CDC174, a novel component of the exon junction complex whose mutation underlies a syndrome of hypotonia and psychomotor developmental delay.

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.

New DSM-5 criteria for ADHD - Does it matter?

OBJECTIVE: The new Diagnostic Statistical Manual (DSM) requires the presence of fewer symptoms to make a diagnosis of adult ADHD while the criteria for diagnosis in childhood are unchanged as compared to previous editions. This study examines the prevalence of adults meeting the revised DSM-5 symptoms cutoff as compared to the previous DSM-IV symptoms cutoff. METHOD: This study is part of a larger nationwide study that evaluated the use of, and the attitudes toward, ADHD medications by university students. 445 students from four major university faculties were surveyed and filled out questionnaires for our study. RESULTS: The proportion of participants that met the minimum threshold of six out of nine current symptoms in either of the two DSM-IV symptom domains (inattentive presentation and hyperactive/impulsive presentation) for ADHD was 12.7% while the proportion that met the minimum threshold of five symptoms in either of the DSM-5 symptom domains was 21%. CONCLUSION: Since the new DSM requires fewer current symptoms for a diagnosis of ADHD, a significant increase (65%) was observed in the number of participants meeting the new cutoff as compared to the old DSM-IV symptoms cutoff. This increase in the number of adults meeting symptoms cutoff may affect the rates of adults diagnosed with ADHD. Using the new criteria may identify more adults with ADHD and fewer diagnoses will be missed. However, meeting the new symptoms cutoff should be considered within the overall clinical context to prevent over-diagnosis.

Memory consolidation in children with epilepsy: does sleep matter?

INTRODUCTION: Children with epilepsy have frequent sleep disturbance and challenges in learning and memory. There is little research on the consolidation of memory during sleep in this population. The goal of this pilot study was to determine whether children with epilepsy are able to consolidate memories better after a sleep versus wake period as has been demonstrated in typically developing children. METHODS: This study was a prospective evaluation of children with epilepsy to determine if sleep improved episodic memory (using word lists) as compared with memory following a wake period of similar duration. The study was conducted in patients in the Epilepsy Monitoring Unit at a single academic health science center. In the sleep recall condition, the learning trials were presented in the evening, and delayed recall of the words was tested in the morning. In the wake condition, the learning took place in the morning, and the delayed recall took place later in the day. Subjects wore an actigraph to evaluate sleep/wake patterns. Data regarding the children's epilepsy, antiepileptic medications, and frequency of interictal epileptiform discharges were also documented. RESULTS: Ten children (agd 8-17years) participated in the study. For the entire sample, recall after sleep was better than recall after awake (p=0.03), and 7 of the 10 children showed this effect. However, reanalyses removing an outlier showed no difference between the two recall conditions. The mean number of interictal epileptiform discharges was 8.8 during the recall after sleep and 7.8 during the recall after awake. Three children had seizures during the evaluation. CONCLUSION: In this pilot study, we demonstrated that a small cohort of children with epilepsy, with similar interictal epileptiform discharges during sleep and wake, showed no advantage in memory for a word list after a period of sleep than after a period of being awake. This finding requires further study in a larger cohort. Poor memory consolidation during sleep may contribute to the cognitive deficits in children with epilepsy.

Sleep disturbances are associated with greater healthcare utilization in children with autism spectrum disorder.

