title: Genetic aetiology of ophthalmological manifestations in children - a focus on mitochondrial disease-related symptoms.
abstract: OBJECTIVE
  To investigate the association of mutations in the mitochondrial DNA (mtDNA) or nuclear candidate genes with mitochondrial disease-related ophthalmic manifestations (nystagmus, ptosis, ophthalmoplegia, optic neuropathy and retinopathy) in children.
  
  
  METHODS
  A retrospective cohort of children (n = 98) was identified from the medical record files of a tertiary care hospital. The entire mtDNA and nuclear genes POLG1, OPA1 and PEO1 were analysed from the available DNA samples (n = 38). Furthermore, some nuclear candidate genes were investigated based on family history and phenotype. Rare mtDNA mutations were evaluated using in silico predictors and sequence alignment.
  
  
  RESULTS
  Three patients had previously identified mutations in mtDNA that are associated with optic neuropathy (in MT-ND6 and MT-ND1) and nystagmus (in tRNA Arg). Nine rare mutations in MT-ATP6 were identified in seven patients, of whom four manifested with retinopathy and three had clusters of MT-ATP6 mutations. Nuclear PEO1 and OPA1 were unchanged in all samples, but a patient with nystagmus had a heterozygous POLG1 mutation. The analysis of nuclear candidate genes revealed mutations in NDUF8 (patient with nystagmus), TULP1 (patient with optic neuropathy, nystagmus and retinopathy) and RP2 (patient with retinopathy) genes.
  
  
  CONCLUSIONS
  Children with retinopathy, nystagmus or optic neuropathy, especially together with developmental delay or positive family history, should be considered for mitochondrial disease. MT-ATP6 should be taken into account for children with retinopathy of unknown aetiology.
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.|Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Widgren
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Anri
authors.initials: A
authors.lastname: Hurme
authors.affiliation: Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Aura
authors.initials: A
authors.lastname: Falck
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Keski-Filppula
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.|Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Moilanen
authors.affiliation: Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Research Unit of Clinical Neuroscience and Medical Research Center Oulu, University of Oulu, Oulu, Finland.|Department of Neurology, Oulu University Hospital, Oulu, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.affiliation: Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Kervinen
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu, Finland.|Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland.|Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
mesh_terms: D000293:Adolescent; D001763:Blepharoptosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D054629:Genome, Mitochondrial; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D009154:Mutation; D009759:Nystagmus, Pathologic / Q000235:genetics; D009886:Ophthalmoplegia / Q000235:genetics; D009901:Optic Nerve Diseases / Q000235:genetics; D012164:Retinal Diseases / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D025261:Mitochondrial Proton-Translocating ATPases
keywords: MT-ATP6; genetics; mitochondrial diseases; nystagmus; optic neuropathy; paediatrics; ptosis; retinopathy