Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.Reportar como inadecuado




Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Institut de Myologie 2 Departamento de Neurología y Neurocirugía Santiago 3 INSERM U836, équipe 4, Muscles et pathologies GIN - Grenoble Institut des Neurosciences, Laboratoire de biochimie et génétique moléculaire, Laboratoire de Biochimie et Génétique Moléculaire and Centre de Référence des Maladies Neuro-Musculaires 4 Thérapie des maladies du muscle strié 5 Centre de référence des maladies neuromusculaires Paris-Est 6 Groupe Myologie 7 Physiopathologie et thérapie du muscle strié 8 Neuropaediatrics 9 Pathology 10 Departement of neuropathology 11 Laboratoire de pathologie cellulaire 12 Anatomie pathologique 13 INSERM U836, équipe 4, Muscles et pathologies GIN - Grenoble Institut des Neurosciences 14 Centre de référence des maladies rares neuromusculaires 15 Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires

Abstract : AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel RYR1. METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor RYR1 gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.





Autor: J. A. Bevilacqua - Nicole Monnier - Marcus Bitoun - Bruno Eymard - Ana Ferreiro - Soledad Monges - Fabiana Lubieniecki - Ana Tara

Fuente: https://hal.archives-ouvertes.fr/



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