BACKGROUND: Sleep disturbances are frequently reported in children with autism spectrum disorder (ASD) and are associated with the severity of co-occurring symptoms. This study's aim was to examine the extent of healthcare utilization and clinical outcomes associated with sleep disturbances in children with ASD. STUDY DESIGN: A retrospective, cross-sectional study of 541 children with ASD from the Azrieli National Center for Autism and Neurodevelopment Research (ANCAN) whose parents completed the Children's Sleep Habits Questionnaire (CSHQ). Children with a total CSHQ score ≥ 48 were defined as having sleep disturbances. Sociodemographic characteristics, ASD diagnostic measures, chronic co-occurring conditions, medication usage, hospitalizations, visits to the emergency room (ER), and visits to specialists were compared in ASD children with and without sleep disturbances. Multivariate logistic regression models were then used to assess the independent association of sleep disturbances with clinical characteristics and healthcare utilization. RESULTS: Of the 541 children with ASD, 257 (47.5%) had sleep disturbances. Children with sleep disturbances exhibited higher rates of multiple (≥ 3) co-occurring conditions (19.1% vs. 12.7%; p = 0.0414) and prescribed medications (45.5% vs. 32.7%; p = 0.0031) than other children. Finally, ASD children with sleep disturbances were 1.72 and 2.71 times more likely to visit the ER and be hospitalized than their counterparts (aOR = 1.72; 99%CI = 1.01-2.95; and aOR = 2.71; 99%CI = 1.10-6.67, respectively). CONCLUSIONS: Our findings suggest that sleep disturbances are associated with greater healthcare utilization among children with ASD. Further studies could examine whether treating sleep disturbances in children with ASD yields additional clinical benefits beyond improvements in sleep.

Sex-Specific Developmental Scales for Surveillance.

BACKGROUND: Developmental surveillance, conducted routinely worldwide, is fundamental for early detection of children at risk for developmental delay. We aimed to explore sex-related difference in attainment rates of developmental milestones and to evaluate the clinical need for separate sex-specific scales. METHODS: This is a cross-sectional, natiowide retrospective study, utilizing data from a national child surveillance program of ∼1000 maternal child health clinics. The main cohort, used for constructing sex-specific developmental scales, included all children born between January 2014 to September 2020, who visited maternal child health clinics from birth to 6 years of age (n = 839 574). Children with abnormal developmental potential were excluded (n = 195 616). A validation cohort included all visits between 2020 and 2021 (n = 309 181). The sex-differences in normative attainment age of 59 developmental milestones from 4 domains were evaluated. The milestones with a significant gap between males and females were identified, and the projected error rates when conducting unified versus sex-specific surveillance were calculated. RESULTS: A new sex-specific developmental scale was constructed. In total, females preceded males in most milestones of all developmental domains, mainly at older ages. Conducting routine developmental surveillance using a unified scale, compared with sex-specific scales, resulted in potential missing of females at risk for developmental delay (19.3% of failed assessments) and over-diagnosis of males not requiring further evaluation (5.9% of failed assessments). CONCLUSIONS: There are sex-related differences in the normative attainment rates of developmental milestones, indicating possible distortion of the currently used unified scales. These findings suggest that using sex-specific scales may improve the accuracy of early childhood developmental surveillance.

Early Prediction of Autistic Spectrum Disorder Using Developmental Surveillance Data.

Importance: With the continuous increase in the prevalence of autistic spectrum disorder (ASD), effective early screening is crucial for initiating timely interventions and improving outcomes. Objective: To develop predictive models for ASD using routinely collected developmental surveillance data and to assess their performance in predicting ASD at different ages and in different clinical scenarios. Design, Setting, and Participants: This retrospective cohort study used nationwide data of developmental assessments conducted between January 1, 2014, and January 17, 2023, with minimal follow-up of 4 years and outcome collection in March 2023. Data were from a national program of approximately 1000 maternal child health clinics that perform routine developmental surveillance of children from birth to 6 years of age, serving 70% of children in Israel. The study included all children who were assessed at the maternal child health clinics (N = 1 187 397). Children were excluded if they were born at a gestational age of 33 weeks or earlier, had no record of gestational age, or were followed up for less than 4 years without an ASD outcome. The data set was partitioned at random into a development set (80% of the children) and a holdout evaluation set (20% of the children), both with the same prevalence of ASD outcome. Exposures: For each child, demographic and birth-related covariates were extracted, as were per-visit growth measurements, quantified developmental milestone assessments, and referral summary covariates. Only information that was available before the prediction age was used for training and evaluating the models. Main Outcome and Measure: The main outcome was eligibility for a governmental disabled child allowance due to ASD, according to administrative data of the National Insurance Institute of Israel. The performance of the models that predict the outcome was evaluated and compared with previous work on the Modified Checklist for Autism in Toddlers (M-CHAT). Results: The study included 1 187 397 children (610 588 [51.4%] male). The performance of the ASD prediction models improved with prediction age, with fair accuracy already at 12 months of age. A model that combined longitudinal measures of developmental milestone assessments with a minimal set of demographic variables, which was applied at 18 to 24 months of age, achieved an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 45.1% at a specificity of 95.0%. A model using single-visit assessments achieved an area under the receiver operating characteristic curve of 0.81 and a sensitivity of 41.2% at a specificity of 95.0%. The best performing prediction models surpassed the pooled performance of M-CHAT (sensitivity, 40%; specificity, 95%) reported in studies with a similar design. Conclusions and Relevance: This cohort study found that ASD can be predicted from routine developmental surveillance data at an accuracy surpassing M-CHAT screening. This tool may be seamlessly integrated in the clinical workflow to improve early identification of children who may benefit from timely interventions.

