Nationwide Prevalence of Inherited Retinal Diseases in the Israeli Population.

Importance: Data regarding the prevalence of various inherited retinal diseases (IRDs) are limited and vary across populations; moreover, nationwide prevalence studies may be limited to a specific IRD phenotype, potentially leading to inaccurate prevalence estimations. Therefore, nationwide prevalence data are needed. Objective: To determine the prevalence of 67 IRD phenotypes in the Israeli population. Design, Setting, and Participants: This cohort study collected nationwide data regarding the number of individuals affected with IRD phenotypes assessed in 10 clinical and academic centers in Israel as part of the research activity of the Israeli inherited retinal disease consortium. Data were collected in May 2023 on 9396 individuals residing in Israel who were diagnosed by an ophthalmologist with an IRD using either electroretinography or retinal imaging where included. Individuals with retinal diseases known to have a nonmendelian basis or without a clear genetic basis and those who were reported as deceased at the time of data collection were excluded from this study. Main Outcomes and Measures: Prevalence of 67 IRD phenotypes. Results: Among the 9396 participants in our cohort, the most common IRD in Israel was retinitis pigmentosa with a disease prevalence of approximately 1:2400 individuals, followed by cone-rod dystrophy (approximately 1:14 000), Stargardt disease (approximately 1:16 000), Usher syndrome (approximately 1:16,000), and congenital stationary night blindness (approximately 1:18 000). The prevalence of all IRDs combined was 1:1043 individuals. Conclusions and Relevance: The current study provides large prevalence dataset of 67 IRD phenotypes, some of which are extremely rare, with only a single identified case. This analysis highlights the potential importance of performing additional nationwide prevalence studies to potentially assist with determining the prevalence of IRDs worldwide.

[VASCULAR OPHTHALMIC MANIFESTATIONS IN COVID-19 PATIENTS].

INTRODUCTION: Although COVID-19 is mainly a respiratory disease, recent evidence has emerged of vascular and procoagulant pathologies even in young and otherwise healthy individuals. Ophthalmic manifestations include, among others, visual impairment due to arteritic and venous retinal obstructions, which at times precedes other aspects of the disease. We present two atypical cases of internal carotid dissection (ICAD) and review the different ocular symptoms of ICAD and its association with the COVID-19 pandemic. BACKGROUND: A 43-year-old otherwise healthy man was referred to the Emergency Department with a headache and monocular blurring of vision. A recent fever (2 weeks prior) was noted on anamnesis, in light of absence of available positive PCR test during the illness period, clinical suspicion of COVID-19 was assumed. An initial ophthalmic evaluation found a mild optic nerve function impairment with preserved visual acuity. Computed tomography (CT) showed sinusitis, and an initial diagnosis was made of mild optic neuropathy secondary to sphenoid sinusitis. A few hours after admission, the patient reported deterioration of symptoms and examination revealed no light perception in his right eye and pale edematous optic nerve. Urgent magnetic resonance angiography (MRA) demonstrated right ICAD with no additional findings. The second patient, a 43-year-old man developed an acute event of strabismus, left limb paralysis, and speech difficulties while on a hospital visit for his son. The patient underwent CT of the brain which demonstrated extensive infarction following the distribution of his right cerebral artery. Continued investigation using computed tomography angiography (CTA) demonstrated a dissection of the right internal carotid artery. The patient was positive for COVID-19. DISCUSSION: In this review, we discuss 2 cases of carotid artery dissection presenting with an acute ocular complaint in two otherwise healthy young individuals. Events were suspected to have been provoked by COVID-19 infection. The pathogenesis and mechanisms behind COVID-19 induced coagulopathy are not clear, and several mechanisms have been proposed including endothelial damage and dysfunction. The virus is thought to enter endothelial cells and lead to a pathological procoagulant state. Awareness should be drawn to uncommon signs especially in young adults. Clotting issues can arise and should be treated quickly as they might be life and vision threatening.

Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.

