Next-generation sequencing-based genetic testing and phenotype correlation in retinitis pigmentosa patients from India

Purpose: Inherited retinal dystrophies (IRD) are a heterogeneous group of retinal diseases leading to progressive loss of photoreceptors through apoptosis. Retinitis pigmentosa (RP) is considered the most common form of IRD. Panel?based testing in RP has proven effective in identifying the causative genetic mutations in 70% and 80% of the patients. This is a retrospective, observational, single?center study of 107 RP patients who had undergone next?generation sequencing?based targeted gene panel testing for IRD genes. These patients were inspected for common phenotypic features to arrive at meaningful genotype–phenotype correlation. Methods: Patients underwent complete ophthalmic examination, and blood was collected from the proband for DNA extraction after documenting the pedigree. Targeted Next Generation Sequencing (NGS) was done by panel?based testing for IRD genes followed by co?segregation analysis wherever applicable. Results: Of the 107 patients, 72 patients had pathogenic mutations. The mean age of onset of symptoms was 14 ± 12 years (range: 5–55). Mean (Best Corrected Visual Acuity) BCVA was 6/48 (0.9 logMAR) (range 0.0–3.0). At presentation, over one?third of eyes had BCVA worse than 6/60 (<1 logMAR). Phenotype analysis with the gene defects showed overlapping features, such as peripheral well?defined chorioretinal atrophic patches in patients with CERKL, PROM1, and RPE65 gene mutations and large macular lesions in patients with RDH12 and CRX gene mutations, respectively. Nummular or clump?like pigmentation was noted in CRB1, TTC8, PDE6A, and PDE6B. Conclusion: NGS?based genetic testing can help clinicians to diagnose RP more accurately, and phenotypic correlations can also help in better patient counselling with respect to prognosis and guidance regarding ongoing newer gene?based therapies.

Choriocapillaris flow deficits in polypoidal choroidal vasculopathy using swept source optical coherence tomography angiography

Purpose: To evaluate the choriocapillaris flow deficits (CCFD) on swept-source optical coherence tomography angiography (SS-OCTA) in eyes with unilateral polypoidal choroidal vasculopathy (PCV), fellow unaffected eyes, and to compare them with age-matched healthy controls. Methods: This study was a cross-sectional study which included treatment-naïve eyes with unilateral PCV (group 1), fellow unaffected eyes of patients with PCV (group 2), and normal eyes (group 3). Using the SS-OCTA, the Choriocapillaris (CC) slab was segmented from the structural optical coherence tomography (OCT) and the corresponding flow map was multiplied after signal compensation. The resultant image was evaluated for CCFD in equidistant squares measuring 1 × 1 mm, 1.5 × 1.5 mm, 2 × 2 mm, 2.5 × 2.5 mm, 3 × 3 mm, and 6 × 6 mm centered on the fovea. Results: The percentage of flow deficits were significantly increased (one-way ANOVA, P = 0.003 and P = 0.049) in the eyes with PCV as compared to the fellow eyes, and age-matched healthy controls. In the multiple pairwise comparison using post hoc Bonferroni, CCFD of 1 mm in group 1 and 2 (P = 0.019), group 1 and 3 (P = 0.003), and CCFD of 1.5 mm in group 1 and 3 (P = 0.044) were statistically significant. Correlation analysis showed no significant correlation between CCFD, age, Best corrected visual acuity (BCVA), foveal thickness (FT), and subfoveal choroidal thickness (SFCT) in our study. Linear regression analysis showed that the CCFD was negatively correlated with the distance from the foveal center in group 1 (? = ?0.613, P = 0.046). Conclusion: Eyes with PCV demonstrated a significant flow impairment in the choriocapillaris layer as compared to the fellow unaffected eyes and age-matched healthy eyes.

Bardet–Biedl syndrome: Genetics, molecular pathophysiology, and disease management.

Primary cilia play a key role in sensory perception and various signaling pathways. Any defect in them leads to group of disorders called ciliopathies, and Bardet–Biedl syndrome (BBS, OMIM 209900) is one among them. The disorder is clinically and genetically heterogeneous, with various primary and secondary clinical manifestations, and shows autosomal recessive inheritance and highly prevalent in inbred/consanguineous populations. The disease mapped to at least twenty different genes (BBS1-BBS20), follow oligogenic inheritance pattern. BBS proteins localizes to the centerosome and regulates the biogenesis and functions of the cilia. In BBS, the functioning of various systemic organs (with ciliated cells) gets deranged and results in systemic manifestations. Certain components of the disease (such as obesity, diabetes, and renal problems) when noticed earlier offer a disease management benefit to the patients. However, the awareness of the disease is comparatively low and most often noticed only after severe vision loss in patients, which is usually in the first decade of the patient’s age. In the current review, we have provided the recent updates retrieved from various types of scientific literature through journals, on the genetics, its molecular relevance, and the clinical outcome in BBS. The review in nutshell would provide the basic awareness of the disease that will have an impact in disease management and counseling benefits to the patients and their families.

Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy.

Purpose: To investigate the effect of optic neuritis (ON), ischemic optic neuropathy (ION) and compressive optic neuropathy (CON) on multifocal visual evoked potential (mfVEP) amplitudes and latencies, and to compare the parameters among three optic nerve disorders. Materials and Methods: mfVEP was recorded for 71 eyes of controls and 48 eyes of optic nerve disorders with subgroups of optic neuritis (ON, n = 21 eyes), ischemic optic neuropathy (ION, n = 14 eyes), and compressive optic neuropathy (CON, n = 13 eyes). The size of defect in mfVEP amplitude probability plots and relative latency plots were analyzed. The pattern of the defect in amplitude probability plot was classified according to the visual field profile of optic neuritis treatment trail (ONTT). Results: Median of mfVEP amplitude (log SNR) averaged across 60 sectors were reduced in ON (0.17 (0.13‑0.33)), ION (0.14 (0.12‑0.21)) and CON (0.21 (0.14‑0.30)) when compared to controls. The median mfVEP relative latencies compared to controls were significantly prolonged in ON and CON group of 10.53 (2.62‑15.50) ms and 5.73 (2.67‑14.14) ms respectively compared to ION group (2.06 (‑4.09‑13.02)). The common mfVEP amplitude defects observed in probability plots were diffuse pattern in ON, inferior altitudinal defect in ION and temporal hemianopia in CON eyes. Conclusions: Optic nerve disorders cause reduction in mfVEP amplitudes. The extent of delayed latency noted in ischemic optic neuropathy was significantly lesser compared to subjects with optic neuritis and compressive optic neuropathy. mfVEP amplitudes can be used to objectively assess the topography of the visual field defect.

Photodynamic monotherapy or combination treatment with intravitreal triamcinolone acetonide, bevacizumab or ranibizumab for choroidal neovascularization associated with pathological myopia.

This retrospective, interventional case series analyses treatment outcomes in eyes with choroidal neovascularization (CNV) secondary to pathological myopia, managed with photodynamic therapy, (PDT), (Group 1, N = 11), PDT and intravitreal triamcinolone acetonide (4 mg/0.1ml) (Group 2, N = 3), PDT and intravitreal anti-vascular endothelial growth factor (anti-VEGF) bevacizumab 1.25 mg/0.05 ml, ranibizumab 0.5 mg/0.05 ml and reduced-fluence PDT and intravitreal ranibizumab 0.5 mg/0.05 ml (Group 3, N=12). All the patients underwent PDT. Intravitreal injections were repeated as required. SPSS 14 software was used to evaluate the data. Wilcoxon signed ranks test was used to evaluate pre- and post-treatment vision. The Kruskal-Wallis test was used for comparison between the groups. All the groups were statistically comparable. All the eyes showed complete regression of CNV, with a minimum follow-up of six months. All groups had visual improvement; significantly in Group 3 (P = 0.003). Combination PDT with anti-VEGF agents appeared to be efficacious in eyes with myopic CNV. However, a larger study with a longer follow-up is required to validate these results.

Coats' disease: An Indian perspective.

Aim: To describe the clinical features, treatment and outcome patterns in 307 eyes with Coats' disease. Materials and Methods: Retrospective chart review of patients diagnosed with Coats' disease between January 1996 and January 2006 from a single referral center in southern India. Results: Two hundred and eighty patients (307 eyes) with mean age of 15.67 years (range: Four months-80 years) were included. Decreased vision (77%), unilateral affection (90%) and male preponderance (83.4%) were chief presenting features. Anterior segment involvement was seen in 67 (21.8%) eyes. Retinal telangiectasia were seen in 302 (99%) eyes, exudation in 274 (89%) eyes and retinal detachment in 158 (51.5%) eyes. Four-quadrant disease was seen in 207 (67.2 %) eyes. Visual acuity was < 20/200 in 249 (80.9%) eyes. One hundred and nine of 176 treated eyes (61.93%) had favorable anatomical outcome; 207 of 280 eyes (74%) had an optimal structural outcome. Seventeen (5.3%) eyes were enucleated. Complications following treatment included phthisis bulbi (7%), neovascular glaucoma (5%), epiretinal membrane (4.4%) and rubeosis iridis (4.4%). Conclusion: Indian patients with Coats' disease have a high male predominance, the majority of whom present with severe visual impairment and extensive four-quadrant exudation. Unusual presentations such as pain, vitreous hemorrhage and a high incidence of anterior segment involvement are distinctive to Indian eyes.