Effectiveness of a positive psychology and mindfulness-based app on mental health for parents of children with a neurodevelopmental disorder: study protocol of a pragmatic international randomized controlled trial.

INTRODUCTION: Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called "Adappt," aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences. METHOD: A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with "Adappt." DISCUSSION: Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care. TRIAL REGISTRATION: This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).

2010 McDonald criteria for diagnosing pediatric multiple sclerosis.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) rests on confirmation of central nervous system inflammatory disease that is disseminated in space and time, as evidenced clinically or by magnetic resonance imaging (MRI). The 2010 McDonald criteria simplified MRI requirements, and newly proposed that the criteria are also suitable for the diagnosis of pediatric MS. METHODS: In a national prospective incident cohort study of children with acute demyelination observed for a minimum of 24 months, baseline and serial clinical and MRI examinations were used to retrospectively evaluate the 2010 and 2005 McDonald criteria using clinically relapsing disease as the gold standard. RESULTS: Of 212 eligible participants, 34 experienced 2 or more clinical attacks, 58 met the 2010 criteria, and 42 met 2005 McDonald criteria. The 2010 criteria demonstrated high sensitivity (100%), specificity (86%), positive predictive value (76%), and negative predictive value (100%) for children older than 11 years with non-acute disseminated encephalomyelitis (ADEM) presentations, as did the 2005 McDonald criteria. In younger children with a non-ADEM presentation, PPV of the 2010 criteria was only 55%. None of the 50 children with ADEM met clinical criteria for MS, but 10 met 2010 and 4 met 2005 criteria. INTERPRETATION: Both 2005 and 2010 McDonald criteria identify children with relapsing-remitting MS, although caution is suggested when applying these criteria in younger children. The 2010 McDonald criteria are simple and enable an early diagnosis of MS, but are not suited for application in the context of ADEM-like presentations.

A Developmental Surveillance Score for Quantitative Monitoring of Early Childhood Milestone Attainment: Algorithm Development and Validation.

