N Deconinck1, P Richard2, V Allamand3, A Behin4, P Lafôret4, A Ferreiro5, A de Becdelievre6, C Ledeuil6, C Gartioux3, I Nelson3, R Y Carlier7, P Carlier8, K Wahbi9, N Romero4, M T Zabot10, F Bouhour11, V Tiffreau12, A Lacour13, B Eymard4, T Stojkovic14. 1. 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. 2. 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. 3. Sorbonne Universités, UPMC Univ Paris 06, Institut de Myologie, Paris, France CNRS, UMR7215, Paris, France Inserm, U974, Paris, France. 4. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France. 5. 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. 6. AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France. 7. AP-HP, Service de Radiologie, Hôpital Raymond Poincaré, Garches, France. 8. Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris, France. 9. 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. 10. Centre de biotechnologie cellulaire, CHU de Lyon-GH Est, Hospices Civils de Lyon, Bron, France. 11. CHU de Lyon, G-H Est, Hôpital Pierre Wertheimer, Service d'explorations fonctionnelles neurologiques, Bron, France. 12. CHRU de Lille, Hôpital Pierre Swynghedauw, Service de médecine physique et de réadaptation, Lille, France. 13. CHRU de Lille, Hôpital Roger Salengro, Clinique neurologique, Lille, France. 14. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: M A Rodríguez; Luís M Del Rio Barquero; Carlos I Ortez; Cristina Jou; Meritxell Vigo; Julita Medina; Anna Febrer; Marta Ramon-Krauel; Jorge Diaz-Manera; Montse Olive; Laura González-Mera; Andres Nascimento; Cecilia Jimenez-Mallebrera Journal: Front Aging Neurosci Date: 2017-08-08 Impact factor: 5.750