title: Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses.
abstract: Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.
authors: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Arnaud V
authors: AV
authors: Vanlander
authors: Department of Pediatrics, Division of Pediatric Cardiology, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Laura
authors: L
authors: Muiño Mosquera
authors: Department of Pediatrics, Division of Pediatric Cardiology, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Joseph
authors: J
authors: Panzer
authors: Laboratories of Neurogenetics and Ultrastructural Neuropathology and Biobank, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Neurogenetics Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
authors: Tine
authors: T
authors: Deconinck
authors: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Joél
authors: J
authors: Smet
authors: Research Group Reproduction and Genetics (REGE), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, B-1090 Brussels, Belgium; Center for Medical Genetics, UZ Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, B-1090 Brussels, Belgium.
authors: Sara
authors: S
authors: Seneca
authors: Department of Pathology, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Jo
authors: J
authors: Van Dorpe
authors: Department of Pathology, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Liesbeth
authors: L
authors: Ferdinande
authors: Laboratories of Neurogenetics and Ultrastructural Neuropathology and Biobank, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
authors: Chantal
authors: C
authors: Ceuterick-de Groote
authors: Laboratories of Neurogenetics and Ultrastructural Neuropathology and Biobank, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Neurogenetics Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Department of Neurology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium.
authors: Peter
authors: P
authors: De Jonghe
authors: Department of Pediatrics, Division of Pediatric Neurology and Metabolism, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, Belgium. Electronic address: rudy.vancoster@ugent.be.
authors: Rudy
authors: R
authors: Van Coster
authors: Laboratories of Neurogenetics and Ultrastructural Neuropathology and Biobank, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Neurogenetics Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, B-2610 Antwerpen, Belgium; Department of Neurology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium.
authors: Jonathan
authors: J
authors: Baets
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis; D002352:Carrier Proteins / Q000032:analysis; D002648:Child; D002797:Choline Kinase / Q000235:genetics*; D018389:Codon, Nonsense; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008853:Microscopy; D008928:Mitochondria / Q000473:pathology; D051336:Mitochondrial Membranes / Q000502:physiology*; D017240:Mitochondrial Myopathies / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D025261:Mitochondrial Proton-Translocating ATPases; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009206:Myocardium / Q000473:pathology*; D010085:Oxidative Phosphorylation
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D008565:Membrane Proteins; C542592:CHKB protein, human; D002797:Choline Kinase; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein
keywords: CHKB; Heart transplantation; Microscopy; Mitochondria; OXPHOS