Search

PurposeDevelopmental assessment is part of a comprehensive autism evaluation. During in-person evaluations, developmental assessment is completed via direct testing by an examiner. In telehealth evaluations, developmental assessment relies on caregiver-report instruments. This study examined correspondence between caregiver report and direct testing of developmental skills.MethodsParticipants were 93 children, aged 18-42 months, undergoing evaluation for possible autism spectrum disorder (ASD). Caregivers were interviewed with the Developmental Profile, 4th edition (DP-4) via telehealth platform and children were tested in person 2-4 weeks later using the Mullen Scales of Early Learning (MSEL).ResultsCorrelations between the DP-4 and MSEL were high (ranging from 0.50 to 0.82) across standard scores, age equivalents, and functional categories, as well as across individual subtests and overall composite scores.ConclusionThe high convergent validity found in this study suggests that the DP-4 provides a suitable proxy for direct developmental testing using the MSEL in the context of telehealth evaluations for ASD in young children, delivering a good estimate of both developmental functioning and presence of delays.Trial registrationData were obtained from registered clinical trial NCT05047224, date of registration 2021-09-07.

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.

IntroductionAdverse childhood experiences (ACEs) are common and have been associated with poor developmental outcomes. We aimed to investigate the relationship between early ACE exposure, subsequent diagnosis of developmental delay, and receipt of developmental delay services by young children. In addition, we aimed to assess the impact of health-promoting behaviors such as breastfeeding and daily reading on these relationships.MethodsIn this cross-sectional analysis of nationally-representative data from the 2017-2018 National Survey of Children's Health, we examined the relationship between ACEs, prior breastfeeding, daily reading, and developmental delay diagnosis among 7837 children aged 3-5 years, using multivariate logistic regression to adjust for family, personal, and sociodemographic characteristics.ResultsWe found a dose-dependent relationship between ACEs and developmental delay diagnosis; compared to those without ACEs, developmental delay was more common among those with either one ACE (aOR = 2.03, 95% CI 1.17-3.52) or two or more ACEs (aOR = 2.34, 95% CI 1.25-4.37). Neither breastfeeding (exclusively breastfed for 6 months vs. never breastfed aOR = 0.70, 95% CI 0.33-1.46) nor daily reading (no reading versus daily reading aOR = 1.15, CI 0.57-2.33) were associated with incidence of developmental delay among study participants. There was no significant difference in receipt of services intended to meet developmental needs between children with and without ACEs.DiscussionChildren with very early ACE exposure are at increased risk for diagnosis of developmental delay. Early screening for ACEs and developmental delay may mitigate the early developmental manifestations of ACE exposure in vulnerable children.

Background Aim Methods Results Conclusion Fragile X messenger ribonucleoprotein 1 gene (FMR1) disorders result from a mutation in the FMR1 gene, leading to a deficiency or absence of the FMRP. Full mutations and premutations of the FMR1 gene are known to cause completely different symptoms.To determine the clinical phenotype of individuals with a full mutation or premutation of the FMR1 gene.We report 6 patients of the same Tunisian family with different clinical phenotypes. We gathered recent findings on the clinical spectrum of FMR1 mutations from 2020 to 2024 using PubMed, Google Scholar, ScienceDirect, and Web of Science.Our observations revealed two first cousins, aged 4 and 13 years, respectively, with a medical history of recurrent infections. They exhibited developmental delay, hyperactivity, concentration difficulties, and autistic traits, with characteristic facial dysmorphia. Family investigation revealed a history of early menopause and primary ovary insufficiency diagnosis in their mothers and one aunt. The 79‐year‐old grandfather presented with recent memory and sleep disturbances, with signs suggestive of fragile X‐associated tremor/ataxia syndrome (FXTAS) on brain MRI. The genetic assessment confirmed the fragile X syndrome (FXS) in children and the fragile X‐associated primary ovarian insufficiency (FXPOI) in their mothers. Our search in literature uncovered a genetically diverse disorder exhibiting clinical variability influenced by factors such as gene size, methylation mosaicism, and the presence of premutations or full mutations, alongside various pathophysiological mechanisms.Clinical signs highlighted in our family report should alert clinicians to consider FXS, particularly facial dysmorphia and intellectual disability or language developmental delay, FXPOI for early menopause, and FXTAS for tremor and ataxia within the family context of FXS. [ABSTRACT FROM AUTHOR]

