A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect.

Cone dystrophies are a rare subgroup of inherited retinal dystrophies and hallmarked by color vision defects, low or decreasing visual acuity and central vision loss, nystagmus and photophobia. Applying genome-wide linkage analysis and array comparative genome hybridization, we identified a locus for autosomal dominant cone dystrophy on chromosome 16q12 in four independent multigeneration families. The locus is defined by duplications of variable size with a smallest region of overlap of 608 kb affecting the IRXB gene cluster and encompasses the genes IRX5 and IRX6. IRX5 and IRX6 belong to the Iroquois (Iro) protein family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissue in vertebrates, including the eye and the retina. All patients presented with a unique progressive cone dystrophy phenotype hallmarked by early tritanopic color vision defects. We propose that the disease underlies a misregulation of the IRXB gene cluster on chromosome 16q12 and demonstrate that overexpression of Irx5a and Irx6a, the two orthologous genes in zebrafish, results in visual impairment in 5-day-old zebrafish larvae.

Evaluation of visual evoked potentials in dysthyroid optic neuropathy.

PURPOSE: To evaluate the findings of visual evoked potentials (VEP) in patients with dysthyroid optic neuropathy (DON). METHODS: In this observational, cross-sectional study 40 eyes (22 patients) with a diagnosis of DON were included. RESULTS: We discovered that in 16 out of 37 eyes with pattern-VEP (p-VEP), the latency of P100 wave was normal in spite of having a diagnosis of DON. The same pattern was also observed in the measurement of the amplitude of P100 wave: in 28 out of 37 eyes with p-VEP the amplitudes were observed as normal. In 3 eyes of 3 patients p-VEP showed no response, therefore a flash-VEP (f-VEP) was performed. Flash-VEPs of those patients indicated a prolonged P100 latency with a reduced amplitude. The sensitivity of abnormal P100 latency was 56.8% (95%CI 39.5-72.9%); and that of reduced P100 amplitude was 24.3% (95%CI 11.8-41.2%). Also, in 40 eyes color vision test by Arden was performed. In 36 eyes (20 patients) the tritan value was pathological (based on a threshold of ≥8%). CONCLUSION: According our data, VEP seems to have a limited potential especially in patients with a good best-corrected visual acuity (BCVA ≤0.2 LogMAR) for identifying the optic nerve involvement. The fact that P100 latency and amplitude were normal even in cases with an optic nerve swelling makes us question the usefulness of the VEP for diagnosing cases of DON in daily clinical life.

Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 µl) or to sham injection. The left eye received the treatment not allocated to the right eye. MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively. CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.

A pathological indicator for dysthyroid optic neuropathy: tritan color vision deficiency.

PURPOSE: To investigate the sensitivity of the color vision test by Arden in patients with dysthyroid optic neuropathy (DON) to improve diagnosis. METHODS: In this observational, retrospective study, we included the medical records of 92 eyes (48 patients) with diagnosis of DON between 2008 and 2019 in order to evaluate the full spectrum of findings from the color vision test by Arden, and to determine potential importance of this test. Thirty-five patients were female, and 13 patients were male. The mean age was 58.0 years (range: 34-79) at the time of the DON diagnosis. RESULTS: Forty-one eyes displayed relatively good BCVA with ≤ 0.2 LogMAR. We found a protan value exceeding the threshold of ≥ 8% in 57 eyes (30 patients) at the time of the diagnosis. The sensitivity of protan was 61.9% (95% CI 51.2-71.8%), while that of tritan was a striking 98.9% (95% CI 94.1-99.9%). We discovered one pathological sign, tritan deficiency (based on a threshold of ≥ 8%) consistently in all eyes but one at the time of the diagnosis, regardless of the visual field defects or any changes in best-corrected visual acuity (BCVA). CONCLUSION: We found blue-yellow (tritan) deficiency, to be a sensitive and reliable indicator of dysthyroid optic neuropathy. We conclude that, in cases with suspected DON, a color vision test that can detect tritan deficiency is an essential tool for the adequate assessment, diagnosis, and treatment of DON.

Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.

Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy.

BACKGROUND: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. RESULTS: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. CONCLUSIONS: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone.

[Gene therapy in ophthalmology]. / Gentherapie in der Augenheilkunde.

In 2017 the gene therapy medication voretigene neparvovec-rzyl was approved by the U.S. Food and Drug Administration (FDA) for retinal gene therapy of hereditary retinal dystrophies caused by mutations in the RPE65 gene. Voretigene neparvovec-rzyl is a gene augmentation therapy using an  adeno-associated virus-based vector to express a healthy copy of the human RPE65 gene in the patient's retinal pigment epithelial (RPE) cells. The success of gene augmentation therapy in RPE65-linked retinal dystrophy encouraged research activities on the concept of gene supplementation to be extended to nongenetic diseases, such as age-related macular degeneration; however, it also showed that the principle of success cannot be easily extended to other retinal dystrophies. This review article presents the most commonly used principles and technologies of gene therapy and provides an overview of the current challenges and limitations. Furthermore, practice-relevant aspects of the indications and the treatment procedure are discussed. Particular attention is paid to the consideration of disease stages, especially with respect to patient's expectations and the evaluation of treatment success.

Achromatopsia: Genetics and Gene Therapy.

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.

Gene Therapy with Voretigene Neparvovec Improves Vision and Partially Restores Electrophysiological Function in Pre-School Children with Leber Congenital Amaurosis.

