SCAPER-Related Autosomal Recessive Retinitis Pigmentosa with Intellectual Disability: Confirming and Extending the Phenotypic Spectrum and Bioinformatics Analyses.

Mutations in the gene SCAPER (S phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) have recently been associated with retinitis pigmentosa (RP) and intellectual disability (ID). In 2011, a possible involvement of SCAPER in human diseases was discovered for the first time due to the identification of a homozygous mutation causing ID in an Iranian family. Later, five studies were published in 2019 that described patients with autosomal recessive syndromic retinitis pigmentosa (arRP) accompanied by ID and attention-deficit/hyperactivity disorder (ADHD). This present study describes three patients from an Arab consanguineous family in Israel with similar clinical features of the SCAPER syndrome. In addition, new manifestations of ocular symptoms, nystagmus, glaucoma, and elevator palsy, were observed. Genetic testing of the patients and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Phenotypic and genotypic descriptions for all available cases described in the literature including our current three cases (37 cases) were carried out, in addition to a bioinformatics analysis for all the genetic variants that was undertaken. Our study confirms and extends the clinical manifestations of SCAPER-related disorders.

Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.

TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a TIMM50 disease causing mutation in human fibroblasts, and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its substrates, challenging the currently accepted import dogma of the essential general import role of TIM23 and suggesting that fully functioning TIM23 complex is not essential for maintaining the steady state level of the majority of mitochondrial proteins. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients' epileptic phenotype.

High CCL2 Levels Detected in CSF of Patients with Pediatric Pseudotumor Cerebri Syndrome.

Pseudotumor cerebri (PTC) is a disorder characterized by increased intracranial pressure in the absence of a structural lesion or other identifiable cause. Cytokines, which are involved in the regulation of immune responses and inflammation, have been implicated in the pathogenesis of PTC. In a prospective, cross-sectional study at three centers in Israel, we analyzed cerebrospinal fluid (CSF) samples from 60 children aged 0.5-18 years, including 43 children with a definitive diagnosis of PTC and a control group of 17 children. Levels of IL-4, IL-10, IL-17, CCL2, CCL7, CCL8, CCL13, BDNF, and IFN-γ were measured using ELISA kits. Levels of CCL2 were significantly higher in the PTC group compared to the control group (p < 0.05), with no other significant differences in the measured cytokines between the two groups. The groups did not differ significantly in clinical presentation, imaging, treatment, or ophthalmic findings. Our findings provide preliminary evidence that CCL2 may be involved in the pathogenesis of PTC and may serve a potential target for therapy in PTC.

PTRH2 Gene Variants: Recent Review of the Phenotypic Features and Their Bioinformatics Analysis.

Peptidyl-tRNA hydrolase 2 (PTRH2) is an evolutionarily highly conserved mitochondrial protein. The biallelic mutations in the PTRH2 gene have been suggested to cause a rare autosomal recessive disorder characterized by an infantile-onset multisystem neurologic endocrine and pancreatic disease (IMNEPD). Patients with IMNEPD present varying clinical manifestations, including global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, sensorineural hearing loss, and abnormalities of thyroid, pancreas, and liver. In the current study, we conducted an extensive literature review with an emphasis on the variable clinical spectrum and genotypes in patients. Additionally, we reported on a new case with a previously documented mutation. A bioinformatics analysis of the various PTRH2 gene variants was also carried out from a structural perspective. It appears that the most common clinical characteristics among all patients include motor delay (92%), neuropathy (90%), distal weakness (86.4%), intellectual disability (84%), hearing impairment (80%), ataxia (79%), and deformity of head and face (~70%). The less common characteristics include hand deformity (64%), cerebellar atrophy/hypoplasia (47%), and pancreatic abnormality (35%), while the least common appear to be diabetes mellitus (~30%), liver abnormality (~22%), and hypothyroidism (16%). Three missense mutations were revealed in the PTRH2 gene, the most common one being Q85P, which was shared by four different Arab communities and was presented in our new case. Moreover, four different nonsense mutations in the PTRH2 gene were detected. It may be concluded that disease severity depends on the PTRH2 gene variant, as most of the clinical features are manifested by nonsense mutations, while only the common features are presented by missense mutations. A bioinformatics analysis of the various PTRH2 gene variants also suggested the mutations to be deleterious, as they seem to disrupt the structural confirmation of the enzyme, leading to loss of stability and functionality.