Purpose: To review all reported disease-causing mutations in BEST1, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population. Methods: Medical records of patients diagnosed with Best disease and allied diseases from nine Israeli medical centers over the past 20 years were collected, as were clinical data including ocular findings, electrophysiology results, and retina imaging. Mutation detection involved mainly whole exome sequencing and candidate gene analysis. Demographic data were obtained from the Israeli Bureau of Statistics (January 2023). A bibliometric study was also conducted to gather mutation data from online sources. Results: A total of 134 patients were clinically diagnosed with Best disease and related conditions. The estimated prevalence of Best disease was calculated to be 1 in 127,000, with higher rates among Arab Muslims (1 in 76,000) than Jews (1 in 145,000). Genetic causes were identified in 76 individuals (57%), primarily showing autosomal-dominant inheritance due to BEST1 mutations (58 patients). Critical conserved domains were identified consisting of a high percentage of dominant missense mutations, primarily in transmembrane domains and the intracellular region (Ca2+ binding domain) of the BEST1 protein. Conclusions: This study represents the largest cohort of patients with Best disease reported in Israel and globally. The prevalence in Israel is akin to that in Denmark but is lower than that in the United States. Critical conserved domains within the BEST1 protein are pivotal for normal functioning, and even minor missense alterations in these areas lead to a dominant disease manifestation. Genetic testing is indispensable as the gold standard for Best disease diagnosis due to the variable clinical presentation of the disease.

Variants in the WDR45 Gene Within the OPA-2 Locus Associate With Isolated X-Linked Optic Atrophy.

Purpose: To describe clinical and molecular findings of two families with X-linked optic atrophy and present two new pathogenic variants in the WDR45 gene. Methods: Case series and molecular analysis of two families of Jewish Ashkenazi descent with early onset bilateral optic atrophy. Whole-exome sequencing (WES) and bioinformatic analysis were performed, followed by Sanger sequencing and segregation analysis. Results: In both families, male siblings (three in family 1, two in family 2) had early-onset isolated bilateral optic atrophy. The sibling's healthy mother (and in the second family also one healthy sister) had a mild presentation, suggesting a carrier state and an X-linked inheritance pattern. All participants were otherwise healthy, apart from mild learning disabilities and autism spectrum disorder in two siblings of the second family. Variants in known optic atrophy genes were excluded. Analysis revealed a point variant in the WDR45 gene-a missense variant in the first family, NM_001029896.2:c.107C>A; NP_001025067.1:p.Pro36His (variant ID: 1704205), and a splice site variant in the second family, NM_001029896.2:c.236-1G>T; NP_009006.2:p.Val80Leu (variant ID: 1704204), located on Xp11.23 (OPA2 locus). Both variants are novel and predicted as pathogenic. In both families, the variant was seen with full segregation with the disease, occurring in all affected male participants and in one allele of the carrier females, as well as none of the healthy participants. Conclusions: Among two families with isolated X-linked optic atrophy, molecular analysis revealed novel variants in the WDR45 gene in full segregation with the disease. This gene resides within the OPA2 locus, previously described to associate with X-linked optic atrophy. Taken together, these findings suggest that certain pathogenic variants in the WDR45 gene are associated with isolated X-linked optic atrophy.

Ocular Torsion in Children with Horizontal Strabismus or Orthophoria.

PURPOSE: To report the rate of ocular torsion in children with horizontal strabismus or orthophoria. METHODS: A retrospective study design was used. Nineteen children were included in the study, including seven girls, aged 4-16 years. All patients were examined for strabismus and 12 were scheduled for surgical intervention. All participants had digital fundus photos (DRSplus, Padova, Italy) of both eyes at presentation, and 5 of 12 also had fundus photos following the strabismus operation. Patient files were reviewed for age, demographic data, type of strabismus, clinical symptoms and signs, orthoptic exams, subjective and objective reports of torsion, inferior oblique overaction, and V pattern. Fundus photos were analyzed for torsion by ImageJ software [ImageJ 1.54f, National Institute of Health, USA]. The disc-foveal angle was calculated for ocular torsion. Disc-foveal angle was defined as the angle formed between a line passing through the center of the optic disc to the fovea and another horizontal line passing through the center of the optic disc, using fundus photographs. RESULTS: Of the 19 children, 18 had horizontal strabismus: 9 with exotropia and 9 with esotropia. One child was orthophoric with torsional strabismus. Inferior oblique overaction was detected in all but 3 children, while V pattern was documented in 10. Visual acuity was reduced (under 6/12) in four eyes of four children. None were symptomatic for ocular torsion. Although extorsion was documented clinically in 3 of 19 children, it was measurable on fundus photos in all patients before surgery with a mean of 8.7 ± 8.5 degrees and 8.5 ± 9.7 degrees in the right and left eyes, respectively. The mean extorsion in both eyes was 19.7 ± 10.1 degrees and improved to a mean of 15.3 ± 7.9 degrees in the children who were operated on and had documented postoperative fundus photographs. CONCLUSIONS: Extorsion was detected on fundus photos at a significantly higher rate than in clinical examination. Notably, inferior oblique overaction was mainly associated with torsion. This study demonstrated that torsion is underdiagnosed in clinical examinations, as the children are often asymptomatic, but fundus photos which are easily obtained can improve its detection.

