CONE DYSTROPHY WITH SUPERNORMAL ROD RESPONSES
CONE DYSTROPHY WITH NIGHT BLINDNESS AND SUPERNORMAL ROD RESPONSES, KCNV2-RELATED
RCD3B
CDSRR
Cone dystrophy with supernormal rod ERG
Cone dystrophy with supernormal rod electroretinogram
Cone dystrophy with supernormal scotopic electroretinogram
Cone dystrophy with supernormal rod responses (CDSRR) is characterized by onset in the first or second decade of life of very marked photophobia, myopia, reduced color vision along the red-green axis with relatively preserved tritan discrimination, and central ... Cone dystrophy with supernormal rod responses (CDSRR) is characterized by onset in the first or second decade of life of very marked photophobia, myopia, reduced color vision along the red-green axis with relatively preserved tritan discrimination, and central scotomata with peripheral widespread sensitivity loss predominating in the superior visual field. Nyctalopia is a later feature of the disorder. There is often retinal pigment epithelium disturbance at the macula with a normal retinal periphery. Autofluorescence (AF) imaging shows either a perifoveal ring or a central macular area of relative increased AF (summary by Michaelides et al., 2005).
Michaelides et al. (2005) examined 10 patients with retinal cone dystrophy and supernormal rod responses from 7 families of varied ethnic origins, including Britain, Somalia, Pakistan, Iran, and the United Arab Emirates. Patients presented in the first or ... Michaelides et al. (2005) examined 10 patients with retinal cone dystrophy and supernormal rod responses from 7 families of varied ethnic origins, including Britain, Somalia, Pakistan, Iran, and the United Arab Emirates. Patients presented in the first or second decade of life with reduced central vision and marked photophobia; 3 had mild nystagmus. All had moderate to high myopia, with variable degrees of astigmatism. Six patients showed progressive deterioration of visual acuity and color vision. The 3 oldest patients complained of nyctalopia, whereas the younger subjects denied difficulties with night vision. Detailed color vision testing revealed that all 10 patients had severely reduced color discrimination, predominantly along the red-green axes with relative sparing of the tritan axis. Funduscopic examination showed a range of macular appearances, including 2 patients with normal fundi. There was mild disturbance of the retinal pigment epithelium and bull's eye maculopathy, and mild pallor of the temporal optic nerve was present in 5 patients. The peripheral retina was normal. Electroretinography (ERGs) showed reduced and delayed cone responses in all patients, with a characteristic appearance of the standard mixed rod-cone ERG, not seen in other retinal disorders: the a-wave commenced normally, but then developed a broadened trough with delay before a high-amplitude, sharply rising b-wave. In all patients, rod ERG amplitudes were subnormal and undetectable at the lowest flash energies, but as stimulus intensity increased, an abrupt increase in amplitude was seen, which at the higher flash energies approached or exceeded the upper limit of normal (supernormal). In 1 patient who underwent repeat electrophysiologic testing, progressive deterioration of retinal function was established. Wissinger et al. (2008) studied 16 patients from 13 families with CDSRR, including 4 patients originally reported by Rosenberg and Simonsen (1993). All of the patients had electroretinographic recordings that were typical of CDSRR, and all had reduced visual acuity, which dated from early childhood in all those for whom that information was available. Color vision deficiency was also found in all patients who were tested; the color vision defects were of mixed red-green type and in 4 patients were characterized as 'extreme protanomaly.' Eleven of the 16 patients had faint horizontal nystagmus, which eventually disappeared in some, and some patients had a history of strabismus that had been surgically corrected. Only a few patients reported difficulties in the dark, and a statement of night blindness was not always confirmed by examination: of 8 patients who underwent dark adaptation testing, 5 had incomplete night blindness. Macular changes were mostly inconspicuous, varying from discrete accentuation of the foveal reflexes with fine stippling of the foveal pigment epithelium to slight irregular foveal depigmentation; 2 patients had a more pronounced circular foveal atrophy. Disease progression in the form of significant decline in visual acuity and concomitant development of distinct foveal atrophy was present in 3 of 10 patients for whom reliable follow-up data were available. Vincent et al. (2013) reported phenotypic characteristics of 7 patients, aged 9 to 18 years, with CDSRR and homozygous KCNV2 mutations. Best-corrected visual acuity was 20/125 or worse in all cases. Vision loss was progressive in 2 cases. Color vision and contrast sensitivity were abnormal in all cases. Retinal exam revealed minimal pigment epithelial changes at the fovea in 4 cases. A peri- or parafoveal ring of hyperfluorescence was the most common fundus autofluorescence abnormality noted (5 cases). The spectral domain-optical coherence tomography (SD-OCT) showed outer retinal abnormalities in all cases. The rod photoreceptor maximal response was reduced but rod sensitivity was normal. Adaptive optics scanning laser ophthalmoscopy (AOSLO) showed markedly reduced cone density in all 6 patients tested. Vincent et al. (2013) concluded that central vision parameters progressively worsened in CDSRR. Structural retinal and lipofuscin accumulation abnormalities were commonly present. The macular cone photoreceptor mosaic was markedly disrupted early in the course of the disease.
