Raised Intraocular Pressure as a Potential Risk Factor for Visual Loss in Leber Hereditary Optic Neuropathy Anais Thouin 1,2 , Philip G. Griffiths 3 , Gavin Hudson 4 , Patrick F. Chinnery 1,4 , Patrick Yu-Wai-Man 3,4 * 1 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom, 2 Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom, 3 Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom, 4 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom Abstract Leber Hereditary Optic Neuropathy (LHON) is an important cause of inherited mitochondrial blindness among young adults. The majority of patients carry one of three mitochondrial DNA (mtDNA) point mutations: m.3460G.A, m.11778G.A and m.14484T.C, all of which affect critical complex I subunits of the mitochondrial respiratory chain. LHON is characterised by marked incomplete penetrance, clearly implying that the mtDNA mutation is insufficient on its own to trigger retinal ganglion cell dysfunction and visual loss. In this case series of three affected patients harbouring the m.11778G.A mutation, we provide evidence suggesting that raised intraocular pressure could be a risk factor triggering visual loss in at- risk LHON carriers. Citation: Thouin A, Griffiths PG, Hudson G, Chinnery PF, Yu-Wai-Man P (2013) Raised Intraocular Pressure as a Potential Risk Factor for Visual Loss in Leber Hereditary Optic Neuropathy. PLoS ONE 8(5): e63446. doi:10.1371/journal.pone.0063446 Editor: Alessandro Achilli, University of Perugia, Italy Received December 31, 2012; Accepted April 3, 2013; Published May 7, 2013 Copyright: ß 2013 Thouin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Medical Research Council (MRC, UK) and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Patrick.Yu-Wai-Man@ncl.ac.uk Introduction Leber Hereditary Optic Neuropathy (LHON) is a primary mitochondrial DNA (mtDNA) disorder that classically presents in the second and third decades of life with bilateral, subacute, severe visual loss [1,2]. The visual prognosis is poor and the majority of patients remain significantly visually impaired. About 90% of patients will harbour one of three common causative mtDNA mutations: m.3460G.A, m.11778G.A, and m.14484T.C [3]. An intriguing, and as yet unexplained, aspect of LHON is the marked incomplete penetrance observed in this mitochondrial disorder, with only ,50% of male carriers and ,10% of female carriers experiencing visual loss during their lifetime [1,2]. The mtDNA mutation is clearly insufficient on its own and a number of secondary nuclear genetic factors and environmental triggers have been implicated to account for this disparity. In a recent large study of 125 independent LHON families, smoking was strongly associated with an increased risk of visual loss and a convincing biological trend was observed when comparing light and heavy smokers [4]. There are also a number of published cases reports where disease conversion seemed to be temporally related to insults such as head trauma [5–7], occupational inhalation of chemical toxins [8], or secondary to iatrogenic exposure to antituberculous or antiretroviral drugs [9–11]. Although these causal links are difficult to prove unequivocally, the identification of modifiable environmental triggers is especially important given the current paucity of effective treatment strategies in LHON [1,2]. In this case series of three affected patients carrying the m.11778G.A mtDNA mutation, we provide evidence suggesting that raised intraocular pressure could be an exacerbating risk factor precipitating retinal ganglion cell (RGC) dysfunction and the onset of visual loss in susceptible LHON carriers. Report of Cases Case 1 A 63-year-old white man presented with sudden-onset, painless visual loss in his right eye down to 6/60 (Table 1). Except for a longstanding, divergent, amblyopic left eye (6/18), there was no other significant past medical history. There was no family history of early-onset visual loss. He was a long-term smoker with a daily consumption of 10–15 cigars. At initial presentation, the intraocular pressure was found to be markedly elevated in the right eye (43 mmHg), but within the normal range in the left eye (14 mmHg). The cornea was clear and gonioscopy showed wide- open drainage angles. There was a right relative afferent pupillary defect and a marked reduction in colour vision in the right eye. Asymmetric cupping of the right optic disc was noted on fundus examination (Figure 1). Fluorescein angiography was normal with no evidence of optic disc leakage or vasculitis. The patient was started on ocular anti-hypertensive treatment, but despite adequate intraocular pressure control being achieved, visual acuity in the right eye deteriorated further to count fingers over a one- month period. The patient was subsequently referred to the neuro- ophthalmology service and he was extensively investigated. Magnetic resonance imaging (MRI) of the brain and orbit was normal with no enhancement of the anterior visual pathways noted with gadolinium contrast. Rather surprisingly, molecular genetic testing eventually revealed the presence of a homoplasmic m.11778G.A LHON mutation as the cause of this patient’s PLOS ONE | www.plosone.org 1 May 2013 | Volume 8 | Issue 5 | e63446