High Diagnostic Yield and Clinical Utility of Next-Generation Sequencing in Children with Epilepsy and Neurodevelopmental Delays: A Retrospective Study.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10-50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.

Interstitial microdeletions of 3q26.2q26.31 in two patients with neurodevelopmental delay and distinctive features.

Interstitial microdeletions in the long arm of chromosome 3 are rare. In this study, we identified two patients with approximately 5-Mb overlapping deletions in the 3q26.2q26.31 region. Both patients showed neurodevelopmental delays, congenital heart defects, and distinctive facial features. One of them showed growth deficiency and brain abnormalities, as shown on a magnetic resonance imaging scan. Haploinsufficiency of NLGN1 and FNDC3B present in the common deletion region was considered to be responsible for neurodevelopmental delay and the distinctive features, respectively. The possibility of unmasked variants in PLD1 was considered and analyzed, but no possible pathogenic variant was found, and the mechanism of the congenital heart defects observed in the patients is unknown. Because 3q26.2q26.31 deletions are rare, more information is required to establish genotype-phenotype correlations associated with microdeletions in this region.

Feeding outcomes in post-discharge feeding clinic for infants following cardiac surgery.

INTRODUCTION: The aim of this study was to describe the development and assess the usefulness of a feeding clinic to help infants with CHD tolerate the highest level of oral feeding while achieving growth velocity and supporting neurodevelopment. MATERIALS AND METHODS: This retrospective, cohort study assessed feeding outcomes for infants who underwent cardiac surgery at <30 days of age with cardiopulmonary bypass between February 2016 and April 2020. Diagnoses, age at surgery, hospitalisation variables, and feeding outcomes were compared between two cohorts, pre- and post-implementation of a specialised feeding clinic using Exact Wilcoxon signed-rank test, chi-squared, or Fisher's exact test. The association between time to full oral feed and risk factors was assessed using univariable and multivariable Cox regression model. RESULTS: Post-clinic infants (n = 116) surgery was performed at a median of 6 days of life (interquartile range: 4, 8) with median hospital length of stay of 19 days (interquartile range: 16, 26). Infants' median age at first clinic visit was at 30 days old (interquartile range: 24, 40) and took median 10 days (interquartile range: 7, 12) after hospital discharge to first clinic visit. In the post-clinic cohort, the median time to 100% oral feeding was 47 days (interquartile range: 27, 96) compared to the 60 days (interquartile range: 20, 84) in the pre-clinic cohort (n = 22), but the difference was not statistically significant. DISCUSSION: The cardiac feeding clinic was utilised by our neonatal surgery population and feasible in coordination with cardiology follow-up visits. Future assessment of cardiac feeding clinic impact should include additional measures of feeding and neurodevelopmental success.

Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome.

Microduplication of chromosome 17p13.1 is a rarely reported chromosome abnormality associated with neurodevelopmental delays. We describe two unrelated patients with overlapping microduplications of chromosome 17p13.1. The first patient is a 2-year-old male who presented with neurodevelopmental delays and macrocephaly. He was found to have a de novo 788 kb copy gain of 17p13.2p13.1 and a de novo 134 kb copy gain of 17p13.1. These duplications include multiple candidate genes, including EFNB3, NLGN2, DLG4, GABARAP, and DULLARD, which may be responsible for neurodevelopmental delays in affected individuals. The second patient is a 29-year-old female with mild intellectual disability and relative macrocephaly. She was found to have a 62.5 kb copy gain of chromosome 17p13.1 that includes the DLG4, GABARAP, and DULLARD genes. The DLG4, GABARAP, and DULLARD genes included in the microduplications of both our patients appear to be candidate genes for neurodevelopmental delays and macrocephaly in individuals with 17p13.1 microduplication syndrome.

Early cognitive assessment in premature infants: the discriminatory value of eye-tracking vs. Bayley Scales.