Introduction: Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals. Methods: In this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features. Results: Proband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs-all indicative signs of developmental delay. Trio-WES revealedcompound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively. Conclusion: This study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations. [ABSTRACT FROM AUTHOR]

School-aged children have consistently shown a surprising developmental lag when attempting to innovate solutions to tool use tasks, despite being capable of learning to solve these problems from a demonstrator. We suggest that this "innovation gap" arises from tool tasks with more complex spatial relations. Following Fragaszy and Mangalam's new tooling theory, we predicted that innovating a new "sticker slide" task should be more challenging when two tools need to be used at the same time (concurrently) rather than one at a time (sequentially), despite the similarity of the other task elements. In line with previous work, both versions of the task were challenging for all ages of children (4–9 years) that we tested. However, the youngest group showed particularly extreme difficulties, which was marked by not a single child innovating the concurrent version. Although success significantly increased with age, even the oldest group failed to reach 50% success on the concurrent version of the task, whereas the majority of the two older groups could solve the sequential version. Thus, in this first study of concurrent tool use in children, we found support for the prediction that increasing the complexity of spatial relations in tooling exacerbates the innovation gap. [ABSTRACT FROM AUTHOR]

Intimate partner violence (IPV), affecting approximately 16.3% of U.S. households annually, has detrimental effects on children who witness it, leading to psychological distress, developmental delays, and behavioral issues. Self‐regulation, a critical skill in managing attention, emotions, and behaviors essential for cognitive and social development, may be significantly impacted. The negative associations between mothers' experience of IPV and child self‐regulation necessitate the examination of the underlying mechanisms, particularly during the sensitive period of early childhood. This study utilized longitudinal data from the Future of Families and Child Wellbeing Study (N = 4338) to investigate the mediating pathways linking mothers' experience of IPV (maternal victimization experiences) during infancy with children's self‐regulation at age five. Results suggested that IPV exposure during infancy was longitudinally and negatively associated with children's behavioral and attentional regulation. This association was mediated by elevated parenting stress and decreased maternal warmth. These findings highlight the importance of programs aimed at reducing IPV and supporting mothers affected by IPV, considering their vital roles in nurturing healthy child self‐regulation skills. [ABSTRACT FROM AUTHOR]

ABSTRACT 5q14.3 microdeletion syndrome is a rare condition involving multiple genes such as MEF2C and RASA1 and is potentially classified as a neurocutaneous syndrome. Deletion of the MEF2C gene accounts for the majority of clinical manifestations, including global developmental delay, intellectual disability, seizures, and behavioral disorders. RASA1 deletion is linked to capillary malformations with arteriovenous malformations (CM‐AVM). Until now, only 17 cases have been described with deletions of both genes. We present the first case described in Spain with the microdeletion in the 5q14.3 cytoband simultaneously affecting both MEF2C and RASA1, exhibiting the typical manifestations of this entity, and review the published cases to date. [ABSTRACT FROM AUTHOR]

Background: a-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. Methods: We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Results: Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel a-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Conclusion: Patients in both the families have manifested peculiar set of clinical symptoms associated with a-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to a-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of a-mannosidosis. [ABSTRACT FROM AUTHOR]

