Significant Developmental Delay Research Articles

Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model.

Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Epilepsies with onset during the first year of life: A prospective study on syndromes, etiologies, and outcomes.

Infantile seizures cause great concern for both doctors and parents. In addition to modern neuroimaging and genetics, clinical tools helpful in predicting the course of the disease are needed. We prospectively studied the incidence, electroclinical characteristics and etiologies of epilepsy syndromes with onset before the age of 12 months and looked for prognostic determinants of outcome by age 24 months. From February 2017 through May 2019, we recruited all eligible infants diagnosed with epilepsy at our unit. Data on electroclinical studies, genetic investigations and drug response were gathered prospectively. The infants were given a structured neurological examination (Hammersmith Infantile Neurological examination [HINE] and Griffiths scales) at predetermined intervals until age 24 months at which age neurocognitive evaluation with Bayley scales was performed. Included were 60 infants (27 female). The mean onset age of epilepsy was 5.3 (±2.5 standard deviation) months. The incidence of epilepsy in the population-based cohort was 131 (95% confidence interval 99-172)/100 000. Epilepsy syndrome was identified in 80% and etiology in 58% of infants. Self-limited infantile epilepsy was the second most common syndrome (incidence 18/100 000) after infantile epileptic spasms syndrome. PRRT2 was the most common monogenic cause. At age 24 months, 37% of the infants had drug-resistant epilepsy (DRE) and half had a global developmental delay (GDD). Abnormal first HINE was the strongest predictor of GDD, followed by DRE and identified etiology. DRE was associated with structural etiology and GDD. Those with normal first HINE and good response to treatment had favorable outcomes, irrespective of the identified etiology. Our results support a high incidence of self-limited epilepsy in infancy and PRRT2 as the genetic cause in the first year of life. Notwithstanding the advances in etiological discovery, we want to highlight the importance of clinical evaluation as standardized neurological examination with HINE proved a valuable tool in prognostication. One in every 700-800 babies develop epilepsy within the first year after birth. Our study identified an epilepsy syndrome in 80% and the cause of epilepsy in 60% of the participants. By age 2 years, over one-third of the children still experienced seizures, and almost half faced significant developmental delay. Structural brain abnormalities increased the likelihood of difficult epilepsy and developmental challenges. Babies whose epilepsy was caused by a gene defect varied widely in development and response to medications. Babies with normal neurological examination at first visit, especially if their seizures stopped quickly, had favorable development.

Developmental Delay and Male-Biased Sex Ratio in esr2b Knockout Zebrafish.

The estrogen receptor signaling pathway plays an important role in vertebrate embryonic development and sexual differentiation. There are four major estrogen receptors in zebrafish: esr1, esr2a, esr2b and gper. However, the specific role of different estrogen receptors in zebrafish is not clear. To investigate the role of esr2b in zebrafish development and reproduction, this study utilized TALENs technology to generate an esr2b knockout homozygous zebrafish line. The number of eggs laid by esr2b knockout female zebrafish did not differ significantly from that of wild zebrafish. The embryonic development process of wild-type and esr2b knockout zebrafish was observed, revealing a significant developmental delay in the esr2b knockout zebrafish. Additionally, mortality rates were significantly higher in esr2b knockout zebrafish than in their wild-type counterparts at 24 hpf. The reciprocal cross experiment between esr2b knockout zebrafish and wild-type zebrafish revealed that the absence of esr2b resulted in a decline in the quality of zebrafish oocytes, while having no impact on sperm cells. The knockout of esr2b also led to an abnormal sex ratio in the adult zebrafish population, with a female-to-male ratio of approximately 1:7. The quantitative PCR (qPCR) and in situ hybridization results demonstrated a significant downregulation of cyp19ab1b expression in esr2b knockout embryos compared to wild-type embryos throughout development (at 2 dpf, 3 dpf and 4 dpf). Additionally, the estrogen-mediated induction expression of cyp19ab1b was attenuated, while the estradiol-induced upregulated expression of vtg1 was disrupted. These results suggest that esr2b is involved in regulating zebrafish oocyte development and sex differentiation.

