The OPA1 gene and optic neuropathy

Department of Ophthalmology, The University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; 

　 Each genetic discovery will help to solve a small piece of the puzzle of optic nerve death

　 Keywords: autosomal dominant optic atrophy; OPA1; phenotype; optic disc cupping

The optic nerve head findings in autosomal dominant optic neuropathy (ADOA) are well described in the literature.¹ These patients demonstrate optic nerve head pallor, cupping, peripapillary atrophy, and unusual grey crescents on the temporal portion of their optic nerve heads. The report by Votruba and colleagues in this issue of the BJO (p 48) improves upon previous descriptions of the optic nerve in ADOA because it includes only patients with genetic confirmation of the diagnosis. All patients had either a mutation in the OPA1 gene or demonstrated linkage in their family to chromosome 3q28-qter. Previous reports used only clinical features to diagnose ADOA and may have included patients with optic atrophy due to other disorders.

Votruba and associates evaluated the optic nerves of 29 patients from 12 pedigrees. Pallor, either temporal or diffuse, was present in all eyes. An enlarged cup to disc ratio (>0.5) was found in 48% of eyes and deep excavation was found in 21% of eyes. Peripapillary atrophy was seen in 69% of eyes and a temporal grey crescent in 31%.

With the exception of pallor, these optic nerve changes are all also seen in glaucoma. Optic nerve cupping is the defining feature of all forms of glaucoma. Peripapillary atrophy is common in glaucoma and can increase as the glaucoma worsens.² The grey crescent on the temporal optic nerve head noted by Votruba et al was first described by Shields among African-American patients with primary open angle glaucoma (POAG).³ There are also histopathological similarities between ADOA and glaucoma. Like glaucoma, ADOA is characterised by retinal ganglion cell degeneration with atrophy of the optic nerve.⁴ Because ADOA eyes typically have normal intraocular pressures (IOP) they would probably not be confused with high pressure POAG. In fact, a study of POAG patients found no increase in prevalence of OPA1 gene sequence variations when compared to normal control subjects.⁵ Patients with ADOA might, however, be mistakenly diagnosed with normal tension glaucoma (NTG).

Perhaps as important as the impact of these genetic studies on ADOA is the potential impact on understanding glaucoma

Fournier and colleagues described nine patients who had been originally diagnosed with NTG, but were eventually found to have ADOA.¹ A large cup to disc ratio was found in at least one eye of eight (89%) of these patients. Patients also frequently had peripapillary atrophy and all nine had grey crescents.¹ While Aung and colleagues found no increase in OPA1 mutations among POAG patients compared with control individuals,⁵ they found OPA1 intervening sequence polymorphisms in 20% of NTG patients compared with only 3.7% of normal control subjects.⁶

Are there large numbers of patients with ADOA who have been misdiagnosed as having NTG? Probably not. Besides the similarities between ADOA and NTG, Votruba and associates catalogue the features of ADOA that should help to differentiate these patients from those with NTG. Unlike NTG, their ADOA patients had a very early age of onset (the mean onset of symptoms was at age 7 years and was never later than age 25 years). Their patients also demonstrated predominantly central visual field loss with relative peripheral visual field sparing. While paracentral visual field loss is not uncommon in NTG, true central loss is unusual. These patients also demonstrated more visual acuity and visual field loss than would be expected from glaucoma with the same degree of optic nerve head cupping. While there can be a family history in NTG it is rare to find autosomal dominant pedigrees with multiple affected individuals. One might find pedigrees with a mixture of POAG and NTG patients.⁷ However, a pure NTG pedigree, like the one Bennett and colleagues described,⁸ is very rare. Patients with ADOA always demonstrate pallor extending beyond the area of cupping. In studies comparing glaucomatous optic neuropathy with other optic neuropathies the presence of pallor was the single most important differentiating feature, being 94% specific for non-glaucomatous optic neuropathies.⁹

Autosomal dominant optic atrophy is an important, but rare, disease. Perhaps as important as the impact of these genetic studies on ADOA is the potential impact on understanding a disease that more commonly leads to retinal ganglion cell death, optic nerve head cupping, and loss of visual function—glaucoma.

Glaucoma has been a difficult disease to study molecularly. Linkage studies on POAG and NTG families are hampered by the late onsets of these diseases. Even when there is a strong family history, the parents of the affected proband and some siblings are probably deceased at the time of family study. The children may be too young to be affected. These problems make the acquisition of the large pedigrees needed for linkage studies difficult. To circumvent this problem researchers have used early onset diseases as models for similar late onset diseases. For POAG the study of autosomal dominant juvenile onset open angle glaucoma led to linkage of the disease to chromosome 1q¹⁰ and ultimately to the discovery of the gene myocilin.¹¹ Myocilin, besides causing most cases of autosomal dominant juvenile onset open angle glaucoma, was also found to cause about 3–5% of the more common adult onset POAG.^11,12 Like myocilin, it may be that some mutations in OPA1 cause early onset severe disease while other mutations cause late onset mild disease that is difficult to distinguish from NTG.^6,12

With further research we may find that OPA1 and genes that interact with OPA1 are involved in a variety of optic neuropathies. Each of these genetic discoveries will help to solve a small piece of the puzzle of optic nerve death.

REFERENCES

1. Fournier AV, Damji KF, Epstein DL, et al. Disc excavation in dominant optic atrophy, differentiation from normal tension glaucoma. Ophthalmology 2001;108:1595–602.

2. Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology 1998;105:1541–5.

3. Shields MB. Gray crescents in the optic nerve head. Am J Ophthalmol 1980;89:238–44.

4. Johnson PB, Gaster RN, Smith VC, et al. A clinicopathologic study of autosomal dominant optic atrophy. Am J Ophthalmol 1979;88:868–75.

5. Aung T, Ocaka L, Ebenezer ND, et al. Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma. Hum Genet 2002;110:513–4.

6. Aung T, Ocaka L, Ebenezer ND, et al. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum Genet 2002;110:52–6.

7. Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open angle glaucoma caused by mutations in optineurin. Science 2002;295:1077–9.

8. Bennett SR, Alward WLM, Folberg R. An autosomal dominant form of low-tension glaucoma. Am J Ophthalmol 1989;108:238–44.

9. Trobe JD, Glaser JS, Cassady J, et al. Nonglaucomatous excavation of the optic disc. Arch Ophthalmol 1980;98:1046–50.

10. Sheffield VC, Stone EM, Alward WLM. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet 1993;4:47–50.

11. Stone EM, Fingert JH, Alward WLM. Identification of a gene that causes primary open angle glaucoma. Science 1997;275:668–70.

12. Alward WLM, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene. N Engl J Med 1998;338:1022–7.

Related articles in BJO:

Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy

M Votruba, D Thiselton, and S S Bhattacharya
BJO 2003 87: 48-53.