Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy.

PURPOSE: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. METHODS: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.

Genotypic-Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.

The cost of genetic diagnosis of suspected hereditary pediatric cataracts with whole-exome sequencing from a middle-income country perspective: a mixed costing analysis.

Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil.

Portable wide-field digital imaging for screening of neonatal visual impairment causes in Rio de Janeiro, Brazil: a budget impact analysis.

OBJECTIVE: To estimate the budget impact of portable wide-field digital imaging incorporation on screening neonatal causes of childhood blindness and visual impairment in Rio de Janeiro, Brazil. DESIGN: Budget impact analysis. SETTING: Rio de Janeiro, Brazil. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the direct cost of indirect binocular ophthalmoscopy, red reflex test and portable wide-field digital image screening comprising all babies born in Rio de Janeiro's government maternity wards. The secondary outcome was the budget impact of implementing portable wide-field digital image screening in Rio de Janeiro, Brazil. RESULTS: Considering 100% coverage of maternity wards, the total budget impact between 2020 and 2024 would be US$3 820 706.04, ranging from US$3 139 844.34 to US$6 099 510.35. The additional cost would be US$3 124 457.28, ranging from US$2 714 492.26 to US$4 880 608.63. CONCLUSION: The cost of universal digital imaging screening corresponds to less than 1% of the government health budget of the city of Rio de Janeiro. The information provided in this study may help government decision-makers evaluate the feasibility of implementing this new strategy in the municipal setting. Further health economic evaluations should be performed to verify the affordability of the implementation of this screening strategy in the Brazilian scenario, taking into account scarce human resources.

Cost-Utility Analysis of Wide-Field Imaging as an Auxiliary Technology for Retinopathy of Prematurity Care in Brazil.

Purpose: To evaluate the cost-utility of wide-field imaging (WFI) as a complementary technology for retinopathy of prematurity (ROP) screening from the Brazilian Unified Health System's perspective. Introduction: ROP is one of the leading causes of avoidable childhood blindness worldwide, especially in middle-income countries. The current ROP screening involves indirect binocular ophthalmoscopy (IBO) by ROP expert ophthalmologists. However, there is still insufficient ROP screening coverage. An alternative screening strategy is the combination of WFI with IBO. Methods: A cost-utility analysis was performed using a deterministic decision-tree simulation model to estimate incremental cost-utility for ROP care. Two screening strategies were compared: (1) IBO and (2) combination of WFI of all eligible preterm infants and IBO for type 2 ROP or worse and for non-readable images. Eligible population included preterm infants <32 weeks of gestational age or birth weight equal to or <1,500 g. The temporal horizon was lifetime. Visual outcome data was converted to utility, and the health benefits were estimated on quality-adjusted life-years (QALY). Incremental cost per QALY gained was calculated from the health system perspective. Costs were estimated considering equipment, maintenance, consumables, and staff. A micro-costing approach was used for WFI. Two technician nurses were trained for imaging execution and had their time evaluated. Two ROP expert ophthalmologists had their time evaluated for imaging reading. One-way sensitivity analysis and probabilistic sensitivity analysis were performed. Results: Combined screening strategy resulted in a cost-effective program considering 90% ROP screening coverage. Costs per examination: (1) screening with IBO: US dollar (US $) 34.36; (2) screening with combination: US $58.20; (3) laser treatment: US $642.09; (4) long-term follow-up: ranged from US $69.33 to 286.91, based on the infant's visual function. Incremental cost per QALY gained was US $1,746.99/QALY per infant screened with the combination strategy. One-way sensitivity analysis resulted in cost-effectiveness for all parameters. Probabilistic sensitivity analyses yielded a 100% probability of combination being cost-effective in a willingness-to-pay threshold of US $1,800/QALY. Conclusion: The combined strategy for ROP screening was cost-effective. It enhances access for appropriate ROP care in middle-income countries and dminishes opportunity costs for ophthalmologists.

Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia.

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.

Congenital Zika syndrome: A systematic review.

BACKGROUND: The signs and symptoms of Zika virus infection are usually mild and self-limited. However, the disease has been linked to neurological complications such as Guillain-Barré syndrome and peripheral nerve involvement, and also to abortion and fetal deaths due to vertical transmission, resulting in various congenital malformations in newborns, including microcephaly. This review aimed to describe the o signs and symptoms that characterize the congenital Zika syndrome. METHODS AND FINDINGS: A systematic review was performed with a protocol and described according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The search strategy yielded 2,048 studies. After the exclusion of duplicates and application of inclusion criteria, 46 studies were included. The main signs and symptoms associated with the congenital Zika syndrome were microcephaly, parenchymal or cerebellar calcifications, ventriculomegaly, central nervous system hypoplasia or atrophy, arthrogryposis, ocular findings in the posterior and anterior segments, abnormal visual function and low birthweight for gestational age. CONCLUSIONS: Zika virus infection during pregnancy can cause a series of changes in the growth and development of children, while impacting the healthcare system due to the severity of cases. Our findings outline the disease profile in newborns and infants and may contribute to the development and updating of more specific clinical protocols.

