Neurodevelopmental Milestones Research Articles

High Environmental Temperature: Insights into Behavioural, Neurodevelopmental and Gut Microbiome Changes Following Gestational Exposure in Rats

Adverse effects of changing climate have been associated with increase average global temperature resulting in environmental changes. We set out to investigate effects of environmental stress due to increased heat exposure on developmental milestones, behaviour, gut microbiota and neuroarchitecture in rat pups.Pregnant Wistar rats were held in standard temperature (ST) (26 ± 2 °C; control) or high temperature (HT) (40 ± 2 °C) housing. After parturition, a cohort of the HT group and their pups were moved to the control/ST housing (gestational-only-exposed pup [GE]) while the other subset remained in the HT housing (gestational and postnatal exposed pups [GE + PE]). At different time points, we examined neurodevelopmental milestones and behaviour in the pups. Following sacrifice changes in gut microbiota, neuroarchitecture, cytokine levels (TNF-α, IL-4, IL-10), SOD, MDA, expression of MBP, NeUN and GFAP were determined.We observed impaired positioning and placing of paws, prolonged righting reflex, delayed ear opening and significant decreased body weight gain in HT pups when compared with control. We identified Firmicutes and Proteobacteria and noted a significant difference in Firmicutes count between GE and GE + PE pups at P15. Furthermore, TNF-α, IL-4, IL-10 and MDA levels were increased in GE and GE + PE pups. There was also a reduction in MBP expression in the HT pups.Taken together, our results revealed a delay in neurodevelopmental milestones in pups exposed to high HT during gestation and post natal life. Pups whose dam were exposed to high HT during gestation also showed some set back but improved over the course of testing.

Placental pathology predicts infantile neurodevelopment

The aim of present study was to investigate the association of placental pathological findings with infantile neurodevelopment during the early 40 months of life. 258 singleton infants were enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were saved in our pathological division. To assess the infantile neurodevelopment, we used Mullen Scales of Early Learning (gross motor, visual reception, fine motor, receptive language, expressive language) at 10, 14, 18, 24, 32, and 40 months. For obtaining placental blocks, we carried out random sampling and assessed eleven pathological findings using mixed modeling identified ‘Accelerated villous maturation’, ‘Maternal vascular malperfusion’, and ‘Delayed villous maturation’ as significant predictors of the relatively lower MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. On the other hand, ‘Avascular villi’, ‘Thrombosis or Intramural fibrin deposition’, ‘Fetal vascular malperfusion’, and ‘Fetal inflammatory response’ were significant predictors of the relatively higher MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. In conclusion, the present study is the first to report that some placental pathological findings are bidirectionally associated with the progression of infantile neurodevelopment during 10–40 months of age.

The Implication of Physiological Ketosis on The Cognitive Brain: A Narrative Review.

Optimal cognitive functions are necessary for activities of daily living and self-independence. Cognitive abilities are acquired during early childhood as part of progressive neurodevelopmental milestones; unfortunately, regressive changes can occur as part of physiological aging, or more ominously, pathological diseases, such as Alzheimer’s disease (AD). Cases of AD and its milder subset, mild cognitive impairment (MCI), are rising and would impose a burdensome impact beyond the individual level. Various dietary and nutritional approaches have potential for promising results in managing cognitive deterioration. Glucose is the core source of bioenergy in the body; however, glucose brain metabolism could be affected in aging cells or due to disease development. Ketone bodies are an efficient alternate fuel source that could compensate for the deficient glycolytic metabolism upon their supra-physiologic availability in the blood (ketosis), which, in turn, could promote cognitive benefits and tackle disease progression. In this review, we describe the potential of ketogenic approaches to produce cognitive benefits in healthy individuals, as well as those with MCI and AD. Neurophysiological changes of the cognitive brain in response to ketosis through neuroimaging modalities are also described in this review to provide insight into the ketogenic effect on the brain outside the framework of purely molecular explanations.

Interaction of sex and cannabis in adult in vivo brain imaging studies: A systematic review.

