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

  • Luísa Panadés-de OliveiraEmail author
  • Claudia Rodríguez-López
  • Diana Cantero Montenegro
  • María del Mar Marcos Toledano
  • Ana Fernández-Marmiesse
  • Jesús Esteban Pérez
  • Aurelio Hernández Lain
  • Cristina Domínguez-González
Original Communication



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.


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.


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.


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


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



There is no funding.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Luísa Panadés-de Oliveira
    • 1
    Email author
  • Claudia Rodríguez-López
    • 1
  • Diana Cantero Montenegro
    • 2
  • María del Mar Marcos Toledano
    • 3
  • Ana Fernández-Marmiesse
    • 4
  • Jesús Esteban Pérez
    • 1
    • 5
  • Aurelio Hernández Lain
    • 2
  • Cristina Domínguez-González
    • 1
    • 5
    • 6
    • 7
  1. 1.Department of NeurologyHospital Universitario 12 de OctubreMadridSpain
  2. 2.Department of NeuropathologyHospital Universitario 12 de OctubreMadridSpain
  3. 3.Department of NeurologyHospital Universitario de BadajozBadajozSpain
  4. 4.Centro de Investigación en Enfermedades Crónicas (CIMUS)-Grupo de Genomas y Enfermedad P2L9Universidad de Santiago de CompostelaSantiago de CompostelaSpain
  5. 5.Neuromuscular Disorders Unit, Department of NeurologyHospital Universitario 12 de OctubreMadridSpain
  6. 6.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723MadridSpain
  7. 7.Instituto de investigación i+12MadridSpain

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