Justine Vandeputte1, Mattias Van Heetvelde2,3, Caroline Van Cauwenbergh1,2,4, Sara Seneca5, Elfride De Baere2,3, Bart P Leroy1,2,4,6,7, Julie De Zaeytijd1. 1. Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium. 2. Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium. 3. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 4. Department of Head & Skin, Ghent University, Ghent, Belgium. 5. Center for Medical Genetics, UZ Brussel, Research Group Reproduction & Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium. 6. Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 7. Center for Cellular & Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (>90%) is related to three primary mitochondrial DNA (mtDNA) variants: ND1 m.3460G>A, ND4 m.11778G>A and ND6 m.14484T>C. The remaining 10% is associated with >40 secondary variants with variable penetrance and incidence between different ethnic backgrounds. MATERIALS AND METHODS: Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed. RESULTS: A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502T>C in MT-ND6, exclusively known to cause optic neuropathy in an Asian population. Three sisters of the proband, two of whom reported tobacco and alcohol abuse, had bilateral temporal optic disc pallor without functional impact. A fourth non-smoker sister had a completely normal eye exam. CONCLUSIONS: The rare Asian m.14502T>C variant in the MT-ND6 gene was linked to a mild LHON phenotype in a Western European family. Penetrance in this family was likely triggered by alcohol and tobacco abuse. A full mtDNA sequencing is warranted in the case of high clinical suspicion of LHON when mutation analysis for the three common pathogenic variants is negative.
BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (>90%) is related to three primary mitochondrial DNA (mtDNA) variants: ND1 m.3460G>A, ND4 m.11778G>A and ND6 m.14484T>C. The remaining 10% is associated with >40 secondary variants with variable penetrance and incidence between different ethnic backgrounds. MATERIALS AND METHODS: Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed. RESULTS: A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502T>C in MT-ND6, exclusively known to cause optic neuropathy in an Asian population. Three sisters of the proband, two of whom reported tobacco and alcohol abuse, had bilateral temporal optic disc pallor without functional impact. A fourth non-smoker sister had a completely normal eye exam. CONCLUSIONS: The rare Asian m.14502T>C variant in the MT-ND6 gene was linked to a mild LHON phenotype in a Western European family. Penetrance in this family was likely triggered by alcohol and tobacco abuse. A full mtDNA sequencing is warranted in the case of high clinical suspicion of LHON when mutation analysis for the three common pathogenic variants is negative.