Prospective, Cross-Sectional Study Finds No Common Viruses in Cerebrospinal Fluid of Children with Pseudotumor Cerebri.

Pseudotumor cerebri (PTC) in children is a rare condition whose underlying cause remains largely unknown. No study has yet systematically examined viral infection as a cause of PTC. The current study aimed to characterize PTC in children and investigate the possible role of acute viral infection of the central nervous system in its pathogenesis. A prospective, cross-sectional study was conducted in three centers in Israel. Participants were 50 children aged 0.5-18 years, of whom 27 had a definitive diagnosis of pseudotumor cerebri (the study group) and 23 comprised a control. Data collected included clinical presentation, imaging, treatment, ophthalmic findings, and cerebrospinal fluid (CSF) analysis. Using the ALLPLEXTM meningitis panel, real-time polymerase chain reaction (PCR) was used to test for the presence of 12 common viruses. PTC patients (mean age 12 ± 4.3 years; 14 males, 13 females) had mean opening pressure of 41.9 ±10.2 mmH2O. All PTC patients had papilledema, and 25 (93%) had PTC symptoms. No viruses were found in the PTC group, while in the control group, one patient tested positive for Epstein-Barr virus and another for human herpesvirus type 6. Overall, in our study, PTC was not found to be associated with the presence of viruses in CSF.

The prevailing trend of consanguinity in the Arab society of Israel: is it still a challenge?

The aim of this study was to determine the trend of consanguineous marriage among the Arab population in Israel. Socio-demographic data for the Arab population were extracted from national health surveys conducted in Israel in 2007 and 2017. The prevalence of consanguineous marriage among the Arab population in Israel increased significantly from 36.3% to 41.6% in the decade from 2007 to 2017. First-cousin and closer marriages constituted about 50% of total consanguineous marriages in the two periods surveyed. Consanguinity was found to be significantly related to religion and place of residence. Thus, the prevalence of consanguineous marriage remains high among the Arab population in Israel, similar to other Arab societies. These findings affect the health of future generations and impose a challenge for health care professionals.

CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses.

The CLN8 disease type refers to one of the neuronal ceroid lipofuscinoses (NCLs) which are the most common group of neurodegenerative diseases in childhood. The clinical phenotypes of this disease are progressive neurological deterioration that could lead to seizures, dementia, ataxia, visual failure, and various forms of abnormal movement. In the current study, we describe two patients who presented with atypical phenotypic manifestation and protracted clinical course of CLN8 carrying a novel compound heterozygous variant at the CLN8 gene. Our patients developed a mild phenotype of CLN8 disease: as they presented mild epilepsy, cognitive decline, mild learning disability, attention-deficit/hyperactivity disorder (ADHD), they developed a markedly protracted course of motor decline. Bioinformatic analyses of the compound heterozygous CLN8 gene variants were carried out. Most of the variants seem likely to act by compromising the structural integrity of regions within the protein. This in turn is expected to reduce the overall stability of the protein and render the protein less active to various degrees. The cases in our study confirmed and expanded the effect of compound heterozygous variants in CLN8 disease.

Multidomain Cognitive Impairment in Children With Pseudotumor Cerebri Syndrome.

BACKGROUND: Although prompt and suitable treatment of pseudotumor cerebri syndrome (PTCS) leads to an excellent prognosis and can prevent optic nerve atrophy, adults show long-lasting neurocognitive deficits even with prompt treatment. The purpose of our study was to evaluate cognitive outcomes in pediatric patients with PTCS. METHODS: We performed a prospective study on children diagnosed with PTCS and a healthy control group. Children with pre-existing neurological conditions or psychiatric drug use were excluded. Both groups underwent a neurocognitive evaluation, using the NeuroTrax computerized battery of tests. The PTCS group were tested 3 months after the initial diagnosis. RESULTS: We evaluated 82 children (49 females [60%], 6.5-16 years old, mean age 13.3), including 26 diagnosed with idiopathic PTC and 56 controls. Global cognitive score (P < 0.001), verbal memory (P < 0.001), executive function (P < 0.001), attention (P< 0.003), and information processing speed (P < 0.004) were all significantly lower in the PTCS group. No differences were found between children currently being treated and those whose symptoms had resolved and treatment was stopped. CONCLUSIONS: Children with PTCS experience comprehensive cognitive decline that persists after the resolution of the symptoms and treatment.