Differential impact of diesel exhaust particles on glutamatergic and dopaminergic neurons in Caenorhabditis elegans: A neurodegenerative perspective

The growing body of evidence links exposure to particulate matter pollutants with an increased risk of neurodegenerative diseases. In the present study, we investigated whether diesel exhaust particles can induce neurobehavioral alterations associated with neurodegenerative effects on glutamatergic and dopaminergic neurons in Caenorhabditis elegans (C. elegans). Exposure to DEP at concentrations of 0.167 µg/cm2 and 1.67 µg/cm2 resulted in significant developmental delays and altered locomotion behaviour. These effects were accompanied by discernible alterations in the expressions of antioxidant genes sod-3 and gst-4 observed in transgenic strains. Behaviour analysis demonstrated a significant reduction in average speed (p < 0.001), altered paths, and decreased swimming activities (p < 0.01), particularly at mid and high doses. Subsequent assessment of neurodegeneration markers in glutamatergic (DA1240) and dopaminergic (BZ555) transgenic worms revealed notable glutamatergic neuron degeneration at 0.167 μg/cm2 (∼30 % moderate, ∼20 % advanced) and 1.67 μg/cm2 (∼28 % moderate, ∼24 % advanced, p < 0.0001), while dopaminergic neurons exhibited structural deformities (∼16 %) without significant degeneration in terms of blebs and breaks. Furthermore, in silico docking simulations suggest the presence of an antagonistic competitive inhibition induced by DEP in the evaluated neuro-targets, stronger for the glutamatergic transporter than for the dopaminergic receptor from the comparative binding affinity point of view. The results underscore DEP's distinctive neurodegenerative effects and suggest a link between locomotion defects and glutamatergic neurodegeneration in C. elegans, providing insights into environmental health risks assessment.

Oral feeding trajectories and neurodevelopmental outcomes at 12 and 24month follow-up for preterm infants.

Few studies characterize feeding performance in the NICU when predicting neurodevelopmental outcomes. Our objective was to investigate the relationship between time to full oral feeds (FULL-PO) and neurodevelopmental and feeding outcomes in the first 2 years in preterm infants admitted to the NICU. This retrospective study included infants born between 01/01/2014-07/31/2017, gestational age < 32 weeks and/or birth weight < 1500 g. We examined feeding difficulties, cerebral palsy, and Bayley scores for those reaching FULL-PO at a post menstrual age (PMA)≤38.0 weeks (EARLY) vs.>38.0 weeks (LATE). Additionally, the oral feeding achieved at various timepoints between 36- and 42-weeks postmenstrual age (PMA) was measured to construct a timeline of oral feeding acquisition. Of 192 infants, 147(77%) achieved FULL-PO EARLY and 45(23%) LATE. Comorbidities and length of stay were higher and unadjusted Bayley scores were lower at 12 months corrected age (CA) and 24 months chronological age (CH) in the LATE group. Feeding difficulties were higher in the LATE group at 24 months CH. Infants born < 27-28 weeks GA were more likely to achieve oral feeding at a later PMA. Infants with bronchopulmonary dysplasia (BPD) had significant feeding and developmental delays. Establishing full oral feeds by 38.0 weeks PMA may be used as a predictor for feeding difficulties at 24 months CH. Infants born < 27-28 weeks GA and those with BPD are more likely to take extended amounts of time to achieve full oral feeding and need additional feeding support. Infants with BPD are high risk for neurodevelopmental delays.

