The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Aetiologies of acquired paediatric sixth nerve palsies in a U.K. based population

Introduction: Due to the low incidence of sixth cranial nerve palsies in children there has been limited evidence published on this subject, especially from a U.K. based population. The incidence of aetiologies has been found to vary within the literature, especially with regards to neoplasms. The main aim of this study is to present the aetiologies of newly diagnosed paediatric sixth nerve palsies in a U.K based population. We also consider how the patients initially presented and if these palsies were isolated or associated with other neurological signs or symptoms.Methods: Retrospective data collection was carried out on the medical records of fifty paediatric patients who presented to a large tertiary referral hospital in the South of the U.K with new onset sixth nerve palsy between 1st January 2007 and 31st December 2017. Data collected included: age, gender, ethnicity, unilateral versus bilateral, other signs and symptoms, aetiology, where patient first presented and whether the sixth was the first presenting featureResults: Thirty-three (66%) patients had a sixth nerve palsy in conjunction with other neurological signs or symptoms and were considered non-isolated. Seventeen cases (34%) were found to be isolated. Aetiologies included high intracranial pressure (18%), neoplasm (14%), surgery for neoplasm (14%), viral (14%), infection (12%), trauma (8%), idiopathic (6%), benign space occupying lesion (4%), congenital (2%), inflammation (2%), Alexander disease (2%), Kawasaki syndrome (2%), diabetes (2%). Conclusion: Our study found non-isolated sixth nerve palsies to be the most common presentation, with these patients having a high number of potentially sinister aetiologies with the most common being high intracranial pressure followed by post-surgery for neoplasm and neoplasm. Isolated sixth nerve palsies were more commonly due to viral or idiopathic aetiology, however two cases of benign space occupying lesion and one of neoplasm were still identified using neuroimaging. <br/

A novel method for examining corneal endothelial cell morphology in infants

Previous studies suggest that central corneal endothelial cell density (ECD) decreases from 6,100 cells/mm2 in neonates to 3,100 cells/mm2 in 10-year-olds. Currently, there is very sparse data regarding ECD in young children as well as the trend in which ECD decreases during childhood. This is because young children were unable to comply with existing clinic-based specular microscopes. Hence, we developed a novel method of imaging young children intra-operatively to help establish age-specific normative data for ECD and hexagonality of cells (%HEX). Children were either imaged using our novel technique whilst under general anesthesia (GA) or awake in clinic using a child friendly technique. 58 children were recruited (mean age: 5.50; range: 0.44-10.36). Our cohort displayed a significant linear decrease in ECD with age (r= -0.56, P&lt;0.001). No correlation was found between %HEX and age (r=-0.10, P=0.48). We show that using a modern specular microscope and a relatively simple technique, it is possible to collect images from young infants and children

Beyond visual acuity: development of a simple test of the slow-to-see phenomenon in children with infantile nystagmus syndrome

Purpose: conventional static visual acuity testing profoundly underestimates the impact of infantile nystagmus on functional vision. The slow-to-see phenomenon explains why many patients with nystagmus perform well in non-time restricted acuity tests but experience difficulty in certain situations. This is often observed by parents when their child struggles to recognise familiar faces in crowded scenes. A test measuring more than visual acuity could permit a more real-world assessment of visual impact and provide a robust outcome measure for clinical trials. Methods:  children with nystagmus and, age and acuity matched controls attending Southampton General Hospital were recruited for two tasks. In the first, eye-tracking measured the time participants spent looking at an image of their mother when alongside a stranger, this was then repeated with a sine grating and a homogenous grey box. Next, a tablet-based app was developed where participants had to find and press either their mother or a target face from up to 16 faces. Here, response time was measured. The tablet task was refined over multiple iterations. Results: in the eye-tracking task, controls spent significantly longer looking at their mother and the grating (P&lt;0.05). Interestingly, children with nystagmus looked significantly longer at the grating (P&lt;0.05) but not their mother (P&gt;0.05). This confirmed a facial target was key to further development. The tablet-based task demonstrated that children with nystagmus take significantly longer to identify the target; this was most pronounced using a 3-minute test with 12-face displays. Conclusion: this study has shown a facial target is key to identifying the time-to-see deficit in infantile nystagmus and provides the basis for an outcome measure for use in clinical treatment trials