Modeling genetic epileptic encephalopathies using brain organoids.

Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain-containing oxidoreductase (WWOX) are associated with a relatively mild autosomal recessive spinocerebellar ataxia-12 (SCAR12) and a more severe early infantile WWOX-related epileptic encephalopathy (WOREE). In this study, we generated an in vitro model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR-engineered human ES cells and from patient-derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.

Gene and Protein Expression in Subjects With a Nystagmus-Associated AHR Mutation.

Recently, a consanguineous family was identified in Israel with three children affected by Infantile Nystagmus and Foveal Hypoplasia, following an autosomal recessive mode of inheritance. A homozygous stop mutation c.1861C > T; p.Q621∗ in the aryl hydrocarbon receptor (AHR) gene (AHR; MIM 600253) was identified that co-segregated with the disease in the larger family. AHR is the first gene to be identified causing an autosomal recessive Infantile Nystagmus-related disease in humans. The goal of this study is to delineate the molecular basis of this newly discovered human genetic disorder associated with a rare AHR gene mutation. The gene and protein expression levels of AHR and selected AHR targets from leukocyte cultures of healthy subjects and the patients were analyzed. We observed significant variation between mRNA and protein expression of CYP1A1, CYP1B1, and TiPARP under rest and AHR-induced conditions. The CYP1A1 enzymatic activity in induced leukocytes also differs significantly between the patients and healthy volunteers. Intriguingly, the heterozygous subjects demonstrate CYP1A1 and TiPARP gene and protein expression similar to homozygous patients. In contrast, CYP1B1 inducibility and expression vary between hetero- and homozygous subjects. Similarity and differences in gene and protein expression between heterozygotes and homozygous patients can give us a hint as to which metabolic pathway/s might be involved in the Nystagmus etiology. Thus, we have a unique human model for AHR deficiency that will allow us the opportunity to study the biochemical basis of this rare human mutation, as well as the involvement of AHR in other physiological processes.

Absence seizure provocation during routine EEG: Does position of the child during hyperventilation affect the diagnostic yield?

PURPOSE: When performed correctly, hyperventilation (HV) for three minutes provokes absence seizures in virtually all children, a finding suggestive of a diagnosis of childhood absence epilepsy (CAE). Interestingly, some children experience absence seizures while performing HV in the office yet do not experience absences during HV on subsequent routine EEG. In most instances, HV during routine EEG is performed in the supine position, while in the office HV is done with the child sitting-up. Therefore, we hypothesized that the position in which HV is performed may influence its yield in provoking absence seizures. METHODS: We conducted a randomized multi-center controlled trial among children (4-10 years old) with suspected CAE. During a routine EEG, children were asked to perform HV twice, in the supine and sitting positions. RESULTS: Twenty children (four males) diagnosed with CAE were included in the analysis. Seventeen of the 20 patients experienced absence seizures while sitting and 13 experienced seizures during supine HV (p = 0.031). All patients that had absence seizures during supine HV also had seizures during sitting HV. Among patients with absences in both positions, seizure duration was significantly shorter during sitting HV (mean 8.69 seconds) than during supine HV (mean 12 seconds) (p = 0.042). An opposite tendency was seen in the younger age group (4-7 years), with shorter seizures in the supine HV group (5.6 seconds supine, 7.57 seconds sitting, p = 0.019). CONCLUSIONS: HV in the sitting position may increase the yield of provoking absence seizures during routine EEGs, thereby improving its sensitivity in the diagnosis of CAE.

First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery.

