Skip to main content
SpringerLink
Log in

“Necklace” fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of “atypical” forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. We reviewed systematically the biopsies of a cohort of patients with an unclassified form of centronuclear myopathy (CNM) and identified four patients presenting a peculiar histological alteration in some muscle fibers that resembled a necklace (“necklace fibers”). We analyzed further the clinical and morphological features and performed a screening of the genes involved in CNM. Muscle biopsies in all four patients demonstrated 4–20% of fibers with internalized nuclei aligned in a basophilic ring (necklace) at 3 μm beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myofibrils of smaller diameter, in oblique orientation, surrounded by mitochondria, sarcoplasmic reticulum and glycogen granules. In the four patients (three women and one man), myopathy developed in early childhood but was slowly progressive. All had mutations in the MTM1 gene. Two mutations have previously been reported (p.E404K and p.R241Q), while two are novel; a c.205_206delinsAACT frameshift change in exon 4 and a c.1234A>G mutation in exon 11 leading to an abnormal splicing and the deletion of nine amino acids in the catalytic domain of MTM1. Necklace fibers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace fibers is useful as a marker to direct genetic analysis to MTM1 in CNM.

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. Biancalana V, Caron O, Gallati S et al (2003) Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet 112:135–142

    PubMed  Google Scholar 

  2. Bitoun M, Bevilacqua JA, Eymard B, Fardeau M, Guicheney P, Romero NB (2009) An atypical phenotype of centronuclear myopathy due to a novel dynamin 2 mutation. Neurology 72(1)

  3. Bitoun M, Bevilacqua JA, Prudhon B et al (2007) Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann Neurol 62:666–670

    Article  PubMed  CAS  Google Scholar 

  4. Bitoun M, Maugenre S, Jeannet P-Y et al (2005) Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet 37:1207–1209

    Article  PubMed  CAS  Google Scholar 

  5. Buj-Bello A, Fougerousse F, Schwab Y et al (2008) AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet 17:2132–2143

    Article  PubMed  CAS  Google Scholar 

  6. Buj-Bello A, Laugel V, Messaddeq N et al (2002) The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci USA 9923:15060–15065

    Article  CAS  Google Scholar 

  7. de Goede CGEL, Kinsley A, Kingston H, Tomlin PI, Hughes MI (2005) Muscle biopsy without centrally located nuclei in a male child with mild X-linked myotubular myopathy. Dev Med Child Neurol 47:835–837

    Article  PubMed  Google Scholar 

  8. de Gouyon BM, Zhao W, Laporte J, Mandel JL, Metzenberg A, Herman GE (1997) Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy. Hum Mol Genet 6:1499–1504

    Article  PubMed  Google Scholar 

  9. Fardeau M, Tomé F (1994) Congenital myopathies. In: Engel AG, Franzini-Armstrong C (eds) Myology, 2nd edn. McGraw Hill, New York, pp 1500–1505

    Google Scholar 

  10. Fischer D, Herasse M, Bitoun M et al (2006) Characterization of the muscle involvement in dynamin 2 related centronuclear myopathy. Brain 129:1463–1469

    Article  PubMed  Google Scholar 

  11. Gardner-Medwin D, Walton JN (1974) The clinical examination of the voluntary muscles. In: Walton JN (ed) Disorders of voluntary muscles. Churchill-Livingstone, Edinburgh, pp 517–560

    Google Scholar 

  12. Goryunov D, Nightingale A, Bornfleth L, Leung C, Liem RKH (2008) Multiple disease-linked myotubularin mutations cause NFL assembly defects in cultured cells and disrupt myotubularin dimerization. J Neurochem 104:1536–1552

    Article  PubMed  CAS  Google Scholar 

  13. Grogan PM, Tanner SM, Ørstavik KH et al (2005) Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations. Neurology 64:1638–1640

    Article  PubMed  CAS  Google Scholar 

  14. Hammans SR, Robinson DO, Moutou C et al (2000) A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy. Neuromuscul Disord 10:133–137

    Article  PubMed  CAS  Google Scholar 

  15. Herman GE, Kopacz K, Zhao W, Mills PL, Metzenberg A, Das S (2002) Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum Mutat 192:114–121

    Article  CAS  Google Scholar 

  16. Hoffjan S, Thiels C, Vorgerd M, Neuen-Jacob E, Epplen J, Kress W (2006) Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404 K mutation in MTM1. Neuromuscul Disord 16:749–753

    Article  PubMed  Google Scholar 

  17. Jungbluth H, Sewry CA, Buj-Bello A et al (2003) Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation. Neuromuscul Disord 13:55–59

    Article  PubMed  CAS  Google Scholar 

  18. Jungbluth H, Zhou H, Sewry CA et al (2007) Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord 17:338–345

    Article  PubMed  Google Scholar 

  19. Laporte J, Biancalana V, Tanner S, Kress W, Schneider V, Wallgren-Pettersson C (2000) MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 15:393–409

    Article  PubMed  CAS  Google Scholar 

  20. Laporte J, Guiraud-Chaumeil C, Vincent MC et al (1997) Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. Hum Mol Genet 6:1505–1511

