Study of Optimal Perimetric Testing In Children (OPTIC): Feasibility, reliability and repeatability of perimetry in children

Purpose: To investigate feasibility, reliability and repeatability of perimetry in children. Methods: A prospective, observational study recruiting 154 children aged 5-15 years, without an ophthalmic condition that affects the visual field (controls), identified consecutively between May 2012 and November 2013 from hospital eye clinics. Perimetry was undertaken in a single sitting, with standardised protocols, in a randomised order using the Humphrey static (SITA 24-2 FAST), Goldmann and Octopus kinetic perimeters. Data collected included test duration, subjective experience and test quality (incorporating examiner ratings on comprehension of instructions, fatigue, response to visual and auditory stimuli, concentration and co-operation) to assess feasibility and reliability. Testing was repeated within 6 months to assess repeatability. Results: Overall feasibility was very high (Goldmann=96.1%, Octopus=89% and Humphrey=100% completed the tests). Examiner rated reliability was ‘good’ in 125 (81.2%) children for Goldmann, 100 (64.9%) for Octopus and 98 (63.6%) for Humphrey perimetry. Goldmann perimetry was the most reliable method in children under 9 years of age. Reliability improved with increasing age (multinomial logistic regression (Goldmann, Octopus and Humphrey), p<0.001). No significant differences were found for any of the three test strategies when examining initial and follow-up data outputs (Bland-Altman plots, n=43), suggesting good test repeatability, although the sample size may preclude detection of a small learning effect. Conclusions: Feasibility and reliability of formal perimetry in children improves with age. By the age of 9 years, all the strategies used here were highly feasible and reliable. Clinical assessment of the visual field is achievable in children as young as 5 years, and should be considered where visual field loss is suspected. Since Goldmann perimetry is the most effective strategy in children aged 5-8 years and this perimeter is no longer available, further research is required on a suitable alternative for this age group

X-linked cataract and Nance-Horan syndrome are allelic disorders

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved

Leber Congenital Amaurosis Associated with AIPL1: Challenges in Ascribing Disease Causation, Clinical Findings, and Implications for Gene Therapy

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood

Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management.

PURPOSE: To describe the clinical features of children with anophthalmos, microphthalmos, and typical coloboma (AMC). DESIGN: Descriptive, observational, cross-sectional study of the United Kingdom. PARTICIPANTS: A total of 135 children with AMC newly diagnosed over an 18-month period beginning in October 2006. METHODS: Cases were identified using active surveillance through an established ophthalmic surveillance system. Eligible cases were followed up 6 months after first notification. MAIN OUTCOME MEASURES: Phenotypic characteristics, both ocular and systemic, clinical investigations, causes, and interventions. RESULTS: A total of 210 eyes (of 135 children) were affected by AMC, of which 153 had isolated coloboma or coloboma with microphthalmos. The most common colobomatous anomaly was a chorioretinal defect present in 109 eyes (71.2%). Some 44% of children were bilaterally visually impaired. Systemic abnormalities were present in 59.7% of children, with craniofacial anomalies being the most common. Children with bilateral disease had a 2.7 times higher odds (95% confidence interval, 1.3-5.5, P = 0.006) of having systemic involvement than unilaterally affected children. Neurologic imaging was the most frequent investigation (58.5%) performed. Less than one third (30.3%) of the children with microphthalmos had ocular axial lengths measured. Eight children had confirmed genetic mutations. Approximately half (49.2%) of the children required ocular intervention. CONCLUSIONS: Colobomatous defects were the most common phenotype within this spectrum of anomalies in the United Kingdom. The high frequency of posterior segment colobomatous involvement means that a dilated fundal examination should be made in all cases. The significant visual and systemic morbidity in affected children underlines the importance of a multidisciplinary approach to management

Anophthalmos, microphthalmos, and typical coloboma in the United Kingdom: a prospective study of incidence and risk.

PURPOSE: Anophthalmos, microphthalmos, and typical coloboma (AMC) form an interrelated spectrum of congenital eye anomalies that can cause significant visual loss and cosmetic disfigurement in children. This prospective study of children born in the United Kingdom was undertaken to determine the incidence of AMC diagnosed by ophthalmologists and to explore sociodemographic risks. METHODS: Recruitment was achieved though an established active surveillance system of U.K. ophthalmologists supported by a new research network of interested specialists, the Surveillance of Eye Anomalies (SEA-UK) Special Interest Group. It started October 1, 2006, and continued over 18 months. RESULTS: One hundred thirty-five children were newly diagnosed with AMC. Typical colobomatous defects were the commonest phenotype, and anophthalmos was rare (n = 7). Both eyes were affected in 55.5% of the children. The cumulative incidence of AMC by age 16 years was 11.9 per 100,000 (95% CI, 10.9-15.4). Of the children examined, 41.5% had not seen an ophthalmologist by 3 months of age. The incidence in Scotland was nearly double that in England and Wales. The children of Pakistani ethnicity had a 3.7 (95% CI, 1.9-7.5) times higher risk of AMC than did white children. There was some evidence to suggest a higher incidence in the more socioeconomically deprived. The sibling risk ratio was 210 (95% CI, 25-722). CONCLUSIONS: This is the first prospective study of AMC, and it establishes the frequency across the United Kingdom. Comparisons with data quoted in the literature are difficult because study methodologies differ, but the frequency appears to be lower than that quoted for other developed countries. There are geographic and ethnic variations in incidence that warrant further investigation

Rose diagrams of the frequency of points plotted along individual meridians for Goldmann and Octopus perimetry for children aged 5–6 years compared to 12–15 years.

<p>A larger area indicates a meridian with a larger number of plotted points. <i>*The empty sectors at 0° for Goldmann perimetry isopters III4e and I4e correspond to the ‘void’ area in the perimeter bowl</i>.</p

Proportion of EBAR (test quality) ratings per perimeter, by age groups.

<p>Proportion of EBAR (test quality) ratings per perimeter, by age groups.</p

Inclusion/exclusion criteria for participants.

<p>Inclusion/exclusion criteria for participants.</p