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.

Choroidal neovascular membrane in a treated choroidal hemangioma.

Association of choroidal neovascular (CNV) membrane with circumscribed choroidal hemangioma is rare, and the CNV development after photodynamic therapy (PDT) is also rare. Etiopathogenesis of these associations is poorly understood. We noted the development of CNV over choroidal hemangioma after PDT therapy in a young female patient in our hospital. Temporal association of CNV development after PDT treatment points toward the possible side effects of PDT. Repeat injections of antivascular endothelial growth factor (ranibizumab) regressed the CNV resulting in a favorable visual outcome.

Adult onset retinoblastoma.

Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes.

How genetics works: An illustrative case report.

In this communication, we report the case of a four year old boy who presented with reduced vision in the right eye. He had visual acuity of light perception right eye and 6/12 in the left eye and anterior segment examination was normal. Fundus examination of the right eye showed a falciform retinal fold extending from the optic nerve temporally involving the entire retina with exudates within the falciform fold and dense pigmentation peripherally. The left eye showed mild macular temporal dragging of the vessels and 360° of peripheral laser scars. In addition he also had some characteristic systemic features such as developmental delay, obesity, dysmorphic facies and tapered fingers. Using this case as an example, we present a systematic, logical approach to a patient with a possible genetic disorder. The growing field of ocular genetics now allows for improved diagnosis using stepwise cost efficient testing as demonstrated herein.

Genetic perspective of retinoblastoma: From present to future.

Retinoblastoma (RB) is the most common malignant intraocular tumor in children. In the last decade, basic research has led to a better understanding of events after two hits in RB susceptibility gene (RB1), molecular mechanism of tumor growth, the cell of origin of RB, etc. This would pave way to identify biomarkers and molecular targeted therapy for better treatment option in the future. Furthermore, improvement in molecular techniques has led to enhanced diagnostic methods for early diagnosis, genetic counseling, and prevention of the disease. This review will help to understand the essence of basic research work conducted in recent times and its implication in the management of RB in the future.

Eye wall resections for intraocular tumors: Our experience.

We conducted a retrospective review of 11 eyes undergoing eye wall resection between October 1998 and October 2009. The median age of 11 patients was 29 years. Decreased vision (eight) was the most common presenting symptom. Ciliary body medulloepithelioma was the most common clinical diagnosis (six). Medulloepithelioma was the most common histopathological diagnosis (four). The duration of follow-up ranged from 0.5 to 67 months (median 11 months). Three eyes needed to be enucleated in the postoperative period (margin involvement two eyes, recurrence one eye). Postoperative complications among others included retinal detachment (three), vitreous hemorrhage (three), cataract (two), and suprachoroidal hemorrhage (two). To conclude, prognosis of this procedure continues to be guarded needing close postoperative follow-up.

Brachytherapy of intra ocular tumors using ‘BARC I-125 Ocu-Prosta seeds’: An Indian experience.

Aim: To report our experience of brachytherapy using ‘BARC I‑125 Ocu‑Prosta seeds’ for the management of intraocular tumors with regard to tumor control, globe preservation visual outcome, and patient survival at Sankara Nethralaya, Chennai, India between September 2003 and May 2011. Materials and Methods: We reviewed records of 35 eyes of 35 patients who underwent ophthalmic brachytherapy between September 2003 and May 2011. Twenty‑one cases had choroidal melanoma, nine had childhood retinoblastoma, two had adult‑onset retinoblastoma, and there were one case each of vasoproliferative tumor, retinal angioma, and ciliary body melanoma. Brachytherapy was administered using a 15‑ or 20‑mm gold plaque with or without a notch. Brachytherapy was the primary treatment modality in all tumors other than retinoblastoma, wherein brachytherapy was done post chemoreduction for residual tumor. Results: For choroidal melanomas, the mean radiation dose was 68.69 ± 15.07 (range, 47.72-94.2) Gy. The eye salvage rate was 13/20 (65%) and tumor control rate was 16/20 (80%) at an average follow‑up of 24.43 ± 24.75 (range, 1.5-87.98) months. For retinoblastoma, the mean dose was 45.85 ± 3.90 (range, 39.51-50.92) Gy. The eye salvage rate and tumor control rate was 5/6 (83.3%) at an average follow‑up of 38.36 ± 31.33 (range, 4.14-97.78) months. All eyes with retinoblastoma needed additional focal therapy for tumor control and eye salvage. Conclusion: The results of this retrospective study confirms that the use of ‘BARC I‑125 Ocu‑Prosta seeds’ in episcleral plaques to treat intraocular tumors offers a viable option for the management of intraocular cancers.

Fifteen-year trends in indications for enucleation from a tertiary care center in South India.

Aim: To analyze the trends in clinicopathologic indications for enucleations over a 15-year period. Materials and Methods: Clinicopathologic details of all eyes that underwent enucleation from January 1996 to December 2010 were drawn up from a computerized database. The study was divided into three periods of 5 years each and comparison tables for each cause of enucleation during these periods were generated. Chi-square test was used to compare proportions. Results: Out of a total 1467 enucleations performed during the study period, 693 (46%) were attributable to retinoblastoma, 189 (12.5%) to uveal melanoma, 228 (15%) to trauma, and 149 (10%) to phthisis bulbi. Intraocular tumors accounted for more than 63% of all enucleations performed. Over the three time periods, proportion of enucleations secondary to retinoblastoma increased from 38% in the 1st period to 58% in the 3rd period (P < 0.001). Enucleations for trauma showed statistically significant reduction in trends over the three periods (24% in the 1st period vs. 4.4% in the 3rd period, P < 0.001). Similar trends were also seen in the proportion of enucleations due to intractable glaucoma and chronic uveitis. The absolute number of enucleations secondary to retinoblastoma out of the total cases seen during the study period did not change over the three periods (range 51–60%). Conclusion: Intraocular tumors were the commonest indications for enucleation in our patient population despite the availability of globe-conserving treatments such as chemotherapy and radioactive plaques. We observed increasing trends in the proportion of enucleations due to retinoblastoma and reduction of enucleations secondary to trauma, chronic uveitis, and glaucoma.

Uveal melanoma presenting as cataract and staphyloma.

Blind eyes can harbor a choroidal melanoma. We report a case of uveal melanoma presenting as staphyloma and complicated cataract in a 45-year-old female. The left eye was blind for six months. She underwent comprehensive ocular examination but fundus examination was precluded due to total cataract. The ultrasound of the eye showed a large mass filling the superior, nasal and inferonasal vitreous cavity with high surface reflectivity and low to moderate internal reflectivity. Magnetic resonance imaging (MRI) confirmed the diagnosis of choroidal melanoma. The patient underwent extended enucleation and histopathology was consistent with uveal melanoma.

Cystoid macular edema after bone marrow transplantation.

We report a case of cystoid macular edema in a patient who underwent bone marrow transplant for aplastic anemia. After having ruled out all the other causes of cystoid macular edema, we concluded that it was secondary to the bone marrow transplant. The patient had mild visual impairment and did not recover the lost vision. In this case report, we describe in detail the clinical presentation, follow-up, and course of medication that this patient had. It is an illustrated case report of cystoid macular edema after bone marrow transplant with mild visual impairment and no recovery.