title: Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.
abstract: OBJECTIVE
  Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce.
  
  
  METHODS
  We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases).
  
  
  RESULTS
  Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12 novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease.
  
  
  CONCLUSIONS
  Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.
authors.affiliation: Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France.
authors.forename: N
authors.initials: N
authors.lastname: Deconinck
authors.affiliation: AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France UMR_S 1166 Equipe "Génomique et Physiopathologie des Maladies Cardiovasculaires", Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Richard
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Allamand
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Behin
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Lafôret
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France Inserm U787, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Ferreiro
authors.affiliation: AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: de Becdelievre
authors.affiliation: AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Ledeuil
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Gartioux
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Nelson
authors.affiliation: AP-HP, Service de Radiologie, Hôpital Raymond Poincaré, Garches, France.
authors.forename: R Y
authors.initials: RY
authors.lastname: Carlier
authors.affiliation: Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Carlier
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Wahbi
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Romero
authors.affiliation: Centre de biotechnologie cellulaire, CHU de Lyon-GH Est, Hospices Civils de Lyon, Bron, France.
authors.forename: M T
authors.initials: MT
authors.lastname: Zabot
authors.affiliation: CHU de Lyon, G-H Est, Hôpital Pierre Wertheimer, Service d'explorations fonctionnelles neurologiques, Bron, France.
authors.forename: F
authors.initials: F
authors.lastname: Bouhour
authors.affiliation: CHRU de Lille, Hôpital Pierre Swynghedauw, Service de médecine physique et de réadaptation, Lille, France.
authors.forename: V
authors.initials: V
authors.lastname: Tiffreau
authors.affiliation: CHRU de Lille, Hôpital Roger Salengro, Clinique neurologique, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Lacour
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Eymard
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Stojkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000375:Aging; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D024142:Collagen Type VI / Q000235:genetics*; D003286:Contracture / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018908:Muscle Weakness / Q000209:etiology; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D009460:Neurologic Examination; D010641:Phenotype; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D024142:Collagen Type VI
keywords: COLLAGEN; GENETICS; MYOPATHY; NEUROMUSCULAR