A De Novo Noncoding RARB Variant Associated with Complex Microphthalmia Alters a Putative Regulatory Element

Retinoic acid receptor beta (RARB) is a transcriptional regulator crucial for coordinating retinoic acid- (RA-) mediated morphogenic movements, cell growth, and differentiation during eye development. Loss- or gain-of-function RARB coding variants have been associated with microphthalmia, coloboma, and anterior segment defects. We identified a de novo variant c.157+1895G&gt;A located within a conserved region (CR1) in the first intron of RARB in an individual with complex microphthalmia and significant global developmental delay. Based on the phenotypic overlap, we further investigated the possible effects of the variant on mRNA splicing and/or transcriptional regulation through in silico and functional studies. In silico analysis identified the possibility of alternative splicing, suggested by one out of three (HSF, SpliceAI, and MaxEntScan) splicing prediction programs, and a strong indication of regulatory function based on publicly available DNase hypersensitivity, histone modification, chromatin folding, and ChIP-seq data sets. Consistent with the predictions of SpliceAI and MaxEntScan, in vitro minigene assays showed no effect on RARB mRNA splicing. Evaluation of CR1 for a regulatory role using luciferase reporter assays in human lens epithelial cells demonstrated a significant increase in the activity of the RARB promoter in the presence of wild-type CR1. This activity was further significantly increased in the presence of CR1 carrying the c.157+1895G&gt;A variant, suggesting that the variant may promote RARB overexpression in human cells. Induction of RARB overexpression in human lens epithelial cells resulted in increased cell proliferation and elevated expression of FOXC1, a known downstream target of RA signaling and a transcription factor whose down- and upregulation is associated with ocular phenotypes overlapping the RARB spectrum. These results support a regulatory role for the CR1 element and suggest that the de novo c.157+1895G&gt;A variant affecting this region may alter the proper regulation of RARB and, as a result, its downstream genes, possibly leading to abnormal development.

Whole-exome sequencing revealed a novel ERCC8 variant in an Iranian large family with Cockayne syndrome

BackgroundCockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. The excision repair cross complementing protein group 6 (ERCC8) gene, which codes for the CS group A (CSA) protein, is usually mutated in cases of CS. MethodWe show two Iranian families who have significant speech delay, microcephaly, developmental delay, and notable growth failure. We have discovered a unique homozygous missense variant (c.742G > T) in CSA in an Iranian family with CS, which we discovered using whole exome sequencing as well. ResultsIn two related probands, we found a homozygous variant (c.742G > T) in the ERCC8 gene that we believe to be a unique pathogenic mutation. ConclusionWES results together with the characteristic clinical manifestations of Cockayne syndrome, provided an accurate diagnosis for two families. Also, our study identified novel variants in Iranian families.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders

BackgroundSCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia.MethodsIn this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing.ResultsClinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Three novel and three reported variants were observed in SCN8A. Electrophysiological analysis in transfected cells revealed a loss-of-function variant in Patient 4.ConclusionsThis work expands the clinical and genotypic spectrum of SCN8A-related disorders and provides electrophysiological results on a novel loss-of-function SCN8A variant.

P38- and ERK-MAPK Signalling Modulate Developmental Neurotoxicity of Nickel and Vanadium in the Caenorhabditis elegans Model

Nickel (Ni) and vanadium (V) are characteristic heavy metal constituents of many crude oil blends in Sub-Saharan Africa, and we have previously demonstrated their neurotoxic impact. However, molecular mechanisms driving Ni and V neurotoxicity are still being elucidated. The p38- and ERKs-MAPK pathways, which are mostly known for their involvement in human immune and inflammatory signalling, have been shown to influence an array of neurodevelopmental processes. In the present study, we attempt to elucidate the role of p38- and ERK-MAPK in neurotoxicity after early life exposures to Ni and V using the Caenorhabditis elegans model. Synchronized larvae stage-1 (L1) worms were treated with varying concentrations of Ni and V singly or in combination for 1 h. Our results show Ni induces lethality in C. elegans even at very low concentrations, while much higher V concentrations are required to induce lethality. Furthermore, we identified that loss-of-function of pmk-1 and pmk-3, which are both homologous to human p38-α (MAPK14), is differentially affected by Ni and V exposures. Also, all exposure scenarios triggered significant developmental delays in both wild-type and mutant strains. We also see increased mitochondrial-derived reactive oxygen species following Ni and V exposures in wild-type worms with differential responses in the mutant strains. Additionally, we observed alterations in dopamine and serotonin levels after metal exposures, particularly in the pmk-1 strain. In conclusion, both Ni and V induce lethality, developmental delays, and mitochondrial-derived ROS in worms, with V requiring a much higher concentration. Further, the results suggest the p38- and ERK-MAPK signalling pathways may modulate Ni and V neurodevelopmental toxicity, potentially affecting mitochondrial health, metal bioavailability, and neurotransmitter levels.

