Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene.

Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.

Central Retinal Vein Occlusion in Younger Swedish Adults: Case Reports and Review of the Literature.

PURPOSE: To investigate associated systemic diseases, other conditions, visual outcome, ocular complications and treatment in Swedish patients younger than 50 years with central retinal vein occlusion (CRVO) and reviewing the literature. METHODS: Twenty-two patients with CRVO, younger than 50 years, were examined with full-field electroretinography (ERG) within 3 months after a thrombotic event, or were periodically examined and were observed for at least 6 months. In 18 of these patients, the initial retinal ischemia was studied using the cone b-wave implicit time in the 30 Hz flicker ERG. Fifteen patients also underwent fluorescein angiography. Optical coherence tomography (OCT) was performed in 14 patients. The patients studied were divided into two groups, non-ischemic and ischemic, which were compared. All patients underwent ocular and systemic examination, as well as complete screening for thrombophilic risk factors. RESULTS: Of the 22 patients, 15 had non-ischemic type of CRVO and 7 the ischemic type. Patients with non-ischemic CRVO showed significantly improved visual acuity (VA) at the final examination (p=0.006). Patients with ischemic CRVO showed no significant reduction in VA at the final examination (p=0.225). Systemic hypertension (27% in non-ischemic CRVO and 29% in ischemic CRVO) was the most prevalent systemic risk factor for CRVO. The mean central foveal thickness (CFT) decreased significantly from 402.3±136.2 (µm) at the initial examination to 243.8±48.1 (µm) at the final examination in the non-ischemic group (p=0.005). The mean initial CFT was 444.5±186.1 (µm) in the ischemic CRVO group, which decreased to 211.5±20.2 (µm) at the final visit (p=0.068). Pigment dispersion syndrome (PDS)/pigmentary glaucoma (PG), ocular hypertension and dehydration were equally frequent; four patients each (18%) out of 22. The clinical course of 4 younger patients with PDS/PG are described. CONCLUSION: The patients with non-ischemic CRVO showed significantly improved VA and significantly decreased CFT at the final examination. Systemic hypertension was the most prevalent risk factor for CRVO. Younger adults with CRVO also had a high prevalence of PDS/PG, ocular hypertension and dehydration. This study highlights the importance of careful IOP monitoring, and the need to investigate possible PDS/PG and to obtain an accurate history of the patient including alcohol intake and intense exercise.

Clinical, optical coherence tomography, and fundus autofluorescence findings in patients with intraocular tumors.

PURPOSE: To describe clinical, optical coherence tomography (OCT) and fundus autofluorescence (FAF) findings in patients with intraocular tumors and determine if OCT and FAF could be helpful in the differential diagnosis and management of different choroidal tumors. METHODS: Forty-nine patients with untreated, macular, midperipheral, and extrapapillary intraocular tumors were included. All patients underwent ophthalmic examination: best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, and standardized B mode, and if possible A mode, ultrasonography, and OCT and FAF imaging of the surface of the intraocular tumors. RESULTS: Of the 49 patients studied, 19 had choroidal nevi, ten had indeterminate choroidal melanocytic lesions (IMLs), ten had malignant melanomas, and ten had other choroidal tumors. The choroidal nevi revealed subretinal fluid (SRF) on OCT in only 11%. FAF detected isoauto-fluorescence in 42%, hypoautofluorescence in 37%, patchy FAF pattern in 16%, and a diffuse FAF pattern in 5%. Seventy percent of patients with IML showed SRF on OCT and 20% showed tumor growth on follow-up, detected only by OCT and FAF imaging. FAF revealed a patchy pattern in 50% and a diffuse pattern in 40% of cases with IML. Ninety percent of the patients with choroidal melanoma had SRF on OCT and FAF revealed a patchy pattern in 60% and a diffuse pattern in 40%. Patients with other choroidal tumors had SRF on OCT in 30% of cases and no characteristic pattern on FAF. CONCLUSION: Both OCT and FAF were helpful in the differential diagnosis of choroidal nevi versus IMLs, choroidal melanomas, and other choroidal tumors. Also, detailed and periodical clinical evaluation of patients with intraocular tumors using OCT and FAF imaging for the detection of both SRF and FAF patterns overlying the tumor can be useful for detection of tumor growth.

