title: DNM1L-related mitochondrial fission defect presenting as refractory epilepsy.
abstract: Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jason R
authors.identifier: 0000-0001-8411-2664
authors.initials: JR
authors.lastname: Vanstone
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Skye
authors.initials: S
authors.lastname: McBride
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Turaya
authors.initials: T
authors.lastname: Naas
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.|Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ghadi
authors.initials: G
authors.lastname: Antoun
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Michaud
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Erick
authors.initials: E
authors.lastname: Sell
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Pranesh
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.identifier: 0000-0003-3572-9558
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baird
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: MacKenzie
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lines
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D000069279:Drug Resistant Epilepsy / Q000235:genetics* / Q000473:pathology; D034281:Dynamins; D059472:Exome; D005347:Fibroblasts / Q000648:ultrastructure; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000648:ultrastructure; D020125:Mutation, Missense; D013577:Syndrome
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins