Megaconial congenital muscular dystrophy due to CHKB gene variants,the first report of thirteen Iranian patients
Affiliation:
1. Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran;2. Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran;3. Neuromuscular Research Center, Tehran University of Medical Sciences, Tehran, Iran;4. Molecular and Clinical Sciences Institute, St. George''s, University of London, Cranmer Terrace, London SW170RE, United Kingdom;5. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran;6. Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran;7. Pediatric Neurology Research Center, Research Institute for Children''s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran;8. Pediatric Neurology Department, Mofid Children''s Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;9. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;10. Pediatric Pathology Research Center, Research Institute for Children''s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran;1. Department of Respiratory Medicine Departments, Sydney Children''s Hospital, Randwick, Australia;2. Department of Sleep Medicine, Sydney Children''s Hospital, Randwick, Australia;3. Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Sydney, Randwick, Australia;4. Department of Neurology, Sydney Children''s Hospital, Randwick, Australia;5. Department of Neurology, Children''s Hospital Westmead, Westmead, Australia;6. Children''s Hospital at Westmead Clinical School, University of Sydney, Australia;7. Department of Respiratory and Sleep Medicine, Children''s Hospital Westmead, Westmead, Australia;1. Department of Neurology, Mayo Clinic, Rochester, MN, USA;2. Division of Neurology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand;3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;4. Division of Hematology, Mayo Clinic, Rochester, MN, USA;1. Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China;2. Department of Neurology, Children''s Hospital Capital Institute of Pediatrics, Beijing, China;3. GrandOmics Biosciences, Beijing, China;1. Neuropathology Unit (Anatomic Pathology Service) and Reference Center for Neuromuscular Pathology, CHU BRUGMANN-HUDERF, Université Libre de Bruxelles, 1020 Brussels, Belgium;2. Centre de Référence Neuromusculaire, Pediatric Neurology department, Hôpital Universitaire des Enfants- Reine Fabiola (HUDERF), Université Libre de Bruxelles, Belgium;3. Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola and Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium. Interuniversity Institute of Bioinformatics in Brussels, Universite Libre de Bruxelles, Brussels, Belgium;4. John Walton Muscular Dystrophy Research Center, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK;5. Pediatric imaging department, Hôpital Universitaire des Enfants- Reine Fabiola (HUDERF), Université Libre de Bruxelles, Brussels, Belgium;6. Centre de Référence Neuromusculaire, Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
Abstract:
Megaconial congenital muscular dystrophy (OMIM: 602,541) related to CHKB gene mutation is a newly defined rare autosomal recessive disorder, with multisystem involvement presenting from the neonatal period to adolescence. Choline kinase beta, lipid transport enzyme, catalyzes the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, two major components of the mitochondrial membrane, on which respiratory enzyme activities are dependent. CHKB gene variants lead to loss-of-function of choline kinase b and lipid metabolism defects and mitochondrial structural changes. To date, many megaconial congenital muscular dystrophy cases due to CHKB gene variants have been reported worldwide. We describe thirteen Iranian megaconial congenital muscular dystrophy cases related to CHKB gene variants, including clinical presentations, laboratory and muscle biopsy findings, and novel CHKB gene variants. The most common symptoms and signs included intellectual disability, delayed gross-motor developmental milestones, language skills problems, muscle weakness, as well as autistic features, and behavioral problems. Muscle biopsy examination showed the striking finding of peripheral arrangements of large mitochondria in muscle fibers and central sarcoplasmic areas devoid of mitochondria. Eleven different CHKB gene variants including six novel variants were found in our patients. Despite the rarity of this disorder, recognition of the multisystem clinical presentations combined with characteristic findings of muscle histology can properly guide to genetic evaluation of CHKB gene.
