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.

Epidemiologic study of rhegmatogenous retinal detachment in Japan from the Diagnosis Procedure Combination database over a 2-year period (2014-2015).

PURPOSE: To determine the incidence of rhegmatogenous retinal detachments (RRDs) and proliferative vitreoretinopathies (PVRs) and their distribution by age and sex in hospitalized patients in Japan. STUDY DESIGN: Retrospective nationwide observational study. METHODS: Information on the number of inpatients primarily diagnosed with RRD or PVR and their age and sex were collected from the Diagnosis Procedure Combination (DPC) database for 2014 and 2015. The incidence was determined using the Japanese population report published by the Public Management Ministry's Statistics Bureau. RESULTS: The incidence of RRD in these hospitalized patients was 10.9/100,000, with 15.0/100,000 in men and 7.1/100,000 in women, and that of PVR was 2.1/100,000, with 2.9/100,000 in men and 1.3/100,000 in women. The incidence in men was twice that in women for both RRD and PVR. The distribution of RRD by age was monophasic, with a peak at 50 years for both sexes, and that of PVR was at peak in the 60 s for men and in the 70 s for women. PVR was more common than RRD in children aged younger than 10 years, but the incidence of RRD was higher in the other age groups. CONCLUSION: A study of the DPC database can provide useful information on the incidences of RRD and PVR in hospitalized patients in Japan.

Familial exudative vitreoretinopathy with TGFBR2 mutation without signs of Loeys-Dietz syndrome.

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder with high genetic heterogeneity, and it is characterized by a defect in the development of the retinal vascular system. Loeys-Dietz syndrome (LDS) is an autosomal dominant systemic connective tissue disorder that is caused by mutations in the genes related to transforming growth factor signaling systems including the TGFBR2 gene. Two earlier studies reported that patients with LDS from mutations in the TGFBR2 gene were associated with FEVR-like retinal phenotype. The purpose of this study was to determine the characteristics of a case of FEVR without systemic abnormalities who had a mutation in the TGFBR2 gene.Materials and Methods: The clinical appearances and surgical outcomes were determined from the medical records. Genetic analysis was performed by whole exome sequencing.Results: A 15-year-old boy was diagnosed with FEVR by the appearance of the peripheral retina of both eyes and a retinal detachment in the left eye. Whole exome sequencing revealed a heterozygous deletion mutation in the TGFBR2 gene. A de novo mutation was confirmed by examining the family members. No systemic abnormalities were detected in the patient including those associated with LDS.Conclusions: FEVR can be associated with a TGFBR2 mutation without showing signs of LDS.

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.

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.

Novel mutations in the RS1 gene in Japanese patients with X-linked congenital retinoschisis.

X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the RS1 gene. We have identified 37 different mutations in the RS1 gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations.

Changes in expression of aquaporin-4 and aquaporin-9 in optic nerve after crushing in rats.

The purpose of this study was to determine the temporal and spatial changes in the expression of AQP4 and AQP9 in the optic nerve after it is crushed. The left optic nerves of rats were either crushed (crushed group) or sham operated (sham group), and they were excised before, and at 1, 2, 4, 7, and 14 days later. Four optic nerves were pooled for each time point in both groups. The expression of AQP4 and AQP9 was determined by western blot analyses. Immunohistochemistry was used to determine the spatial expression of AQP4, AQP9, and GFAP in the optic nerve. Optic nerve edema was determined by measuring the water content in the optic nerve. The barrier function of the optic nerve vessels was determined by the extravasated Evans blue dye on days 7 and 14. The results showed that the expression of AQP4 was increased on day 1 but the level was significantly lower than that in the sham group on days 4 and 7 (P<0.05). In contrast, the expression of AQP9 gradually increased, and the level was significantly higher than that in the sham group on days 7 and 14 (P<0.05, Tukey-Kramer). The down-regulation of AQP4 was associated with crush-induced optic nerve edema, and the water content of the nerve was significantly increased by 4.3% in the crushed optic nerve from that of the untouched fellow nerve on day 7. The expression of AQP4 and GFAP was reduced at the crushed site where AQP4-negative and AQP9-positive astrocytes were present. The barrier function was impaired at the crushed site on days 7 and 14, restrictedly where AQP4-negative and AQP9-positive astrocytes were present. The presence of AQP9-positive astrocytes at the crushed site may counteract the metabolic damage but this change did not fully compensate for the barrier function defect.