BACKGROUND: Developmental surveillance, conducted routinely worldwide, is fundamental for timely identification of children at risk of developmental delays. It is typically executed by assessing age-appropriate milestone attainment and applying clinical judgment during health supervision visits. Unlike developmental screening and evaluation tools, surveillance typically lacks standardized quantitative measures, and consequently, its interpretation is often qualitative and subjective. OBJECTIVE: Herein, we suggested a novel method for aggregating developmental surveillance assessments into a single score that coherently depicts and monitors child development. We described the procedure for calculating the score and demonstrated its ability to effectively capture known population-level associations. Additionally, we showed that the score can be used to describe longitudinal patterns of development that may facilitate tracking and classifying developmental trajectories of children. METHODS: We described the Developmental Surveillance Score (DSS), a simple-to-use tool that quantifies the age-dependent severity level of a failure at attaining developmental milestones based on the recently introduced Israeli developmental surveillance program. We evaluated the DSS using a nationwide cohort of >1 million Israeli children from birth to 36 months of age, assessed between July 1, 2014, and September 1, 2021. We measured the score's ability to capture known associations between developmental delays and characteristics of the mother and child. Additionally, we computed series of the DSS in consecutive visits to describe a child's longitudinal development and applied cluster analysis to identify distinct patterns of these developmental trajectories. RESULTS: The analyzed cohort included 1,130,005 children. The evaluation of the DSS on subpopulations of the cohort, stratified by known risk factors of developmental delays, revealed expected relations between developmental delay and characteristics of the child and mother, including demographics and obstetrics-related variables. On average, the score was worse for preterm children compared to full-term children and for male children compared to female children, and it was correspondingly worse for lower levels of maternal education. The trajectories of scores in 6 consecutive visits were available for 294,000 children. The clustering of these trajectories revealed 3 main types of developmental patterns that are consistent with clinical experience: children who successfully attain milestones, children who initially tend to fail but improve over time, and children whose failures tend to increase over time. CONCLUSIONS: The suggested score is straightforward to compute in its basic form and can be easily implemented as a web-based tool in its more elaborate form. It highlights known and novel relations between developmental delay and characteristics of the mother and child, demonstrating its potential usefulness for surveillance and research. Additionally, it can monitor the developmental trajectory of a child and characterize it. Future work is needed to calibrate the score vis-a-vis other screening tools, validate it worldwide, and integrate it into the clinical workflow of developmental surveillance.

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data.

Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants' functional and clinical consequences requires integrating multifaceted genomic information. We compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (< 1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by the InterVar and TAPES tools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool, Psi-Variant, that integrates results from seven in-silico prediction tools. Overall, 372 variants in 311 genes distributed in 168 probands were detected by these tools. The overlap between the tools was 64.1, 22.9, and 23.1% for InterVar-TAPES, InterVar-Psi-Variant, and TAPES-Psi-Variant, respectively. The intersection between InterVar and Psi-Variant (I âˆ© P) was the most effective approach in detecting variants in known ASD genes (PPV = 0.274; OR = 7.09, 95% CI = 3.92-12.22), while the union of InterVar and Psi Variant (I U P) achieved the highest diagnostic yield (20.5%).Our results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.

Adherence to treatment and parents' perspective about effectiveness of melatonin in children with autism spectrum disorder and sleep disturbances.

OBJECTIVE: Melatonin is considered an effective pharmacological treatment for the sleep disturbances that are reported in > 50% of children with autism spectrum disorder (ASD). However, real-life data about the long-term course and effectiveness of melatonin treatment in children with ASD is lacking. METHODS: In this retrospective cohort study, we assessed the adherence to melatonin treatment and parents' perspective of its effect on sleep quality and daytime behavior in children with ASD via a parental phone survey of children in the Azrieli National Center for Autism and Neurodevelopment Research (ANCAN) database. Cox regression analysis was used to assess the effect of key demographic and clinical characteristics on treatment adherence. RESULTS: Melatonin was recommended for ~ 8% of children in the ANCAN database. These children were characterized by more severe symptoms of autism. The median adherence time for melatonin treatment exceeded 88 months, with the most common reason for discontinuation being a lack of effectiveness (14%). Mild side-effects were reported in 14% of children, and 86%, 54%, and 45% experienced improvements in sleep onset, sleep duration and night awakenings, respectively. Notably, melatonin also improved the daytime behaviors of > 28% of the children. Adherence to treatment was independently associated with improvements in night awakenings and educational functioning (aHR = 0.142, 95%CI = 0.036-0.565; and aHR = 0.195, 95%CI = 0.047-0.806, respectively). CONCLUSIONS: Based on parents' report, melatonin is a safe and effective treatment that improves both sleep difficulties and daily behavior of children with ASD.

Sleep disturbances are associated with irritability in ASD children with sensory sensitivities.