Cannabis has been shown to cause structural and functional neurocognitive changes in heavy users. Cannabis use initiation aligns with brain development trajectories; therefore, it is imperative that the potential neurological implications of cannabis use are understood. Males and females reach neurodevelopmental milestones at different rates making it necessary to consider biological sex in all cannabis and brain-based research. Through use of a systamatic review in accordance with PRISMA guidelines, we aimed to understand the interaction between biological sex and cannabis use on brain-based markers. In total, 18 articles containing a sex-based analysis of cannabis users were identified. While the majority of studies (n = 11) reported no sex by cannabis use interactions on brain-based markers, those that reported findings (n = 8) suggest females may be more susceptible to cannabis’ neurotoxic effects. Unfortunately, a large portion of the literature was excluded due to no sex-based analysis. In addition, studies that reported no sex differences often contained a reduced number of females which may result in some studies being underpowered for sex-based analyses, making it difficult to draw firm conclusions. Suggestions to improve cannabis and sex-based reseach are proposed.

Associations Between Infant Developmental Delays and Secondhand Smoke Exposure Modified by Maternal Prepregnancy Overweight and Obesity Status.

Secondhand smoke exposure during pregnancy has long been associated with adverse health outcomes in children, but only a few studies have examined its effect modifiers. In this study, we applied effect modification analysis for maternal prepregnancy weight status on detrimental neurodevelopmental effect of secondhand smoke exposure during pregnancy and infancy in a nationwide representative population. Term singleton mother-infant pairs with nonsmoking mothers were included for main analysis (N = 15 987) from the Taiwan Birth Cohort Study (TBCS), and were further matched with propensity score (n = 5434). We extracted secondhand smoke exposure during pregnancy and infancy, and eight neurodevelopmental milestones from the responses in the baseline visit at 6 months, and 18-month follow-up of TBCS. The associations between secondhand smoke exposure and neurodevelopmental achievement were analyzed with multivariable logistic regression and Cox model. Propensity score weighting and matching were applied for high-versus-low analysis, and relative excess risk due to interaction were used to estimate effect modification. Higher secondhand smoke exposure was associated with increased likelihood of delayed milestone achievement across gross motor, fine motor, language-related, and social-related domains. The associations in fine motor domains remained observable in propensity score-weighted and -matched models. We identified additive interaction with self-reported maternal overweight and obesity status before pregnancy in milestone development for walking with support, scribbling, and waving goodbye. Secondhand smoke exposure during pregnancy and infancy were associated with delayed neurodevelopmental milestone achievement at 18 months, and the associations were modified by maternal prepregnancy overweight and obesity status. The study results suggested the association between maternal secondhand smoke exposure during pregnancy and infancy and delayed fine motor and language-related milestone achievement at 18 months in multivariable, propensity score weighting, and matching populations. The results of positive effect modifications for maternal prepregnancy overweight and obesity status suggested the importance of concurrent interventions on smoke-free environment and maternal health during pregnancy.

Hot water epilepsy under 3 years of age: A short term follow-up study

Aim: Hot water epilepsy (HWE) is a type of reflex epilepsy that occurs as a result of immersing or pouring hot water over the head. Clinical and laboratory findings and short-term neurodevelopmental outcomes of patients were discussed in this report. Materials and Methods: Eight patients under the age of three and followed-up with a diagnosis of HWE between 2017 and 2020 were enrolled in the study. Patient files were evaluated retrospectively. Results: All our patients except one were boys. The patients’ mean age at admission was 16.6 months (min: 10, max: 36), and the mean follow-up period was 13.5 months (min: 6, max: 25). Two patients also experienced non-reflex motor seizures not related to bathing, and these received daily oral antiepileptic therapy. Six patients had focal onset secondary generalized seizures, while one had focal seizures and one has hypomotor seizures accompanied by loss of consciousness. neurodevelopmental milestones were compatible with the patient’s age in all followed-up cases. Clobazam administration before bathing is currently an effective and easily applicable method for this condition. Conclusion: Hot water epilepsy is mostly benign. Clobazam before bathing is an effective option. Daily oral antiepileptic therapy should be administered to patients with seizures accompanying HWE.

