68 2 Hereditary Retinal and Allied Diseases
Enhanced S-cone syndrome (ESCS) is a newly identified hereditary retinal disorder with several unique functional properties [1, 2]. Ini- tially, this disorder was classified as a type of congenital stationary night blindness, but it was later found that most of the cones in these eyes were the short-wavelength-sensitive cones (S-cones) [3, 4].
The syndrome is caused by mutations in the PNR (photoreceptor-specific nuclear receptor) gene [5]. The PNR gene is a retinal orphan nuclear receptor that determines the pheno- type of the cones during embryogenesis; it is required for the differentiating middle- and
long-wavelength-sensitive cones (ML-cones) from S-cones. Mutation of the PNR gene arrests cone differentiation at a stage where most cones are still S-cones.
The clinical findings associated with ECSC include congenital night blindness, progressively decreasing visual acuity, supernormal S-cone ERGs, and characteristic fundus alterations. The inheritance is autosomal recessive [1–5].
At present, we have studied three patients with ESCS who had PNR gene mutations [6, 7].
The fundus shows cystic changes in the macula with or without annular pigmentary retinopa- thy just outside the vascular arcades (Fig. 2.27).
2.7 Enhanced S-Cone Syndrome
Fig. 2.27. Fundus photograph, fluorescein angiograms, and optical coherence tomography (OCT) from two patients with enhanced S-cone syndrome (ESCS). The cystic changes in the macula can be seen in the photograph (A) and the OCT image (C) from a 20-year-old man.The fluorescein angiogram shows the macula to be normal, with some pigmentary change just outside the vascular arcade (B) (case 2). Note the association of submacular proliferation (D) with choroidal neovascularization (E), as well as the OCT image (F) in a 10-year-old boy with ESCS (case 1). (From Nakamura et al. [7])
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2.7 Enhanced S-Cone Syndrome 69
One of our younger patients (a 10-year-old boy) had neovascular maculopathy in one eye [7].
Fluorescein angiography is essentially normal in the macular area of these patients without leakage of fluorescein dye. These findings indi- cate that the cystoid changes in the macula are not similar to that in eyes with macular edema, and the pathology is more comparable to that of retinoschisis.
Optical coherence tomography (OCT) images of an eye with ESCS show the cystic changes in the macula that are present in most patients.
The macular changes are subtle in some patients, but OCT can detect the small cysts.
Full-field ERGs reveal the diagnostic findings in this disorder (Fig. 2.28). The rod
ERGs are undetectable. The amplitudes of the a-wave and b-wave of the bright flash, mixed rod–cone ERGs may be normal or supernor- mal, with a significant delay in the implicit times; the OPs are essentially absent. The cone ERGs are larger than that of normal controls with delayed implicit times. It is interesting that the amplitude and shape of the cone ERGs recorded under light-adapted conditions are almost identical to the ERGs recorded under dark-adapted conditions (bright flash ERGs).
This finding is one of the keys to the diagnosis of ESCS. It indicates that the main component of the ERG is cone-driven. Despite such large cone ERGs, the 30 Hz flicker ERG is extremely small with delayed implicit times, suggesting
Fig. 2.28. Full-field ERGs from a normal control and three patients with ESCS. All patients with ESCS have unrecordable rod ERGs but large bright flash (mixed rod–cone) ERGs with delayed a-waves and b-waves and no OPs. The cone ERGs are large, but the 30-Hz flicker ERGs are markedly reduced. The cone ERGs were recorded under background illumina- tion to suppress the rod activity, and the same intensity was used for the bright flash ERGs. In the normal control, the cone ERG was markedly decreased in amplitude with the background illumination, and the implicit time of the b-wave was shortened. However, in all patients with ESCS, the amplitude and implicit time of the cone ERG was essentially the same as the bright flash ERG in the dark. (From Miyake [6])
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70 2 Hereditary Retinal and Allied Diseases
that the large cone ERGs reflect the function of the S-cone.
The unusual enhancement of the S-cone ERGs in these patients can be clearly demon- strated by comparing the cone ERGs recorded with stimuli that selectively stimulate S-cones and selectively stimulate the ML-cones. When the intensities of the red (ML-cones) and blue (S-cones) wavelength stimuli are balanced to produce equal-amplitude cone ERG b-waves from normal eyes, the blue stimuli elicit much larger b-waves than the red stimuli in ESCS patients (Fig. 2.29). These ERG results indicate
that the supernormal ERGs elicited by bright white stimuli are S-cone driven in ESCS patients.
As was shown in Section 1-1-3-5, the S-cone ERG has a depolarizing waveform with a large b-wave (on response), and the a-wave and d- wave (off response) are essentially absent. This is because S-cones connect only to on bipolar cells in primates. However, it is interesting that the S-cone ERGs in patients with ESCS have large a-waves and d-waves (Fig. 2.30), indicat- ing that the S-cones in eyes with ESCS may have connections not only to on bipolar cells but also to off bipolar cells [8].
Fig. 2.29. ERGs elicited by photopically balanced red and blue stimuli in a normal subject and three patients with ESCS. ERGs elicited by red stimuli show extremely small responses, whereas those elicited by blue stimuli show large responses. (From Miyake [6])
Fig. 2.30. Photopic long-flash ERGs from a normal subject and a patient with ESCS. Unlike the waveform of blue cone ERGs, a large a-wave and d-wave are recorded from a patient with ESCS. (From Miyake [6])
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References
1. Marmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG (1990) Diagnostic clinical findings of a new syndrome with night blindness, maculopathy and enhanced S cone sensitivity. Am J Ophthalmol 110:124–134
2. Hood DC, Cideciyan AV, Roman AJ, Jacobson SG (1995) Enhanced S-cone syndrome: evidence for an abnormally large number of S cones. Vis Res 35:
1473–1481
3. Fishman GA, Peachey NS (1989) Rod-cone dystro- phy associated with a rod system electroretino- gram obtained under photopic conditions.
Ophthalmology 96:913–918
4. Marmor MF (1989) Large rod-like photopic signals in a possible new form of congenital stationary night blindness. Doc Ophthalmol 71:265–269
5. Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, et al. (2000) Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24:127–131
6. Miyake Y (2003) Hereditary retinal diseases with selective abnormalities in blue cone function. Folia Ophthalmol Jpn 54:673–682
7. Nakamura M, Hotta Y, Piao CH, Kondo M, Terasaki H, Miyake Y (2002) Enhanced S-cone syndrome with subfoveal neovascularization. Am J Ophthal- mol 133:575–577
8. Kolb H, Lipets LE (1991) The anatomical basis for color vision in the vertebrate retina. In: Gouras P (ed) The perception of colour. Macmillan, London, pp 128–145
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