Farrah Islam

Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140

PURPOSE Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated retinal dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study. METHODS Five probands and available affected family members underwent detailed phenotyping including retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells. RESULTS Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism. CONCLUSIONS This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder retinal dystrophy than that associated with the syndromic disease.

Clinical and Genetic Features of Choroideremia in Childhood

PURPOSE To review the functional and anatomic characteristics of choroideremia in the pediatric population, aiming to describe the earliest features of the disease and to identify biomarkers useful for monitoring disease progression. DESIGN Retrospective case series. PARTICIPANTS Children diagnosed with choroideremia at a single institution. METHODS Patients were identified using an electronic patient record system. Case notes and retinal imaging (color fundus photography [CFP], spectral-domain [SD] optical coherence tomography [OCT], and fundus autofluorescence [FAF]) then were reviewed. The results of genetic testing also were recorded. MAIN OUTCOME MEASURES Presenting symptoms, visual acuity, fundus changes (CFP, SD OCT, FAF), and CHM sequencing results. RESULTS Twenty-nine patients were identified with a mean age at referral of 9 years (range, 3-16 years). CHM mutations were identified in 15 of 19 patients tested. Nyctalopia was the predominant symptom (66%). Five of 29 patients were asymptomatic at presentation. At the final follow-up visit (mean age, 16 years; range, 7-26 years), most maintained excellent visual acuity (mean, 0.98±0.13 decimalized Snellen acuity). The first sign of retinopathy was widespread pigment clumping at the level of the retinal pigment epithelium (RPE). This later evolved to chorioretinal atrophy, most marked in the mid-peripheral retina. Peripapillary atrophy also was an early feature and was progressive in nature. Three different zones of FAF change were visible. Persistence of the inner retinal layers, detected by SD OCT, was visible at presentation in 15 of 27 patients. Subfoveal choroidal thickness decreased with age, whereas central retinal thickness increased over a similar interval. Four patients in whom visual acuity decreased over the follow-up period recorded a reduction in central retinal thickness. CONCLUSIONS Progressive structural changes occur at a time when central visual function is maintained. Pigmentary changes at the level of the RPE occur early in the disease course. Peripapillary chorioretinal atrophy, central retinal thickness, and subfoveal choroidal thickness are likely to be valuable in monitoring disease progression and should be considered as potential biomarkers in future therapeutic trials.

Vitamin A deficiency due to bi-allelic mutation of RBP4: There’s more to it than meets the eye

ABSTRACT Vitamin A deficiency is the leading cause of preventable blindness in children worldwide and results in a well-recognized ocular phenotype. Herein we describe a patient presenting to the eye clinic with a retinal dystrophy and ocular colobomata. This combination of clinical signs and consanguineous pedigree structure suggested a genetic basis for the disease, a hypothesis that was tested using whole genome sequencing. Bi-allelic mutations in RBP4 were identified (c.248+1G>A), consistent with a diagnosis of inherited vitamin A deficiency. We describe a constellation of signs that appear to be characteristic for this disease, increasing clinical awareness of this rare condition.

FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY.

Purpose: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). Methods: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. Results: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8–6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6–72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1–10). The median gain in visual acuity was greater in the treated versus the observed group—0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P < 0.05 Mann–Whitney U test). Although a significant reduction in central macular thickness was evident in both groups, 150 &mgr;m (treated) and 104 &mgr;m (observed), active treatment was not associated with greater thinning than observation (P > 0.05 Mann–Whitney U test). Conclusion: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone.

Detailed Retinal Imaging In Carriers Of Ocular Albinism

Background: Albinism refers to a group of disorders primarily characterized by hypopigmentation. Affected individuals usually manifest both ocular and cutaneous features of the disease, but occasionally hair and skin pigmentation may appear normal. This is the case in ocular albinism, an X chromosome linked disorder resulting from mutation of GPR143. Female carriers may be recognized by a “mud-splatter” appearance in the peripheral retina. The macula is thought to be normal, however. Methods: Obligate female carriers of pathogenic GPR143 alleles were recruited. Molecular confirmation of disease was performed only for atypical cases. Detailed retinal imaging was performed (colour fundus photography, optical coherence tomography, fundus autofluorescence. Results: Eight individuals were ascertained. A novel GPR143 mutation was identified in one family (p.Gln328Ter). Foveal fundus autofluorescence was subjectively reduced in 6/6 patients imaged. A “tapetal-like” pattern of autofluorescence was visible at the macula in 3/6. Persistence of the inner retinal layers at the fovea was observed in 6/8 females. Conclusion: Female carriers of ocular albinism may manifest signs of retinal pigment epithelium mosaicism at the macula and the peripheral fundus. A tapetal-like reflex on fundus autofluorescence may be considered the macular correlate of “mud-splatter.”

Safety profile and efficacy of tacrolimus in the treatment of birdshot retinochoroiditis: a retrospective case series review

Aim Evaluation of the use of tacrolimus in the treatment of birdshot retinochoroiditis (BRC) at a tertiary referral centre with the aim to describe its safety and efficacy. Methods The medical records of 25 patients diagnosed with BRC at uveitis service, Moorfields Eye Hospital, and who had received tacrolimus treatment were retrospectively reviewed. The main outcome measures of the study were (1) safety of tacrolimus in terms of side effects and (2) efficacy, as measured both by control of inflammation and visual function assessed by Humphrey visual fields and electrophysiological testing over at least 6 months and then 1 year. Results Tacrolimus was commenced in 25 patients (mean age 50.4±10.8 years) and was well tolerated in 21 patients (84%). It was necessary to stop the tacrolimus in four patients. No patient showed major changes in renal function: 3/21 patients (14.28%) showed slightly abnormal (less than 30%) function at the end of the first month of treatment; 1/21 (4.76%) patients at 3 months, but at the end of a 6-month treatment period only 1/21 patients (4.76%) showed minor abnormality in renal function. The mean daily prednisolone dose was 19.7 mg at the beginning of the study, which had fallen to 6.9 mg at the end (t=5.071, p=0.001). Visual acuity mostly remained stable. Visual fields improved over time (mean improvement in Humphrey mean deviation, right eye=1.8±2.4 dB, t=3.821, p=0.004; left eye=1.9±2.7, dB, t=3.06, p=0.007). Electrophysiological function showed improvement in 10 patients, and in four patients an initial deterioration in function improved following tacrolimus dose adjustment. Conclusion Tacrolimus has a good safety profile for long-term use in patients with BRC as a second-line agent enabling steroid sparing and visual function stabilisation or improvement.