Spatiotemporal Dynamics of Human Microglia are Linked with Brain Developmental Processes Across the Lifespan

Microglia, the brain’s resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 post-mortem tissues enabling quantitative, sex-matched, detailed analysis of microglia across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Association of Environmental Tobacco Smoke Exposure and Infant Neurodevelopmental Achievements and Effect Modification by Maternal Overweight and Obesity: Results from the Taiwan Birth Cohort Study

Background: Environmental tobacco smoke (ETS) is a common indoor air pollutant associated with multiple adverse health effects, but it remains unclear regarding effect modifiers and susceptible groups for detrimental neurodevelopmental effect of ETS. We examine the associations between ETS exposure and infant neurodevelopmental parameters in a national-wide representative population. Methods: We extracted the information via structured questionnaires upon home interview from Taiwan Birth Cohort Study (TBCS). The associations between ETS exposure and infant neurodevelopmental milestones were evaluated with multivariate conditional logistic regression and the Cox model and with propensity score (PS) weighting and matching based upon preselected covariates. Results: In this study, 15 987 term singletons were included, and 3598 mother-infant pairs were further selected to PS-matched subpopulation. Higher ETS exposure was associated with increased likelihood of delay in caregiver-reported fine motor (adjusted odds ratio (aOR)=1.29, 95% CI=1.07-1.55; adjusted hazard ratio (aHR)=1.06, 95% CI=1.01-1.11 for clapping hands; aOR=1.21, 95% CI=1.03-1.43; aHR=1.05, 95% CI=1.00-1.10 for scribbling), language-related (aOR=1.25, 95% CI=1.03-1.50; aHR=1.08, 95% CI=1.03-1.13 for waving goodbye; aOR=1.22, 95% CI=1.01-1.47; aHR=1.08, 95% CI=1.04-1.14 for calling a parent meaningfully), and it was consistent in PS-weighted, PS-matched, and among non-smoking families. We also detected positive interaction for both maternal overweight and obesity before pregnancy and after delivery upon the association between high ETS exposure and delayed milestone achievement in scribbling. Conclusions: Maternal peripartum ETS exposure was associated with delayed neurodevelopmental milestone achievement at eighteen months among non-smoking families, and effect modification by maternal overweight and obesity status indicated possible intervention targets for pregnant women.

Association between in utero HIV exposure and auditory brainstem response.

Implementation of combination antiretroviral therapy (cART) has transformed HIV from a fatal disease to a chronic manageable illness. Despite this advance in treatment, a new lingering challenge has emerged in the battle against HIV, namely managing the associated comorbidities.1 Specifically, individuals with HIV have an increased risk of developing various systemic disorders, such as cancer and neurocognitive impairment.2 This risk increases as a function of life span, therefore, infected children although spared complications associated with opportunistic infections due to the efficacy of cART, are at significantly greater risk of developing chronic neurocognitive complications.2 Furthermore, children merely exposed to HIV in utero have also been shown to exhibit structural CNS abnormalities and multiple delays in neurodevelopmental milestones.3,4

Dietary Polar Lipids and Cognitive Development: A Narrative Review

Polar lipids are amphiphilic lipids with a hydrophilic head and a hydrophobic tail. Polar lipids mainly include phospholipids and sphingolipids. They are structural components of neural tissues, with the peak rate of accretion overlapping with neurodevelopmental milestones. The critical role of polar lipids in cognitive development is thought to be mediated through the regulation of signal transduction, myelination, and synaptic plasticity. Animal products (egg, meat, and dairy) are the major dietary sources of polar lipids for children and adults, whereas human milk and infant formula provide polar lipids to infants. Due to the differences observed in both concentration and proportion of polar lipids in human milk, the estimated daily intake in infants encompasses a wide range. In addition, health authorities define neither intake recommendations nor guidelines for polar lipid intake. However, adequate intake is defined for 2 nutrients that are elements of these polar lipids, namely choline and DHA. To date, limited studies exist on the brain bioavailability of dietary polar lipids via either placental transfer or the blood-brain barrier. Nevertheless, due to their role in pre- and postnatal development of the brain, there is a growing interest for the use of gangliosides, which are sphingolipids, as a dietary supplement for pregnant/lactating mothers or infants. In line with this, supplementing gangliosides and phospholipids in wild-type animals and healthy infants does suggest some positive effects on cognitive performance. Whether there is indeed added benefit of supplementing polar lipids in pregnant/lactating mothers or infants requires more clinical research. In this article, we report findings of a review of the state-of-the-art evidence on polar lipid supplementation and cognitive development. Dietary sources, recommended intake, and brain bioavailability of polar lipids are also discussed.