BACKGROUND: Parent reports suggest that 44-84% of children with ASD exhibit sleep disturbances that are of clinical concern. Previous studies have reported that, in children with ASD, the severity of sleep disturbances is associated with the severity of either sensory problems or aberrant behaviors, but none have performed combined analyses with measures of both sensory and aberrant behaviors symptom domains from the same children. METHODS: We examined parent reports of 237 children with ASD, 1.4-8.7 years old, using the child sleep habits questionnaire (CSHQ), sensory profile (SP), and aberrant behaviors checklist (ABC). RESULTS: The analyses revealed that sleep disturbances were most strongly associated with SP sensory sensitivity and ABC irritability scores. Together these scores explained 35% of the variance in total CSHQ scores. Moreover, sensory sensitivity scores moderated the association between irritability and sleep disturbances, indicating that sleep disturbances were significantly associated with irritability only in children with moderate to severe sensory sensitivities. CONCLUSION: We suggest that the three symptom domains may interact and exacerbate each other such that successful intervention in one symptom domain may have positive impact on the others. Further intervention studies testing this hypothesis are highly warranted.

Increased rates of unattained developmental milestones among Israeli children between 2016 and 2020: a national report.

BACKGROUND: The early years of children's lives are critical for their healthy development. Although children's growth and development rates may vary, a significant delay during early childhood could indicate a medical or a developmental disorder. Developmental surveillance is used worldwide by healthcare providers in routine encounters, as well as by educators and parents, to elicit concerns about child development. In this work, we used a national dataset of developmental assessments to describe temporal trends of milestone attainment rates and associations between milestone attainment and various sociodemographic factors. METHODS: The study included 1,002,700 children ages birth until 6 years with 4,441,689 developmental visits between the years 2016 and 2020. We used the Israeli developmental scale to assess the annual rates of failure to attain language, social and motoric milestones by the entire population, as well as by subgroups stratified by sociodemographic factors. In addition, we evaluated the rates of parental concern for child development and of the nurse's report of development inadequate for age. We used multivariable logistic regression to analyze the impact of different sociodemographic factors on the odds of failure to attain milestones, while controlling for confounding. RESULTS: Milestone failure rates progressively increased over the examined years in all developmental domains, and most prominently in the language domain. Conversely, the rates of parental concern for developmental delay remained constant. In multivariable analysis, higher risk of milestone attainment failure was observed in children whose mothers were divorced, unemployed, immigrant, had lower education, of Bedouin origin or were over 40 years old when giving birth. CONCLUSIONS: This report describes national trends of child development in the gross motor, fine motor, language, and social domains. A periodic report of these trends should be published to objectively evaluate subgroups in need for intervention, and to assess the effectiveness of intervention programs in attempt to maximize the developmental potential of children in Israel.

Trends in the Prevalence of Chronic Medication Use Among Children in Israel Between 2010 and 2019: Protocol for a Retrospective Cohort Study.

BACKGROUND: Prescription of psychostimulants has significantly increased in most countries worldwide for both preschool and school-aged children. Understanding the trends of chronic medication use among children in different age groups and from different sociodemographic backgrounds is essential. It is essential to distinguish between selected therapy areas to help decision-makers evaluate not only the relevant expected medication costs but also the specific services related to these areas. OBJECTIVE: This study will analyze differences in trends regarding medications considered psychobehavioral treatments and medications considered nonpsychobehavioral treatments and will identify risk factors and predictors for chronic medication use among children. METHODS: This is a retrospective study. Data will be extracted from the Clalit Health Services data warehouse. For each year between 2010 and 2019, there are approximately 1,500,000 children aged 0-18 years. All medication classes will be identified using the Anatomical Therapeutic Chemical code. A time-trend analysis will be performed to investigate if there is a significant difference between the trends of children's psychobehavioral and nonpsychobehavioral medication prescriptions. A logistic regression combined with machine learning models will be developed to identify variables that may increase the risk for specific chronic medication types and identify children likely to get such treatment. RESULTS: The project was funded in 2019. Data analysis is currently underway, and the results are expected to be submitted for publication in 2022. Understanding trends regarding medications considered psychobehavioral treatments and medications considered nonpsychobehavioral treatments will support the identification of risk factors and predictors for chronic medication use among children. CONCLUSIONS: Analyzing the response of the patient (and their parents or caregivers) population over time will hopefully help improve policies for prescriptions and follow-up of chronic treatments in children. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36756.