A high rate of consanguinity leads to a high prevalence of autosomal recessive disorders in inbred populations. One example of inbred populations is the Arab communities in Israel and the Palestinian Authority. In the Palestinian Authority in particular, due to limited access to specialized medical care, most patients do not receive a genetic diagnosis and can therefore neither receive genetic counseling nor possibly specific treatment. We used whole-exome sequencing as a first-line diagnostic tool in 83 Palestinian and Israeli Arab families with suspected neurogenetic disorders and were able to establish a probable genetic diagnosis in 51% of the families (42 families). Pathogenic, likely pathogenic or highly suggestive candidate variants were found in the following genes extending and refining the mutational and phenotypic spectrum of these rare disorders: ACO2, ADAT3, ALS2, AMPD2, APTX, B4GALNT1, CAPN1, CLCN1, CNTNAP1, DNAJC6, GAMT, GPT2, KCNQ2, KIF11, LCA5, MCOLN1, MECP2, MFN2, MTMR2, NT5C2, NTRK1, PEX1, POLR3A, PRICKLE1, PRKN, PRX, SCAPER, SEPSECS, SGCG, SLC25A15, SPG11, SYNJ1, TMCO1, and TSEN54. Further, this cohort has proven to be ideal for prioritization of new disease genes. Two separately published candidate genes (WWOX and PAX7) were identified in this study. Analyzing the runs of homozygosity (ROHs) derived from the Exome sequencing data as a marker for the rate of inbreeding, revealed significantly longer ROHs in the included families compared with a German control cohort. The total length of ROHs correlated with the detection rate of recessive disease-causing variants. Identification of the disease-causing gene led to new therapeutic options in four families.

Pre-endoscopic tachycardia predicts increased sedation dose and lower adenoma detection rate in patients undergoing endoscopic procedures: a case control study.

BACKGROUND: Tachycardia prior to endoscopic procedures is commonly encountered which reflect patient anxiety status. Despite this frequent occurrence, it is unclear if in a patient with tachycardia sedation dose should be modified. The aim of our study was to assess the effect of pre-endoscopic tachycardia on sedation dose. METHODS: A retrospective analysis of all patients who underwent upper endoscopy and colonoscopy at EMMS Nazareth hospital were performed. We excluded patients with diseases and medications affecting the heart rate. RESULTS: A total of 2855 patients were included in the study. Two-hundred and thirty-seven patients had tachycardia before endoscopy (8.3%, group A) as compared to 2618 (group B) patients who had heart rate ≤100 beats per minute. The mean dosage of propofol in group A was significantly higher (62.6±33.2 mg vs. 57.4±29.9 mg) than in group B (P=0.01). There was no difference in the cecal intubation rate among the two groups (P=0.9). Notably, the adenoma detection rate was significantly lower among group A patients as compared to group B (13.6% vs. 22.8%, P=0.02) patients. There were no sedation related complications. CONCLUSIONS: Tachycardia prior to endoscopic procedures was associated with higher sedative dosage and lower adenoma detection rate, however no major complications were recorded. These data should be taken into consideration to optimize procedure quality.

Pseudotumor Cerebri Syndrome: From Childhood to Adulthood Risk Factors and Clinical Presentation.

INTRODUCTION: Although considered uncommon, pseudotumor cerebri syndrome (PTC) is a significant cause of headache among children and adults. However, the presenting symptoms may be different among diverse age groups. In the present study, we compared the risk factors and clinical presentation of PTC across life-from childhood to adulthood. METHODS: A retrospective survey of PTC patients aged 7 years or older between 2011 and 2013 was carried out. Pooled analyses were performed comparing characteristics from our data with those of published data subdivided into 3 age groups: pre-young children, adolescents, and adults. RESULTS: Our cohort consisted of 72 patients: 32 children (10 pre-young children, 22 adolescents) and 40 adults. Within the pre-young children age group: 20% were females versus 82% in the adolescent age group and 85% of the adult age group. Obesity was found in 10% of the young children group, 64% of the adolescents, and 80% of the adults. Headache was reported in 70% young children, 82% adolescents, and 83% adults. Pooled analysis of 1499 patients showed that young children with PTC tend to complain less about headache compared with older ones. Vomiting and visual impairment were most common among adolescents, and dizziness and tinnitus were most common in adults. CONCLUSION: PTC has different risk factors and clinical presentation throughout life. In young children, there is no gender preference and most patients are not obese. Risk factors in adolescents resemble those of adults.