Leber congenital amaurosis caused by mutations in the RPE65 gene belongs to the most severe early-onset hereditary childhood retinopathies naturally progressing to legal blindness. The novel gene therapy voretigene neparvovec is the first approved causative treatment option for this devastating eye disease and is specifically designed to treat RPE65-mediated retinal dystrophies. Herein, we present a follow-up of the youngest treated patients in Germany so far, including four pre-school children who received treatment with voretigene neparvovec at a single treatment center between January 2020 and May 2022. All patients underwent pars plana vitrectomy with circumferential peeling of the internal limiting membrane at the injection site and subretinal injection of voretigene neparvovec. Pre- and postoperative diagnostics included imaging (spectral domain optical coherence tomography, fundus autofluorescence, fundus wide-angle imaging), electrophysiologic examination (ERG), retinal light sensitivity measurements (FST) and visual acuity testing. Behavioral changes were assessed using a questionnaire and by observing the children's vision-guided behavior in different levels of illumination. All children showed marked increase in vision-guided behavior shortly after therapy, as well as marked increase in visual acuity in the postoperative course up to full visual acuity in one child. Two eyes showed partial electrophysiological recovery of an ERG that was undetectable before treatment-a finding that has not been described in humans before.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.

Importance: Treatment trials require sound knowledge on the natural course of disease. Objective: To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. Design, Setting, and Participants: This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included. Exposures: Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. Main Outcomes and Measures: Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). Results: Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). Conclusions and Relevance: Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.

Functional outcome of indocyanine green-assisted macular surgery: 7-year follow-up.

PURPOSE: To evaluate the long-term functional results after surgery for macular pucker and macular holes with indocyanine green (ICG) staining of the internal limiting membrane. METHODS: Long-term functional and anatomical outcomes of 16 eyes of 16 patients were evaluated for 7.3 years after ICG-assisted macular surgery. Examinations performed included best-corrected visual acuity, Goldmann perimetry, Arden color contrast test, optical coherence tomography, and fundus photography. Ten eyes had undergone surgery for macular holes, and 6 eyes had been treated for macular pucker. Indocyanine green with a concentration of 0.05% and an osmolarity of 275 mOsm had been used to stain the internal limiting membrane. RESULTS: Mean follow-up time was 7.3 years. Eighty-eight percent (14) of the eyes had undergone cataract surgery either in a combined intervention primarily (n = 3) or in the years after the ICG-assisted macular surgery (n = 11). One patient was still phakic with a pronounced cataract at last follow-up. Over all patients, best-corrected visual acuity did not increase significantly from 20/200 (median) before macular surgery to the present 20/70 (median). Large visual field defects (VFDs) were found in 10 of 16 patients after internal limiting membrane staining using ICG. In 8 of these 10 eyes, the VFDs had been diagnosed immediately after vitrectomy and remained unchanged throughout the period of review. In 2 eyes, a VFD was noted at the last follow-up visit despite an unremarkable Goldmann perimetry performed at follow-up visits after 3 months and 6 months. Pathologic color testing was found in 15 of 16 patients when comparing the operated and the fellow eye. A nonglaucomatous optic nerve atrophy was found in 11 of 16 eyes. The optical coherence tomography revealed macular hole closure in all 10 patients. CONCLUSION: Indocyanine green-assisted macular surgery might lead to optic nerve atrophy in the long-term and persistent VFDs. In addition, new VFDs may occur in the postoperative course. An affection of color vision also underlines the potential impact of ICG on visual function. A long-term observation of patients after ICG-assisted vitrectomy seems mandatory to reliably detect functional adverse events.

Extraocular muscles involved in convergence are innervated by an additional set of palisade endings that may differ in their excitability: A human study.

Palisade endings are located at the myotendinous junction of extraocular muscles in most mammals. Irrespective of their unclarified function as motor or sensory nerve endings, a specialized role in convergence is proposed, based on their high number in the medial rectus muscle (MR). Further support comes from a study in monkey demonstrating that only the MR and inferior rectus muscle (IR) contain an additional population of palisade endings that express the calcium-binding protein calretinin (CR) in addition to choline acetyltransferase (ChAT). Here we studied, whether CR-positive palisade endings are present in human as well and confined to extraocular muscles most active during convergence. The systematic analysis of all eye muscles of 17 human specimen revealed that only the MR and IR contain an additional population of CR-positive palisade endings and multiple en-grappe endings, which target non-twitch muscle fibers along their whole length. Approximately 80% of all palisade endings in the MR expressed CR. Furthermore, the intrafusal muscle fibers of some muscle spindles in the MR were innervated by CR-positive annulospiral nerve endings that transmit the signals of muscle length changes to the brain. All extraocular muscles contained few thin CR-positive, but ChAT-negative nerve fibers, possibly representing free sensory or autonomic endings arising from the trigeminal ganglion. As in monkey, in the medial periphery of the human oculomotor nucleus ChAT-positive neurons were found to co-express CR. Therefore these neurons most likely represent the cell bodies of CR-positive palisade endings in the MR. Unlike in monkey, these neurons do not lie within a compact cell group, but are more scattered. In conclusion, the MR and IR in human contain two histochemically different populations of palisade and multiple endings that may contribute to ocular alignment and convergence in a different way.

ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies.

The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2.

PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior METHODS: Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.