Assessing the Attainment Rates of Updated CDC Milestones Using a New Israeli Developmental Scale.

OBJECTIVES: Developmental milestones norms are widely used worldwide and are fundamental for early childhood developmental surveillance. We compared a new Israeli evidence-based national developmental scale with the recently updated Centers for Disease Control and Prevention (CDC) checklists. METHODS: We used a cohort of nearly 4.5 million developmental assessments of 758 300 full-term born children aged 0 to 6 years (ALL-FT cohort), who visited maternal child health clinics in Israel for routine developmental surveillance. Among the assessed milestones of 4 developmental domains (gross motor, fine motor, language, and personal-social) we identified milestones that had equivalents on the CDC checklists and assessed the attainment rates of the Israeli children at the ages recommended by the CDC, at which ≥75% of the children would be expected to achieve the milestone. The analysis was repeated on a subgroup of 658 958 children who were considered healthy, typically developing by their birth and growth characteristics (NORMAL-FT cohort). RESULTS: There were 29 milestones, across all developmental domains and assessment ages, whose definitions by both tools were compatible, and could be compared. The attainment rate at the CDC-recommended age was >90% for 22 (76%) and 23 (79%) milestones, and the median attainment rates were 95.2% and 96.3% in the ALL-FT and NORMAL-FT cohorts, respectively. CONCLUSIONS: For almost all comparable milestones of all domains and all ages, children of the Israeli cohorts achieved the milestones earlier than expected by the CDC-defined threshold age. Evidence-based analysis of milestone norms among different populations may enable adjustments of developmental scales and facilitate more personalized developmental surveillance.

Transcript-Based Diagnosis and Expanded Phenotype of an Intronic Mutation in TPM3 Myopathy.

INTRODUCTION: Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia. METHODS: Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies. RESULTS: We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript. DISCUSSION: This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.

Home-quarantine during the initial Covid-19 outbreak in Israel: parent perceived impact on children with ASD.

Background: Studies have reported that Covid-19 home-quarantine periods have had mostly negative psychological impact on children with ASD and their families. Here we examined parent perceived impact of a 6-week quarantine period imposed in Israel at the beginning of the Covid-19 outbreak, in mid-March 2020. Methods: An anonymous online questionnaire was completed by parents of 268 children with ASD. Parents rated deterioration/improvement in their child's behaviors, abilities, mood, sleep, and anxiety along with changes in their own mood, sleep, parenting skills, and family relationships. We performed t-tests and ANOVA analyses to assess the significance of perceived impact on each domain and potential differences in the impact across families with children of different ages, genders, and levels of required support as well as families that experienced different magnitudes of economic hardships. Results: Parents reported significant deterioration in their mood and sleep along with significant improvements in relationships with their spouse and child with ASD, and in their parenting skills. Parents also reported significant increases in the severity of tantrums, anxiety, and restricted and repetitive behavior symptoms along with significant improvements in social and communication abilities of their child with ASD. Ratings were significantly lower in families of ASD children who regularly require more support and in families that experienced economic hardships. Conclusions: While periods of home-quarantine create numerous hardships for families of children with ASD, they may also offer an opportunity for improving parenting skills, family relationships, and children's social communication abilities with potential relevance for improving remote services.

Standardization of a Developmental Milestone Scale Using Data From Children in Israel.

