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Bethlem myopathy: a series of 16 patients and description of seven new associated mutations

Journal of Neurology volume 266, pages 934–941 (2019)Cite this article

Abstract

Background

Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations.

Methods

A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing.

Results

The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation.

Conclusions

Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.

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References

  1. Briñas L, Richard P, Quijano-Roy S, Gartioux C, Ledeuil C, Lacène E et al (2010) Early onset collagen VI myopathies: genetic and clinical correlations. Ann Neurol 68(4):511–520

    Article  CAS  PubMed  Google Scholar 

  2. Merlini L, Martoni E, Grumati P, Sabatelli P, Squarzoni S, Urciuolo A et al (2008) Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71(16):1245–1253

    Article  CAS  PubMed  Google Scholar 

  3. Scacheri PC, Gillanders EM, Subramony SH, Vedanarayanan V, Crowe CA, Thakore N et al (2002) Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 58(4):593–602

    Article  CAS  PubMed  Google Scholar 

  4. Okada M, Kawahara G, Noguchi S, Sugie K, Murayama K, Nonaka I et al (2007) Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan. Neurology 69(10):1035–1042

    Article  CAS  PubMed  Google Scholar 

  5. Kim SY, Kim WJ, Kim H, Choi SA, Lee JS, Cho A et al (2018) Collagen VI-related myopathy: expanding the clinical and genetic spectrum. Muscle Nerve 58(3):381–388

    Article  CAS  PubMed  Google Scholar 

  6. Foley AR, Hu Y, Zou Y, Columbus A, Shoffner J, Dunn DM et al (2009) Autosomal recessive inheritance of classic Bethlem myopathy. Neuromuscul Disord 19(12):813–817

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M et al (2009) Autosomal recessive Bethlem myopathy. Neurology 73(22):1883–1891

    Article  CAS  PubMed  Google Scholar 

  8. González-Pérez A, López-Bigas N (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 88(4):440–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67–e67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mercuri E, Lampe A, Allsop J, Knight R, Pane M, Kinali M et al (2005) Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy. Neuromuscul Disord 15(4):303–310

    Article  Google Scholar 

  11. Fu J, Zheng Y-M, Jin S-Q, Yi J-F, Liu X-J, Lyn H et al (2016) “Target” and “Sandwich” signs in thigh muscles have high diagnostic values for collagen VI-related myopathies. Chin Med J 129(15):1811

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lampe AK, Dunn DM, von Niederhausern AC, Hamil C, Aoyagi A, Laval SH et al (2005) Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet 42(2):108–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hunter JM, Ahearn ME, Balak CD, Liang WS, Kurdoglu A, Corneveaux JJ et al (2015) Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. Mol Genet Genom Med 3(4):283–301

    Article  CAS  Google Scholar 

  14. Martins AI, Maarque C, Pinto-Basto K, Negrão L (2017) Bethlem myopathy in a Portuguese patient—case report. Acta Myol 36(3):178–181

    PubMed  PubMed Central  Google Scholar 

  15. Fan Y, Liu A, Wei C, Yang H, Chang X, Wang S et al (2018) Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies. Clin Genet 93(6):1159–1171

    Article  CAS  PubMed  Google Scholar 

  16. Suárez B, Lozano-Arango A, Araneda D, Cortés F, Hervias C, Calcagno G et al (2018) Collagen VI related myopathies. When to suspect, how to identify. The contribution of muscle magnetic resonance. Rev Chil Pediatr 89(3):399–408

    PubMed  Google Scholar 

  17. Butterfield RJ, Foley AR, Dastgir J, Asman S, Dunn DM, Zou Y et al (2013) Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. Hum Mutat 34(11):1558–1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pace RA, Peat RA, Baker NL, Zamurs L, Mörgelin M, Irving M et al (2008) Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity: collagen VI glycine mutations. Ann Neurol 64(3):294–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Reddy HM, Cho K-A, Lek M, Estrella E, Valkanas E, Jones MD et al (2017) The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet 62(2):243–252

    Article  CAS  PubMed  Google Scholar 

  20. Giusti B, Lucarini L, Pietroni V, Lucioli S, Bandinelli B, Sabatelli P et al (2005) Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy. Ann Neurol 58(3):400–410

    Article  CAS  PubMed  Google Scholar 

  21. Deconinck N, Richard P, Allamand V, Behin A, Laforet P, Ferreiro A et al (2015) Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution. J Neurol Neurosurg Psychiatry 86(12):1337–1346

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Author notes

  1. Luísa Panadés-de Oliveira and Claudia Rodríguez-López: Both authors contributed equally.

Affiliations

  1. Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain

    Luísa Panadés-de Oliveira, Claudia Rodríguez-López, Jesús Esteban Pérez & Cristina Domínguez-González

  2. Department of Neuropathology, Hospital Universitario 12 de Octubre, Madrid, Spain

    Diana Cantero Montenegro & Aurelio Hernández Lain

  3. Department of Neurology, Hospital Universitario de Badajoz, Badajoz, Spain

    María del Mar Marcos Toledano

  4. Centro de Investigación en Enfermedades Crónicas (CIMUS)-Grupo de Genomas y Enfermedad P2L9, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

    Ana Fernández-Marmiesse

  5. Neuromuscular Disorders Unit, Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain

    Jesús Esteban Pérez & Cristina Domínguez-González

  6. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid, Spain

    Cristina Domínguez-González

  7. Instituto de investigación i+12, Madrid, Spain

    Cristina Domínguez-González

Authors
  1. Luísa Panadés-de Oliveira
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  2. Claudia Rodríguez-López
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  3. Diana Cantero Montenegro
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  4. María del Mar Marcos Toledano
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  5. Ana Fernández-Marmiesse
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  6. Jesús Esteban Pérez
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  7. Aurelio Hernández Lain
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  8. Cristina Domínguez-González
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Corresponding author

Correspondence to Luísa Panadés-de Oliveira.

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Panadés-de Oliveira, L., Rodríguez-López, C., Cantero Montenegro, D. et al. Bethlem myopathy: a series of 16 patients and description of seven new associated mutations. J Neurol 266, 934–941 (2019). https://doi.org/10.1007/s00415-019-09217-z

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  • DOI: https://doi.org/10.1007/s00415-019-09217-z

Keywords

  • Bethlem myopathy
  • Joint contractures
  • Proximal muscular weakness
  • COL6 genes
  • Collagen type VI-related myopathies