Genetic causes of inherited retinal diseases among Israeli Jews of Ethiopian ancestry.

Purpose: This study sought to describe the phenotype frequency and genetic basis of inherited retinal diseases (IRDs) among a nationwide cohort of Israeli Jewish patients of Ethiopian ancestry. Methods: Patients' data-including demographic, clinical, and genetic information-were obtained through members of the Israeli Inherited Retinal Disease Consortium (IIRDC). Genetic analysis was performed by either Sanger sequencing for founder mutations or next-generation sequencing (targeted next-generation sequencing or whole-exome sequencing). Results: Forty-two patients (58% female) from 36 families were included, and their ages ranged from one year to 82 years. Their most common phenotypes were Stargardt disease (36%) and nonsyndromic retinitis pigmentosa (33%), while their most common mode of inheritance was autosomal recessive inheritance. Genetic diagnoses were ascertained for 72% of genetically analyzed patients. The most frequent gene involved was ABCA4. Overall, 16 distinct IRD mutations were identified, nine of which are novel. One of them, ABCA4-c.6077delT, is likely a founder mutation among the studied population. Conclusions: This study is the first to describe IRDs' phenotypic and molecular characteristics in the Ethiopian Jewish community. Most of the identified variants are rare. Our findings can help caregivers with clinical and molecular diagnosis and, we hope, enable adequate therapy in the near future.

Azithromycin and Sildenafil May Have Protective Effects on Retinal Ganglion Cells via Different Pathways: Study in a Rodent Microbead Model.

Decreased blood flow to the optic nerve (ON) and neuroinflammation are suggested to play an important role in the pathophysiology of glaucoma. This study investigated the potential neuroprotective effect of azithromycin, an anti-inflammatory macrolide, and sildenafil, a selective phosphodiesterase-5 inhibitor, on retinal ganglion cell survival in a glaucoma model, which was induced by microbead injection into the right anterior chamber of 50 wild-type (WT) and 30 transgenic toll-like receptor 4 knockout (TLR4KO) mice. Treatment groups included intraperitoneal azithromycin 0.1 mL (1 mg/0.1 mL), intravitreal sildenafil 3 µL, or intraperitoneal sildenafil 0.1 mL (0.24 µg/3 µL). Left eyes served as controls. Microbead injection increased intraocular pressure (IOP), which peaked on day 7 in all groups and on day 14 in azithromycin-treated mice. Furthermore, the retinas and ON of microbead-injected eyes showed a trend of increased expression of inflammatory- and apoptosis-related genes, mainly in WT and to a lesser extent in TLR4KO mice. Azithromycin reduced the BAX/BCL2 ratio, TGFß, and TNFα levels in the ON and CD45 expression in WT retina. Sildenafil activated TNFα-mediated pathways. Both azithromycin and sildenafil exerted a neuroprotective effect in WT and TLR4KO mice with microbead-induced glaucoma, albeit via different pathways, without affecting IOP. The relatively low apoptotic effect observed in microbead-injected TLR4KO mice suggests a role of inflammation in glaucomatous damage.

Simplifying the diagnosis of optic tract lesions.