Corrected Age at Bayley Assessment and Developmental Delay in Extreme Preterms.

Research on outcomes of prematurity frequently examines neurodevelopment in the toddler years as an end point, but the age range at examination varies. We aimed to evaluate whether the corrected age (CA) at Bayley-III assessment is associated with rates of developmental delay in extremely preterm children. This retrospective cohort study included children born at <29 weeks' gestation who were admitted in the Canadian Neonatal Network between 2009 and 2017. The primary outcomes were significant developmental delay (Bayley-III score <70 in any domain) and developmental delay (Bayley-III score <85 in any domain). To assess the association between CA at Bayley-III assessment and developmental delay, we compared outcomes between 2 groups of children: those assessed at 18 to 20 months' CA and 21-24 months. Overall, 3944 infants were assessed at 18-20 months' CA and 881 at 21-24 months. Compared with infants assessed at 18-20 months, those assessed at 21-24 months had higher odds of significant development delay (20.0% vs 12.5%; adjusted odds ratio, 1.75; 95% confidence interval [CI], 1.41-2.13) and development delays (48.9% vs 41.7%, adjusted odds ratio 1.33; 95% CI, 1.11-1.52). Bayley-III composite scores were on average 3 to 4 points lower in infants evaluated at 21-24 months' CA (for instance, adjusted mean difference and 95% CI for language: 3.49 [2.33-4.66]). Conversely, rates of cerebral palsy were comparable (4.6% vs 4.7%) between the groups. Bayley-III assessments performed at 21-24 months' CA were more likely to diagnose a significant developmental delay compared with 18- to 20-month assessments in extremely preterm children.

Evaluation of Developmental Delay in Term Babies on Ventilator Support: A Cross-sectional Study

Introduction: Developmental limitation in two or more developmental domains that affects children under the age of five is termed as developmental delay. Due to various reasons such as drug-induced toxicity and maternal variables like a history of drinking, smoking, or infections during pregnancy (e.g., rubella), neonates may require admission to the Neonatal Intensive Care Unit (NICU). Although NICU admission improves survival rates, the extended stay and the use of different types of equipment in the NICU may lead to developmental delay. Aim: To identify the developmental delays in critically ill fullterm babies on ventilator support, using the Ages and Stages Questionnaire-3 (ASQ-3) scale. Materials and Methods: A cross-sectional study was designed to evaluate developmental delays in term babies receiving ventilator support. A total of 35 babies who met the inclusion criteria were included in the study. Once the babies reached 17 to 18 months of age, parents were given ASQ-3 to complete. The data were analysed and expressed as mean, standard deviation, frequency, and percentage. Results: Out of the 35 full-term babies on ventilator support, 22 babies (62.9%) showed lower values in gross motor function, 12 (34.3%) in fine motor function, and 12 (34.3%) in problem-solving skills compared to communication and other components, according to ASQ-3. Conclusion: The findings of this research suggest that critically ill full-term infants on ventilator support exhibit significant developmental delays, particularly in gross motor, fine motor, and problem-solving skills.

Pallister-Hall syndrome: A 3-year-old girl with short stature and polydactyly

A 3.1-year-old girl presented with short stature and developmental delay. She had a high-pitched voice, broad forehead, midfacial hypoplasia, hypoplastic labia, and bilateral mesoaxial polydactyly involving upper limbs. Biochemical reports were suggestive of isolated growth hormone deficiency (GHD) and magnetic resonance imaging revealed a large hypothalamic hamartoma (HH). The presence of auxological, clinical, and biochemical findings of GHD together with polydactyly and HH clinched the diagnosis of Pallister-Hall Syndrome. There are approximately 100 cases reported worldwide, which points toward the rarity of this disorder. Moreover, in contrast to most cases, our case had significant developmental delay.