Overlapping Spectrum of Retinochoroidal Scarring in Congenital Zika Virus and Toxoplasmosis Infections.

BACKGROUND AND OBJECTIVE: Antenatal Zika virus (ZIKV) or toxoplasmosis infections may present with isolated eye abnormalities with absence of other apparent birth defects. The purpose of this article is to discuss the overlapping spectrum of clinical presentation and retinochoroidal scarring in congenital ZIKV and toxoplasmosis infections. PATIENTS AND METHODS: Prenatal ultrasound abnormalities seen from antenatal ZIKV and toxoplasmosis infections overlap and may include intracranial calcifications, microcephaly, and intrauterine growth restriction. The clinical spectrum of both infections in less severely affected infants and children may include nonspecific neurological impairment such as developmental delay and seizures. RESULTS: Inherent limitations in serological testing pose additional barriers in establishing a diagnosis. Retinal pigment epithelium (RPE) mottling in ZIKV infection can occur in isolation or adjacent to retinochoroidal atrophy. In contrast, RPE mottling outside of the borders of retinochoroidal atrophy is not typically seen in toxoplasmosis. To date, postnatal reactivation of congenital eye lesions as seen in toxoplasmosis have not been reported with ZIKV infection. CONCLUSIONS: As children infected with congenital ZIKV grow older, subclinical eye abnormalities may be indistinguishable from toxoplasmosis. Brazil has had high prevalence of both diseases with long-term information available on toxoplasmosis only. Surveillance guidelines for asymptomatic eye abnormalities will likely evolve. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:779-784.].

Gasto catastrófico em crianças com deficiência visual: estudo transversal com cuidadores no Rio de Janeiro, Brasil / Catastrophic expenditure in children with visual impairment: a cross-sectional study with caregivers in Rio de Janeiro, Brazil / Gasto catastrófico en niños con discapacidad visual: estudio transversal con cuidadores en Río de Janeiro, Brasil

Resumo: O cuidado de um filho com deficiência visual pode vir a afetar a renda do cuidador e, por sua vez, a renda da família. Sob essa realidade, há de se considerar o gasto catastrófico consequente do aumento de despesas e da redução de renda, seja pelo desemprego, pela redução do número de horas trabalhadas ou pela dificuldade de (re)inserção no mercado de trabalho. Perante esse cenário, o objetivo principal deste estudo foi estimar o gasto catastrófico atribuído ao cuidador de crianças cegas ou com baixa visão em centros de referência em educação para cegos, oftalmologia e saúde infantil localizados no Município do Rio de Janeiro, Brasil, identificando quais fatores estão associados a uma maior ou menor prevalência desse gasto. Observou-se que 53,3% dos cuidados de crianças com cegueira comprometem 40% ou mais da renda. Entre os cuidadores de crianças com baixa visão, o gasto catastrófico é mais ameno, comprometendo no mínimo 40% da renda para 36,8% dos cuidadores. Os fatores associados à maior prevalência de gasto catastrófico foram idade do cuidador, número de moradores na residência, maior escolaridade, menor renda domiciliar, reformas na residência, plano de saúde, aquisição de empréstimos, venda de bens, quantidade de unidades de saúde que a criança recebe tratamento e parentesco do cuidador principal. A carga que recai sobre os cuidadores de crianças com deficiência visual indica uma situação de vulnerabilidade que mostra a necessidade de acesso aos mecanismos de proteção financeira e social, por meio de políticas que sejam capazes de atender esse grupo.

Abstract: Caring for a visually impaired child can affect the caregiver's income and, in turn, the family's. Catastrophic spending resulting from increased expenses and reduced income must be taken into account, whether due to unemployment, a reduction in the number of hours worked or the difficulty of entering or reentering the job market. Given this scenario, the main objective of this study was to estimate the catastrophic spending attributed to the caregiver of blind or low-vision children in reference centers for education for the blind, ophthalmology and child health located in the city of Rio de Janeiro, Brazil, identifying which factors are associated with a higher or lower prevalence of this expenditure. It was found that 53.3% of care for blind children involved 40% or more of their income. Among the caregivers of children with low vision, catastrophic spending is milder, compromising at least 40% of income for 36.8% of the caregivers. The factors associated with a higher prevalence of catastrophic spending were the caregiver's age, the number of residents in the household, higher schooling, lower household income, renovations to the home, health insurance, taking out loans, selling assets, the number of health units where the child receives treatment and the relationship of the main caregiver. The burden placed on caregivers of visually impaired children indicates a situation of vulnerability that shows the need for access to financial and social protection mechanisms, through policies that are capable of serving this group.