Optic tract lesions (OTL) are often difficult to diagnose. We suggest an algorithm to simplify the often-challenging diagnosis of OTL. Clinical and imaging data were retrospectively collected from the electronic files of 6 patients diagnosed with OTL at a tertiary medical center in 2016-2020. The series included 4 children and 2 adults with an OTL caused by a glioma (n = 5) or motor vehicle accident (n = 1). Magnetic resonance imaging (MRI) revealed a suprasellar glioma involving the chiasm and tract alone (n = 1) and the ipsilateral optic nerve (n = 2) and only optic tract (3). Perimetry showed incongruent homonymous hemianopia in 3 patients. In two patients, perimetry could only be performed in one eye, and demonstrated hemianopia. In one patient perimetry was unreliable. Fundus examination revealed bow-tie atrophy in all patients. On optical coherence tomography (OCT) of the peripapillary retinal nerve fiber layer (RNFL) horizontal thinning was observed in the contralateral eye (n = 6). By presenting the information in a predefined order-visual field damage, OCT RNFL thickness, and MRI-the diagnosis could be easily reached even in children, and when other structures like the chiasm were involved. Fundus photographs easily detect bow tie atrophy in children. Systematic presentation of the data in a predefined order can ease the diagnostic process of OTLs.

Neuroprotective Effect of Azithromycin Following Induction of Optic Nerve Crush in Wild Type and Immunodeficient Mice.

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal ganglion cell (RGC) preservation were noted in the AZ-treated mice as shown by TUNEL staining-in the WT mice more than in the NSG mice. The increased microglial activation following ONC was reduced with the AZ treatment. In the molecular analysis of WT and NSG mice, similar trends were detected regarding apoptosis, as well as stress-related and inflammatory markers examining BCL2-associated X (Bax), heme oxygenase 1 (Ho-1), interleukin 1 beta (Il1ß), superoxide dismutase 1 (Sod1), and nuclear factor-kappa B (Nfkb) levels. In the optic nerve, AZ increased the levels of expression of Sod1 and Nfkb only in the WT mice and decreased them in the NSG mice. In the retinas of the WT and NSG mice, the Bax and Ho-1 levels of expression decreased following the AZ treatment, while the Sod1 and Nfkb expression decreased only in the WT mice, and remained stable near the baseline in the NSG mice. Il1ß remained at the baseline in WT mice while it decreased towards the baseline in AZ-treated NSG mice. The neuroprotective effects demonstrated by the reduced RGC apoptosis in AZ-treated WT mice retinae, and in the optic nerves as stress-related and inflammatory gene expression increase. This did not occur in the immunodeficient NSG mice. AZ modulated the inflammatory reaction and microglial activation. The lack of an effect in NSG mice supports the assumption that AZ acts by immunomodulation, which is known to play a role in ONC damage. These findings have implications for the development and repurposing of drugs to preserve RGCs after acute optic neuropathies.

Trace Elements in Tears: Comparison of Rural and Urban Populations Using Particle Induced X-ray Emission.

We aimed to evaluate the types and concentrations of trace elements in tears of individuals living in urban and rural environments using particle induced X-ray emission (PIXE) and the possible association with exposure to air pollution and suggest a novel method for tear-based biomonitoring studies. This cross-sectional pilot study comprised 42 healthy subjects, 28 living in a rural area and 14 in an industrial city. Tears were collected with Schirmer paper and characterized by PIXE. Trace element concentrations from both eyes were averaged together with environmental pollution data. Main outcome measures were between-group differences in types and concentrations of trace elements in tears and comparison to environmental data. The rural group included 12/28 men, mean age 45.2 ± 14.8 years. The urban group consisted of 11/14 men of mean age 27 ± 5.9 years. Six rural and all urban were active smokers. Air pollution data showed more toxic elements in the rural environment. On PIXE analysis, chlorine, sodium, and potassium were found in similar concentrations in all samples. Normalizing to chlorine yielded higher values of aluminum, iron, copper, and titanium in the rural group; aluminum was found only in the rural group. The higher levels of certain trace elements in the rural group may, in part, be a consequence of exposure to specific environmental conditions. No direct association was found with air pollution data. PIXE is useful to analyze trace elements in tears, which might serve as a marker for individual exposure to environmental pollutants in biomonitoring studies.

[ACUTE VISION LOSS ASSOCIATED WITH HYPEREOSINOPHILIC SYNDROME].

INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare disorder, in which eosinophilic toxins damage capillary and coronary endothelium and neuronal axons, at different target organs; 12% of patients experience stroke as a result of endothelial dysfunction, cardiomyopathy with secondary embolism, hyperviscosity and hypercoagulability. The treatment target is to lower the eosinophil count and shorten its tissue survival time. Supportive care and anticoagulants are given as required. We report a case of myocarditis, respiratory failure and cortical blindness due to rapidly deteriorating HES. The case demonstrates how early recognition and appropriate treatment can reduce tissue toxicity and functional loss due to hypereosinophilic syndrome.

Histological and molecular characterization of glaucoma model induced by one or two injections of microbeads to the anterior chamber of mice.

PURPOSE: To characterize glaucoma-induced damage following injections of plastic microbeads into the anterior chamber of mice. METHODS: Mice were divided into three groups: a single plastic microbeads injection (n = 21); two consecutive plastic microbead injections to the right eye at 1-week intervals, 4 of which with two consecutive saline injections in the left eye (n = 15); and an additional control group of two consecutive saline injections at 1-week intervals (n = 6). Intraocular pressure (IOP) was measured weekly. Retinal thickness, ganglion cells (RGCs) and axonal loss, inflammatory and gliosis reactions were measured at week four. Molecular analysis using qRT-PCR in the microbeads injection groups focused on expression levels of inflammation and glaucoma-related genes. RESULTS: Mean IOP following single injection at 4 weeks was significantly elevated compared to baseline in injected eyes (14.5 ± 3.3 mmHg vs. 11.1 ± 2.5 mmHg, respectively, p = 0.003) and not in fellow eyes (13.2 ± 2.9 mmHg vs. 12.2 ± 2.9, respectively, NS). Six (35.3%) bead-injected eyes had IOP ≥ 17 mmHg compared with 2 (11.8%) saline-injected control eyes. Retinal thickness in injected and fellow eyes was 193.7 ± 15.5 µm and 223.9 ± 15.5 µm, respectively (p = 0.03). RGC loss in injected and fellow eyes was 16.0 ± 0.5 and 17.6 ± 0.7 cells per 200 µm, respectively (p = 0.005). Retinal gliosis, axonal loss and inflammatory cell infiltration to the bead-injected eyes were noted. Molecular analysis following double injection showed STAT3 expression decreased in the glaucoma-induced optic nerves (0.69 ± 0.3 vs. 1.16 ± 0.3, p = 0.04), but increased in the glaucoma-induced retinae (p = 0.05) versus saline; retinal IL-1ß decreased significantly (0.04 ± 0.04 vs. 0.36 ± 0.2, p = 0.02). TNF-α, NFkB and SOD-1 expression did not change. CONCLUSION: One/two injections of microbeads elevated IOP, with measurable neuronal damage. An inflammatory response was detected in the injured retina and optic nerve. The therapeutic significance of these findings should be explored.

Genetic Alteration Analysis of IDH1, IDH2, CDKN2A, MYB and MYBL1 in Pediatric Low-Grade Gliomas.

Objective: To investigate pediatric low-grade gliomas for alterations in IDH1, IDH2, CDKN2A, MYB, and MYBL1. Materials and Methods: DNA and RNA were extracted from 62 pediatric gliomas. Molecular methods included PCR, RT-PCR, and RNA sequencing; Sanger sequencing was used for validation. Results: Analysis for hotspot genetic alterations in IDH1 R132 and IDH2 R172 (45 and 33 samples) was negative in all cases. CDKN2A deletions were detected in exons 1 and 2 in 1 (pleomorphic xanthoastrocytoma) sample of 9 samples analyzed. Of 10 samples analyzed for MYB translocation, 4 each were positive for translocations with exon 2 and exon 3 of PCDHGA1. Six samples showed MYBL rearrangement. The lack of IDH1/2 genetic alterations is in accordance with the literature in pediatric tumors. Alterations in MYB, MYBL were recently reported to characterize diffuse grade II, but not grade I, gliomas. Conclusion: We optimized methods for analyzing gene variations and correlated the findings to pathological grade. The high incidence of MYB and MYBL need further evaluation. We also compared DNA, RNA, and RNA sequencing results for fusion, translocation, and genetic alterations. More accurate identification of the underlying biology of pediatric gliomas has implications for the development of targeted treatment.

Characterization of Diabetic Retinopathy in Two Mouse Models and Response to a Single Injection of Anti-Vascular Endothelial Growth Factor.