Associations between Household Incense Burning and Motor Development of Preterm Infants: Results from the Taiwan Birth Cohort Study with Propensity Score Weighting Analysis

Background: Household incense burning is a common ritual behavior in Taiwan, but was found to be associated with negative neurodevelopmental outcomes in term infants. We further examined the associations between exposure status and neurodevelopmental development among preterm infants. Methods: We extracted the information from structured questionnaires upon home interview during six and eighteen months of Taiwan Birth Cohort Study (TBCS) survey. We conducted multivariate Cox proportional hazards to model the association between household exposure status and the corrected age for infant neurodevelopmental milestone achievements and we further weighted the effect with multinomial propensity score (PS). The effect among late preterm infants (gestational age 34-36 weeks) were examined with stratified analysis. Results: In this study, 1062 preterm singletons were included, and 933 of them were late preterm. Household incense burning exposure was associated with increased hazards of delay in gross motor neurodevelopmental milestones (aHR=1⋅19, 95% CI=1⋅01-1⋅41 for walking steadily), and the effects were also observed after PS-weighting (Persistent exposure: aHR=1⋅20, 95% CI=1⋅01-1⋅42 for walking with support; aHR=1⋅25, 95% CI=1⋅05-1⋅48 for walking steadily). Similar effects in gross motor neurodevelopmental milestones were observed among late preterm infants, while the effects for other preterm infants were observed in fine motor neurodevelopmental milestones. Conclusions: This study shows negative associations between household incense burning and delayed motor neurodevelopmental milestone achievement. The effects were shown in different domains for late preterm infants and earlier preterm infants. Funding Statement: Bureau of Health Promotion, Department of Health, Ministry of Science and Technology and Ministry of Education, Taiwan. Declaration of Interests: No conflicts of interest have been declared. Ethical Approval Statement: All subjects in this study provided informed consent according to the protocol approved by the institutional Ethics Review Board of the College of Public Health, National Taiwan University and the Institutional Review Board of the Bureau of Health Promotion, Ministry of Health and Welfare, Executive Yuan, Taiwan, which was in comply with the principles of the Declaration of Helsinki.

Association between maternal shift work and infant neurodevelopmental outcomes: results from the Taiwan Birth Cohort Study with propensity-score-matching analysis.

Maternal shift work is associated with preterm delivery, small-for-gestational-age new-borns, childhood obesity and future behavioural problems. However, the adverse effects on and interactions of maternal shift work with infant neurodevelopment remain uncertain. Therefore, we examined the associations between maternal-shift-work status and infant neurodevelopmental parameters. The Taiwan Birth Cohort Study is a nationwide birth cohort study following representatively sampled mother-infant pairs in 2005. The participants' development and exposure conditions were assessed by home interviews with structured questionnaires at 6 and 18 months of age. Propensity scores were calculated with predefined covariates for 1:1 matching. Multivariate conditional logistic regression and the Cox proportional-hazards model were used to examine the association between maternal-shift-work status and infant neurodevelopmental-milestone-achievement status. In this study, 5637 term singletons were included, with 2098 cases selected in the propensity-score-matched subpopulation. Persistent maternal shift work was associated with increased risks of delays in gross-motor neurodevelopmental milestones [aOR = 1.36, 95% confidence interval (CI) = 1.06-1.76 for walking steadily], fine-motor neurodevelopmental milestones (aOR = 1.39, 95% CI = 1.07-1.80 for scribbling) and social neurodevelopmental milestones (aOR = 1.35, 95% CI = 1.03-1.76 for coming when called upon). Moreover, delayed gross-motor and social development were identified in the propensity-score-matched sub-cohort. This study shows negative associations between maternal shift work and delayed neurodevelopmental-milestone achievement in the gross-motor, fine-motor and social domains at 18 months. Future research is necessary to elucidate the possible underlying mechanisms and long-term health effects.

