title: Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant.
abstract: We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease.
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Université Montpellier 2, Montpellier, France.
authors.forename: Majida
authors.initials: M
authors.lastname: Charif
authors.affiliation: CHRU Montpellier, Centre de Référence Maladies Sensorielles Génétiques, Montpellier, France.
authors.forename: Salah Mohamed Cherif
authors.initials: SM
authors.lastname: Titah
authors.affiliation: CHRU Montpellier, Service de Neuropédiatrie, Montpellier, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: Département de Biochimie et Génétique, CHRU Angers, Angers, France.|UMR CNRS 6214-INSERM U1083, Université Angers, Angers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Desquiret-Dumas
authors.affiliation: Département de Biochimie et Génétique, CHRU Angers, Angers, France.|UMR CNRS 6214-INSERM U1083, Université Angers, Angers, France.
authors.forename: Naig
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Université Montpellier 2, Montpellier, France.|CHRU Montpellier, Centre de Référence Maladies Sensorielles Génétiques, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.affiliation: Ophthalmology, Eye Center, Pau, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Leid
authors.affiliation: Ophthalmology, Eye Center, Pau, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massal
authors.affiliation: Clinique Sourdille, Visual Explorations, Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Zanlonghi
authors.affiliation: CHRU Montpellier, CERAMM, Montpellier, France.|INSERM U1046, Médecine et Physiologie Expérimentale du Cœur et des Muscles, Montpellier, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mercier
authors.affiliation: CHRU Montpellier, CERAMM, Montpellier, France.|INSERM U1046, Médecine et Physiologie Expérimentale du Cœur et des Muscles, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Raynaud de Mauverger
authors.affiliation: Département de Biochimie et Génétique, CHRU Angers, Angers, France.|UMR CNRS 6214-INSERM U1083, Université Angers, Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: Service des Maladies Héréditaires du Métabolisme, Centre de Biologie et de Pathologie Est, CHU Lyon, Bron, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mousson de Camaret
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Université Montpellier 2, Montpellier, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Université Montpellier 2, Montpellier, France.|CHRU Montpellier, Centre de Référence Maladies Sensorielles Génétiques, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics; D042963:Electron Transport Complex II / Q000235:genetics; D014450:Electron Transport Complex III / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009898:Optic Disk / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012360:RNA, Transfer, Phe / Q000235:genetics*; D016601:RNA-Binding Proteins; D014792:Visual Acuity
chemical_list: D002352:Carrier Proteins; C492006:MTO1 protein, human; D012360:RNA, Transfer, Phe; D016601:RNA-Binding Proteins; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III
keywords: MTO1; cardiomyopathy; cognitive disability; mitochondria; mitochondrial tRNA; mtDNA; optic neuropathy; respiratory chain