H - 60 Navigating Cultural and Medical Factors in Pediatric Neuropsychological Assessment: a Case Study.

The current case study focuses on a neurodevelopmental evaluation for a child with a complex medical history, suspected genetic disorder, and significant developmental delays within the context of cultural diversity, linguistic barriers, and interpretation services. Patient is a 4-year-old male of Oromo decent who is exposed to both Oromo and English. Medical background is significant for congenital glaucoma and global developmental delay. He is nonverbal and uses few gestures to communicate. He presented with spastic motor movements and dysmorphic facial features. There is no history of genetic testing nor consults with neurology. Developmentally appropriate measure of neurocognitive functioning was administered with the use of an Oromo interpreter. Results revealed impaired performance within the areas of cognition, language, and motor functioning. Cognitive abilities measured similar to a 26-month-old. The patient's social communication and emotional reciprocity varied; there was consideration of an autism spectrum disorder. Diagnostic challenges included medical complexity (i.e., vision differences with eye contact and visual referencing, motor functioning), unanswered diagnostic questions (i.e., underlying genetic or neurological condition), and cultural considerations. The evaluation yielded diagnoses of a global developmental delay and unspecified neurodevelopmental disorder. Recommendations included referrals to neurology, genetics, care coordination, and outpatient therapies. Given the complexity of phenotypical behavioral manifestations of genetic disorders and cultural differences in terms of appropriate social behaviors convolute behaviors observed during the evaluation. The case study brings to light the consideration of cultural differences when interpreting behaviors as well as the value of a multidisciplinary approach to neuropsychological evaluation for diagnostic clarification.

Neurodevelopmental Profiles of 4-Year-Olds in the Navajo Birth Cohort Study

Native American children disproportionally face many risk factors for poor developmental outcomes; these factors include poverty, environmental toxicant exposure, and limited medical, and intervention services. To understand these risks, comprehensive documentation of developmental and behavioral phenotypes are needed. In the current descriptive study, we assessed the neurodevelopment of young Diné (Navajo) children using standardized assessment instruments in combination with expert clinician judgment. As part of an ongoing, population-based, prospective birth cohort study, we conducted comprehensive neurodevelopmental assessments of 138, 3-5-year-old, Diné children residing on or near the Navajo Nation. We report results from standardized parent reports, psychiatric examinations, and direct assessments of children's language, cognitive, adaptive, and social-emotional development, as well as best estimate clinical diagnoses. Forty-nine percent of our sample met DSM-5 criteria for a neurodevelopmental disorder (NDD) diagnosis. Language and speech sound disorders were most common, although autism spectrum disorder (ASD) was also elevated compared to the general population. Though language performance was depressed amongst all groups of children with, and without, NDDs, those meeting criteria for certain NDDs performed significantly lower on all language measures, when compared to those without. Social-emotional, behavioral, and nonverbal cognitive ability were in the average range overall. Diné children in our study were found to have a high percentage of clinically significant developmental delays. Overall, children presented with a pervasive pattern of depressed language performance across measures, irrespective of diagnosis (or no diagnosis), while other domains of functioning were similar to normative samples. Findings support the need to identify appropriate intervention and educational efforts for affected youth, while also exploring the causes of the specific developmental delays. However, longitudinal studies are necessary to establish best practices for identifying delays and delineating resilience factors to optimize development of Diné children.