Cognitive and social-emotional development in the first three years of life is associated with later skills. However, little is known about the paths of developmental delays in both cognitive and social-emotional skills before age 3 or to what extent these paths predict later developmental outcomes. The aim of this study is to examine the associations between the different paths of developmental delays in both cognitive and social-emotional skills of children before age 3 and the levels of development of the children when they are preschool age. Using a longitudinal data collected at three time points from 1245 children and their caregivers in rural China, we identified four different paths of developmental delays in cognitive and social-emotional before age 3 and examined how these paths are associated with different levels of developmental outcomes at preschool age. We used a non-parametric standardization approach and an ordinary least squares model to perform our analyses. Findings show that rates of developmental delays in either cognitive or social-emotional domain or both domains are high at all different time points, ranging from 20% to 55% for cognitive delays and 42% to 61% for social-emotional delays. Over half of children experienced deteriorating levels of either cognitive or social-emotional development before age 3. A large share of children was found to be persistently delayed in either domain. Only a small share of children raised their levels of development in either domain before age 3. In addition, we identified certain socioeconomic status of the family that are associated with never or deteriorating path of child developmental delays. More importantly, we revealed that different paths of developmental delays before age 3 have predictive power on different levels of developmental outcomes at preschool age. Our results suggest that actions are needed at the earliest times to improve child development when children are still infants or toddlers. [ABSTRACT FROM AUTHOR]

Background/Objectives: We aimed to investigate the relationship between deformational plagiocephaly (DP) severity and anterior fontanelle size and to explore the connection between fontanelle size and developmental delay. Methods: We enrolled 189 (122 boys and 67 girls; mean corrected age, 119.79 days) of the 256 infants who visited our clinic for plagiocephaly between March 2022 and June 2023. This study analyzed the correlation between cranial vault asymmetry (CVA) and anterior fontanelle size as measured using skull anteroposterior (AP) radiography and ultrasonography. The severity of DP was graded from minimal to severe based on the Argenta classification. Infants were grouped according to CVA severity as follows: Group 1 (CVA ≤ 5 mm), Group 2 (5 mm < CVA < 10 mm), and Group 3 (CVA ≥ 10 mm). Additionally, 40 infants underwent the Denver Developmental Screening Test II (DDST-II) for neurodevelopmental delays and were divided into groups based on the presence or absence of developmental delays for fontanelle size comparison. Results: Age showed a significant negative correlation with fontanelle size (correlation coefficient −0.234, p < 0.05), indicating that fontanelle size decreases as infants age. No significant differences in fontanelle size were observed among the three CVA groups (p = 0.074) or between the developmentally delayed and non-delayed groups (p = 0.09). This study found no correlation between CVA and fontanelle size or between fontanelle size and developmental delay. Conclusions: The findings show that, while anterior fontanelle size decreased with age, there was no significant correlation between the fontanelle size and the severity of deformational plagiocephaly or developmental delays. [ABSTRACT FROM AUTHOR]

Microcephaly, epilepsy and diabetes syndrome 1 (MEDS1) is a rare autosomal recessive disorder caused by defects in the immediate early response 3 interacting protein 1 (IER3IP1) gene. Only nine cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who was homozygous for the c.53C>T p.(Ala18Val) variant. This case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain magnetic resonance imaging, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. [ABSTRACT FROM AUTHOR]

Background and Objective: CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database. Methods: Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population. Results: The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits. Conclusions: The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. We enrolled individuals with BPTF -related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. We studied 11 individuals with a null variant in BPTF , including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. Our study provides the first characterization of BPTF -related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). Methods: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. Results: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0–9.1) but not NEC as compared with controls. Conclusion: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA. [ABSTRACT FROM AUTHOR]

Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo , one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype. [ABSTRACT FROM AUTHOR]

Motivation is a key factor for child development, but very few studies have examined child and family predictors of both child task and perceived motivation. Thus, the three aims of this 6-month longitudinal study in preschoolers with global developmental delays (GDD) were to explore: 1) differences between task and perceived motivation in cognitive domain; 2) differences among three domains of perceived motivation: cognitive, gross motor, and social; and 3) early child and family predictors of cognitive task motivation and the three domains of perceived motivation 6 months later. Results indicated that preschoolers with GDD showed higher cognitive task motivation than cognitive perceived motivation, and lower perceived cognitive motivation than the other two perceived motivation domains. Different child and family factors predicted cognitive task motivation and the three domains of perceived motivation. Practitioners should educate caregivers on how to observe children's motivation to enhance children's active participation. [ABSTRACT FROM AUTHOR]

CASK (MIM#300172), encoding a calcium/calmodulin‐dependent serine protein kinase, is crucial for synaptic transmission and gene regulation during neural development. Pathogenic variants of CASK are known to cause several neurodevelopmental disorders, including X‐linked intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH). This study introduces a novel, de novo synonymous CASK variant (NM_001367721.1: c.1737G>A, p.(Glu579=)), discovered in a male patient diagnosed with MICPCH, characterized by microcephaly, developmental delay, visual impairment, and myoclonic seizures. The variant disrupts a donor splice‐site at the end of exon 18. Transcriptomic analysis of blood identified 12 different CASK transcripts secondary to the synonymous variant. Nearly one third of these transcripts were predicted to result in nonsense mediated decay or protein degradation. Protein modeling revealed structural alterations in the PDZ functional domain of CASK, due to exon 18 deletion. Our findings highlight the utility of transcriptomic analysis in demonstrating the underlying disease mechanism in neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH).This is a retrospective, single‐center cohort study of IPH diagnosed on fetal MRI (1996–2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death.Forty‐four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22–28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin‐twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty‐two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow‐up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy.An etiology for fetal IPH with or without GMH‐IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background: Copy number variants (CNVs) have become increasingly instrumental in understanding the etiology of all diseases and phenotypes, including Neurocognitive Disorders (NDs). Among the well-established regions associated with ND are small parts of chromosome 16 deletions (16p11.2) and chromosome 15 duplications (15q3). Various methods have been developed to identify associations between CNVs and diseases of interest. The majority of methods are based on statistical inference techniques. However, due to the multi-dimensional nature of the features of the CNVs, these methods are still immature. The other aspect is that regions discovered by different methods are large, while the causative regions may be much smaller. Results: In this study, we propose a regularized deep learning model to select causal regions for the target disease. With the help of the proximal [20] gradient descent algorithm, the model utilizes the group LASSO concept and embraces a deep learning model in a sparsity framework. We perform the CNV analysis for 74,811 individuals with three types of brain disorders, autism spectrum disorder (ASD), schizophrenia (SCZ), and developmental delay (DD), and also perform cumulative analysis to discover the regions that are common among the NDs. The brain expression of genes associated with diseases has increased by an average of 20 percent, and genes with homologs in mice that cause nervous system phenotypes have increased by 18 percent (on average). The DECIPHER data source also seeks other phenotypes connected to the detected regions alongside gene ontology analysis. The target diseases are correlated with some unexplored regions, such as deletions on 1q21.1 and 1q21.2 (for ASD), deletions on 20q12 (for SCZ), and duplications on 8p23.3 (for DD). Furthermore, our method is compared with other machine learning algorithms. Conclusions: Our model effectively identifies regions associated with phenotypic traits using regularized deep learning. Rather than attempting to analyze the whole genome, CNVDeep allows us to focus only on the causative regions of disease. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion The BCL11A gene is involved in disorders including intellectual disability syndrome (IDS), encodes a zinc finger protein highly expressed in haematopoietic and brain and acts as a transcriptional repressor of foetal haemoglobin (HbF). De novo variants in BCL11A have been associated with IDS, which is characterized by developmental delays, autism spectrum disorder (ASD) and speech and language delays. The reports of BCL11A gene variants are still limited worldwide, and additional cases are needed to expand the variant and phenotype spectrums.The patient is a 5‐year‐old girl who was hospitalized due to developmental delays. After analysing her clinical and pathological characterizations, whole‐exome sequencing (WES) was performed for pathogenic genetic variants of developmental delay and behavioural differences. Candidate variant in BCL11A gene was identified and further validated by Sanger sequencing.A heterozygous variant, c.1442delA (p.Glu481Glyfs*25), was identified in exon 4 of the BCL11A gene through WES. This variant results in a truncated expression of the encoded protein. This de novo variant was confirmed by Sanger sequencing. The language delay and behavioural differences were prominent in our patient.Our finding demonstrates that BCL11A variant may cause developmental delay and behavioural differences, expanding the genetic spectrum of the BCL11A gene. [ABSTRACT FROM AUTHOR]