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing

BackgroundRett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective...

Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations

It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and universal, as long as nutritional and health needs are met.

M13 - BEHAVIOR PHENOTYPING OF A MOUSE MODEL OF PHELAN MCDERMID SYNDROME WITH A FULL DELETION OF SHANK3 GENE

Background Phelan-McDermid Syndrome (PMS) is a rare genetic syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated leading to a global developmental delay, hypotonia, delayed or absent speech, intellectual disability, and autistic behaviors. SHANK3, a gene coding for a key structural part of the post-synaptic density, is the critical gene for the core neurological and behavioral symptoms in this syndrome, and the loss of one copy of SHANK3, occurring through intragenic deletion or point mutation, is sufficient to cause Phelan-McDermid syndrome. However, the size of the region affected can be highly variable, from point mutation to up to 8 Mb deletions and the deletion size seems to be correlated with the syndrome severity. Due to multiple intragenic promoters and alternatively spliced coding exons within the gene, several Shank3 isoforms have been identified in human and mouse brains. Methods Numerous mouse models have been generated but most target only some of those isoforms while the vast majority of SHANK3 mutations found in PMS patients are deletions of the entire gene. Our aim is based on a novel mouse model, in which all Shank3 isoforms are disrupted and which more closely mirrors the most common genetic mutations found in PMS and our goal was to investigate the behavioral consequences of a disruption of all isoforms of Shank3. Results Our laboratory had previously created a mouse model with a deletion of exons 4 to 9 leading to the disruption of the full length Shank3 protein. We used a Cre-LoxP strategy to add an additional LoxP site flanking exon 22 and disrupt all isoforms. We carried an extensive behavioral phenotyping of neonate, young and adult wild-type, heterozygote and homozygote mice with a battery of test designed to assess the main feature of PMS including neurodevelopmental milestones, sensory and motor functions, sociability, stereotypies and cognitive functioning. Discussion Mice with a full deletion of Shank3 are more severely affected than previously published mouse model with a partial deletion. Abnormal Mendelian ratios at the time of weaning were observed showing a significant deficit for homozygote mice that can be partially explained by an increase of early postnatal lethality. Both sensory and motor disabilities were detected in neonate and adult mice. While social performances and interest for social stimuli were not impaired, the homozygote mice displayed a strong object avoidance and escape behavior. Additionally, we observed a deficit in both initial training and reversal of Barnes maze, a spatial memory task involving hippocampal-prefrontal circuits. Electrophysiological recording showed that both long-term potentiation and long-term depression are impaired in Shank3 deficient mice. Our new mouse model of PMS recapitulates the core symptoms of PMS providing an improvement of both construction and face validity compared to previous model. Ongoing experiments will identify neural mechanisms and brain circuitry involved in PMS and will use this model to screen potential treatments for Shank3-haploinsufficiency.

2349. Long-Term Neurological Outcome and Neutralizing Antibody Titers Against Paraechovirus-A3 (PeV-A3) in Children who Developed PeV-A3-Related Diseases in Neonatal and Infantile Periods

BackgroundParechovirus-A3 (PeV-A3) is an emerging pathogen causing sepsis and meningoencephalitis in neonates and young infants. We previously reported that maternal antibodies against PeV-A3 are important to protect neonates and young infants from the infection. We showed that all neonates and infants who developed PeV-A3-related diseases had low neutralizing antibody titers (NATs) against PeV-A3 at the onset of disease, subsequently developed high NATs at 3 and 6 months of age. Subsequent changes in NATs against PeV-A3 in children who suffered from PeV-A3-related diseases are currently unknown. Additionally, their long-term neurological outcome is not well described in such population.MethodsSubjects were PeV-A3-infected infants less than 4 months in Niigata, Japan during 2013–2014, and follow-up serum samples were obtained longitudinally from the patients at 3, 6 months, 1 and 3 years after the infection. NATs against PeV-A3 were measured using LLC-MK2 cells. Neurological outcomes of the patients were evaluated by their pediatricians at their study visits.ResultsWe evaluated 45, 34, 33, 26, and 16 serum samples at onset, 3, 6 months, 1 and, 3 years after the infection, respectively. All 45 serum samples at onset had low NATs against PeV-A3 less than 1:32 which was regarded as a cutoff to prevent PeV-A3 infection. Subsequently, the NATs had elevated to the high level (≥1:512) after the infection in all patients. Three years after the infection, all patients except one achieved normal neurodevelopmental milestones. Only one patient who was diagnosed as severe status epileptics due to meningoencephalitis had developmental delay with difficulties in sitting and walking with support.ConclusionThis study showed that NATs against PeV-A3 sustained high levels in patients who had severe PeV-A3-related diseases in their neonatal or young infantile periods. Neurological outcomes of the patients who suffered from PeV-A3-related diseases seem to be excellent, except for the case with complicated clinical course. Disclosures All authors: No reported disclosures.

