Micronutrient Deficiencies Presenting with Optic Disc Swelling Associated with or without Intracranial Hypertension:A Systematic Review

Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by optic disc swelling secondary to raised intracranial pressure (ICP) of unknown cause. Obesity is the most established and prevalent risk factor in developed countries. As obesogenic diets are high in calories and nutrient-poor, there may be associated nutritional deficiencies that contribute to the clinical presentation of IIH. Yet none, aside from iron deficiency, are currently included in the inclusion or exclusion criteria for the diagnosis of IIH. Our primary aim was to determine which micronutrient deficiencies, aside from iron deficiency, could present with optic disc swelling associated with or without intracranial hypertension that could potentially meet current IIH diagnostic criteria. To this end, we conducted a systematic search of articles published between 1 January 1980 and 18 December 2020 reporting cases of optic disc swelling associated with micronutrient deficiencies. In total, 65 cases met the eligibility criteria from initial searches: all were case reports and case series with a high risk of bias. Our findings suggest that patients with IIH or unexplained optic disc swelling ought to be screened, investigated, and treated for associated micronutrient deficiencies in vitamin A, B1 and B12; and weight loss interventions in IIH patients ought to promote better nutrition in addition to overall calorie restriction

Joubert Syndrome Presenting with Motor Delay and Oculomotor Apraxia

We describe two sisters who presented in early childhood with motor delay and unusual eye movements. Both demonstrated hypotonia and poor visual attention. The older girl at 14 weeks of age showed fine pendular horizontal nystagmus more pronounced on lateral gaze, but despite investigation with cranial MRI no diagnosis was reached. The birth of her younger sister four years later with a similar presentation triggered review of the sisters' visual behaviour. Each had developed an unusual but similar form of oculomotor apraxia (OMA) with head thrusts to maintain fixation rather than to change fixation. MRI of the older sibling demonstrated the characteristic “molar tooth sign” (MTS) of Joubert syndrome which was subsequently confirmed on MRI in the younger sibling. We discuss the genetically heterogeneous ciliopathies now grouped as Joubert syndrome and Related Disorders. Clinicians need to consider this group of disorders when faced with unusual eye movements in the developmentally delayed child

Hyperopia is not causally associated with a major deficit in educational attainment

Purpose: Hyperopia (farsightedness) has been associated with a deficit in children's educational attainment in some studies. We aimed to investigate the causality of the relationship between refractive error and educational attainment. Methods: Mendelian randomization (MR) analysis in 74,463 UK Biobank participants was used to estimate the causal effect of refractive error on years spent in full-time education, which was taken as a measure of educational attainment. A polygenic score for refractive error derived from 129 genetic variants was used as the instrumental variable. Both linear and nonlinear (allowing for a nonlinear relationship between refractive error and educational attainment) MR analyses were performed. Results: Assuming a linear relationship between refractive error and educational attainment, the causal effect of refractive error on years spent in full-time education was estimated as −0.01 yr/D (95% confidence interval, −0.04 to +0.02; P = 0.52), suggesting minimal evidence for a non-zero causal effect. Nonlinear MR supported the hypothesis of the nonlinearity of the relationship (I2 = 80.3%; Cochran's Q = 28.2; P = 8.8e-05) but did not suggest that hyperopia was associated with a major deficit in years spent in education. Conclusions: This work suggested that the causal relationship between refractive error and educational attainment was nonlinear but found no evidence that moderate hyperopia caused a major deficit in educational attainment. Importantly, however, because statistical power was limited and some participants with moderate hyperopia would have worn spectacles as children, modest adverse effects may have gone undetected. Translational Relevance: These findings suggest that moderate hyperopia does not cause a major deficit in educational attainment

A comparative analysis of rod bipolar cell transcriptomes identifies novel genes implicated in night vision

Abstract In the mammalian retina, rods and a specialised rod-driven signalling pathway mediate visual responses under scotopic (dim light) conditions. As rods primarily signal to rod bipolar cells (RBCs) under scoptic conditions, disorders that affect rod or RBC function are often associated with impaired night vision. To identify novel genes expressed by RBCs and, therefore, likely to be involved in night vision, we took advantage of the adult Bhlhe23 −/− mouse retina (that lacks RBCs) to derive the RBC transcriptome. We found that genes expressed by adult RBCs are mainly involved in synaptic structure and signalling, whereas genes that influence RBC development are also involved in the cell cycle and transcription/translation. By comparing our data with other published retinal and bipolar cell transcriptomes (where we identify RBCs by the presence of Prkca and/or Pcp2 transcripts), we have derived a consensus for the adult RBC transcriptome. These findings ought to facilitate further research into physiological mechanisms underlying mammalian night vision as well as proposing candidate genes for patients with inherited causes of night blindness

Education and myopia: assessing the direction of causality by mendelian randomisation

Objectives To determine whether more years spent in education is a causal risk factor for myopia, or whether myopia is a causal risk factor for more years in education. Design Bidirectional, two sample mendelian randomisation study. Setting Publically available genetic data from two consortiums applied to a large, independent population cohort. Genetic variants used as proxies for myopia and years of education were derived from two large genome wide association studies: 23andMe and Social Science Genetic Association Consortium (SSGAC), respectively. Participants 67 798 men and women from England, Scotland, and Wales in the UK Biobank cohort with available information for years of completed education and refractive error. Main outcome measures Mendelian randomisation analyses were performed in two directions: the first exposure was the genetic predisposition to myopia, measured with 44 genetic variants strongly associated with myopia in 23andMe, and the outcome was years in education; and the second exposure was the genetic predisposition to higher levels of education, measured with 69 genetic variants from SSGAC, and the outcome was refractive error. Results Conventional regression analyses of the observational data suggested that every additional year of education was associated with a more myopic refractive error of −0.18 dioptres/y (95% confidence interval −0.19 to −0.17; P<2e-16). Mendelian randomisation analyses suggested the true causal effect was even stronger: −0.27 dioptres/y (−0.37 to −0.17; P=4e-8). By contrast, there was little evidence to suggest myopia affected education (years in education per dioptre of refractive error −0.008 y/dioptre, 95% confidence interval −0.041 to 0.025, P=0.6). Thus, the cumulative effect of more years in education on refractive error means that a university graduate from the United Kingdom with 17 years of education would, on average, be at least −1 dioptre more myopic than someone who left school at age 16 (with 12 years of education). Myopia of this magnitude would be sufficient to necessitate the use of glasses for driving. Sensitivity analyses showed minimal evidence for genetic confounding that could have biased the causal effect estimates. Conclusions This study shows that exposure to more years in education contributes to the rising prevalence of myopia. Increasing the length of time spent in education may inadvertently increase the prevalence of myopia and potential future visual disability

Cohort profile:rationale and methods of UK Biobank repeat imaging study eye measures to study dementia

Purpose: the retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study.Participants: UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40-69 enrolled in 2006-2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs.Findings to date: UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes.Future plans: the collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022-2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia

A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus.

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus