREFGENSEP, and the Celis, Histomics and Bioinformatics/Biostatistics (iCONICS) core facilities of the ICM for precious technical support. We also thank Hybridoma Bank for their anti-neurofilament antibody (2H3).

Author information

Author notes

  1. Stéphanie Bauché

    Present address: Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Hôpital de la Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013, Paris, France

  2. Tanya Stojkovic

    Present address: AP-HP, Hôpital Pitié-Salpêtrière, 75013, Paris, France

Authors and Affiliations

  1. Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Hôpital de la Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013, Paris, France

    Geoffroy Vellieux, Damien Sternberg, Marie-Joséphine Fontenille, Elodie De Bruyckere, Claire-Sophie Davoine, Julien Messéant, Jeanine Koenig, Emmanuel Fournier, Daniel Hantaï, Bertrand Fontaine, Laure Strochlic, Bruno Eymard & Sophie Nicole

  2. UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Damien Sternberg

  3. AP-HP, Hôpital Pitié-Salpêtrière, 75013, Paris, France

    Guy Brochier, Michel Fardeau, Emmanuelle Lacène, Norma Romero, Emmanuel Fournier, Pascal Laforêt, Bertrand Fontaine & Bruno Eymard

  4. Unité de pathologies neuromusculaires, Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06 UMRS 974, Inserm U974, CNRS UMR 7215, 75013, Paris, France

    Guy Brochier, Michel Fardeau, Emmanuelle Lacène, Norma Romero, Pascal Laforêt, Bruno Eymard & Tanya Stojkovic

  5. Myology Institute, Center of Research in Myology, Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, 75013, Paris, France

    Pascal Laforêt & Tanya Stojkovic

  6. Institute of Neuropathology, University-Hospital Erlangen, schwabachanlage 6, Erlangen, Germany

    Lucie Wolf & Frédéric Chevessier

  7. Département d’Éthique de l’Université et des enseignements de Physiologie de la Faculté de Médecine Pitié-Salpêtrière, 75013, Paris, France

    Emmanuel Fournier

  8. Centre de Neuropathologie Est, Hospices Civils de Lyon, Université Claude Bernard Lyon1, Institut NeuroMyogène, CNRS UMR 5310, INSERM U1217, Lyon, France

    Nathalie Streichenberger

  9. Service d’Epileptologie Clinique, des Troubles du Sommeil et de Neurologie Fonctionnelle de l’Enfant, Hôpital Femme Mère Enfant, Lyon, France

    Veronique Manel

  10. Clinique neurologique et centre de référence des maladies rares neuromusculaires, Hôpital Roger-Salengro, CHRU de Lille, rue Emile-Laine, Lille, France

    Arnaud Lacour

  11. Centre de Référence des Maladies Neuromusculaires Nantes-Angers, Service de Neurologie, Centre Hospitalier Universitaire d’Angers, 49933, Angers, France

    Aleksandra Nadaj-Pakleza

  12. Service des consultations externes pédiatrie, Centre Hospitalier Béthune Beuvry, 62408, Béthune, France

    Sylvie Sukno

  13. Hôpital Neurologique Pierre Wertheimer, Service d’ENMG-Pathologies neuromusculaires, Hospices Civils de Lyon, 69677, Lyon-Bron, France

    Françoise Bouhour

Authors
  1. Stéphanie Bauché
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geoffroy Vellieux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Damien Sternberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie-Joséphine Fontenille
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elodie De Bruyckere
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claire-Sophie Davoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guy Brochier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julien Messéant
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lucie Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michel Fardeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Emmanuelle Lacène
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Norma Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jeanine Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Emmanuel Fournier
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniel Hantaï
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nathalie Streichenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Veronique Manel
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Arnaud Lacour
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Aleksandra Nadaj-Pakleza
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Sylvie Sukno
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Françoise Bouhour
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Pascal Laforêt
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Bertrand Fontaine
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Laure Strochlic
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Bruno Eymard
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Frédéric Chevessier
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Tanya Stojkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Sophie Nicole
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Stéphanie Bauché or Tanya Stojkovic.

Ethics declarations

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bauché, S., Vellieux, G., Sternberg, D. et al. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. J Neurol 264, 1791–1803 (2017). https://doi.org/10.1007/s00415-017-8569-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-017-8569-x

Keywords

Search

Navigation