Autosomal-recessive cutis laxa type 2 (ARCL2) is a rare genetic disorder caused by pyrroline-5-carboxylate reductase 1 (PYCR1) mutations and characterized by loose and sagging skin, typical facial features, intrauterine growth retardation, and developmental delay. To study the effect of PYCR1 mutations on protein function and clinical features, we identified a homozygous missense mutation c.559G > A (p.Ala187Thr) in PYCR1 in a Chinese child with typical clinical features, especially severe developmental delays. The three-dimensional (3D) model showed the modification of the hydrogen bonds produce a misfolding in the mutant PYCR1 protein. Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function. Our findings confirmed abnormal enzymatic activity and neurodevelopmental trajectory of this PYCR1 mutation. [ABSTRACT FROM AUTHOR]

Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D‐related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in‐person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D‐related NDD. Forty‐two individuals (median age 6 years, range = 0.8–25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure‐66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland‐3 adaptive behavior composite score (VABS‐3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS‐3 growth scale value scores increased from baseline in all subdomains (range = 0.6–5.9) after a mean follow‐up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS‐3 score; p < 0.05. Individuals had a mean Quality‐of‐life inventory‐disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D‐related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials. [ABSTRACT FROM AUTHOR]

Background: Developmental delay in children under 5 years old, which occurs globally with an incidence of 10%-15%, is caused by multiple factors including genetics, prenatal conditions, perinatal complications, postnatal influences, social factors, and nutritional deficiencies. Gene variants such as EFNB1, MECP2 and TRAPPC9 play a significant role in protein deformation and downregulation of nuclear factor κB (NF-κB) activity. Methods: A 3-year-old girl, who exhibits poor gross motor skills, personal-social development, auditory language, hand-eye coordination, and visual performance, was diagnosed with global developmental delay. Trio whole exome sequencing was conducted to identify the genetic etiology of her condition. The identified genetic etiology was then validated through Sanger sequencing and quantitative polymerase chain reaction (qPCR). Results: Genetic analysis revealed that the patient had compound heterozygous variants in the TRAPPC9 gene. These include a c.1928del frameshift variant inherited from the unaffected father and a deletion in exon 12 inherited from the unaffected mother. According to the American College of Medical Genetics (ACMG) guidelines, these variants were classified as "likely pathogenic". Conclusion: The study revealed that compound heterozygous TRAPPC9 gene variants cause developmental delay in a Chinese girl. These variants have been classified as having significant pathogenic effect according to the ACMG criteria, suggesting a recessive genetic pattern and highlighting the importance of prenatal testing for future offspring. Furthermore, our findings expand the genotype spectrum of the TRAPPC9 gene, and provide more comprehensive information regarding genetic counseling for children experiencing developmental delay. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Previous studies assessing factors associated with drug‐resistant epilepsy (DRE) were constrained by their amalgamation of all epilepsy syndromes in their analyses and the absence of uniform criteria for defining DRE. Our objective was to identify predictors of DRE among the four primary childhood epilepsy syndrome groups within a cohort of children with new onset seizures, using the International League Against Epilepsy (ILAE) definition of DRE and the recent classification of epilepsies.This is a prospective study of 676 children with new onset seizures initiated on antiseizure medication. Patients were monitored for the occurrence of DRE according to the ILAE criteria and were categorized into one of four epilepsy groups: self‐limited focal epilepsies (SeLFEs), genetic generalized epilepsies (GGEs), developmental epileptic encephalopathies (DEEs), and focal epilepsies. Cox regression analysis was performed to identify predictors of DRE within each epilepsy group.Overall, 29.3% of children were classified as having DRE, with the highest incidence observed among children diagnosed with DEEs (77.7%), followed by focal epilepsies (31.5%). Across the entire cohort, predictors of DRE included the presence of an epileptogenic lesion, a higher pretreatment number of seizures, experiencing multiple seizure types, presence and severity of intellectual and developmental delay, myoclonus, and younger age at epilepsy onset. Within the GGEs, only a younger age at seizure onset and experiencing multiple seizure types predicted DRE. Among focal epilepsies, predictors of DRE included the presence of an epileptogenic lesion, experiencing multiple seizure types, and having a greater number of pretreatment seizures. Within the DEEs, predictors of DRE were the occurrence of tonic seizures. Predictors of DRE within SeLFEs could not be identified.This study indicates that different epilepsy syndromes are associated with distinct predictors of drug resistance. Anticipation of drug resistance within various groups is feasible using accessible clinical variables throughout the disease course. [ABSTRACT FROM AUTHOR]

