Bradyopsia

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Bradyopsia, also known as "prolonged electro-retinal response suppression" is a visual condition in which the photoreceptor cells in the retina have a slower-than-normal recovery of light sensitivity after exposure to light. It is inherited as an autosomal recessive disease. It is uncommon with only a few dozen patients described in the medical literature as of 2025.

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Because of the subtle nature of the symptoms, because many ophthalmologists and optometrists are unaware of it, and because non-standard electroretinogram (ERG) testing is needed to confirm the diagnosis, many cases are likely to be undiagnosed.

Symptoms and signs

Patients with bradyopsia can have nearly normal visual acuity (20/25 to 20/40) when tested with stationary, high-contrast standard visual acuity charts such as the Snellen chart with a dimly lit background. [1] However, the acuity may vary from visit to visit and can be as poor 20/200 when tested with a bright background. The visual acuity improves with a pinhole occluder even after any refractive error is corrected. [1] [2] Patients have difficulty seeing in bright light (photophobia) and especially seeing low-contrast objects moving against a bright background. They have trouble playing ball sports because they can have trouble seeing a moving ball. It can take them 5-10 times longer than normal to visually adapt when going from a bright environment to a dark environment (such driving on a sunny day into a tunnel or seeing objects in the shadow of a bridge).

Color vision measured with the Farnsworth D-15 test or the Farnsworth-Munsell 100 hue test is normal. Beyond 30 seconds after a bright light bleaches the retina, the subsequent rate of dark adaptation is normal. The ability to discern flickering or modulating light can be normal or even better than normal for dim lights. [3] However, when tested with bright light, patients with bradyopsia cannot discern flickering faster than about 11 Hz (flashes per second) compared to about 21 Hz for normal individuals tested in under the same conditions. [3]

The fundi are normal. The neural layers of the retina are normal as determined by optical coherence tomography (OCT). [1] [4]

Electroretinogram (ERG): In a dark-adapted eye, the first rod-plus-cone ERG response to a single flash of bright light is normal, but subsequent responses are absent or subnormal if the interval between flashes is less than about 20-30 seconds. [1] [5] [6] [7] [8] If one allows 2 minutes between stimuli, the responses are normal. Cone responses to 30-Hz flickering light are absent.

The symptoms and ERG abnormalities do not worsen with age. [1]

Because of the unusual symptoms, the variation in visual acuity measured from visit to visit, and the absence of anatomic abnormalities visible by fundus examination or OCT, some patients are erroneously diagnosed as having psychological problems causing their visual symptoms.

Genetics and pathophysiology

The disease is caused by recessive mutations in either of two genes: RGS9 (regulator of G protein signaling 9) or RGS9BP (regulator of G protein signaling 9 binding protein, also known as R9AP). Mouse models with defects in the corresponding mouse genes provided the basis for our understanding of the function of RGS9 and R9AP. [9] [10] [11] RGS9 normally speeds up the deactivation of the G-proteins in rod and cone photoreceptors (i.e., rod transducin and cone transducin). [9] RGS9BP anchors RGS9 to the disk membranes of the photoreceptor outer segments, thereby facilitating the interaction between RGS9 and its target G proteins. [12] It may also help to transport RGS9 to the photoreceptor outer segments. [11] The pathogenic mutations identified in the RGS9 and RGS9BP genes create null alleles encoding no functional protein.

In the normal phototransduction cascade, rod and cone transducins (G-proteins) are shut off in less than a second after activation by rhodopsin or a cone opsin. Without functional RGS9, or without RGS9 being anchored to outer segment disk membranes, it takes 7-10 times longer to deactivate the GTP-bound forms of rod transducin and cone transducin. [9] [11] Since some patients with symptoms and signs of bradyopsia have no identified mutations in RGS9 or RGS9BP, [7] it is possible that defects in genes other than RGS9 or RGS9BP can also cause this disease. No histopathologic evaluations of patients with the disease have been reported. Mice with absent RGS9 have normal retinal morphology up to at least 8 months of age. [9]

History

The disease was first reported in 1991 in Dutch patients. [5] Some earlier cases may have been described but the clinical information in the associated publications is not sufficient to be conclusive. Genetic testing was not possible prior to the discovery in 2004 of RGS9 and RGS9BP mutations. [6] A 1973 paper by van Lith presents a possible case and cites prior reports of possible cases. [13]

Prevalence

The disease is rare with about 25 patients being reported in the medical literature as of May, 2025. Patients from the Netherlands, [1] [5] [6] Guatemala, [6] Singapore, [8] Pakistan, [7] Afghanistan, [7] Great Britain, [3] [7] Saudi Arabia, [2] and Japan [14] have been described. As mentioned above, many patients with the disease are likely undiagnosed because of the unusual symptoms and the necessary diagnostic tests are not available to most ophthalmologists.

