Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicentre, randomised controlled trial.

BACKGROUND: Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial. METHODS: EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference ≥0·30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, ≤0·20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting. FINDINGS: Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0·019) after 12 weeks of patching. No serious adverse events related to the interventions occurred. INTERPRETATION: The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments. FUNDING: Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation.

Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability.

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. X-linked ID (XLID) disorders, caused by defects in genes on the X chromosome, affect 1.7 out of 1,000 males. Employing exome sequencing, we identified three missense mutations (c.475C>G; p.H159D, c.1373C>A; p.T458N, and c.1585G>A; p.E529K) in the SRPK3 gene in seven XLID patients from three independent families. Clinical features common to the patients are intellectual disability, agenesis of the corpus callosum, abnormal smooth pursuit eye movement, and ataxia. SRPK proteins are known to be involved in mRNA processing and, recently, synaptic vesicle and neurotransmitter release. In order to validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. In day 5 of larval stage, KO zebrafish showed significant defects in spontaneous eye movement and swim bladder inflation. In adult KO zebrafish, we found agenesis of cerebellar structures and impairments in social interaction. These results suggest an important role of SRPK3 in eye movements, which might reflect learning problems, intellectual disability, and other psychiatric disorders.

Retinal Development in Infants and Young Children With Albinism: Evidence for Plasticity in Early Childhood.

MEETING PRESENTATION: Presented at the 2016 Association for Research in Vision and Ophthalmology meeting and at the 2015 British Isles Paediatric, Ophthalmology and Strabismus Association meeting. PURPOSE: To investigate the time course of foveal development after birth in infants with albinism. DESIGN: Prospective, comparative cohort optical coherence tomography study. METHODS: Thirty-six children with albinism were recruited. All participants were between 0 and 6 years of age and were seen at Leicester Royal Infirmary. A total of 181 mixed cross-sectional and longitudinal optical coherence tomography examinations were obtained, which were analyzed for differences in retinal development in comparison to 297 cross-sectional control examinations. RESULTS: Normal retinal development involves migration of the inner retinal layers (IRLs) away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the outer retinal layers (ORLs) over time. In contrast to controls where IRL migration from the fovea was almost completed at birth, a significant degree of IRL migration was taking place after birth in albinism, before arresting prematurely at 40 months postmenstrual age (PMA). This resulted in a significantly thicker central macular thickness in albinism (Δ = 83.8 ± 6.1, P < .0001 at 69 months PMA). There was evidence of ongoing foveal ORL elongation in albinism, although reduced in amplitude compared with control subjects after 21 months PMA (Δ = -17.3 ± 4.3, P < .0001). CONCLUSIONS: We have demonstrated evidence of ongoing retinal development in young children with albinism, albeit at a reduced rate and magnitude compared with control subjects. The presence of a period of retinal plasticity in early childhood raises the possibility that treatment modalities, which aim to improve retinal development, could potentially optimize visual function in albinism.

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Discordant phenotypes in twins with infantile nystagmus.

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Current and emerging treatments for albinism.

Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis. The reduction of melanin synthesis leads to hypopigmentation of the skin and eyes. A wide range of ophthalmic manifestations arise from albinism, including reduction of visual acuity, nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm. Currently, albinism is incurable, and treatment aims either surgically or pharmacologically to optimize vision and protect the skin; however, novel therapies that aim to directly address the molecular errors of albinism, such as l-dihydroxyphenylalanine and nitisinone, are being developed and have entered human trials though with limited success. Experimental gene-based strategies for editing the genetic errors in albinism have also met early success in animal models. The emergence of these new therapeutic modalities represents a new era in the management of albinism. We focus on the known genetic subtypes, clinical assessment, and existing and emerging therapeutic options for the nonsyndromic forms of albinism.

Does the EyeChart App for iPhones Give Comparable Measurements to Traditional Visual Acuity Charts?