#5295 SECONDARY MEMBRANOUS NEPHROPATHY WITH IGA DEPOSITS IN A PATIENT WITH PRIMARY CILIARY DYSKINESIA

Abstract Background and Aims Membranous nephropathy and IgA nephropathy are two types of common glomerulonephritis worldwide. There are reports of the coexistence of these glomerulopathies, mostly with mesangial expansion and IgA deposits. Furthermore, primary ciliary dyskinesia is rarely associated to glomerulopathy. Thus, we report a case of a patient with primary ciliary dyskinesia with renal biopsy demonstrating membranous glomerulopathy associated with IgA and IgG deposits exclusively in glomerular basement membrane, without complement deposition. Method Case report. Results A 18 years-old man was referred from the nephropediatric outpatient clinic with subnephrotic hematuria and proteinuria. His medical history included a clinical diagnosis of primary ciliary dyskinesia due to a history of several respiratory infections since birth, asthma, rhinitis and bronchiectasis and a 15 years-old brother with a similar history. He was diagnosed with idiopathic thrombocytopenic purpura at age of one year-old and received prednisone. At 3 years-old he presented with nephrotic syndrome, hematuria and hypertension, and was treated with intravenous methylprednisolone and oral cyclophosphamide for three months. Renal biopsy demonstrated mesangial expansion and thickening of the glomerular basement membrane (GBM), without adequate material for immunofluorescence. Because proteinuria and hematuria persisted, the prednisone dose was increased to 2 mg/kg/day and cyclosporine was started. After 5 years on these medications, persisting with proteinuria, a second biopsy was performed and showed 16 glomeruli, three globally sclerosed and the others with diffuse thickening of the GBM, without other alterations, focal interstitial fibrosis and tubular atrophy and diffuse granular deposits of IgA 1+ and IgG 2+ along the GBM. Cyclosporine and prednisone were discontinued. At age of 18 years-old, he was admitted to adult glomerulonephritis clinic with significant developmental delay (weight 28.6kg and height 1.29m2), no edema and normal arterial blood pressure with RAAS inhibition. Laboratory tests: Hb 8.9 g/dL, serum iron 12 mcg/dL, Creatinine 0.7 mg/dL, albumine 2.3 g/dL. Serologies were negative for syphilis, hepatitis B and C, HIV, ANA and anti-DNA, with normal complement C3, C4 and C1q. Urinalysis revealed proteinuria 1+, hematuria 16.000/mL and proteinuria 1.400 mg/d. CT scan showed symmetrical bronchiectasis in both lungs, with mucoid endobronchial impingement and diffuse bronchial parietal thickening; and chronic post-thrombotic changes with calcified thrombi in the left renal vein, extending into the inferior vena cava. A third renal biopsy was performed showing 38 of 45 (84%) globally sclerosed glomeruli without mesangial matrix changes or capsular adhesions. GBM was thickened with spicules and holes and reactive podocytes. The tubulointerstitial compartment showed moderate atrophy and fibrosis (40-50%). Immunofluorescence microscopy evidenced strong immunoreactivity of IgG 3+/3+, IgA 3+/3+, Kappa 3+/3+ and Lambda 2+/3+, in granular pattern exclusively in GBM, without C3. Electron microscopy showed four sclerosed glomeruli, without deposits. Immunohistochemistry staining for IgG1 2+/3+, and it was negative for PLA2R, NELL-1, THSD7A, Exostosin-1 and 2, IgG 2, IgG3 and IgG4. The patient was maintained with supportive treatment, with RAAS inhibition and SGLT2 inhibitors, without immunosuppression. Conclusion This case highlights the codominance of IgG1 and IgA deposits along the MBG, without proliferation or mesangial deposition and without complement activation, in a patient with membranous nephropathy and primary ciliary dyskinesia, a condition rarely associated with glomerulopathies. Although rare, such renal biopsy findings reinforce the need for a better understanding of the different mechanisms of membranous nephritis, in addition to better understanding and management of treatment in this situation.