Gender affects early psychomotor milestones and long‐term neurodevelopment of preterm infants

AbstractTemporal differences of neurodevelopmental milestones' achievement are commonly taken into account in preterm infant assessment during the first year of life, especially when minor or none neurological signs arise from clinical examination. The influence of gender on neurodevelopment in preterm infants was examined by a milestones‐based neurological approach. Two‐hundred twenty‐seven moderate and late preterm and full‐term infants (51.9% male), without evidence of severe white matter insults, were early assessed by classic neurological examination. Griffiths Mental Developmental Scale was used at long‐term observation. Children were sorted into three gestational age groups (Group 1: 32–33 weeks, Group 2: 34–36 weeks, and Group 3: ≥37 weeks) and compared according to their neurodevelopmental pathways and gender. The achievement of head control was slightly earlier in females. The pointing, one of the main communicative hand gesture, appeared significantly earlier in females across all the groups. At the Griffiths Scale, the majority of gender‐related differences emerged in personal–social and eye and hand coordination subscale. An independent role of male gender was evidenced in personal–social, language, and eye and hand coordination subscales. Gender and gestational age likely addressed different temporal profiles of neurodevelopment in early and late assessments in preterm and full‐term infants. The role of gender and gestational age on these findings has been discussed.Highlights A classic, milestones‐based neurological evaluation disclosed different developmental profiles in males versus females preterm infants. Moderate preterm and full‐term infants showed similar developmental profiles. Gender and gestational age may influence neurodevelopment.

Household incense burning and infant gross motor development: Results from the Taiwan Birth Cohort Study

BackgroundAir pollution from biomass burning were associated with neurodevelopmental deceleration, but limited studies concerned about the effect of indoor biomass burning. Incense burning is a common household ritual practice in Taiwan, while past studies mainly focused on birth weight and allergic disease. ObjectivesWe aimed to find the association between incense burning exposure and children's neurodevelopment. MethodsIn Taiwan Birth Cohort Study (TBCS), a nationwide representative birth cohort study, children were assessed upon home interview with structured questionnaires upon six and eighteen months old. Multivariate logistic and Cox proportional hazard regression adjusting confounding factors were applied to explore the odds ratio (OR) and hazard ratio (HR) between household incense burning exposure and caregiver-reported neurodevelopment milestones. ResultsIn this study, 15,310 term singletons were included, and household incense burning was associated with delay in gross motor neurodevelopment milestone, such as walking with support (Occasional incense burning: OR = 1.26, 95% confidence interval (CI): 1.08 to 1.47, HR = 1.07, 95% CI: 1.03 to 1.11; persistent incense burning: OR = 1.44, 95% CI: 1.22 to 1.69, HR = 1.11, 95% CI: 1.07 to 1.16) and walking steadily (Occasional incense burning: OR = 1.14, 95% CI: 0.98 to 1.32, HR = 1.07, 95% CI: 1.03 to 1.11, persistent incense burning: OR = 1.24, 95% CI: 1.06 to 1.45, HR = 1.09, 95% CI: 1.04 to 1.13). ConclusionsOur study suggested household incense burning exposure was associated with delay in gross motor neurodevelopmental milestones. Further research is warranted to elucidate the possible mechanism and causal relationship.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Phenotype and genotype of 87 patients with Mowat\u2013Wilson syndrome and recommendations for care

PurposeMowat–Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype–phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.