Paula Widgren1,2,3,4, Anri Hurme1,2,4, Aura Falck3,4, Riikka Keski-Filppula1,4,5, Anne M Remes6,7, Jukka Moilanen1,4,5, Kari Majamaa4,8,9, Marko Kervinen3,4, Johanna Uusimaa1,2,4. 1. PEDEGO Research Unit, University of Oulu, Oulu, Finland. 2. Department of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, Finland. 3. Department of Ophthalmology, Oulu University Hospital, Oulu, Finland. 4. Medical Research Center Oulu, University of Oulu, Oulu, Finland. 5. Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland. 6. Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland. 7. Department of Neurology, Kuopio University Hospital, Kuopio, Finland. 8. Research Unit of Clinical Neuroscience and Medical Research Center Oulu, University of Oulu, Oulu, Finland. 9. Department of Neurology, Oulu University Hospital, Oulu, Finland.
Abstract
PURPOSE: 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.
PURPOSE: 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.