Manu Jokela1, Giorgio Tasca2, Anna Vihola2, Eugenio Mercuri2, Per-Harald Jonson2, Sara Lehtinen2, Salla Välipakka2, Marika Pane2, Maria Donati2, Mridul Johari2, Marco Savarese2, Sanna Huovinen2, Pirjo Isohanni2, Johanna Palmio2, Päivi Hartikainen2, Bjarne Udd2. 1. From the Neuromuscular Research Center (M. Jokela, S.L., J.P., B.U.), Department of Neurology, University Hospital and University of Tampere; Division of Clinical Neurosciences (M. Jokela), Department of Neurology, Turku University Hospital and University of Turku; Kiinamyllynkatu 4-8 (M. Jokela), Turku, Finland; Unità Operativa Complessa di Neurologia (G.T.), Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Folkhälsan Institute of Genetics and Department of Medical Genetics (A.V., P.-H.J., S.V., M. Johari, M.S.), Haartman Institute, University of Helsinki, Finland; Institute of Pediatric Neurology (E.M., M.P.), Catholic University School of Medicine, Rome, Italy; Department of Pathology (S.H.), Fimlab Laboratories, Tampere University Hospital, Finland; Metabolic and Neuromuscular Unit (M.D.), Meyer Hospital, Florence, Italy; Department of Pediatric Neurology (P.I.), Children's Hospital, University of Helsinki and Helsinki University Hospital; Department of Neurology (P.H.), Kuopio University Hospital and University of Eastern Finland; and Department of Neurology (B.U.), Vasa Central Hospital, Finland. mejoke@utu.fi. 2. From the Neuromuscular Research Center (M. Jokela, S.L., J.P., B.U.), Department of Neurology, University Hospital and University of Tampere; Division of Clinical Neurosciences (M. Jokela), Department of Neurology, Turku University Hospital and University of Turku; Kiinamyllynkatu 4-8 (M. Jokela), Turku, Finland; Unità Operativa Complessa di Neurologia (G.T.), Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Folkhälsan Institute of Genetics and Department of Medical Genetics (A.V., P.-H.J., S.V., M. Johari, M.S.), Haartman Institute, University of Helsinki, Finland; Institute of Pediatric Neurology (E.M., M.P.), Catholic University School of Medicine, Rome, Italy; Department of Pathology (S.H.), Fimlab Laboratories, Tampere University Hospital, Finland; Metabolic and Neuromuscular Unit (M.D.), Meyer Hospital, Florence, Italy; Department of Pediatric Neurology (P.I.), Children's Hospital, University of Helsinki and Helsinki University Hospital; Department of Neurology (P.H.), Kuopio University Hospital and University of Eastern Finland; and Department of Neurology (B.U.), Vasa Central Hospital, Finland.
Abstract
OBJECTIVE: To identify the genetic defect causing a distal calf myopathy with cores. METHODS: Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family. RESULTS: A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families. CONCLUSIONS: Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.
OBJECTIVE: To identify the genetic defect causing a distal calfmyopathy with cores. METHODS: Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family. RESULTS: A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families. CONCLUSIONS: Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.
Authors: Tokunbor A Lawal; Joshua J Todd; Jessica W Witherspoon; Carsten G Bönnemann; James J Dowling; Susan L Hamilton; Katherine G Meilleur; Robert T Dirksen Journal: Skelet Muscle Date: 2020-11-16 Impact factor: 4.912
Authors: Marco Savarese; Jaakko Sarparanta; Anna Vihola; Per Harald Jonson; Mridul Johari; Salla Rusanen; Peter Hackman; Bjarne Udd Journal: Acta Myol Date: 2020-12-01