    Article  PubMed  CAS  Google Scholar 

  21. Laporte J, Hu LJ, Kretz C et al (1996) A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 13:175–182

    Article  PubMed  CAS  Google Scholar 

  22. Li D, Gonzalez O, Bachinski LL, Roberts R (2000) Human protein tyrosine phosphatase-like gene: expression profile, genomic structure, and mutation analysis in families with ARVD. Gene 256:237–243

    Article  PubMed  CAS  Google Scholar 

  23. Marty I, Thevenon D, Scotto C et al (2000) Cloning and characterization of a new isoform of skeletal muscle triadin. J Biol Chem 275:8206–8212

    Article  PubMed  CAS  Google Scholar 

  24. Mercuri E, Pichiecchio A, Allsop J, Messina S, Pane M, Muntoni F (2007) Muscle MRI in inherited neuromuscular disorders: past, present, and future. J Magn Reson Imaging 25:433–440

    Article  PubMed  Google Scholar 

  25. Nicot AS, Toussaint A, Tosch V et al (2007) Mutations in amphiphysin 2 BIN1 disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet 33:1134–1139

    Article  CAS  Google Scholar 

  26. Oldfors A, Kyllerman M, Wahlström J, Darnfors C, Henriksson KG (1989) X-linked myotubular myopathy: clinical and pathological findings in a family. Clin Genet 361:5–14

    Google Scholar 

  27. Pénisson-Besnier I, Biancalana V, Reynier P, Cossée M, Dubas F (2007) Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: a clinical and genetic study. Neuromuscul Disord 172:180–185

    Article  Google Scholar 

  28. Pierson CR, Tomczak K, Agrawal P, Moghadaszadeh B, Beggs AH (2005) X-linked myotubular and centronuclear myopathies. J Neuropathol Exp Neurol 64(7):555–564

    Google Scholar 

  29. Ralston E, Lu Z, Biscocho N et al (2006) Blood vessels and desmin control the positioning of nuclei in skeletal muscle fibers. J Cell Physiol 209:874–882

    Article  PubMed  CAS  Google Scholar 

  30. Schara U, Kress W, Tücke J, Mortier W (2003) X-linked myotubular myopathy in a female infant caused by a new MTM1 gene mutation. Neurology 60:1363–1365

    Article  PubMed  Google Scholar 

  31. Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174

    Article  PubMed  CAS  Google Scholar 

  32. Sutton IJ, Winer JB, Norman AN, Liechti-Gallati S, MacDonald F (2001) Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 57:900–902

    PubMed  CAS  Google Scholar 

  33. Yu S, Manson S, White S et al (2003) X-linked myotubular myopathy in a family with three adult survivors. Clin Genet 64:148–152

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Nigel Clarke, MD, PhD, for his helpful advice; Michael Walls, PhD, for critical reading of the manuscript; Isabelle Marty, PhD, for providing anti-triadin antibodies; Andrée Rouche, MSc, Svetlana Maugenre, BSc, Bernard Prudhon, BSc, and Nicolas Dondaine, BSc, for expert technical assistance. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Association Française contre les Myopathies (AFM). J. A. Bevilacqua was supported by the Program Alban; The European Union Program of High Level Scholarships for Latin America (Scholarship No. E04E028343CL); and the Association Institut de Myologie (AIM), France.

Conflict of interest statement

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. INSERM, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Jorge A. Bevilacqua, Marc Bitoun, Pascal Laforêt, Bruno Eymard, Pascale Guicheney & Norma Beatriz Romero

  2. Unité de Morphologie Neuromusculaire, Association Institut de Myologie (AIM), Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Jorge A. Bevilacqua, Gisela Stoltenburg, Kristl G. Claeys, Emmanuelle Lacène, Guy Brochier, Linda Manéré, Michel Fardeau & Norma Beatriz Romero

  3. Departamento de Neurología y Neurocirugía, HCUCH and Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    Jorge A. Bevilacqua

  4. UPMC Univ Paris 06, UMR S582, IFR14, 75013, Paris, France

    Marc Bitoun, Pascal Laforêt, Bruno Eymard, Pascale Guicheney & Norma Beatriz Romero

  5. Laboratoire Diagnostic Génétique et EA3949, Faculté de Médecine, CHRU, Strasbourg, France

    Valérie Biancalana

  6. Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden

    Anders Oldfors

  7. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France

    Kristl G. Claeys, Emmanuelle Lacène, Guy Brochier, Pascal Laforêt, Bruno Eymard, Pascale Guicheney, Michel Fardeau & Norma Beatriz Romero

  8. INSERM U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47, Bd de l’Hôpital, 75651, Paris, France

    Norma Beatriz Romero

Authors
  1. Jorge A. Bevilacqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Bitoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valérie Biancalana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anders Oldfors
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gisela Stoltenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kristl G. Claeys
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emmanuelle Lacène
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guy Brochier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Linda Manéré
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pascal Laforêt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bruno Eymard
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pascale Guicheney
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michel Fardeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Norma Beatriz Romero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norma Beatriz Romero.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure (25.9 MB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bevilacqua, J.A., Bitoun, M., Biancalana, V. et al. “Necklace” fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. Acta Neuropathol 117, 283–291 (2009). https://doi.org/10.1007/s00401-008-0472-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-008-0472-1

Keywords

Search

Navigation