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Atypical Leber Hereditary Optic Neuropathy: 18 Year Interval Between Eyes

Ohden, Kaitlyn L. BS; Tang, Peter H. MD, PhD; Lilley, Chrystia C. MD; Lee, Michael S. MD

Journal of Neuro-Ophthalmology: September 2016 - Volume 36 - Issue 3 - p 304
doi: 10.1097/WNO.0000000000000346
Clinical Observation

Abstract: A 5-year-old boy developed profound loss of vision in his right eye and was found to have a 11778 mitochondrial point mutation consistent with Leber hereditary optic neuropathy (LHON). He maintained 20/20 vision in the left eye for 18 years until age 23, when he experienced loss of vision in that eye. This 18 year interval between eye involvement in LHON is the longest reported to date and reinforces the variability in presentation and progression seen in this disease.

Department of Ophthalmology and Visual Neurosciences (KLO, PHT, CCL, MSL), University of Minnesota, Minneapolis, Minnesota.

Address correspondence to Michael S. Lee, MD, Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware Street SE, MMC 493, Minneapolis, MN 55455; E-mail:

Unrestricted grant from Research to Prevent Blindness, New York, NY.

The authors report no conflicts of interest.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease caused by a defect involving Complex I of the respiratory chain (1) that results in impaired mitochondrial adenosine triphosphate generation and increased accumulation of toxic reactive oxygen species. Subsequently, this affects highly energy-dependent tissues such as the optic nerve (2,3). Most patients eventually experience progressive, painless vision loss affecting both eyes with marked deficits in color vision and contrast sensitivity (4). The disease most commonly affects males between the second and fourth decades; however, childhood and elderly presentations can occur (5–8). In nearly all cases, vision loss develops in the fellow eye within weeks to months of initial presentation (1).

We report the case of a patient with LHON who presented with unilateral vision loss, but the fellow eye did not become involved until 18 years later. To our knowledge, this is the longest reported interval in fellow eye involvement in a documented case of LHON to date.

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A 5-year-old boy with previously documented visual acuities of 20/20 in both eyes presented with the chief concern of decreased vision in the right eye discovered at a screening. His past medical and ocular histories were unremarkable. He denied trauma and took no medications. Pertinent negatives include no pain, iris nodules, café-au-lait spots, or neurologic symptoms. Family history revealed no consanguinity, and a maternal male second cousin with LHON who lost vision in both eyes over the course of 3 weeks at the age of 30. The patient's mother, father, and sister were healthy and had no visual problems. There were 2 maternal male first cousins and 4 maternal female cousins, all in good health.

The patient's vision was counting fingers, right eye and 20/20, left eye. His examination revealed a right relative afferent pupillary defect (RAPD) and an 18-prism diopter right exotropia and full ductions. He identified none and all the Ishihara color plates with the right and left eyes, respectively. Slit-lamp examination was unremarkable. Fundus examination showed mild optic atrophy in the right eye and a hyperemic optic nerve with microangiopathy in the left eye (Fig. 1). Kinetic (Goldmann) visual fields revealed central scotoma, right eye and normal results, left eye. Orbital magnetic resonance imaging (MRI) showed atrophy of the right optic nerve compared with the left. Genetic testing revealed the 11778 point mitochondrial mutation associated with LHON.

FIG. 1

FIG. 1

The patient underwent routine, annual examinations with documented 20/20 acuity in the left eye for 18 years until he experienced decreased vision of the left eye over the course of 5 months. Examination at age 23 showed acuities of 20/400 in both eyes. He identified 5/11 Ishihara plates, right eye and 1/11, left eye. No RAPD was detected. Slit-lamp examination was unremarkable. Examination of the fundus revealed moderate optic atrophy in the right eye and prominence of the nerve fiber layer with subtle peripapillary yellow flecks in the left eye (Fig. 1). Automated visual fields showed central scotomas in both eyes (Fig. 2). Optical coherence tomography showed significant thinning of the retinal nerve fiber layers (RNFL) in superior, temporal, and inferior sectors of the right eye and temporal sector of the left eye. The inferior, nasal, and superior RNFL in the left eye was normal. Orbital MRI with gadolinium was normal. Repeat genetic testing confirmed the 11778 point mutation.

FIG. 2

FIG. 2

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We evaluated a patient with 11778 mutation-associated LHON with an 18 year interval in vision loss in the fellow eye. There are few reports of unilateral or delayed presentation of LHON. Two articles document unilateral vision loss with subsequent visual recovery in the affected eye (9,10). Several reports describe a delay in fellow eye involvement for 3–8 years (11,12). Other reports document cases of unilateral involvement with a follow-up period of 18 months (13), 10 years (14), and 16 years (15).

The cause of such an extended delay observed in our patient is not well understood. Heteroplasmy can occur with mitochondrial DNA, and higher cellular levels of mutant mtDNA have been correlated with increased expression in LHON (14). Our patient may have had significantly greater mutant mtDNA in his right optic nerve compared with his left optic nerve, which led to vision loss earlier in his right eye. Alternatively, cells may be able to increase their mitochondrial expression to compensate for cellular respiratory chain defects. Some studies suggest carriers of LHON express higher levels of mtDNA compared with those expressing the disease phenotype (13). Conceivably, the left optic nerve was able to upregulate its mitochondria and delay visual loss. Finally, it has been proposed that visual loss in LHON may be triggered by various environmental triggers such as anemia (15), trauma (10), vitamin B12 deficiency (16), raised intraocular pressure (17), antiretroviral therapy (18), toxin exposure (19), and excessive smoking and alcohol use (20,21). We did not find a difference in these triggers between the 2 ages of presentation in our case. The only significant difference was that our patient consumed occasional alcohol as an adult; however, this exposure is an implausible cause of delay in fellow eye involvement.

Several unique aspects of LHON are highlighted by our patient. First, the vision of the fellow eye may remain unaffected for months to years after initial presentation. Next, involvement of the fellow eye may occur at any time after initial presentation—even after decades of stable unilateral vision loss. Finally, with advancements in therapeutics for LHON, it is important to note that any delay in involvement of the fellow eye may represent the natural disease course, rather than an effect of therapy.


Category 1: a. Conception and design: M. S. Lee and C. C. Lilley; b. Acquisition of data: K. L. Ohden, P. H. Tang, and C. C. Lilley; c. Analysis and interpretation of data: K. L. Ohden, P. H. Tang, C. C. Lilley, and M. S. Lee. Category 2: a. Drafting the article: C. C. Lilley and K. L. Ohden; b. Revising it for intellectual content: P. H. Tang and M. S. Lee. Category 3: a. Final approval of the completed article: M. S. Lee, C. C. Lilley, P. H. Tang, and K. L. Ohden.

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