Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/ß-Catenin Signaling Genes.

Purpose: To determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/ß-catenin genes. Design: This was a multicenter, cross-sectional, observational, and genetic study. Subjects: Two-hundred eighty-one probands with FEVR were studied. Methods: Whole-exome sequence and/or Sanger sequence was performed for the Norrin/ß-catenin genes, the FZD4, LRP5, TSPAN12, and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/ß-catenin genes. Main Outcome Measures: The phenotype associated with or without pathogenic variants of the Norrin/ß-catenin genes. Results: One-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, P < 0.0001), progression during infancy (75.0% vs. 53.8%, P = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%, P = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at stage 4 in both groups (40.7% vs. 34.7%). However, the advanced stages of 3 to 5 in the more severe eye were found more frequently in probands with variants than in those without variants (83.3% vs. 58.4%, P < 0.0001). Patients with rhegmatogenous retinal detachments progressed from stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs. 17.3%, P = 0.0346). Nine probands with NDP variants had features different from probands with typical Norrin/ß-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease. Conclusions: The results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/ß-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Measuring macular pigment optical density using reflective images of confocal scanning laser system.

PURPOSE: To develop a method to measure the macular pigment optical density (MPOD) using scanning laser ophthalmoscopic images in young adults and children. STUDY DESIGN: Cross-sectional study. METHODS: Blue light reflectance fundus images of 32 healthy subjects were used. A profile of the linear reflectance changes across the center of the fovea on a grayscale fundus image was generated. The ratio of the macula-to-periphery reflection was designated as the peak value of the MPOD (MPOD[FR]) based on established fundamentals. In the MPOD profile, the basal width of the pixels at MPOD < 0 (wMP) and width at one-half value of the MPOD[FR] (wMP0.5) were determined. The MOPD at eccentricity of 0.5° was measured by heterochromatic flicker photometry (MPOD[HFP]), and the correlation between the MPOD[FR] and MPOD[HFP] was evaluated. RESULTS: The MPOD[FR] ranged from 0.17 to 0.73 with a mean of 0.40 ± 0.13. The wMP ranged from 88 to 173 pixels with a mean of 121.7 ± 24.2 pixels, and the wMP0.5 ranged from 38 to 83 pixels with a mean of 54.1 ± 10.3 pixels. A significant correlation was found between the MPOD[FR] and MPOD[HFP] (r = 0.41, P = 0.02). CONCLUSIONS: This simplified method can provide accurate and reliable values of the MPOD comparable to heterochromatic flicker photometry. Obtaining the fundus images in this fast and easy way should be suitable for children thus enabling clinicians to determine the MPODs for children.

Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome.

Congenital acorea is a rare disease with the absence of a pupil in the eye. To date, only one family and two isolated cases with congenital acorea have been reported. The gene associated with acorea has not been identified. In this study, we recruited a Chinese family acorea-microphthalmia-cataract syndrome. By analyzing the whole-exome sequencing (WES) data of this Chinese family, we revealed the association of a novel heterozygous variant, NM_005267.5:c.137G>A (p.G46E) in the gap junction protein alpha 8 (GJA8) gene encoding connexin 50 or CX50, with familial acorea-microphthalmia-cataract syndrome. Additionally, another variant, NM_005267.5:c.151G>A (p.D51N) in GJA8, was identified to co-segregate with this syndrome in an unrelated Japanese family. Ectopic expression of p.G46E and p.D51N mutant GJA8 genes in cultured cells caused protein mislocalization, suggesting that the p.G46E and p.D51N mutations in GJA8 impaired the function of the gap junction channels. These results established GJA8 as the first gene associated with familial acorea-microphthalmia-cataract syndrome.

Optical coherence tomography findings of the peripheral retina in patients with congenital X-linked retinoschisis.

