title: Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation.
abstract: BACKGROUND
  Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.
  
  
  OBJECTIVE
  To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.
  
  
  METHODS
  We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.
  
  
  RESULTS
  Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients' muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.
  
  
  CONCLUSIONS
  We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.
authors.affiliation: Pediatric Department B', Genetic Institute, Emek Medical Center, Afula, Israel Genetic Institute, Emek Medical Center, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Padraig J
authors.initials: PJ
authors.lastname: Flannery
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Burté
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Devorah
authors.initials: D
authors.lastname: Soiferman
authors.affiliation: Genetic Institute, Emek Medical Center, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Morad
authors.initials: M
authors.lastname: Khayat
authors.affiliation: Department of Cellular and Molecular Biology, School of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Verónica
authors.initials: V
authors.lastname: Eisner
authors.affiliation: Department of Pathology, Rambam Medical Center, Haifa, Israel.
authors.forename: Eugene
authors.initials: E
authors.lastname: Vladovski
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Metabolic Unit, Rambam Medical Center.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Microbiology and Molecular Genetics, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Schuler-Furman
authors.affiliation: Genetic Institute, Emek Medical Center, Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007223:Infant; D017237:Mitochondrial Encephalomyopathies / Q000209:etiology / Q000235:genetics*; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation; D009896:Optic Atrophy / Q000209:etiology / Q000235:genetics*; D011247:Pregnancy
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human
keywords: Clinical genetics; Metabolic disorders; Neuromuscular disease; Neuroophthalmology