Wu et al. (2006) analyzed the KCNV2 gene, which mapped within the chromosome 9p24 region they had identified for retinal dystrophy in a consanguineous Middle Eastern family, and identified a homozygous nonsense mutation (607604.0001). Mutations were also found ... Wu et al. (2006) analyzed the KCNV2 gene, which mapped within the chromosome 9p24 region they had identified for retinal dystrophy in a consanguineous Middle Eastern family, and identified a homozygous nonsense mutation (607604.0001). Mutations were also found in 17 alleles of 10 other unrelated families with the same disorder, a subset of which had previously been examined by Michaelides et al. (2005). In situ hybridization demonstrated KCNV2 expression in human rod and cone photoreceptors. Wissinger et al. (2008) screened the 4 exons and 5-prime untranslated region of the PDE6H gene in 13 probands with retinal cone dystrophy (CDSRR) and supernormal rod responses, including 4 patients originally reported by Rosenberg and Simonsen (1993), but found no disease-causing variation. Subsequent analysis of the KCNV2 gene revealed homozygosity or compound heterozygosity for mutations in KCNV2 in all of the probands, including 5 nonsense and 3 missense mutations, a 1-bp insertion, a 9-bp in-frame deletion, and a gross deletion of parts of the KCNV2 gene (see, e.g., 607604.0004 and 607604.0006-607604.0009). The mutations segregated with disease in the respective families, and the point mutations were excluded in more than 100 Danish controls. Wissinger et al. (2011) analyzed the KCNV2 gene in a cohort of 367 unrelated patients referred with various diagnoses of cone-related retinal dystrophies. In 12 of the patients, they identified homozygosity or compound heterozygosity for 5 missense, 2 nonsense, and 2 frameshift mutations, as well as a 9-bp in-frame deletion and several larger deletions, respectively (see, e.g., 607604.0004, 607604.0006, and 607604.0009-607604.0012). In addition, they screened the probands of 3 new families with a diagnosis of CDSRR and found homozygous or compound heterozygous KCNV2 mutations in affected members of all 3. Reassessment of 10 of the mutation-positive patients with a diagnosis other than CDSRR resulted in a retrospective diagnosis of CDSRR in 9 of them; only 1 patient had bright flash responses in ERG recordings that were still in the normal range and thus did not fully qualify for a diagnosis of CDSRR. Noting that variability in ERG responses had been reported in CDSRR patients, Wissinger et al. (2011) suggested that the amplitude of the rod b-wave might not be an unambiguous criterion for CDSRR. These results indicated that mutations in KCNV2 accounted for about 2.2 to 4.3% of cases of cone dysfunction; Wissinger et al. (2011) concluded that CDSRR is underdiagnosed and more common than previously thought. Another notable finding was the substantial proportion of large deletions present in this sample, accounting for 15.5% of the mutant alleles and ranging in size from 10.9 kb to 236.8 kb. In 7 patients with CDSRR, including 2 sibs, Vincent et al. (2013) identified 6 different homozygous mutations in the KCNV2 gene, 3 of which were novel.