Introduction: Congenital X-linked retinoschisis (XLRS) presents as macular retinoschisis/degeneration in almost all patients and as peripheral retinoschisis in half the patients. Although the optical coherence tomography (OCT) findings of macular retinoschisis have been well investigated, those of peripheral retinoschisis have rarely been reported. This study aimed to report the ultra-widefield OCT findings of the peripheral retina in patients with XLRS. Methods: Medical records of 10 Japanese patients (19 eyes) with clinically and/or genetically diagnosed XLRS were retrospectively reviewed. Funduscopic, electroretinographic, and OCT findings were reviewed and evaluated. Some were also genetically evaluated for the RS1 gene. Results: OCT of the macula revealed schises and/or cystoid changes in the inner nuclear layer (INL) and outer nuclear layer. In contrast, OCT of the peripheral retina revealed schises and/or cystoid changes in the INL in eight eyes (44%), and/or splitting in the ganglion cell layer (GCL) in 10 (56%) of the 18 eyes with clear OCT images. No schisis or cystoid changes were found in the peripheral OCT images of eight eyes (44%). A 16-year-old boy presented with retinal splitting of the GCL and INL of the inferior retina, although he had no ophthalmoscopic peripheral retinoschisis. Genetic examinations were performed on three patients, all of whom had reported missense mutations in the RS1 gene. Conclusion: In XLRS, peripheral bullous retinoschisis results from GCL splitting in the retina. One of the 10 patients with XLRS showed intraretinal retinoschisis in the GCL in the inferior periphery, which was unremarkable on ophthalmoscopy (occult retinoschisis). Although both peripheral bullous retinoschisis and occult retinoschisis showed splitting/cystic changes in the GCL, further studies are needed to determine whether occult retinoschisis progresses to bullous retinoschisis.

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia.

The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.

Late Vitreoretinal Complications of Regressed Retinopathy of Prematurity: Retinal Break, Vitreous Hemorrhage, and Retinal Detachment.

PURPOSE: To investigate late vitreoretinal complications and visual outcomes in patients with regressed retinopathy of prematurity (ROP) with or without prior treatment. DESIGN: International, multicenter, noncomparative retrospective case series. PARTICIPANTS: We analyzed 264 eyes of 238 patients from 13 centers worldwide who developed vitreoretinal complications (retinal detachment [RD], vitreous hemorrhage [VH], or retinal break) ≥ 2 years after resolution of acute ROP. METHODS: Each participant was assigned to 1 of 3 groups (the RD, VH, and retinal break groups) according to their primary diagnosis. The average age at presentation, visual acuities, refractive error, axial length, gestational age, birth weight, acute ROP classification, prior treatments for acute ROP, postoperative visual acuity (VA), and concomitant eye conditions in the 3 groups were documented and compared. MAIN OUTCOME MEASURES: Clinical features and visual outcomes of late vitreoretinal complications in patients with regressed ROP. RESULTS: A total of 264 eyes of 238 patients were included. The prior acute ROP status was comparable among the 3 groups, except that the VH group had a higher proportion of patients with type 1 ROP (P = 0.03) and prior treatment (P < 0.001) than the other groups. The average age at presentation was earlier in the RD (20.3 ± 15.5 years) and VH (21.4 ± 18.9 years) groups than in the retinal break group (31.9 ± 18.2 years; P < 0.001). The retinal break group had the best presenting best-corrected VA, followed by the RD and VH groups (P < 0.001). Surgical intervention improved VA in both the RD and VH groups (both P < 0.05). The overall trend of VA was the most favorable in the retinal break group, followed by that in the VH and RD groups. Cicatricial changes in the fellow retina were observed in > 90% of patients with unilateral involvement. CONCLUSIONS: Infants with acute ROP remain at a high risk of vision-threatening complications throughout childhood and adulthood. Continual follow-up of patients with ROP is important. When severe complications, such as RD or VH, are detected, timely surgical intervention is necessary to ensure favorable visual outcomes in these patients.

EFFICACY OF INNER WALL RETINECTOMY FOR BULLOUS SCHISIS CAVITY HANGING OVER OR THREATENING THE MACULA IN PATIENTS WITH CONGENITAL X-LINKED RETINOSCHISIS.