Introduction: The testing of visuocognitive development in preterm infants shows strong interactions between perinatal characteristics and cognition, learning and overall neurodevelopment evolution. The assessment of anticipatory gaze data of object-location bindings via eye-tracking can predict the neurodevelopment of preterm infants at the age of 3 years; little is known, however, about the early cognitive function and its assessment methods during the first year of life. Methods: The current study presents data from a novel assessment tool, a Delayed Match Retrieval (DMR) paradigm via eye-tracking was used to measure visual working memory (VWM) and attention skills. The eye-tracking task that was designed to measure infants' ability to actively localize objects and to make online predictions of object-location bindings. 63 infants participated in the study, 39 preterm infants and 24 healthy full term infants - at a corrected age of 8-9 months for premature infants and similar chronological age for full term infants. Infants were also administered the Bayley Scales of Infant and Toddler Development. Results: The analysis of the Bayley scores showed no significant difference between the two groups while the eye-tracking data showed a significant group effect on all measurements. Moreover, preterm infants' VWM performance was significantly lower than full term's. Birth weight affected the gaze time on all Areas Of Interest (AOIs), overall VWM performance and the scores at the Cognitive Bayley subscale. Furthermore, preterm infants with fetal growth restriction (FGR) showed significant performance effects in the eye-tracking measurements but not on their Bayley scores verifying the high discriminatory value of the eye gaze data. Conclusion: Visual working memory and attention as measured via eye-tracking is a non-intrusive, painless, short duration procedure (approx. 4-min) was found to be a significant tool for identifying prematurity and FGR effects on the development of cognition during the first year of life. Bayley Scales alone may not pick up these deficits. Identifying tools for early neurodevelopmental assessments and cognitive function is important in order to enable earlier support and intervention in the vulnerable group of premature infants, given the associations between foundational executive functional skills and later cognitive and academic ability.

Infant nutrition (donor human milk vs. maternal milk) and long-term neurodevelopmental and growth outcomes in very low birth weight infants.

BACKGROUND: Human milk, the ultimate source of nutrition for premature infants, enhances host defense mechanism, gastrointestinal maturation, lowers infection rate, improves neurodevelopmental outcomes, and reduces long-term cardiovascular and metabolic disease. Recently, there has been an increase in donor breast milk (DBM) use for premature infants; however, data are limited on the long-term effects of DBM on the infant's growth and neurodevelopmental outcomes. OBJECTIVE: To determine if there is an association between type of infant nutrition (maternal breast milk (MBM) or DBM) and neurodevelopmental and growth outcomes in very low birth weight (VLBW) infants. DESIGN/METHODS: Retrospective cohort study of VLBW (<1500 g) infants admitted to the Baylor Scott & White Memorial Hospital Neonatal Intensive Care Unit from January 2014 to December 2016. Infants with major congenital anomalies, born at an outside hospital, who were nil per os (NPO) for >15 days, or who died before NICU discharge were excluded. Infants were stratified into two groups (MBM or DBM) based on predominant nutrition (>50%) received in the first month of life. Primary outcomes of neurodevelopmental delay(s) between 2 and 4 years of age identified via ICD 9/10 codes. Growth data (weight, length, and head circumference) were obtained from well-check visits at 12-, 18-, 24-, 36-, and 48-months. Severity of illness was determined using the Clinical Risk Index in Babies-II (CRIB-II) score. Generalized linear models were used to assess the relationship between nutrition and neurodevelopmental delay and trends in growth over time. RESULTS: Two hundred and nine infants were included: 146 MBM; 63 DBM. Median gestational age was 28 weeks (range, 23-35) and median birthweight was 1050 g (range, 410-1470). There were no significant differences in birthweight, gestational age, CRIB-II score, or length of stay between the groups. Infants fed DBM had a significantly larger weight z-score (p=.005), length z-score (p=.01), and head circumference z-score (p=.04), on average from birth to 48 months compared to MBM infants, while controlling for NICU length of stay and number of follow-up months; however, this only equated to DBM infants being 0.5 in taller and 0.9 lbs heavier at 48 months. There were no statistically significant differences among type of infant nutrition and long-term neurodevelopmental outcomes, while controlling for CRIB-II score. CONCLUSIONS: Infants fed DBM have a slightly greater propensity for growth over time compared to infants fed MBM. Longer follow-up is needed to further determine the effect, infant nutrition has on neurodevelopmental outcomes.