Changes in the early communicative behaviors of young children with significant cognitive and motor developmental delays in a two-year span

IntroductionThis study examines longitudinal changes in communicative behavior of young children with significant cognitive and motor developmental delays (SDD) and determines their individual communicative trajectories. A second focus of this study is the relation of changes in communicative behavior with motor skills. MethodsData consists of codes resulting from a self-developed coding scheme used on observations of 23 children in three different settings and responses on a questionnaire. First, group trends were determined to find out whether communication-related variables tend to significantly change over the course of two years. Furthermore, these findings were contrasted with the individual trajectories of the children. Next, the association of initial communicative skills and (the acquisition of) specific motor skills with the change in their communicative functioning was studied. Wilcoxon Signed Ranks and correlational analyses were used to answer the research questions. ResultsOut of sixteen different variables related to communicative behavior, ten changed significantly over the course of two years. Children with more focus on prompt on the first datapoint showed a significantly larger increase of signs of functionality. Still, all children showed highly individual trajectories. Children with better motor skills on the first datapoint showed a significantly larger increase in communication rate. ConclusionsResults show that if a myriad of detailed variables are taken into account children with significant cognitive and motor developmental disabilities do change regarding their communicative functioning, but that they tend to all show unique developmental trajectories. Children with stronger skills in some aspects of communication and motor functioning, can be considered advantaged regarding their communicative development.

CRISPR/Cas9-Mediated Knockout of tnfaip1 in Zebrafish Plays a Role in Early Development.

TNF α-induced protein 1 (TNFAIP1) was first identified in human umbilical vein endothelial cells and can be induced by tumor necrosis factor α (TNFα). Early studies have found that TNFAIP1 is involved in the development of many tumors and is closely associated with the neurological disorder Alzheimer's disease. However, little is known about the expression pattern of TNFAIP1 under physiological conditions and its function during embryonic development. In this study, we used zebrafish as a model to illustrate the early developmental expression pattern of tnfaip1 and its role in early development. First, we examined the expression pattern of tnfaip1 during early zebrafish development using quantitative real-time PCR and whole mount in situ hybridization and found that tnfaip1 was highly expressed in early embryonic development and, subsequently, expression became localized to anterior embryonic structures. To investigate the function of tnfaip1 during early development, we constructed a model of a stably inherited tnfaip1 mutant using the CRISPR/Cas9 system. Tnfaip1 mutant embryos showed significant developmental delays as well as microcephaly and microphthalmia. At the same time, we found decreased expression of the neuronal marker genes tuba1b, neurod1, and ccnd1 in tnfaip1 mutants. Analysis of transcriptome sequencing data revealed altered expression of the embryonic development related genes dhx40, hspa13, tnfrsf19, nppa, lrp2b, hspb9, clul1, zbtb47a, cryba1a, and adgrg4a in the tnfaip1 mutants. These findings suggest an important role for tnfaip1 in the early development of zebrafish.

Does chromosome 16p12.1-p12.2 harbor a novel gene for essential tremor? (P5-11.012)

<h3>Objective:</h3> To describe a patient with de novo duplication of 16p12.1-p12.2 associated with severe action tremor and developmental delay, and genetic analysis of candidate genes within the duplicated chromosomal segment. <h3>Background:</h3> A family history of essential tremor (ET) can be found in 30–80% of all affected patients, suggesting a strong genetic contribution to its etiology. However, discovery of disease-causing genes has been largely elusive. Candidate genes can be identified using linkage analysis, whole exome or genome sequencing, and genetic association studies. Detection of genomic rearrangements with gene dosage changes in tremor patients provides another unique opportunity to identify additional candidate genes. <h3>Design/Methods:</h3> Case report and genetic analysis of the candidate chromosomal region. Chromosomal microarray analysis was performed in patient and both parents. We designed PCR primers for all coding exons of selected candidate genes. We included 75 unrelated probands from kindreds with familiar ET. Candidate genes were sequenced in all ET controls. <h3>Results:</h3> The proband is a 20-year-old female with significant developmental delay who developed progressive tremor at age of 15 years. Her tremor was a moderate to severe 4–5 Hz postural and action distal tremor, not present at rest, minimally responsive to propranolol. Additional examination revealed diffusely brisk reflexes with positive Hoffman and cross adductor sign, and upgoing toes. MRI brain did not show evidence of hypomyelination. She underwent chromosomal microarray analysis that identified duplications 12p13.33 and 16p12.2-p12.1. Chromosome 12p duplication was also detected in her father. Duplication of 12p was considered nonpathogenic and duplication 16p was <i>de novo</i>. The duplicated segment on chromosome 16p contained eight genes and six were considered possible candidate for tremor: <i>UQCRC2</i>, <i>CDR2</i>, <i>EEF2K</i>, <i>POLR3A</i>, <i>LOG23117</i>, and c16orf65. No putative deleterious mutations have been identified in ET controls. <h3>Conclusions:</h3> We report identification and genetic analysis of six novel candidate genes on chromosome 16p12.1-p12.2 that may be associated with ET. <b>Disclosure:</b> Dr. D’Aguiar Rosa has nothing to disclose. Dr. Yousaf has nothing to disclose. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Hedera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Hedera has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for University of Louisville.