In this study, we characterized diabetic retinopathy in two mouse models and the response to anti-vascular endothelial growth factor (VEGF) injection. The study was conducted in 58 transgenic, non-obese diabetic (NOD) mice with spontaneous type 1 diabetes (n = 30, DMT1-NOD) or chemically induced (n = 28, streptozotocin, STZ-NOD) type 1 diabetes and 20 transgenic db/db mice with type 2 diabetes (DMT2-db/db); 30 NOD and 8 wild-type mice served as controls. Mice were examined at 21 days for vasculopathy, retinal thickness, and expression of genes involved in oxidative stress, angiogenesis, gliosis, and diabetes. The right eye was histologically examined one week after injection of bevacizumab, ranibizumab, saline, or no treatment. Flat mounts revealed microaneurysms and one apparent area of tufts of neovascularization in the diabetic retina. Immunostaining revealed activation of Müller glia and prominent Müller cells. Mean retinal thickness was greater in diabetic mice. RAGE increased and GFAP decreased in DMT1-NOD mice; GFAP and SOX-9 mildly increased in db/db mice. Anti-VEGF treatment led to reduced retinal thickness. Retinas showed vasculopathy and edema in DMT1-NOD and DMT2-db/db mice and activation of Müller glia in DMT1-NOD mice, with some response to anti-VEGF treatment. Given the similarity of diabetic retinopathy in mice and humans, comparisons of type 1 and type 2 diabetic mouse models may assist in the development of new treatment modalities.

The Management of Congenital Microphthalmia With Orbital Cyst: A Case Series.

PURPOSE: To describe a series of patients treated for congenital microphthalmia associated with orbital cyst and recommend a management protocol. METHODS: This retrospective case series comprised 6 patients (7 eyes) who attended an oculoplastic tertiary medical center from 2001 to 2018. Clinical, treatment, and outcome data were collected from the electronic files. Main outcome measures were preservation of vision and cosmetic appearance. RESULTS: Four patients were diagnosed at birth. Six cysts were located inferiorly and one superiorly. Two patients had a visual potential of light perception or better in the affected eye. In 4 eyes, the cyst was initially retained and the eye was fitted with a custom-made conformer. In 1 eye, the fornices were too shallow for a conformer, warranting fornix reconstruction and cyst excision. Early surgery was required in 1 eye for an expanded cyst and large orbit volume, and in another eye the cyst had overgrown the orbit, causing bone erosion and remodeling. Cosmetic results were good in 3 of the eyes in which the cyst was retained in early childhood, stimulating orbital growth. CONCLUSIONS: Congenital microphthalmia with orbital cyst is rare. Management should focus on preserving visual potential, especially in unilateral cyst cases when the other eye is also microphthalmic. Otherwise cosmetic symmetry is the main concern; cyst retention combined with ocular conformers may stimulate socket expansion. The authors found that, in most cases, if treated early, enucleation was avoidable during cyst excision. Early assessment, meticulous follow-up, and individually tailored treatment are warranted. [J Pediatr Ophthalmol Strabismus. 2022;59(3):192-199.].

Optic Nerve Drusen Is Highly Prevalent Among Children With Pseudotumor Cerebri Syndrome.

Introduction: The clinical presentation of pseudotumor cerebri syndrome (PTCS) usually includes headache, nausea, and vomiting with normal physical examination apart from papilledema and diplopia. However, pseudopapilledema, which can be caused by optic nerve drusen, may lead to misdiagnosis. The prevalence of optic nerve drusen in the general population is 0.5-2%. The purpose of our study was to evaluate the prevalence and risk factors of optic nerve drusen among patients with PTCS. Materials and Methods: Medical records of children evaluated in the pediatric department at Bnai Zion Medical Center due to PTCS between 2008 and 2020 were assessed. Inclusion criteria were children age under 18 years with a PTCS diagnosis and ophthalmic B-mode ultrasonography (US). Exclusion criteria were secondary intracranial hypertension. Results: Thirty-four children were included with a mean age 10.1 years which included 50% boys. A majority of the patients, 24 (72.4%), complained of headaches, while 15 (45.5%) complained of transient visual obscuration, and 9 (26.5%) of vomiting. Visual acuity on presentation was normal (20/20-20/30) in 23 of the children (67%), moderately diminished (20/40-20/80) in 9 (26%), and showing profound loss (20/200) in 2 (7%). Five patients (14.7%) were diagnosed with optic nerve drusen via B-mode ophthalmic ultrasonography (US). However, they still fulfilled the diagnostic criteria for PTCS, and disc swelling improved after treatment. There were no statistically significant differences between the group with optic nerve drusen and the rest of the patients. Conclusions: Optic nerve drusen are common among pediatric patients with PTCS. Diagnosis of optic nerve drusen should not rule out the presence of increased intracranial pressure.