The Value of a Motor Intervention for 3 to 6-Year-Old Children Infected with and Affected by HIV.

Human immunodeficiency virus (HIV)/Aquired Immune Deficiency Syndrome (AIDS) is a large threat to human health and is challenging to address. This study aims to determine if motor intervention is a possibility for promoting the life expectancy and quality of life of children with HIV. The group consisted of 22 participants: 11 HIV-infected (51.73 months, SD 10.15) and 11 HIV-affected children (44.45 months, SD 10.76). A two-group (intervention and control group) pre-test−post-test research design was followed. The HIV-infected and affected children were randomly matched and grouped into an intervention and control group. The intervention group participated in a 12-week motor intervention of 60 min per session, twice per week. The effect of the program was analyzed with regard to motor skills, as established by the PDMS-2 and two strength capabilities. An ANCOVA adjusted for pre-test differences (p < 0.05) indicated statistically significant improvement (p < 0.05) with large practical significance (d > 0.8) in locomotor, fine motor and overall motor skills. The infected children also showed better improvement compared to the affected children. Motor intervention is recommended in the health care path of children affected and infected with HIV, although modifications for improvement of the program are suggested, based on the results attained.

Early life exposure to indoor air pollutants and the risk of neurodevelopmental delays: The Japan Environment and Children's Study.

Air pollution has been associated with childhood neurodevelopment. However, the role of indoor air pollution, especially volatile organic compounds (VOCs), on childhood neurodevelopment has been poorly explored to date. We investigated the association between indoor air pollutants and childhood neurodevelopment in 5,017 randomly selected children from the Japan Environment and Children's Study. When the participants reached 1.5 and 3 years of age, they were followed up with home visits and neurodevelopmental tests using the Ages and Stages Questionnaire (ASQ). At both ages, we collected indoor air samples for 1 week and measured 13 indoor air pollutants: particulate matter with an aerodynamic diameter of ≤2.5 µm, ozone, nitrogen dioxide, sulfur dioxide, and nine VOCs. The associations between air pollutants and ASQ scores were estimated using linear mixed effects models and weighted quantile sum regressions (WQS) at each age separately. Stratified analysis by sex was conducted. Exposure to m,p-xylene at the age of 3 was associated with lower communication, fine motor, and overall ASQ scores (coefficients: -0.18 [99% confidence intervals (CI): -0.35, -0.02], -0.23 [99 %CI: -0.43, -0.03], and - 0.72 [99 %CI: -1.41, -0.04] per 1 µg/m3 increase, respectively). Exposure to o-xylene at the age of 3 was associated with lower communication, gross motor, fine motor, and overall ASQ scores (coefficients: -0.48 [99 %CI: -0.90, -0.07], -0.45 [99 %CI: -0.78, -0.13], -0.65 [99 %CI: -1.14, -0.16], and -2.15 [99 %CI: -3.83, -0.47] per 1 µg/m3 increase, respectively). The WQS index was associated with lower gross motor ASQ scores at the age of 3 (coefficient: -0.27 [95 %CI: -0.51, -0.03] for one-unit WQS index increases), which was attributed to benzene (33.96%), toluene (26.02%), o-xylene (13.62%), and ethylbenzene (9.83%). Stratified analysis showed similar results. Although further investigations are required, our results suggest an association of neurodevelopmental delays with indoor low-level exposure to m,p-xylene and o-xylene in early life.

Prenatal fine particulate matter exposure associated with placental small extracellular vesicle derived microRNA and child neurodevelopmental delays.