Resumen: El cuidado de un niño con discapacidad visual puede impactar los ingresos del cuidador y, a su vez, de la familia. En este escenario, es necesario considerar el gasto catastrófico resultante del aumento de los gastos o la reducción de los ingresos, ya sea por desempleo, reducción del número de horas trabajadas o por la dificultad de inserción o reinserción en el mercado laboral. Ante esto, el objetivo principal de este estudio fue estimar el gasto catastrófico atribuido al cuidador de niños ciegos o con baja visión en centros de referencia en educación para ciegos, oftalmología y salud infantil, ubicados en el municipio de Río de Janeiro, Brasil, con el fin de identificar qué factores se asocian con una mayor o menor prevalencia de este gasto. Se observó que el 53,3% de los cuidados de niños con discapacidad visual comprometen más del 40% de los ingresos totales. Mientras tanto, el cuidado de niños con baja visión tiene un menor gasto catastrófico, comprometiendo menos del 40% de los ingresos según el 36,8% de los cuidadores. La mayor prevalencia de gasto catastrófico estuvo asociada a los siguientes factores: edad del cuidador, número de residentes en el hogar, mayor nivel de estudios, bajos ingresos familiares, remodelaciones en el hogar, seguro de salud, adquisición de préstamos, venta de bienes, cantidad de centros de salud en las que el niño acude al tratamiento y parentesco del cuidador principal. Los cuidadores de niños con discapacidad visual enfrentan una situación de vulnerabilidad, lo que apunta a una necesidad de acceder a acciones de protección financiera y social mediante políticas dirigidas a esta población.

Eye Findings in Infants With Suspected or Confirmed Antenatal Zika Virus Exposure.

: media-1vid110.1542/5804915134001PEDS-VA_2018-1104Video Abstract OBJECTIVES: To characterize ophthalmic manifestations of confirmed or suspected antenatal Zika virus (ZIKV) exposure. METHODS: Infants with antenatal ZIKV exposure were referred for evaluation during the 2015-2016 Rio de Janeiro outbreak. Mothers with symptomatic ZIKV infection during pregnancy and/or infants with microcephaly or other findings that were suggestive of suspected antenatal exposure were tested with reverse transcriptase polymerase chain reaction (RT-PCR). Complete eye examinations were performed by pediatric ophthalmologists between January 2016 and February 2017. The main outcome measure was eye abnormalities in RT-PCR-positive and suspected (ie, not tested or RT-PCR-negative) antenatal ZIKV cases. RESULTS: Of 224 infants, 189 had RT-PCR testing performed. Of 189 patients, 156 had positive RT-PCR results in their blood, urine, and/or placenta. Of 224 infants, 90 had central nervous system (CNS) abnormalities, including microcephaly (62 infants). Eye abnormalities were present in 57 of 224 (25.4%) infants. Optic nerve (44 of 57; 77.2%) and retina abnormalities (37 of 57; 64.9%) were the most common. The group with suspected ZIKV infection (68 infants) had proportionally more eye (36.8% vs 20.5%; P = .022) and CNS abnormalities (68.3% vs 28.1%; P = .008), likely because of referral patterns. Eye abnormalities consistent with ZIKV infection were clinically comparable in both RT-PCR-positive and unconfirmed groups, including 4 RT-PCR-positive infants of 5 without any CNS abnormalities. CONCLUSIONS: Similar eye manifestations were identified regardless of laboratory confirmation. Well-appearing infants were also found to have eye abnormalities. Therefore, all infants born after ZIKV outbreaks should be universally screened for eye abnormalities.

Visual function in infants with antenatal Zika virus exposure.

PURPOSE: To report the findings of a cross-sectional study of visual function in infants with confirmed or suspected antenatal Zika virus (ZIKV) infection seen at a single referral center in Rio de Janeiro. METHODS: Infants were examined following the ZIKV outbreak period at Instituto Fernandes Figueira/FIOCRUZ. Visual function was considered abnormal if an infant could not fix and follow a standardized high-contrast target (10 cm) by 3-6 months of age. Visual function and associations with structural eye abnormalities, central nervous system (CNS) abnormalities, microcephaly, and nystagmus were assessed. Sensitivity and specificity of screening criteria for structural eye abnormalities was assessed. RESULTS: A total of 173 infants met inclusion criteria. Abnormal visual function was found in 52 infants (30.0%) and was significantly associated with eye abnormalities (40/52; OR = 44.2; 95% CI, 16.6-117.6), CNS abnormalities (50/52; OR = 64.0; 95% CI, 14.7-277.6), microcephaly (44/52; OR = 31.5; 95% CI, 12.7-77.8), and nystagmus (26/52; OR = 120.0; 95% CI, 15.6-924.5). Using microcephaly as screening criteria for the detection of eye abnormalities provided a sensitivity of 88.9% (95% CI, 76.0-96.3) and specificity of 82.8% (95% CI, 75.1-88.9). Using both abnormal visual function and microcephaly increased sensitivity to 100% (95% CI, 92.1-100.0) and decreased specificity to 80.5% (95% CI, 72.5-86.9). CONCLUSIONS: Infants with suspected antenatal ZIKV infection and reduced visual function should be referred to an ophthalmologist. Visual function assessments are helpful in screening for antenatal ZIKV exposure in resource-limited settings and can identify infants who may benefit from visual habilitation.