AIM: To investigate if the EyeChart app gives accurate visual acuity (VA) measurements that are comparable to those achieved using traditional VA charts. METHOD: Twenty-four participants (aged 18-27 years, mean 20.13 ± 1.78 years) with VA of 6/60 Snellen or better regardless of any strabismus, amblyopia, or ocular pathology volunteered for this prospective study. The best-corrected monocular VA of each participant's right eye was measured on the Snellen chart at 6 m, the ETDRS chart at 3 m, and the EyeChart app presented on an iPhone SE at 1.2 m (4ft). RESULTS: The mean VA scores obtained were: -0.13 ± 0.08 logMAR on the Snellen chart, -0.11 ± 0.08 logMAR on the ETDRS chart, and -0.09 ± 0.07 logMAR on the EyeChart app. After Bonferroni Correction adjustments were applied, a significant difference was found between the EyeChart app and the Snellen chart (t = -3.756, p = 0.003), however the difference between the EyeChart app and the ETDRS chart did not reach statistical significance (t = -2.391, p = 0.076). The EyeChart app had a strong correlation with both the Snellen (r = 0.79, p < 0.01) and ETDRS charts (r = 0.88, p < 0.01). The Coefficients of Agreement revealed a variation of less than one logMAR line between the EyeChart app and the traditional VA charts (Snellen: 0.09 logMAR; ETDRS: 0.08 logMAR). CONCLUSION: This study found that the EyeChart app gives accurate VA scores that are comparable to those achieved using the gold-standard ETDRS chart in a healthy young adult population. However, the accuracy and repeatability of the EyeChart app when testing a patient population must be investigated before it can be integrated into clinical practice.

Recurrent Rare Copy Number Variants Increase Risk for Esotropia.

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia. Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints. Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4-14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications. Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Congenital monocular elevation deficiency associated with a novel TUBB3 gene variant.

BACKGROUND: The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality. METHODS: Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members. RESULTS: Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell's phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of TUBB3 revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of ß-tubulin and is one of three putative kinesin binding sites. CONCLUSION: We show that familial MED can arise from a TUBB3 variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for TUBB3 mutation screening.

Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

The treatment of amblyopia: current practice and emerging trends.

PURPOSE: The purpose of this review is to provide an update on current management and recent research for amblyopia treatment. Part I will review patching, atropine penalization, and pharmacological treatments. Part II will focus on perceptual learning, video gaming, and binocular dichoptic approaches. METHODS: A literature search was performed in PubMed, ClinicalTrials.gov , Google Scholar, and reference lists of retrieved articles until December 20, 2018, for all papers containing "amblyopia treatment" or "amblyopia therapy." We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS: The mainstay of treatment for amblyopia has been based on increasing visual stimulation of the amblyopic eye by occlusion, atropine, or optical penalization of the dominant eye. It has been established that refractive adaptation alone can significantly enhance visual acuity. However, the duration of optical correction varies between studies and the effectiveness of spectacle wear over early beginning of patching is still under investigation. Additionally, by means of occlusion dose monitors, it was found that adherence to occlusion affects the outcome, as a dose-response relationship exists between adherence and visual acuity. Treatment efficiency declines with age; however, recent evidence indicates cortical plasticity beyond the "critical period" and recommends that an attempt at treatment should be offered to all amblyopic children regardless of age, including those in later childhood. Novel approaches targeted to the restoration of binocular functions, such as perceptual learning, video gaming, and dichoptic training, have shown small effects on visual acuity and have failed to demonstrate non-inferiority over standard treatments. CONCLUSIONS: On review, significant evidence for the successful management of amblyopia, with occlusion therapy and atropine, has been found. However, the management of amblyopia remains challenging, mainly due to compliance issues and suboptimal treatment outcomes during occlusion and atropine penalization. Recent studies have found evidence of new ways of treating amblyopia particularly in regard to binocular treatment although these remain under investigation. Further robust clinical trials on these new treatment modalities are still warranted in order to establish their role in treating amblyopia.

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect.

Purpose: To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods: White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results: A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions: This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.

The Effects of Feedback on Adherence to Treatment: A Systematic Review and Meta-analysis of RCTs.

CONTEXT: The aim of this systematic review is to determine whether providing feedback, guided by subjective or objective measures of adherence, improves adherence to treatment. EVIDENCE ACQUISITION: Data sources included MEDLINE, Embase, CINAHL, and PsycINFO, and reference lists of retrieved articles. Only RCTs comparing the effect of feedback on adherence outcome were included. Three independent reviewers extracted data for all potentially eligible studies using an adaptation of the Cochrane Library data extraction sheet. The primary outcome, change in adherence, was obtained by measuring the difference between adherence at baseline visit (prior to feedback) and at the last visit (post-feedback). EVIDENCE SYNTHESIS: Twenty-four studies were included in the systematic review, and 16 found a significant improvement in adherence in the intervention group (change in adherence range, -13% to +22%), whereas adherence worsened in the control group (change in adherence range, -32% to 10.2%). Meta-analysis included six studies, and the pooled effect showed that mean percentage adherence increased by 10.02% (95% CI=3.15%, 16.89%, p=0.004) more between baseline and follow-up in the intervention groups compared with control groups. Meta-regression confirmed that study quality, form of monitoring adherence, delivery of feedback, or study duration did not influence effect size. CONCLUSIONS: Feedback guided by objective or subjective measures of adherence improves adherence and, perhaps more importantly, prevents worsening of adherence over time even when only small absolute improvements in adherence were noted. Increased use of feedback to improve treatment adherence has the potential to reduce avoidable healthcare costs caused by non-adherence.

Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing.

Infantile nystagmus (IN) is a genetically heterogeneous disorder arising from variants of genes expressed within the developing retina and brain. IN presents a diagnostic challenge and patients often undergo numerous investigations. We aimed to develop and assess the utility of a next-generation sequencing (NGS) panel to enhance the diagnosis of IN. We identified 336 genes associated with IN from the literature and OMIM. NimbleGen Human custom array was used to enrich the target genes and sequencing was performed using HiSeq2000. Using reference genome material (NA12878), we show the sensitivity (98.5%) and specificity (99.9%) of the panel. Fifteen patients with familial IN were sequenced using the panel. Two authors were masked to the clinical diagnosis. We identified variants in 12/15 patients in the following genes: FRMD7 (n=3), CACNA1F (n=2), TYR (n=5), CRYBA1 (n=1) and TYRP1 (n=1). In 9/12 patients, the clinical diagnosis was consistent with the genetic diagnosis. In 3/12 patients, the results from the genetic diagnoses (TYR, CRYBA1 and TYRP1 variants) enabled revision of clinical diagnoses. In 3/15 patients, we were unable to determine a genetic diagnosis. In one patient, copy number variation analysis revealed a FRMD7 deletion. This is the first study establishing the clinical utility of a diagnostic NGS panel for IN. We show that the panel has high sensitivity and specificity. The genetic information from the panel will lead to personalised diagnosis and management of IN and enable accurate genetic counselling. This will allow development of a new clinical care pathway for IN.

Association Between Adherence to Glasses Wearing During Amblyopia Treatment and Improvement in Visual Acuity.

IMPORTANCE: Occlusion dose monitors have helped establish that better adherence to occlusion is associated with improved visual outcomes in patients undergoing amblyopia treatment. However, the role of adherence to glasses wearing is unknown. OBJECTIVES: To establish the feasibility and reliability of objectively monitoring adherence to glasses wearing using age-based norms, establish the association between adherence to glasses wearing and improvement in visual acuity (VA) after optical treatment and occlusion therapy, and analyze the effect of age, sex, refractive errors, type of amblyopia, and adherence to glasses wearing on improvement in VA. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, nonmasked, cohort study was conducted between June 8, 2008, and June 30, 2013, among patients at a pediatric ophthalmology clinic of a tertiary care hospital who were newly diagnosed with anisometropic and/or strabismic amblyopia and had not undergone previous treatment. The study consisted of a glasses phase (18 weeks) and a patching phase (glasses and occlusion for 10 hours per day for 12 weeks). Reliability of the glasses monitors was assessed by comparing diary entries and monitor recordings in adults. INTERVENTIONS: Objective monitoring of glasses wearing and occlusion. MAIN OUTCOMES AND MEASURES: Adherence to glasses wearing (hours per day) and effect on VA. RESULTS: Among 20 children with anisometropia (mean [SD] age, 6.20 [2.16] years; 11 boys and 9 girls) and 20 with strabismic or mixed amblyopia (mean [SD] age, 4.90 [1.36] years; 10 boys and 10 girls), adherence to glasses wearing was successfully monitored in all but 1 patient. Agreement between diaries and monitored times wearing glasses in adults was high (intraclass correlation coefficient, 1.00; 95% CI, 0.999-1.00). Median (SD) adherence to glasses wearing was 70% (25.3%). A moderate correlation was observed between adherence to glasses wearing and percentage improvement in VA during the glasses phase (r = 0.462; P = .003). Multiple regression revealed that age (ß = -0.535; P = .001), type of amblyopia (ß = -0.347; P = .02), and adherence to glasses wearing (ß = 0.287; P = .04) were independently associated with improvement in VA after the glasses phase and explained 42% of the variability (F3,35 = 8.457; P < .001). A strong correlation between glasses wearing and occlusion adherence was observed (r = 0.719; P < .001). CONCLUSIONS AND RELEVANCE: The results suggest that adherence to glasses wearing is less than optimal and highly variable but is important in achieving good VA. This study emphasizes the importance of encouraging children to not only have good adherence to occlusion therapy but also to glasses wearing.