BACKGROUND AND AIMS: Prenatal fine particulate matter (PM2.5) exposure has been linked to adverse neurodevelopment. However, epidemiological evidence remains inconclusive and little information about the effects of various PM2.5 components on child neurodevelopment is currently known. The underlying mechanism was also not elucidated. The study aimed to evaluate the effects of PM2.5 and components exposure on child neurodevelopmental delays and the role of placental small extracellular vesicles (sEVs)-derived miRNAs in the associations. METHODS: We included 267 mother-child pairs in this analysis. Prenatal PM2.5 and components (i.e. elements, water-soluble ions, and PAHs) exposure during three trimesters were monitored through personal PM2.5 sampling. Child neurodevelopment at 2, 6, and 12 months old were evaluated by Ages and Stages Questionnaire (ASQ). We isolated sEVs from placental tissue to analyze the change of sEVs-derived miRNAs in response to PM2.5. Associations between the PM2.5-associated miRNAs and child neurodevelopment were evaluated using multivariate linear regression models. RESULTS: The PM2.5 exposure levels in the three trimesters range from 2.51 to 185.21 µg/m3. Prenatal PM2.5 and the components of Pb, Al, V and Ti exposure in the second and third trimester were related to decreased ASQ scores communication, problem-solving and personal-social domains in children aged 2 or 6 months. RNA sequencing identified fifteen differentially expressed miRNAs. The miR-101-3p and miR-520d-5p were negatively associated with PM2.5 and Pb component. miR-320a-3p expression was positively associated with PM2.5 and V component. Meanwhile, the miR-320a-3p was associated with decreased ASQ scores, as reflected by ASQ-T (ß: -2.154, 95 % CI: -4.313, -0.516) and problem-solving domain (ß: -0.605, 95 % CI: -1.111, -0.099) in children aged 6 months. CONCLUSION: Prenatal exposure to PM2.5 and its Pb, Al, V & Ti component were associated with infant neurodevelopmental delays. The placenta sEVs derived miRNAs, especially miR-320a-3p, might contribute to an increased risk of neurodevelopmental delays.

ß-Tubulinopathy caused by a mutation of the TUBB2B gene: magnetic resonance imaging findings of the brain.

Patients with mutations in tubulin-related genes usually present with brain malformations, intellectual disability, epilepsy, microcephaly and ocular abnormalities. In these patients the diagnosis can be suggested by neuroimaging findings. We report a 5-year-old patient with characteristic magnetic resonance imaging findings including malformation of cortical development, fused basal ganglia, large head of the caudate nuclei, absent anterior limbs of the internal capsules, corpus callosum dysgenesis and dysplastic cerebellar vermis. Sequencing of the TUBB2B gene confirmed a heterozygous mutation: c. 260C>A (p. Pro87Gln).

Importance of genetic testing in global health during the evaluation of familial microcephaly.

A focused genetic workup is useful in determining the cause of familial microcephaly, especially in the setting of mildly different phenotypes. As illustrated by this case from an impoverished international urban location, one must not assume the etiology for the apparent familial microcephaly is the same for all affected members.

Association Between Antidepressants Use During Pregnancy and Autistic Spectrum Disorders: A Meta-analysis.

OBJECTIVE: Antidepressants have been reported in several studies in the literature to be associated with the development of autistic disorder symptoms in children exposed to them during the time of their mothers' pregnancies. There have also been reports of neurodevelopment delays associated with exposure to antidepressants in the same conditions. DESIGN: We searched the PUBMED, MEDLINE, PsycARTICLES, and ERIC for original articles published between January 1983 and May 2013 to identify studies on the association between autistic spectrum disorders (ASD) and neurodevelopment delays in children and exposure to antidepressants during pregnancy. CONCLUSION: At the end of our preliminary work, we retained only three articles that were pertinent to the purpose of our study. We extracted the available data in Excel files and then did a meta-analysis. The final results showed a positive association between the exposure to antidepressants in utero and autistic spectrum disorders.