{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:13:21Z","timestamp":1785838401940,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fighting Blindness","award":["FB21STE"],"award-info":[{"award-number":["FB21STE"]}]},{"name":"Eithne Walls Fellowship, Trinity College Dublin","award":["FB21STE"],"award-info":[{"award-number":["FB21STE"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leber Hereditary Optic Neuropathy (LHON) affects a minority of carriers of causative mitochondrial DNA mutations. We investigated a cohort of patients with LHON, including m.11778G&gt;A, m.3460G&gt;A, m.14484T&gt;C and DNAJC30 c.152A&gt;G variants, and their asymptomatic maternal carrier relatives for additional potential associations with vision loss. We assessed visual acuity, optical coherence tomography (OCT) of the peripapillary retinal nerve fibre layer (RNFL), visually evoked potential including P-100 latency, and full mitochondrial genome sequencing. Comparison was made with a reference standard for OCT; European Descent, Heidelberg Engineering \u00a9; and electrophysiology measurements with in-house normative ranges. RNFL was thinned overall in LHON patients (n = 12); median global RNFL \u221254 \u03bcm in the right eye (RE) and \u221250 \u03bcm in the left eye (LE) versus normal, and was found to be normal overall in asymptomatic carriers at +1 \u03bcm RE and \u22122 \u03bcm LE (n = 16). In four asymptomatic carriers there was RNFL thinning found either unilaterally or bilaterally; these cases were associated with isolated delay in P-100 latency (25%), delay and reduced visual acuity (50%), or reduced visual acuity without P-100 latency delay (25%). Optic nerve dysfunction was associated with mitochondrial haplogroup H and HV, versus non-H haplogroups, in the asymptomatic carriers (Fisher\u2019s exact test, p = 0.05). Our findings suggest that optic nerve abnormalities may be identified in asymptomatic LHON mitochondrial mutation carriers, which may be associated with optic nerve dysfunction. For asymptomatic carriers these findings were associated with mitochondrial haplogroup H and HV.<\/jats:p>","DOI":"10.3390\/ijms24021068","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"1068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Optic Nerve Structural and Functional Changes in LHON-Affected and Asymptomatic Maternal Relatives: Association with H and HV Mitochondrial Haplogroups"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6914-7447","authenticated-orcid":false,"given":"Clare","family":"Quigley","sequence":"first","affiliation":[{"name":"Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-7725","authenticated-orcid":false,"given":"Kirk A. J.","family":"Stephenson","sequence":"additional","affiliation":[{"name":"Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Kenna","sequence":"additional","affiliation":[{"name":"Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Royal Victoria Eye and Ear Hospital, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF01694557","article-title":"On hereditary and congenital optic nerve disorders","volume":"17","author":"Leber","year":"1871","journal-title":"Graefes Arh. Ophthalmol."},{"key":"ref_2","first-page":"481","article-title":"Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy","volume":"59","author":"Mackey","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.survophthal.2009.10.002","article-title":"The neuro-ophthalmology of mitochondrial disease","volume":"55","author":"Fraser","year":"2010","journal-title":"Surv. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/ana.10177","article-title":"Mitochondrial DNA C4171A\/ND1 is a novel primary causative mutation of Leber\u2019s hereditary optic neuropathy with a good prognosis","volume":"51","author":"Kim","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/ana.20236","article-title":"The ND1 gene of complex I is a mutational hot spot for Leber\u2019s hereditary optic neuropathy","volume":"56","author":"Valentino","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s00439-001-0660-8","article-title":"The role of mtDNA background in disease expression: A new primary LHON mutation associated with Western Eurasian haplogroup J","volume":"110","author":"Brown","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/ajmg.a.20456","article-title":"Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation","volume":"124A","author":"Gropman","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/ajmg.a.20449","article-title":"Clinical variability in maternally inherited leber hereditary optic neuropathy with the G14459A mutation","volume":"124A","author":"Tarnopolsky","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1086\/302049","article-title":"Low-penetrance branches in matrilineal pedigrees with Leber hereditary optic neuropathy","volume":"63","author":"Howell","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/JCI138267","article-title":"Impaired complex I repair causes recessive Leber\u2019s hereditary optic neuropathy","volume":"131","author":"Stenton","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/sj.ejhg.5201828","article-title":"Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland","volume":"15","author":"Puomila","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_12","first-page":"145","article-title":"Inherited mitochondrial optic neuropathies","volume":"46","author":"Griffiths","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/brain\/awq276","article-title":"Oestrogens ameliorate mitochondrial dysfunction in Leber\u2019s hereditary optic neuropathy","volume":"134","author":"Giordano","year":"2011","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1093\/brain\/awp158","article-title":"Gene-environment interactions in Leber hereditary optic neuropathy","volume":"132","author":"Kirkman","year":"2009","journal-title":"Brain"},{"key":"ref_15","first-page":"51","article-title":"Subclinical carriers and conversions in Leber hereditary optic neuropathy: A prospective psychophysical study","volume":"104","author":"Sadun","year":"2006","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1167\/iovs.13-13365","article-title":"Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy","volume":"55","author":"Guy","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_17","first-page":"381","article-title":"Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage","volume":"60","author":"Brown","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","first-page":"1107","article-title":"Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484","volume":"60","author":"Torroni","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1086\/519394","article-title":"Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background","volume":"81","author":"Hudson","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/ajmg.a.20135","article-title":"Low penetrance of the 14484 LHON mutation when it arises in a non-haplogroup J mtDNA background","volume":"119A","author":"Howell","year":"2003","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10571-008-9325-7","article-title":"Mitochondrial mutation in Iranian patients with multiple sclerosis, correlation between haplogroups H, A and clinical manifestations","volume":"29","author":"Ghabaee","year":"2009","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_22","first-page":"201","article-title":"Mitochondrial tRNAAla 5601C>T variant may affect the clinical expression of the LHONrelated ND4 11778G>A mutation in a family","volume":"21","author":"Ding","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, A.M., Jia, X., Bi, R., Salas, A., Li, S., Xiao, X., Wang, P., Guo, X., Kong, Q.P., and Zhang, Q. (2011). Mitochondrial DNA haplogroup background affects LHON, but not suspected LHON, in Chinese patients. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027750"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s11011-020-00605-3","article-title":"Mitochondrial genome variation in male LHON patients with the m.11778G > A mutation","volume":"35","author":"Krawczynski","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"ref_25","unstructured":"Gleeson, M. (2021, October 04). What Are the Most Common mtDNA Subclades in Ireland?. Available online: https:\/\/dnaandfamilytreeresearch.blogspot.com\/2020\/03\/what-are-most-common-mtdna-subclades-in.html#:~:text=Here%20are%20the%20analyses%20for,with%20various%20hotspots%20(including%20Ireland)."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1136\/bjo.67.5.310","article-title":"Abnormal evoked potential latencies in amblyopia","volume":"67","author":"Sokol","year":"1983","journal-title":"Br. J. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1177\/11206721211036811","article-title":"Evaluation of macular and optic nerve head parameters in amblyopic eyes: An optical coherence tomography study","volume":"32","author":"Guagliano","year":"2022","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1001\/archopht.124.6.878","article-title":"Causes and associations of amblyopia in a population-based sample of 6-year-old Australian children","volume":"124","author":"Robaei","year":"2006","journal-title":"Arch Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1016\/j.ophtha.2010.03.004","article-title":"Prevalence of eye disease in early childhood and associated factors: Findings from the millennium cohort study","volume":"117","author":"Cumberland","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1016\/j.ophtha.2009.04.034","article-title":"Prevalence of amblyopia and strabismus in white and African American children aged 6 through 71 months the Baltimore Pediatric Eye Disease Study","volume":"116","author":"Friedman","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1167\/iovs.09-4461","article-title":"Prevalence of amblyopia and strabismus in young singaporean chinese children","volume":"51","author":"Chia","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1097\/WNO.0000000000000346","article-title":"Atypical Leber Hereditary Optic Neuropathy: 18 Year Interval Between Eyes","volume":"36","author":"Ohden","year":"2016","journal-title":"J. Neuroophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1055\/s-0035-1563574","article-title":"Therapeutic Approaches to Inherited Optic Neuropathies","volume":"35","year":"2015","journal-title":"Semin. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e227977","DOI":"10.1136\/bcr-2018-227977","article-title":"Late-onset Leber\u2019s hereditary optic neuropathy: The role of environmental factors in hereditary diseases","volume":"12","author":"Cunha","year":"2019","journal-title":"BMJ Case Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/WNO.0000000000001023","article-title":"Real-World Clinical Experience with Idebenone in the Treatment of Leber Hereditary Optic Neuropathy","volume":"40","author":"Catarino","year":"2020","journal-title":"J. Neuroophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1111\/aos.15153","article-title":"Clinical outcomes of treatment with idebenone in Leber\u2019s hereditary optic neuropathy in the Netherlands: A national cohort study","volume":"100","author":"Pott","year":"2022","journal-title":"Acta Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/01658107.2022.2032761","article-title":"The Natural History of Leber\u2019s Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers","volume":"46","author":"Stephenson","year":"2022","journal-title":"Neuroophthalmology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"377","DOI":"10.4321\/S0365-66912007000600012","article-title":"Response to idebenone and multivitamin therapy in Leber\u2019s hereditary optic neuropathy","volume":"82","author":"Barnils","year":"2007","journal-title":"Arch. Soc. Esp. Oftalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1136\/jmedgenet-2021-108235","article-title":"DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber\u2019s hereditary optic neuropathy and optic atrophy","volume":"59","author":"Kieninger","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1093\/brain\/awac052","article-title":"DNAJC30 defect: A frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome","volume":"145","author":"Stenton","year":"2022","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e147734","DOI":"10.1172\/JCI147734","article-title":"DNAJC30 biallelic mutations extend mitochondrial complex I-deficient phenotypes to include recessive Leber\u2019s hereditary optic neuropathy","volume":"131","author":"Wiggs","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00417-021-05354-2","article-title":"Characteristics of peripapillary retinal nerve fiber layer atrophy in glaucoma, optic nerve sheath meningioma, and sphenoid wing meningioma","volume":"260","author":"Tonagel","year":"2022","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ajo.2022.04.016","article-title":"Capturing the Pattern of Transition from Carrier to Affected in Leber Hereditary Optic Neuropathy","volume":"241","author":"Carbonelli","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.preteyeres.2010.11.002","article-title":"Mitochondrial optic neuropathies\u2014Disease mechanisms and therapeutic strategies","volume":"30","author":"Griffiths","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ophtha.2004.09.033","article-title":"Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber\u2019s hereditary optic neuropathy mutations","volume":"112","author":"Savini","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0002-9394(03)00099-0","article-title":"Extensive investigation of a large Brazilian pedigree of 11778\/haplogroup J Leber hereditary optic neuropathy","volume":"136","author":"Sadun","year":"2003","journal-title":"Am. J. Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/eye.2015.3","article-title":"The Royal College of Ophthalmologists\u2019 National Ophthalmology Database study of cataract surgery: Report 1, visual outcomes and complications","volume":"29","author":"Day","year":"2015","journal-title":"Eye"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s00439-014-1421-9","article-title":"Characterization of mitochondrial haplogroups in a large population-based sample from the United States","volume":"133","author":"Mitchell","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1068\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:00:41Z","timestamp":1760119241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,5]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021068"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021068","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,5]]}}}