The subject of this investigation is an unusual, autosomal recessive visual disorder, first described in 1983 in 2 siblings,
1 with a generalized and sometimes progressive loss of cone vision, including reduced visual acuity, abnormal color vision, photophobia, and an attenuation of the cone ERG, all of which are consistent with cone dystrophy. A pathognomonic symptom, not associated with most other cone dystrophies, is that the rod b-wave is delayed and markedly reduced or absent at low flash intensities yet normal or “supernormal” in amplitude at the upper end of the scotopic region.
2–8 This electrophysiologic enhancement has led to the disorder being referred to as “cone dystrophy with supernormal rod ERG” (CDSR).
1 Although electrophysiologically appropriate (but see Robson et al.
9 ), the name of the disease seems strangely at odds with consistent reports, beginning with the initial description of the disease by Gouras et al.,
1 of night blindness (nyctalopia). Rod sensitivity losses of approximately 2 log
10 units have typically been reported.
6–8 Surprisingly, night blindness is not reported in some CDSR observers,
9–12 even in cases with reduced rod b-waves at low flash intensities. Subsequent to the initial report, the phenotype of this disorder has been the focus of several studies.
2–10,12
Our primary goal was to better characterize this disorder psychophysically under both scotopic (rod) and photopic (cone) conditions by using standard behavioral assessments of temporal acuity measured as a function of light level. These measures allow us to compare the losses for rod- and cone-mediated vision. Are they similar, or are they more pronounced for cone-mediated vision? And, in particular, is there any visual advantage to the “supernormal” rod ERG response found at higher scotopic levels? One complication is that any progressive deterioration associated with the disease is likely to affect central cone-mediated vision more than peripheral rod-mediated vision.
9,13 Yet, any deficits due to the
KCNV2 mutation (as distinct from deficits resulting from progressive deterioration) should be more clearly apparent in rod sensitivity measurements.
Because the initial slope of ERG a-waves, which is receptoral in origin, is typically normal in CDSR,
14,15 the deficit is reasonably assumed to arise after the transduction cascade, but before the inner nuclear layer.
6–8 More recently, sequence variants in the gene
KCNV2 have been found to underlie the disorder.
KCNV2 encodes a subunit of a voltage-gated potassium channel found in both rod and cone photoreceptors.
11,16–18 Thus, it has been suggested that the variants might affect the potassium current within photoreceptor inner segments.
16 Potassium channels in the inner segment are important for shaping the photoreceptor output response and setting the resting potential,
19 but precisely how defects in such channels might affect visual performance remains unclear. Our secondary goal was therefore to use psychophysical measures of cone temporal sensitivity to reveal more about the nature of the underlying molecular deficit. On the basis of previous findings we predicted that features of the temporal sensitivity functions that can be related to processes in the transduction cascade (such as activation and sensitivity regulation) would be relatively normal.
20,21
Our results suggest that the supernormal rod ERG response confers no benefit to rod-mediated visual performance in CDSR observers near threshold: rod-mediated visual performance seems as deficient as S-cone– and L-cone–mediated performance, thus the disorder is consistent with a generalized cone-rod dystrophy. In light of this, we suggest renaming the disease “cone-rod dystrophy with supernormal rod ERG,” and we shall use this descriptor. One plausible interpretation of our measurements is that the mutant voltage-gated potassium channels attenuate and distort the cone response after transduction processes in the cone outer segment.