Importance: Routine developmental screening tests for children are used worldwide for early detection of developmental delays. However, assessment of developmental milestone norms lacks strong normative data, and there are inconsistencies among different screening tools. Objective: To establish milestone norms and build an updated developmental scale. Design, Setting, and Participants: This is a cross-sectional, population-based study conducted between 2014 and 2020. Developmental assessments were conducted by trained public health nurses, documented in national maternal child health clinics, known as Tipat Halav, which serve all children in Israel. Participants included all children born between January 2014 and September 2020, who were followed at the maternal child health clinics from birth to age 6 years. Exclusion criteria were preterm birth, missing gestational age, low birth weight (<2.5 kg), abnormal weight measurement (<3% according to standardized child growth charts), abnormal head circumference measurement (<3% or >97% according to standardized child growth charts), and visits without developmental data or without the child's age. Data analysis was performed from September 2020 to June 2021. Exposures: In total, 59 milestones in 4 developmental domains were evaluated, and the achievement rate per child's age was calculated for each milestone. Main Outcomes and Measures: A contemporary developmental scale, the Tipat Halav Israel Screening (THIS) Developmental Scale, was built, presenting the 75%, 90%, and 95% achievement rates for each milestone. The THIS scale was compared with other commonly used screening tests, including the Denver Developmental Screening Test II (Denver II), the Alberta Infant Motor Scale (AIMS), and the Centers for Disease Control and Prevention (CDC) Developmental Assessment. Results: A total of 839 574 children were followed in the maternal child health clinics between January 2014 and September 2020 in Israel, and 195 616 children were excluded. A total of 3 774 517 developmental assessments were performed for the remaining 643 958 children aged 0 to 6 years (319 562 female children [49.6%]), resulting in the establishment of new developmental norms. In terms of the comparable milestones, THIS milestones had a match of 18 of 27 (67%) with the Denver II, 7 of 7 (100%) with AIMS, and 10 of 19 (53%) with the CDC Developmental Assessment. The remaining unmatched milestones were achieved earlier in the THIS scale compared with other screening tools. Conclusions and Relevance: The THIS developmental scale is based on the largest population evaluated to date for developmental performance, representing the heterogeneous, multicultural population comprising this cohort. It is recommended for further evaluation worldwide.

Early Childhood Shigellosis and Attention Deficit Hyperactivity Disorder: A Population-Based Cohort Study with a Prolonged Follow-up.

BACKGROUND: Although the short-term neurological complications of Shigella spp. are well described, potential neuropsychiatric outcomes have not been studied yet. We investigated the association between early childhood shigellosis and subsequent ADHD. METHODS: This is a retrospective population-based cohort. Using a large Health Maintenance Organization database, the prevalence of ADHD was investigated among children aged 5-18 years who underwent stool culture prior to the age of 3 years. RESULTS: Of 52,761 children with a stool culture examined, 5,269 (9.98%) had Shigella-positive results. The rate of ADHD was 10.6% and 8.6% among children with Shigella-positive and Shigella-negative stool cultures, respectively (p < .001). Adjusted odds ratio for ADHD after controlling for gender and socioeconomic status was 1.21 (CI 1.13-1.29, p < .001). The younger the child was during Shigella gastroenteritis, the higher was the association with ADHD (p < .001). CONCLUSION: Early childhood shigellosis is associated with an increased rate of long-term ADHD.

The Effect of Antibiotic Treatment of Early Childhood Shigellosis on Long-Term Prevalence of Attention Deficit/Hyperactivity Disorder.

It has recently been shown that children with early shigellosis are at increased risk of attention deficit/hyperactivity disorder (ADHD). This study aimed to evaluate the association between antibiotic treatment of shigellosis with long-term ADHD rates. A retrospective cohort study was conducted that included all the Leumit Health Services (LHS) enrollees aged 5-18 years between 2000-2018 with a documented Shigella-positive gastroenteritis before the age of 3 years. Of the 5176 children who were positive for Shigella gastroenteritis before the age of 3 years, 972 (18.8%) were treated with antibiotics early (<5 days), 250 (4.8%) were treated late (≥5 days), and 3954 children (76.4%) were not prescribed antibiotics. Late antibiotic treatment was associated with significantly increased rates of ADHD (adjusted OR = 1.61; 95% CI, 1.1-2.3). Early treatment with antibiotics was not associated with increased ADHD rates (adjusted OR = 1.02; 95% CI, 0.8-1.3). In conclusion, late antibiotic treatment of early childhood shigellosis was associated with increased rates of ADHD.