title: Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA.
abstract: Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.
authors.affiliation: Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Claudia B
authors.initials: CB
authors.lastname: Catarino
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ahting
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Gusic
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Iuso
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Repp
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Peters
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: von Livonius
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilians-Universität München, Munich, Germany; DZNE-German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address: Thomas.Klopstock@med.LMU.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D004272:DNA, Mitochondrial / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000473:pathology*; D017354:Point Mutation; D012744:Sex Ratio
chemical_list: D004272:DNA, Mitochondrial
keywords: Complex I; LHON; Mitochondrial DNA; Mitochondriopathy; Oxidative phosphorylation; Respiratory chain