Bonding and Infants' Development and Quality of Life: A Study Among Mothers with Severe Mental Illnesses in Remission.

Maternal mental health has specific implications for bonding and infants' mental health. However, most of the evidence comes from mothers who are either symptomatic or did not have adequate mental health support. In this context, our objective was to explore if symptom status in mothers and bonding share any significant association with the infants' development and quality of life (QOL), in case of mothers with severe mental illnesses in remission. The study included 41 mother-infant dyads from the outpatient perinatal psychiatry services and the mother-baby unit of the current study center. Symptom status, self-reported bonding, mother-infant interactions, and infants' development and QOL were assessed with Clinical Global Impressions, Postpartum Bonding Questionnaire, Pediatric Infant-Parent Exam, Developmental Assessment Scales for Indian Infants, and Pediatric Quality of Life Scale, respectively. Most mothers had a complete recovery or minimal symptoms. Nine (22%) infants had a significant developmental delay. Atypical play-based interactions were observed in nine (22%) mothers. Self-reported bonding and bonding as evinced over play-based interactions did not significantly correlate with the QOL or development of the infants. Mothers who have recovered and are functioning well reported good bonding with their infants, though objective assessment revealed specific difficulties. Symptom severity correlated with poor physical QOL in infants. The association between mothers' bonding and infants' mental health is domain-specific and differential than linear and robust. Infants of mothers with severe mental illnesses postpartum should be routinely monitored for mother-infant bonding, development, and quality of life.

Maternal SARS-CoV-2, Placental Changes and Brain Injury in 2 Neonates.

Long-term neurodevelopmental sequelae are a potential concern in neonates following in utero exposure to severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2). We report 2 neonates born to SARS-CoV-2 positive mothers, who displayed early-onset (day 1) seizures, acquired microcephaly, and significant developmental delay over time. Sequential MRI showed severe parenchymal atrophy and cystic encephalomalacia. At birth, neither infant was SARS-CoV-2 positive (nasopharyngeal swab, reverse transcription polymerase chain reaction), but both had detectable SARS-CoV-2 antibodies and increased blood inflammatory markers. Placentas from both mothers showed SARS-CoV-2-nucleocapsid protein and spike glycoprotein 1 in the syncytiotrophoblast, fetal vascular malperfusion, and significantly increased inflammatory and oxidative stress markers pyrin domain containing 1 protein, macrophage inflammatory protein 1 βη, stromal cell-derived factor 1, interleukin 13, and interleukin 10, whereas human chorionic gonadotropin was markedly decreased. One infant (case 1) experienced sudden unexpected infant death at 13 months of age. The deceased infant's brain showed evidence of SARS-CoV-2 by immunofluorescence, with colocalization of the nucleocapsid protein and spike glycoprotein around the nucleus as well as within the cytoplasm. The constellation of clinical findings, placental pathology, and immunohistochemical changes strongly suggests that second-trimester maternal SARS-CoV-2 infection with placentitis triggered an inflammatory response and oxidative stress injury to the fetoplacental unit that affected the fetal brain. The demonstration of SARS-CoV-2 in the deceased infant's brain also raises the possibility that SARS-CoV-2 infection of the fetal brain directly contributed to ongoing brain injury. In both infants, the neurologic findings at birth mimicked the presentation of hypoxic-ischemic encephalopathy of newborn and neurologic sequelae progressed well beyond the neonatal period.