Biallelic Mutations in the BEST1 Gene: Additional Families with Autosomal Recessive Bestrophinopathy.

PURPOSE: To describe the genotype and phenotype of patients with autosomal recessive bestrophinopathy (ARB), and heterozygous carriers. METHODS: The members of three unrelated ARB families were investigated. Molecular genetic analysis was performed on 11 members of these families. Ten members were examined clinically; including visual acuity, slit-lamp examination, biomicroscopy, fundus photography, and Goldmann applanation tonometry. Measurements were also made of the anterior chamber depth and axial length, and optical coherence tomography (OCT), electrooculography (EOG), and full-field electroretinography (full-field ERG) were performed. Multifocal electroretinography (mfERG) was performed on eight members of these families. RESULTS: Two novel combinations of missense mutations in the BEST1 gene were identified: p.R141H/p.M325T in three patients with ARB in two unrelated Norwegian families, and p.R141H/p.I201T was found in an ARB patient in a Swedish family. All four patients with ARB had clinical and electrophysiological features of ARB. All the heterozygous carriers of the p.R141H mutation were clinically normal, and showed normal OCT, EOG and full-field ERG findings, but had mildly abnormal mfERG results. Only one heterozygous carrier of the p.M325T mutation was studied and he was clinically normal, showing normal OCT and full-field ERG results, but subnormal EOG and mfERG findings. The heterozygous carrier of the p.I201T mutation was clinically normal, showing normal OCT, EOG and full-field ERG results, but subnormal mfERG results. CONCLUSIONS: We have shown that the two novel combinations of compound heterozygous mutations p.R141H/p.M325T and p.R141H/p.I201T in the BEST1 gene can also lead to the ARB phenotype.

Genotype-phenotype correlations, and retinal function and structure in von Hippel-Lindau disease.

PURPOSE: To investigate genotype-phenotype correlation and to analyze functional and structural changes in the retina of patients with von Hippel-Lindau (VHL) disease. METHODS: Thirteen patients from four families (A, B, C and D) with known VHL disease and known mutations in the VHL gene were examined. All patients underwent clinical examination and optical coherence tomography (OCT). Full-field electroretinography (full-field ERG) was performed in twelve patients. RESULTS: Family A, with deletion of exon 3 in the VHL gene, and family B, with the missense mutation p.R79P, exhibited type 1 VHL characterized by the absence of pheochromocytoma and a high incidence of central nervous system hemangioblastomas. One member of family B exhibited Goldenhar syndrome. A novel missense mutation (p.L198P) was identified in the VHL gene in the patient from family C. This p.L198P mutation caused a phenotype with early onset of a neuroendocrine tumor of the pancreas, bilateral pheochromocytomas, and optic nerve hemangioblastoma. Full-field ERG showed significantly prolonged implicit times of the b-wave and maximal combined a-wave in VHL patients, compared to controls. Examination of the retinal structure in all patients with VHL, using OCT, showed a significant decrease in retinal thickness in VHL patients without ocular hemangioblastomas, compared to controls. CONCLUSIONS: Our findings support previously established genotype-phenotype correlations. However, we here describe an unusual phenotype with a novel missense mutation, p.L198P, and report the finding that VHL disease can be associated with Goldenhar syndrome. Electrophysiological and structural findings suggest that VHL disease is a progressive, neurodegenerative disease of the retina.

Clinical and electrophysiologic outcome in patients with neovascular glaucoma treated with and without bevacizumab.

