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Brief Communication

A novel mutation in a case of dominant optic atrophy?

Ramkumar, Hema L; Savino, Peter J

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Indian Journal of Ophthalmology: October 2014 - Volume 62 - Issue 10 - p 1034-1036
doi: 10.4103/0301-4738.146043
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Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, and its incidence is 1 in 50,000 persons in the United States and 1 in 10,000 persons in Denmark. Vision loss in DOA is related to retinal ganglion cell loss from mitochondrial dysfunction. DOA is a heterogeneous disease that has been mapped to chromosome 3q28, and OPA1 has been identified as the responsible gene. OPA1 codes for a dynamin-related GTPase protein targeted to the mitochondrial inner membrane, which regulates the fusion, oxidative phosphorylation, and cell death. Of the 204 different reported OPA1 mutations in DOA, 82 are truncative N-terminal mutations; 55 are missense mutations; and 55 are splice variants.[123]

Case Report

A 39-year-old healthy woman complained of difficulty focusing. She stated things have not been clear at distance or near and colors, were not vivid. This has slowly been getting worse over the last 4 years. She denied any other ocular symptoms. She went to multiple optometrists and ophthalmologists who stated that nothing was wrong with her eyes except for a slightly abnormal visual field. Her vision could not be corrected with glasses.

Her past ocular history is completely unremarkable. She used artificial tears as needed for comfort. She denied any known family history of decreased vision or glaucoma. Her past medical history is only notable for migraines, carpal tunnel syndrome, cholecystectomy, nephrolithiasis, rhinoplasty, and breast augmentation. She uses oral pregabalin and meclizine and has no medication allergies. She is a nonsmoker and nondrinker. Review of systems is only positive for her typical headaches.

Prior to her presentation, a magnetic resonance imaging of her brain and orbits were done with and without contrast, and the interpretation was normal. A neurology evaluation demonstrated a normal electroencephalogram, electromyogram, and nerve conduction velocities. A heavy metal screen, B12, B6, folate, erythrocyte sedimentation rate, rapid plasma reagin, and Lyme titer were normal.

Her best-corrected visual acuities vision were 20/80 oculus dexter (OD) and 20/70 oculus sinister (OS). Her external examination was unremarkable. Color vision in each eye was 1/8 Ishihara plates. Her applanation pressures were 14 mm Hg Oculus uterque (OU). Confrontation visual fields were normal in both eyes. The pupils were sluggish bilaterally with no relative afferent pupillary defect. Ocular motility was full. Slit lamp examination was unremarkable. The macula, retinal vessels and periphery were normal. The optic discs were pale bilaterally with pallor out of proportion to cupping. There was a temporal crescent and peripapillary atrophy in the right eye [Fig. 1]. Automated perimetry demonstrated severe general depression bilaterally with a possible inferior arcuate defect in the left eye [Fig. 2].

Figure 1
Figure 1:
Optic nerve photos demonstrate pallor out of proportion to cupping OU and a temporal crescent in the right eye
Figure 2
Figure 2:
Humphrey visual fields demonstrates generalized depression and an inferior arcuate defect in the left eye

The ERG was normal; the visual evoked potential (VEP) was unrecordable in both eyes. Optic nerve optical coherence tomography (OCT) demonstrated symmetric severe retinal nerve fiber layer (RNFL) thinning (average 59 μm OD and 58 μm OS), most superiorly and inferiorly with temporal sparing [Fig. 3]. OCT of the macula revealed a preserved photoreceptor inner segment/outer segment junction and a normal fovea. OPA1 gene sequencing at Athena diagnostics® (Worcester, MA, USA) revealed DNA variant transition T >C at nucleotide position IVS12+10. There is currently no published research on this gene variant.

Figure 3
Figure 3:
Optical coherence tomography of the retinal nerve fiber layer demonstrated severe thinning in both eyes


The OPA1 mutation that this patient has, T >C at nucleotide position IVS12+10 has not previously been reported in clinical cases of DOA. While this mutation is in the noncoding region of the OPA1 gene, the patient has a clinical phenotype of DOA, making this possibly clinically significant.

Dominant optic atrophy can insidiously present as mild to moderate vision loss, typically in school-aged children ages 4-6 years of age, with a potential for progressive vision loss later in life (30-50%). About 40% of patients have a visual acuity of 20/60 or better; 45% are between 20/60 and 20/200; and 15% are below 20/200.[45] Visual fields commonly demonstrate central and cecocentral visual field defects, but altitudinal defects have also been reported.[6] Generalized, blue-yellow, and red-green dyschromatopsias have been described. Optic nerve pallor has been described to affect only the temporal nerve (52%) and the entire nerve (48%), as seen in this patient.[5] Other clinical findings reported in DOA patients include peripapillary atrophy (69%), a temporal grey crescent (31%), and an enlarged cup to disc ratio, >0.5 (48%).[3] In addition, up to 20% of OPA1-mutated patients develop “OPA1 plus” phenotype with deafness, progressive external ophthalmoplegia and myopathy, starting from the third decade of life onward.[1]

This patient had a subacute decrease in visual acuity, diffusely depressed visual fields, severe diffuse bilateral RNFL loss, symmetric dyschromatopsia, peripapillary atrophy with a temporal crescent, enlarged cup to disc ratio, and a VEP that was nonrecordable. Sequencing of the OPA1 gene revealed a novel mutation that describes a classic phenotype of DOA.


The authors than Dr. Kang Zhang for his analysis of the genetic mutation.

1. Amati-Bonneau P, Milea D, Bonneau D, Chevrollier A, Ferré M, Guillet V, et al OPA1-associated disorders: Phenotypes and pathophysiology Int J Biochem Cell Biol. 2009;41:1855–65
2. Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel CP. OPA1 (Kjer type) dominant optic atrophy: A novel mitochondrial disease Mol Genet Metab. 2002;75:97–107
3. Votruba M. Molecular genetic basis of primary inherited optic neuropathies Eye (Lond). 2004;18:1126–32
4. Eliott D, Traboulsi EI, Maumenee IH. Visual prognosis in autosomal dominant optic atrophy (Kjer type) Am J Ophthalmol. 1993;115:360–7
5. Kline LB, Glaser JS. Dominant optic atrophy. The clinical profile Arch Ophthalmol. 1979;97:1680–6
6. Brown J Jr, Fingert JH, Taylor CM, Lake M, Sheffield VC, Stone EM. Clinical and genetic analysis of a family affected with dominant optic atrophy (OPA1) Arch Ophthalmol. 1997;115:95–9

Source of Support: Nil.

Conflict of Interest: None declared.


Dominant optic atrophy (group together); OPA1; IVS12+10T >C

© 2014 Indian Journal of Ophthalmology | Published by Wolters Kluwer – Medknow