Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Mutations in the ciliary transport gene IFT140 cause syndromic congenital retinal dystrophy.

Early-onset, severe retinal dystrophy can be isolated or syndromic, presenting as part of an underlying systemic disease. Mainzer-Saldino syndrome, a rare systemic ciliopathy characterized by skeletal and renal disease, is caused by recessive mutations in the intraflagellar transport 140 chlamydomonas homologue (IFT140) gene. We present a series of 13 cases of early-onset retinal dysfunction with confirmed IFT140 mutations from 8 unrelated Saudi families belonging to 3 well-known tribes. All carried the same homozygous missense IFT140 mutation (c.1990G>A; p.Glu664Lys) except for a single family, which included 4 affected subjects, 3 of whom were aborted fetuses, with compound heterozygous pathogenic IFT140 variants (c.1525-1G>A and c.1990G>A; p.Glu664Lys). Severe retinal dystrophy was present in all living subjects, phenotypically apparent as hyperopia, nystagmus, nyctalopia, poor vision and nonrecordable full-field electroretinography. All affected individuals had skeletal abnormalities, and neurological abnormalities were common, but there was no evidence of chronic renal failure.

Refractive Changes among Diode Laser-treated Retinopathy of Prematurity Patients: A Retrospective Study.

PURPOSE: The purpose of this study was to assess the refractive outcomes of patients who underwent indirect laser photocoagulation for prethreshold type 1 retinopathy of prematurity (ROP) and high-risk type 2 prethreshold ROP in comparison to conservatively managed low-risk prethreshold type 2 ROP. METHODS: A retrospective analysis was carried out on infants screened for ROP between the years 2015 and 2020. Surviving children who had developed ROP in one or both eyes and received diode laser photocoagulation and those with conservatively managed regressed type 2 ROP who underwent at least one cycloplegic retinoscopy were included in the study. RESULTS: A total of 144 patients were screened for ROP between 2015 and 2020 at our institution. One hundred and thirty patients (260 eyes) fulfilled the study criteria and were included in this study. The treated group consisted of 132 eyes of 66 infants, of which 38 (14.6%) eyes had prethreshold type 1 ROP while 94 (36.2%) eyes had high-risk prethreshold type 2. The nontreated control group consisted of 128 (49.2%) eyes of 64 infants with low-risk type 2 prethreshold ROP. Earlier prematurity was found to be a significant determinant of the mean change in spherical equivalent among different gestational age groups (P = 0.035). In our cohort, we found that myopia is significantly related to Zone II ROP in comparison to Zone III ROP in the treated eyes (22% vs. 9%) (P = 0.002). No statistically significant difference was found in the final refraction among the treated eyes in relation to the birth weight or stage of prematurity. CONCLUSION: In the present study, the majority of patients who were treated with diode laser for ROP had favorable anatomical and refractive outcomes. In contrast to previous studies that had suggested a trend toward myopia in laser-treated patients, in our study, the majority (71%) were hyperopes. This study suggests that other factors such as the stage and zone of ROP possibly contribute more to the development of myopia than the laser photocoagulation itself.

Phenotype and genotype of 15 Saudi patients with achromatopsia: A case series.

PURPOSE: Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus, reduced visual acuity (VA), and color blindness. Multiple genes responsible for achromatopsia have been identified (e.g. cyclic nucleotide-gated channel subunit alpha 3 [CNGA3] and activating transcription factor 6). Studies have assessed the role of gene therapy in achromatopsia. Therefore, for treatment and prevention, the identification of phenotypes and genotypes is crucial. Here, we described the clinical manifestations and genetic mutations associated with achromatopsia in patients from Saudi Arabia. METHODS: This case series study included 15 patients with clinical presentations, suggestive of achromatopsia, who underwent ophthalmological and systemic evaluations. Patients with typical achromatopsia phenotype underwent genetic evaluation using whole-exome testing. RESULTS: All patients had nystagmus (n = 15) and 93.3% had photophobia (n = 14). In addition, all patients (n = 15) had poor VA. Hyperopia with astigmatism was observed in 93.3% (n = 14) and complete color blindness in 93.3% of the patients (n = 14). In the context of family history, both parents of all patients (n = 15) were genetic carriers, with a high consanguinity rate (82%, n = 9 families). Electroretinography showed cone dysfunction with normal rods in 66.7% (n = 10) and both cone-rod dysfunction in 33.3% (n = 5) patients. Regarding the genotypic features, 93% of patients had variants in CNGA3 (n = 14) categorized as pathogenic Class 1 (86.7%, n = 13). Further, 66.7% (n = 10) of patients also harbored the c.661C>T DNA variant. Further, the patients were homozygous for these mutations. Three other variants were also identified: c.1768G>A (13.3%, n = 2), c.830G>A (6.6%, n = 1), and c. 822G >T (6.6%, n = 1). CONCLUSION: Consanguinity and belonging to the same tribe are major risk factors for disease inheritance. The most common genotype was CNGA3 with the c.661C>T DNA variant. We recommend raising awareness among families and providing genetic counseling for this highly debilitating disease.