Classifying Medulloblastoma Subgroups Based on Small, Clinically Achievable Gene Sets.

As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques-e.g., NanoString, microarrays, or DNA methylation assays-which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning-based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Group 3 and Group 4 MB. We found that the 22-gene set can be reduced to only six genes (IMPG2, NPR3, KHDRBS2, RBM24, WIF1, and EMX2) without compromising accuracy. The identified gene set is sufficiently small to make a qPCR-based MB subgroup classification easily accessible to clinicians, even in developing, poorly equipped countries.

Differences in RNA and microRNA Expression Between PTCH1- and SUFU-mutated Medulloblastoma.

BACKGROUND/AIM: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. PATIENTS AND METHODS: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. RESULTS: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). CONCLUSION: Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

Association of pediatric idiopathic intracranial hypertension with olfactory performance.

OBJECTIVE: To assess the association between pediatric Idiopathic intracranial hypertension (IIH) and olfactory performance. METHODS: A cross-sectional comparative study was conducted including 17 patients under 18 years diagnosed with IIH at a tertiary hospital and 17 healthy age- and sex-matched subjects. All participants underwent the semi-objective chemosensory Sniffin' Sticks test for evaluation of odor threshold (OT), indicative of peripheral olfactory function, and odor identification (OI), reflecting higher cognitive olfactory processing. Scores were compared and referred to the updated normative values. Demographic, clinical, and neuroimaging data were collected from the medical files. The patients with IIH were reassessed for olfactory function and clinical state at the subsequent follow-up, under treatment. RESULTS: Compared to controls, the IIH group had a significantly lower mean OT score (6.41 ± 3.43 vs 10.21 ± 2.79, p = 0.001) and higher rate of OT score below the 10th percentile for age and sex according to the normative values (47.1% vs 0%, p = 0.001). There was no significant between-group difference in mean OI scores (9.82 ± 1.63, vs 10.59 ± 1.84, p = 0.290). OT scores were not associated with sex, age, body mass index, neuroimaging abnormalities, or lumbar puncture opening pressure. At the follow-up assessment, the OT scores were improved (9.36 ± 4.17 vs 6.7 ± 3.32, p = 0.027) whereas the OI scores were unchanged (9.88 ± 2.5 vs 9.69 ± 1.58, p = 0.432). CONCLUSIONS: As reported in adults, children and adolescents with IIH appear to have a selective reversible deficit in olfactory detection threshold, which may imply a reduction in peripheral olfactory perceptual ability. Future studies should examine the predictive value of olfactory function for IIH.

High Myopia and Strabismus Induced by a Deep Intronic Mutation in COL2A1.

Purpose: To characterize a genetic mutation causing Stickler syndrome in a previously undiagnosed family.Methods: Five generations of a single family suspected of having Stickler syndrome were evaluated clinically and genetically.Results: The demographic and clinical data yielded specific clinical phenotypes of Stickler syndrome in 13 family members; 7 had more than one clinical feature. Four family members underwent genetic analysis: the proband (index patient) and his mother, maternal grandfather, and healthy father. No relevant mutation was detected in the proband on whole exome analysis, but subsequent extension of the analysis to intronic areas yielded a deep intronic mutation, NM_001844.5:c.1527 + 135 G > A. Sanger sequencing was used to validate the results in the family members.Conclusions: Stickler syndrome has several subtypes with variable clinical features. Therefore, predicting the genetic locus of the disease based on clinical characteristics is challenging. We present a rarely described intronic mutation in COL2A1. Genetic testing may aid in the early diagnosis of Stickler syndrome, which is important for genetic counselling, proper clinical management, and improved prognosis.