Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders

Introduction Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. Methods and results Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. Discussion We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms

Mutations in PRDM5 in Brittle Cornea Syndrome Identify a Pathway Regulating Extracellular Matrix Development and Maintenance

Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS. We show that ZNF469 and PRDM5, two genes that when mutated cause BCS, participate in the same regulatory pathway

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.</p