PURPOSE: To present the clinical characteristics, surgical outcomes, and surgical complications of patients with congenital X-linked retinoschisis who underwent vitrectomy for bullous schisis cavity hanging over or threatening the macula. METHODS: Nine patients with congenital X-linked retinoschisis (12 eyes) who underwent vitrectomy at three tertiary hospitals and completed ≥3 years of postoperative follow-up were retrospectively investigated. Data were collected from patients' charts, including age at vitrectomy, surgical procedures, and postoperative complications. RESULTS: The age at vitrectomy ranged 4 months to 103 months (median: 14 months). Inner wall retinectomy was performed during the initial vitrectomy in eight eyes. Among the eight eyes that initially underwent inner wall retinectomy, one (12.5%) required subsequent retinal surgery for postoperative complication. Furthermore, four eyes did not undergo initial inner wall retinectomy but required subsequent retinal surgeries for postoperative complications. Three of five eyes (60.0%) treated with silicone oil tamponade and two of seven eyes (28.6%) that were not treated with silicone oil tamponade during the initial vitrectomy required subsequent retinal surgeries for postoperative complications. All eyes maintained a clear central visual axis at the last examination. CONCLUSION: Inner wall retinectomy seems beneficial in achieving a clear visual axis in eyes with bullous schisis cavity hanging over or threatening the macula in patients with congenital X-linked retinoschisis.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Severe foveal hypoplasia and macular degeneration in Stickler syndrome caused by missense mutation in COL2A1 gene.

BACKGROUND: The aim is to determine the retinal changes in patients with Stickler syndrome caused by a p.R565C missense mutation of the COL2A1 gene. METHODS: We reviewed the clinical records of 10 eyes of six patients from two families with the Stickler syndrome. The members of both families were heterozygous for the p.R565C mutation. The clinical features including the visual acuity, fundus appearances, fundus autofluorescence (FAF), optical coherence tomographic (OCT) images, and electroretinograms were examined. RESULTS: Myopia of -12 diopters (D) to -24 D with an average of -16.8 D was observed in 9 eyes of the 5 patients. The FAF images showed different degrees of hyper and hypoautofluorescent patterns in the macula in all but the two youngest patients (7 of 9 eyes, 78%). The OCT images showed the absence of a foveal pit and destruction of the outer retinal layers in the macular area in all patients. The ellipsoid zone (EZ) in the macular region was disrupted in eight eyes (80%) of which seven were fovea sparing. CONCLUSION: Two families with Stickler syndrome with the p.R565C mutation showed more severe foveal hypoplasia, macular degeneration, and extensive retinal degeneration. A correlation of the OCT and FAF images with the genotype is helpful in determining the prognosis of Stickler syndrome.

Vitrectomy and external drainage of subretinal fluid containing high concentration of vascular endothelial growth factor for advanced coats disease.

This study investigated the surgical outcomes of Coats disease and the role of external drainage (XD) of subretinal fluid (SRF). The study is a multicenter retrospective interventional case series of 26 consecutive eyes of 26 patients who underwent surgeries for advanced Coats disease with retinal detachment. Main outcomes measured were: 1) comparison of complete SRF resolution with or without XD, and 2) variables that were associated with functional postoperative best-corrected visual acuity (BCVA) defined as BCVA of 0.1 or better, 3) intraocular vascular endothelial growth factor (VEGF) levels. Complete SRF resolution was achieved in all 14 eyes in which XD had been performed and in 75% of 12 eyes in which XD had not been performed (P = .03). Multivariable logistic regression analysis revealed that initial BCVA was the only variable associated with functional postoperative BCVA (odds ratio 3.24, 95% CI 0.93-11.33; P = .04). Markedly elevated VEGF levels were noted in the SRF compared with those in the vitreous humor (49,760 ± 52,990 vs. 707 ± 611 pg/mL, P = .03). XD seems to provide better anatomical success than without XD in the treatment of advanced Coats disease as XD could effectively eliminate substantial amount of VEGF in the SRF.

Study protocol for a multicentre, open-label, single-arm phase I/II trial to evaluate the safety and efficacy of ripasudil 0.4% eye drops for retinopathy of prematurity.

INTRODUCTION: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP. METHODS AND ANALYSIS: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints. ETHICS AND DISSEMINATION: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT04621136 and jRCT2071200047.

Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene.

Purpose: To determine the clinical characteristics of patients and family members with familial exudative vitreoretinopathy (FEVR) caused by mutations in the KIF11 gene. Methods: Twenty-one patients from 10 FEVR families with mutations in the KIF11 gene were studied. The retinal and systemic features were examined. The genetic analyses performed included Sanger sequencing of the KIF11 gene, whole exome sequencing, as well as array comparative genomic hybridization (CGH) analysis and multiple ligation probe assay (MLPA). Results: Sequence analysis revealed seven different KIF11 mutations. Array CGH with MLPA revealed two different exon deletions. All probands had advanced FEVR with retinal detachments (RDs) and microcephaly with or without developmental disabilities. Patients with bilateral RDs were more frequently associated with developmental disabilities (P = 0.023). Multimodal imaging of the family members revealed that six of nine patients without RDs (66%) had varying degrees of chorioretinopathy. The retinal folds in FEVR patients were associated with severe retinal avascularization. However, funduscopic changes in the peripheral retina were unremarkable in family members without RDs. A score representing the peripheral vascular anomalies determined from the fluorescein angiograms was lower than that of control eyes of patients with mutations of the Wnt signaling genes (P = 0.0029). Conclusions: The probands with KIF11 mutations were associated with severe ocular and systemic pathologies, whereas affected family members showed highly variable clinical manifestations. Peripheral vascular anomalies can often be unremarkable in eyes without RDs. Translational Relevance: These findings highlight more diverse mechanisms that underlie the pathological changes in patients with FEVR.

Homozygous single nucleotide duplication of SLC38A8 in autosomal recessive foveal hypoplasia: The first Japanese case report.

PURPOSE: To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene. METHODS: We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation. RESULTS: In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting. CONCLUSIONS: This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

ULTRA-WIDE FIELD FUNDUS AUTOFLUORESCENCE IMAGING OF EYES WITH STICKLER SYNDROME.

PURPOSE: To determine the characteristics of fundus autofluorescence (FAF) images and visual functions in eyes with Stickler syndrome using ultra-widefield FAF images. METHODS: Forty-six eyes of 26 patients with mutations in the COL2A1 gene underwent ultra-widefield FAF imaging. The eyes were categorized into three types; no signs of abnormal AF, predominantly hyperfluorescent AF (hyper-AF), and predominantly hypofluorescent AF (hypo-AF). Goldmann perimetry was performed on 34 eyes, and line-scan images of the abnormal AF lesions were obtained by swept-source optical coherence tomography in 4 eyes. RESULTS: Abnormal AF lesions were found in 37 eyes of 21 (80.7%) of the 26 patients. Hyper-AF was found in 15 eyes and hypo-AF was found in 22 eyes. The FAF changes corresponded with the funduscopically observed radial paravascular retinal degeneration. The average age at the examination was significantly younger in patients who had eyes with hyper-AF or no abnormal AF than in those with hypo-AF (12.8 vs. 28.4 years; P = 0.009). Abnormal AF-associated visual field defects were found in 5/10 (50%) eyes with hyper-AF and 17/18 (94%) eyes with hypo-AF. Hyper-AF changes tended to appear before retinal changes were detectable by fluorescein angiography. An absence of the ellipsoid zone and the outer nuclear layer and a thinning of the overall retinal thickness were found corresponding to the hypo-AF lesions in the swept source optical coherence tomography images. CONCLUSION: Abnormal FAF is characteristic of eyes with Stickler syndrome. Age-related alterations of the FAF was associated with visual field defects and disruption of the photoreceptors and retinal pigment epithelial cells.

Autosomal dominant foveal hypoplasia without visible macular abnormalities and PAX6 mutations.

PURPOSE: Autosomal dominant foveal hypoplasia (FVH1) is a rare disorder associated with mutations in the PAX6 gene. As an isolated disease entity, FVH1 does not include ocular disorders such as aniridia, microphthalmia, albinism, and achromatopsia. However, it only includes isolated foveal hypoplasia and foveal hypoplasia with presenile cataract. The purpose of this report is to present our findings in four patients from two families with FVH1 without visible ophthalmic macular abnormalities. STUDY DESIGN: A review of the medical records of two families with FVH1 and genetic confirmation of mutations in the PAX6 gene. METHODS: Fundus photographs, optical coherence tomographic (OCT) and OCT angiographic (OCTA) images, and slit-lamp anterior segment findings were determined. The type of mutation of the PAX6 gene was determined. RESULTS: A 3-year-old girl (Patient 1) had signs and symptoms of an impairment in the development of vision without other retinal abnormalities OU. OCT images showed a shallow foveal pit, and OCTA showed the absence of the foveal avascular zone. The second patient (Patient 2) was a 6-year-old girl with unilateral mild cataract and shallow foveal pits OU. Similar shallow foveal pits were found in her asymptomatic mother (Patient 3) and maternal grandfather (Patient 4). Although the iris and posterior fundus were normal, all patients with FVH1 had goniodysgenesis. Genetic testing of the PAX6 gene revealed that Patient 1 had a novel heterozygous mutation (p.Asn365Lys) as a de novo mutation, and Patients 2, 3 and 4 had a novel heterozygous mutation (p.Pro20Ser). CONCLUSIONS: Heterozygous mutations in the PAX6 gene can cause FVH1 with nearly normal appearing macula. FVH1 is difficult to diagnose, but detailed observations of the foveal structure and vasculature, and detecting the presence of goniodysgenesis can be helpful in identifying patients with FVH1.