Relationship Between Screen Time and Dry Eye Symptoms During the COVID-19 Pandemic in the Pediatric Population of the Western Region of Saudi Arabia.

Objective To measure the prevalence of dry eye disease (DED) and study the relationship between screen time and dry eye symptoms in the pediatric population during the coronavirus disease 2019 (COVID-19) pandemic using the Ocular Surface Disease Index (OSDI) questionnaire. Methods In this descriptive, observational, cross-sectional study, our survey included the pediatric population, ages 1 to 18 years, of both genders, who attended outpatient clinics of two main hospitals in Jeddah, Saudi Arabia. Collected data included age, gender, dry eye symptoms, and common DED risk factors, followed by the Ocular Surface Disease Index (OSDI) questionnaire, which consists of 12 items graded on a five-point scale (0 = never to 4 = all the time). Results A total of 329 pediatric participants were included, with more than half of the participants (56.1%) males and 58.5% aged 12-18 years. The most frequently reported symptoms (reported as often or always) were decreased vision (23.0%) and itchy eyes (22.1%). Environmental factors have an effect on developing DED symptoms, as some participants (21.8%) have reported being uncomfortable in windy weather and 15.8% have reported this in places with air conditioners. Based on the OSDI diagnostic criteria, 250 (76.1%) participants had DED. Furthermore, in terms of severity, 44 (13.3%) participants had mild DED, 62 (18.8%) participants had moderate DED, and 145 (43.9%) participants had severe DED. We found that prolonged exposure to mobile screens for two to three hours or four hours or more was associated with a higher DED incidence compared to those exposed for shorter periods. Older age categories were more likely to experience DED (80.8% and 78.2% in age categories 12-18 and 7-12, respectively, versus 57.6% in the youngest age category (p = 0.001)). Additionally, DED was independently associated with participants with a previous history of eyeglasses prescription and those experiencing dry eyes while using electronic devices. Conclusion Since many children use electronic devices for education and entertainment, we found that symptoms of DED due to prolonged screen time have increased among the pediatric population during the COVID-19 pandemic. Therefore, awareness efforts should be directed to reduce the rate of controllable risk factors like personal computer use. In addition, educational campaigns are warranted to provide all possible preventive measures against DED, especially to children with uncontrollable risk factors for developing DED.

Effects of Early Treatment of Retinopathy of Prematurity at a Tertiary Care Hospital in Saudi Arabia: A Retrospective Study.

PURPOSE: To estimate the prevalence of retinopathy of prematurity (ROP) among high-risk neonates and to illuminate the benefits of early treatment in type 2 ROP (zone II, stage 3 without plus) and ROP milder than type 1 with pre-plus disease (zone III, stage 3). METHODS: This retrospective cross-sectional study was conducted among 307 high-risk neonates (614 eyes) with a gestational age of 32 weeks or younger at birth and a birth weight of 1,500 g or less, from 2011 to 2016. Treatment was initiated for neonates with low-risk type 2 ROP and ROP milder than type 1 with pre-plus disease, whenever retinopathy was evident for 3 clock hours with or without vitreous hemorrhage. Post-treatment progression was recorded. RESULTS: The prevalence of ROP in the current study was 33.71%. Two hundred seven eyes had ROP; 47.34% had mild retinopathy that did not require treatment, and 52.66% received laser treatment, including the early treated group. Of the 207 eyes with ROP, 46.86% had low-risk type 2 ROP disease and ROP milder than type 1 with pre-plus disease, and underwent photocoagulation therapy. After treatment, 15.38% and 10.71% eyes were stable, 84.62% and 88.10% eyes had regressed retinopathy, and 0% and 1.19% progressed in both groups, respectively. CONCLUSIONS: Early treatment of type 2 ROP and ROP milder than type 1 with pre-plus disease in certain cases significantly decreased the rate of progression to more advanced stages and resulted in good clinical outcomes. [J Pediatr Ophthalmol Strabismus. 2021;58(4):240-245.].