PURPOSE: To investigate the clinical and electrophysiologic effect of a single intravitreal injection of bevacizumab for neovascular glaucoma (NVG) after ischemic central retinal vein occlusion (iCRVO). METHODS: Nineteen eyes from 19 patients with NVG secondary to iCRVO were randomly allocated to either an intravitreal bevacizumab injection and panretinal photocoagulation (PRP) (10 eyes) or PRP alone (9 eyes). The primary outcome measure was the change in the total retinal function 6 months after treatment, demonstrated by full-field electroretinography (ERG). Secondary outcomes included visual acuity, intraocular pressure (IOP), glaucoma medication, additional IOP-lowering treatment, and the presence of ocular neovascularization before treatment, and 1 week, 2 months, and 6 months after treatment. RESULTS: The regression of ocular neovascularization in the bevacizumab/PRP group was confirmed 1 week after injection. Patients in both study groups had very poor visual acuity at baseline. This remained unchanged. There was no significant difference in the mean IOP between the groups at any point in time. The a-wave amplitudes of combined rod-cone response were significantly decreased after 6 months in the bevacizumab/PRP group (p=0.028), compared with the baseline values. The a- and b-wave amplitudes of combined rod-cone response and the b-wave amplitudes of the 30-Hz flicker response were also markedly reduced compared with the PRP group (-60%, -43%, -47% vs +23%, -36%, -16%, respectively). CONCLUSIONS: This study suggests that intravitreal injection of bevacizumab is valuable in the treatment of NVG by hastening the resolution of neovascularization, while the full-field ERG results indicate that bevacizumab may reduce the photoreceptor function in NVG patients.

Anterior segment abnormalities and angle-closure glaucoma in a family with a mutation in the BEST1 gene and Best vitelliform macular dystrophy.

PURPOSE: To present the clinical and electrophysiological findings in four members of a family with Best vitelliform macular dystrophy (BVMD) and angle-closure glaucoma (ACG). METHODS: Four members of a family with BVMD were examined clinically, including visual acuity, slit-lamp examination, biomicroscopy, Goldmann applanation tonometry and gonioscopy. Measurements of the anterior chamber depth and axial length, visual field, optical coherence tomography, full-field electroretinography, multifocal electroretinography and electrooculography were performed. In addition molecular genetic analysis of the bestrophin-1 gene (BEST1), the microphthalmia-associated transcription factor gene (MITF) and the cone-rod homeobox gene (CRX) were performed. RESULTS: Four family members with the c.253T>C p.Y85H mutation in the BEST1 gene and BVMD in different stages also exhibited anterior segment abnormalities such as shallow anterior chambers (two cases), and reduced axial lengths in all cases. Microphthalmos (axial length ≤ 20mm) was found in the index patient and in her son. Hyperopia was found in all four examined patients. Closed angles/narrow angles were observed in patients with microphthalmos. The index patient developed ACG at the age of 12 years. Her son inherited microphthalmos, severe hyperopia, and narrow angles. He is at risk of developing ACG. No pathogenic mutation of the MITF or the CRX genes was detected in the index patient. CONCLUSIONS: BVMD could be associated with anterior segment abnormalities such as shallow anterior chambers, closed/narrow anterior chamber angles and ACG. Ophthalmologists should be aware of the association between ACG and BVMD. Examination of the anterior segment, gonioscopy and intraocular pressure control are recommended in patients with BVMD.

Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1.

PURPOSE: To describe morphological and functional changes in a single patient with multifocal Best vitelliform macular dystrophy (BVMD) and to perform a genotype/phenotype correlation. METHODS: The proband with multifocal BVMD and three of her family members were examined with electrooculography (EOG), full-field electroretinography (full-field ERG), multifocal electroretinography (mfERG) and optical coherence tomography (OCT). Genomic DNA was screened for mutation in the BEST1 gene by DNA sequencing analysis. RESULTS: The proband was observed regularly during a follow-up period of 4 years. Full-field ERG demonstrated reduced and delayed responses of both rods and cones. OCT demonstrated intra- and subretinal fluid which seemed to fluctuate with periods of stress, similar to that seen in chronic central serous chorioretinopathy. Two distinct heterozygous BEST1 mutations were identified in the proband, the recurrent p.R141H mutation and the p.P233A mutation. Heterozygous p.R141H mutations were also identified in two family members, while p.P233A was a de novo mutation. Abnormal EOG findings were observed in both the proband and in the carriers of p.R141H. Heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. CONCLUSIONS: The p.R141H mutation is frequently seen together with multifocal vitelliform retinopathy and biallelic mutations in BEST1. Our results show that carriers of the p.R141H mutation are clinically unaffected but present with abnormal EOG and full-field ERG findings. A patient with biallelic mutations of the BEST1 gene, causing multifocal BVMD with progressive, widespread functional disturbance of the retina, confirmed by full-field and mfERG is described.