Electroretinograms of eyes with Stickler syndrome.

PURPOSE: To determine the characteristics of the full-field electroretinograms (ERGs) of eyes with Stickler syndrome. METHODS: Twenty-two eyes of 14 Japanese patients from nine families with Stickler syndrome were studied. All of the patients were found to have mutations in the COL2A1 gene and had undergone ERG recordings. The ERGs from one of the two eyes were compared to 11 eyes of 11 normal control subjects who were matched by age, sex, and refractive error. RESULTS: One patient had non-recordable ERGs under both scotopic and photopic conditions. For the remaining 13 patients, the amplitudes of the b-waves of the scotopic combined, rod, and cone responses were significantly smaller than those of the control subjects (P = 0.0001, P = 0.015, P = 0.0006, respectively). The implicit times of the b-wave of the scotopic combined and photopic responses were significantly prolonged (P = 0.0037 and P = 0.0126). The age was inversely and significantly correlated with the amplitudes of the scotopic combined a-wave (P = 0.0184) and b-wave (P = 0.0076) in 13 eyes. The amplitudes of the scotopic combined b-wave amplitudes were not significantly correlated with the refractive error. CONCLUSIONS: The reduced or absent full-field ERGs in eyes with Stickler syndrome indicate that the physiology of the entire retina was negatively altered. The greater reduction in the ERGs with increasing age suggests that the physiological alterations of the retina are progressive.

Foveal Hypoplasia in Patients with Stickler Syndrome.

PURPOSE: To determine the microstructure of the fovea in patients with Stickler syndrome using imaging by spectral-domain optical coherence tomography (SD OCT) and swept-source OCT. DESIGN: Retrospective case series study. PARTICIPANTS: A total of 39 eyes of 25 patients with genetically confirmed Stickler syndrome were studied. METHODS: All of the patients had mutations in the COL2A1 gene and were diagnosed with Stickler syndrome. Cross-sectional OCT images, OCT angiography (OCTA), and en face OCT images were assessed. The ratio of the foveal inner retinal layer (fIRL) thickness to the parafoveal inner retinal layer (pIRL) thickness, the ratio of the foveal outer retinal layer (fORL) thickness to the parafoveal outer retinal layer (pORL) thickness, and the size of the foveal avascular zone (FAZ) were determined. MAIN OUTCOME MEASURES: The degree of foveal hypoplasia and the best-corrected visual acuity in patients with Stickler syndrome. RESULTS: A persistence of the inner retinal layers in the fovea with an fIRL/pIRL ratio >0.2 was present in 32 of the 39 eyes (82%). Optical coherence tomography angiography showed that the FAZ was smaller, 0 to 0.19 mm2, than that of normal eyes, in 25 eyes of 17 patients who underwent OCTA. There was no significant correlation between the visual acuities and the fIRL/pIRL ratios. CONCLUSIONS: A mild foveal hypoplasia with a persistence of the IRL is characteristic of eyes with Stickler syndrome. The visual acuities were not correlated with the fIRL/pIRL ratios.

Novel mutations in the COL2A1 gene in Japanese patients with Stickler syndrome.

Stickler syndrome is an inherited connective tissue disorder that affects the eyes, cartilage and articular tissues. The phenotypes of Stickler syndrome include congenital high myopia, retinal detachment, premature joint degeneration, hearing impairment and craniofacial anomalies, such as cleft palate and midline facial hypoplasia. The disease is genetically heterogeneous, and the majority of the cases are caused by mutations in the COL2A1 gene. We examined 40 Japanese patients with Stickler syndrome from 23 families to determine whether they had mutations in the COL2A1 gene. This analysis was conducted by examining each patient's genomic DNA by Sanger sequencing. Five nonsense, 4 splicing and 8 deletion mutations in the COL2A1 gene were identified, accounting for 21 of the 23 families. Different mutations of the COL2A1 gene were associated with similar phenotypes but with different degrees of expressivity.