Therapy

There is no known therapy to reverse or correct the condition. Some patients report that their symptoms are partially ameliorated by wearing sunglasses in bright environments. [1] [6]

References

  1. 1 2 3 4 5 6 7 Hartong, Dyonne T.; Pott, Jan-Willem R.; Kooijman, Aart C. (2007). "Six patients with bradyopsia (slow vision): clinical features and course of the disease". Ophthalmology. 114 (12): 2323–2331. doi:10.1016/j.ophtha.2007.04.057. ISSN   1549-4713. PMID   17826834.
  2. 1 2 Khan, Arif O. (December 2017). "The clinical presentation of bradyopsia in children" . Journal of American Association for Pediatric Ophthalmology and Strabismus. 21 (6): 507–509.e1. doi:10.1016/j.jaapos.2017.07.212. PMID   29107794.
  3. 1 2 3 Stockman, A; Smithson, HE; Webster, AR; Holder, GE; Rana, NA; Ripamonti, C; Sharpe, LT (2008). "The loss of PDE6 deactivating enzyme, RGS9, results in precocious light adaptation at low light levels". J. Vision. 8 (1): 10.1–10. doi: 10.1167/8.1.10 . PMID   18318613.
  4. Aboshiha, J; Dubis, AM; Carroll, J; Hardcastle, AJ; Michaelides, M (2015). "The cone dysfunction syndromes". Br J Ophthalmol. 100 (1): 115–121. doi:10.1136/bjophthalmol-2014-306505. PMC   4717370 . PMID   25770143.
  5. 1 2 3 Kooijman, KM; Houtman, A; Damhof, A; van Essen, AJ (1991). "Prolonged electro-retinal response suppression (PERRS) in patients with stationary subnormal visual acuity and photophobia". Documenta Ophthalmologica. 78 (3–4): 245–254. doi:10.1007/BF00165687. PMID   1790747.
  6. 1 2 3 4 5 Nishiguchi, KM; Sandberg, MA; Kooijman, AC; Martemyanov, KA; Pott, JWR; Hagstrom, SA; Arshavsky, VY; Berson, EL; Dryja, TP (2004). "Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation". Nature. 427 (6969): 75–78. Bibcode:2004Natur.427...75N. doi:10.1038/nature02170. PMID   14702087.
  7. 1 2 3 4 5 Michaelides, M; Li, Z; Rana, NA; Richardson, EC; Hykin, PG; Moore, AT; Holder, GE; Webster, AR (2010). "Novel mutations and electrophysiologic findings in RGS9- and R9AP-associated retinal dysfunction (bradyopsia)". Ophthalmology. 117 (1): 120–127. doi:10.1016/j.ophtha.2009.06.011. PMID   19818506.
  8. 1 2 Cheng, JYC; Luu, CD; Yong, VHK; Mathur, R; Aung, T; Vithana, EN (2007). "Bradyopsia in an Asian man". Arch Ophthalmol. 125 (8): 1138–1140. doi:10.1001/archopht.125.8.1138. PMID   17698770.
  9. 1 2 3 4 Chen, C-K; Burns, ME; He, W; Wensel, TG; Baylor, DA; Simon, MI (2000). "Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1". Nature. 403 (6769): 447–560. Bibcode:2000Natur.403..557C. doi:10.1038/35000601. PMID   10676965.
  10. Lyubarsky, AL; Naarendorp, F; Zhang, X; Wensel, T; Simon, MI; Pugh, EN Jr. (2001). "RGS9-1 is required for normal inactivation of mouse cone phototransduction". Mol. Vision. 7: 71–78. PMID   11262419.
  11. 1 2 3 Martemyanov, KA; Lishko, PV; Calero, N; Keresztes, G; Sokolov, M; Strissel, KJ; Leskov, IB; Hopp, JA; Kolesnikov, AV; Chen, C-K; Lem, J; Heller, S; Burns, ME; Arshavsky, VY (2003). "The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo". J. Neurosci. 23 (32): 10175–10181. doi:10.1523/JNEUROSCI.23-32-10175.2003. PMC   6741003 . PMID   14614075.
  12. Hu, G; Wensel, TG (2002). "R9AP, a membrane anchor for the photoreceptor GTPase accelerating protein, RGS9-1". Proc Natl Acad Sci USA. 99 (15): 9755–9760. Bibcode:2002PNAS...99.9755H. doi: 10.1073/pnas.152094799 . PMC   125004 . PMID   12119397.
  13. van Lith, GHM (1973). "General Cone Dysfunction without Achromatopsia". XTH I.S.C.E.R.G. Symposium. Documenta Ophthalmologica Proceedings Series. Vol. 2. pp. 175–180. doi:10.1007/978-94-010-2697-0_17. ISBN   978-90-6193-142-3.
  14. Oishi, Maho; Oishi, Akio; Gotoh, Norimoto; Ogino, Ken; Higasa, Koichiro; Iida, Kei; Makiyama, Yukiko; Morooka, Satoshi; Matsuda, Fumihiko; Yoshimura, Nagahisa (2016). "Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies". Molecular Vision. 22: 150–160. ISSN   1090-0535. PMC   4764614 . PMID   26957898.