Improved retinal function after trabeculectomy in glaucoma patients.

PURPOSE: To investigate retinal function after reduction of intraocular pressure (IOP) by filtration surgery in patients with medically uncontrolled glaucoma. METHODS: Eleven patients (11 eyes) with medically uncontrolled glaucoma underwent trabeculectomy. Clinical investigation, visual field (testing with standard automated perimetry (SAP-Humphrey), optical coherence tomography (OCT), full-field electroretinography (full-field ERG) and multifocal electroretinography (mfERG) were performed preoperatively as well as 2 and 6 months after surgery. DESIGN: Interventional prospective, consecutive case series. RESULTS: No significant reduction was seen in mean log MAR visual acuity 2 or 6 months after filtration surgery. The mean preoperative intraocular pressure of 27.1 (+/-6.2) mmHg decreased to 19.0(+/-6.1) mmHg 2 months after surgery and to 17.1 (+/- 3.4) mmHg 6 months after surgery (both p = 0.001). The reduction in IOP significantly decreased the number of anti-glaucoma agents used, from 3.7 +/- 1.6 at baseline to 0.8 +/- 0.9 2 months after surgery and to 1.3 +/- 1.2 6 months after surgery (p = 0.004 and p = 0.008 respectively). The results of SAP, OCT and full-field ERG did not show any significant difference between pre- and postoperative values at any point in time. No significant improvement was found with regard to the first positive peak (P(1)) amplitudes in the macular retina (area 1) or in the perimacular retina/periphery (area 2) when measured with mfERG 2 months after surgery. The mfERG examinations revealed significantly improved P(1) amplitudes 6 months after surgery in both area 1 and area 2, compared with the preoperative values (p = 0.042 and p = 0.014 respectively). The implicit time of P(1) decreased significantly 6 months after surgery in area 2 compared with the preoperative values (p = 0.023). CONCLUSION: A significant lowering of IOP seems to improve the function of the central retina, as demonstrated by increased amplitudes and reduced implicit times assessed with mfERG.

Electrophysiological evaluation and visual outcome in patients with central retinal vein occlusion, primary open-angle glaucoma and neovascular glaucoma.

PURPOSE: To evaluate patients with central retinal vein occlusion (CRVO) and neovascular glaucoma (NVG) using electrophysiology in order to gain better understanding of visual outcome and risk factors, such as previously diagnosed primary open-angle glaucoma (POAG). METHODS: Eighty-three patients (83 eyes) initially presenting with CRVO and examined with full-field electroretinography (ERG) within 3 months of the thrombotic event were analysed retrospectively regarding treatment, risk factors and visual outcome. In addition, 30 patients initially presenting with NVG caused by CRVO were also investigated regarding risk factors using electrophysiology in order to determine the cause of their visual impairment. RESULTS: Nineteen (23%) of the 83 patients initially presenting with CRVO had been diagnosed previously with POAG. Ninety-five per cent (18/19) of all the patients with previously diagnosed glaucoma developed ischaemic CRVO. Thirty-four per cent of the patients initially presenting with CRVO (28/83) developed NVG. Sixty-eight per cent (13/19) of the patients with previous glaucoma developed NVG, compared to 23% (15/64) of the patients without previous POAG. In the patients who initially presented with NVG, full-field ERG demonstrated a remaining retinal function of both cones and rods, indicating that the main cause of visual impairment is ischaemia of the ganglion cell layer. CONCLUSION: Glaucoma is a significant risk factor for developing ischaemic CRVO and subsequent NVG. The presence of POAG in CRVO worsens visual outcome. NVG is associated with preserved photoreceptor function, thus indicating ischaemia of the ganglion cell layer as the primary cause of visual impairment. This emphasizes the importance of prompt treatment of ischaemia and elevated intraocular pressure in these patients.