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority.

Visual impairment due to inherited ophthalmic disorders is amongst the most common disabilities observed in populations practicing consanguineous marriages. Here we investigated the molecular genetic basis of an unselected broad range of ophthalmic disorders in 20 consanguineous families from Arab villages of Israel and the Palestinian Authority. Most patients had little or very poor prior clinical workup and were recruited in a field study. Homozygosity mapping followed by candidate gene sequencing applying conventional Sanger sequencing or targeted next generation sequencing was performed in six families. In the remaining 14 families, one affected subject per family was chosen for whole exome sequencing. We discovered likely disease-causing variants, all homozygous, in 19 of 20 independent families (95%) including a previously reported novel disease gene for congenital nystagmus associated with foveal hypoplasia. Moreover, we found a family in which disease-causing variants for two collagenopathies - Stickler and Knobloch syndrome - segregate within a large sibship. Nine of the 19 distinct variants observed in this study were novel. Our study demonstrated a very high molecular diagnostic yield for a highly diverse spectrum of rare ophthalmic disorders in Arab patients from Israel and the Palestinian Authority, even with very limited prior clinical investigation. We conclude that 'genetic testing first' may be an economic way to direct clinical care and to support proper genetic counseling and risk assessment in these families.

The Clinical Characteristics of ADHD Diagnosed in Adolescents in Comparison With Younger Children.

Objective: The aim of this study is to identify the clinical characteristics in adolescents newly diagnosed with ADHD. Method: Data of patients aged 7 to 17 years diagnosed with ADHD were collected and analyzed. The patients were divided into adolescents aged 13 to 17 years (Group I) and children aged 7 to 12 years (Group II): 592 males and 231 females. Group I consists of 450 participants, and Group II consists of 373 participants. Results: Adolescents were predominantly inattentive (63.8%); most of Group II patients had combined or hyperactive ADHD (70.8%). Learning disorders were more common in adolescents (51.2% vs. 39.7%) and treated mainly with long-acting methylphenidate (MPH), and Group II patients were treated mainly with short- and medium-acting MPH. Newly diagnosed adolescents were less likely to exhibit behavioral comorbidities. Headache and insomnia were reported more in adolescents, and stimulant rebound effect was more in younger children. Conclusion: Although the biological nature of ADHD is similar in both age groups, the primary symptomatology and associated comorbidities are prone to age-dependent changes.

Exploration of Risk Factors for Type 2 Diabetes among Arabs in Israel.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is becoming increasingly prevalent and is considered to be a major public health threat worldwide. Behavioral and sociodemographic factors associated with T2DM vary within different societies. OBJECTIVE: The aim of this study is to determine the various behavioral and sociodemographic factors associated with T2DM in the Arab society in Israel. METHODS: A cross-sectional study was conducted based on data from 1,894 residents over the age of 21 belonging to the Arab population in Israel. The data collected from the subjects were subjected to statistical analyses using the SPSS program. FINDINGS: Of the total sample population, 13.7% were found to be affected with T2DM. The prevalence of T2DM increased sharply in the successive age groups of both men and women. The prevalence of T2DM was found to increase progressively particularly in women with an increase in BMI (~20%, 37% and 44% respectively), while, in men it increased sharply (from 25% to ~50%) until a BMI of 29.9; it then decreased drastically (to ~24%) for a BMI of ≥30. About 85% of the men affected with T2DM were physically inactive, while 97% of the affected women were physically inactive. Almost half of the participants with diabetes have a family history of the disease in both genders. In the multivariate analysis, it was found that age, obesity, physical inactivity and family history of the disease were the significant factors associated with the prevalence of diabetes. CONCLUSIONS: It could be concluded that age, obesity, family history and physical inactivity were the significant factors associated with the prevalence of T2DM within the Arab society in Israel.