Wait, are you white or Asian?

by Juan Ding, OD, PhD

No, the real character in this story does not look like this. Her eyes look identical from the outside.

I want to tell another story of pigment… in the back of the eye. A bit like the previous post, but no one has poor vision this time and it’s all happy… at least till now.

You know you can tell if a person is white or black or Asian or Hispanic usually by their appearance, right? A large part is the difference in skin color- no brainer here. But do you know that eye doctors can tell the racial differences by the color of the retina? Like the skin and iris (blue or brown eyed), the retina, the tissue in the back of the eye, is also lined by pigment cells that show different amounts of pigment. Similar to skin color, white people typically have less pigment in their retina, which shows up more pinkish in color compared to those of darker colors, eg, Asians. However, most of the time, the two eyes will be identical in coloration. So this lady’s eyes are really unique. 

I first met her a few years ago, a healthy middle aged white female interested in new glasses and contact lenses. Her vision was normal and eyes healthy in every aspect, except when I looked at her retina with a lighted magnifier, I felt very confused. Her right and left retinas looked like they belonged to two different people- the right one being very light, just like from a typical white person, but her left retina looked much darker, as if she were Asian (Figure 1). I checked everywhere and both retinas looked completely healthy. There was absolutely nothing wrong with the retinas, just with different shades of pigment. This almost felt like a person had two arms or legs of different skin tones and that is not commonly seen unless a tanning session was done only on one side of the body. 

Figure 1. Color photos of right and left eyes of the same person with a marked different hue. Copy right: Boston Eye Blink

Though everything looked normal, I did refer her to a retinal specialist. 

She came back next year with a diagnosis of ocular melanocytoma in the left eye. 

This is a condition that usually looks like this (Figure 2a) or this (Figure 2b). It’s typically a cluster of pigment cells forming a defined area of pigmentation that can be easily identified.

Figure 2. Examples of ocular melanocytoma. A) optic nerve melanocytoma. Copy right: New York Eye Cancer Center. B) Iris melatocytoma. Copy right: Ophthalmology and Visual Sciences, University of Iowa. In both images, an arrow points to the melanocytoma.

In my patient’s case, her pigment cells are diffused and dispersed, with almost no visible clumps, that it looks natural, smooth and just belongs. There is also no other pigment difference between the two eyes, including on eyelids, conjunctiva and iris. The secret only lies behind the eyes, unrevealed by a dilated retinal exam.

I think it’s marvelous that a pigment disorder turns out just right for her. It’s as beautiful as those people who have different eye colors, iris heterochromia (Figure 3), but it’s well hidden and more mysterious.

Figure 3. Iris heterochromia, where two eyes can be of different colors. Copy right: American Academy of Ophthalmology

Cancer chemo drug to treat retinitis pigmentosa?

Recently US FDA granted orphan drug designation of ADX-2191(methotrexate for intravitreal injection) by Aldeyra Therapeutics, Inc for the treatment of retinitis pigmentosa (RP) [1]. RP is a serious genetic condition that leads to retinal cell death and vision loss. It is a rare condition, which is defined as affecting fewer than 200,000 people in the United States. It has no cure, and limited treatment options, and is one of those eye conditions that doctors cannot do much about. So it is great to hear that now a drug is being developed to improve RP. 

What is also surprising is that methotrexate is not a new drug. In fact, it has been around for quite some time now, and primarily used to treat cancer of the blood, bone, lung, breast, head, and neck. It can also treat rheumatoid arthritis and psoriasis. It works by inhibiting cancer cells and certain immune cells to replicate, thereby can be used to treat cancer and certain autoimmune conditions. Now that it is injected into the eyeball for RP, does it mean it inhibits cells to grow and divide in the retina? In RP, retinal cells die, so it does not appear to be helpful to have a drug that further reduces cell duplication. Plus, the retinal cells are already terminally differentiated and do not divide anyways. So how does methotrexate work to help RP?

I am very curious now about this and looked into literature. It turns out it is a brand new mechanism of action of this old drug that renders it effective against RP. Scientists from University of Pittsburgh, University of Cincinnati and National Institute of Health discovered that methotrexate can reduce the misfolding of a protein called rhodopsin that is frequently mutated in RP, without affecting the healthy version of this protein. Rhodopsin is THE molecule to mediate vision in the retina. When it is mutated such as in RP, it folds in the wrong shape, leading to loss of function and death of retinal cells. Methotrexate could help the body’s natural garbage disposal system to work better to clear these wrongly formed proteins, and improved vision in a mouse model of RP [2].

Note this study using mice was published in 2020, and the FDA designation of orphan drug in 2021. The company moved fast!

Of course, orphan drug designation does not mean it’s already approved or will be approved by the FDA eventually for the treatment of RP. Phase 1 clinical trial was being planned and investigated at Mass Eye and Ear/ Harvard Medical School [3]. Hopefully data in humans will give some hope to those with this condition.


[1] Aldeyra Therapeutics receives Orphan Drug designation from the U.S. Food and Drug Administration for ADX-2191 to treat retinitis pigmentosa. News release. Aldeyra Therapeutics, Inc. Accessed August 4, 2021. https://www.businesswire.com/news/home/20210804005122/en/Aldeyra-Therapeutics-Receives-Orphan-Drug-Designation-from-the-U.S.-Food-and-Drug-Administration-for-ADX-2191-to-Treat-Retinitis-Pigmentosa

[2] Liu X, Feng B, Vats A, Tang H, Seibel W, Swaroop M, Tawa G, Zheng W, Byrne L, Schurdak M, Chen Y. Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa. FASEB J. 2020 Aug;34(8):10146-10167. doi: 10.1096/fj.202000282R. Epub 2020 Jun 14. PMID: 32536017; PMCID: PMC7688577.

[3] https://adisinsight.springer.com/drugs/800053948