• a de novo missense mutation c.671 T > C (p.F224S) in the GABRB2 gene. • The patient bearing this mutant has epilepsy and developmental delay. • GABA A R bearing mutant β2 subunit showed decreased response to GABA. Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABA A R) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the β2 subunit of GABA A R. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABA A R channel function, we conducted transient expression experiments using GABA A R subunits in HEK293T cells. The GABA A Rs containing mutant β2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABA A R containing the β2 (F224S) subunit was significantly smaller compared to the wild type GABA A R. We propose that GABRB2 variant F224S is pathogenic and GABA A Rs containing this β2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy. [ABSTRACT FROM AUTHOR]

Tetrasomy X or 48,XXXX is a rare sex chromosome aneuploidy. The parental origin of tetrasomy X in a female patient with developmental delay was analyzed; all four X chromosomes were derived from the mother, and there were no paternally derived sex chromosomes. This finding indicates a rare incidental co-occurrence of maternal and paternal nondisjunction or polysomy rescue. The mechanism of 48,XXYY, which is related to developmental delay in males, was analyzed for comparison. [ABSTRACT FROM AUTHOR]

Non-obstructive azoospermia (NOA) is found in up to 15% of infertile men. While several causes for NOA have been identified, the exact etiology remains unknown in many patients. Advances in assisted reproductive technology, including intracytoplasmic sperm injection (ICSI) and testicular sperm retrieval, have provided hope for these patients. This review summarizes the chances of success with ICSI for NOA patients and examines preoperative factors and laboratory techniques associated with positive outcomes. Furthermore, we reviewed possible consequences for offspring by the use of ICSI with testicular sperm retrieved from NOA patients and the interventions that could potentially mitigate risks. Testicular sperm retrieved from NOA patients may exhibit increased chromosomal abnormalities, and although lower fertilization and pregnancy rates are reported in NOA patients compared to other forms of infertility, the available evidence does not suggest a significant increase in miscarriage rate, congenital malformation, or developmental delay in their offspring compared to the offspring of patients with less severe forms of infertility or the offspring of fertile men. However, due to limited data, NOA patients should receive specialized reproductive care and personalized management. Counseling of NOA patients is essential before initiating any fertility enhancement treatment not only to mitigate health risks associated with NOA but also to enhance the chances of successful outcomes and minimize possible risks to the offspring. [ABSTRACT FROM AUTHOR]

Structured follow-up visits should be accessible for children at risk for developmental delay. Follow-up visits should include a serial neuromotor assessment in the first two years of life (e.g., 3–6, 12, 24 months corrected age), which are repeated during the transition to school. The diagnosis of neuromotor development may be prognostic for important skills later in life. The early diagnosis of a child's general movements can be helpful in planning appropriately for proper treatment and intervention. These diagnostic assessments should be conducted by qualified healthcare professionals. The evaluation of neuromotor developmental health is specified in the national guidelines and funded by either a national government or public or private healthcare insurance and based on standardized assessment scales. The aim of this study is to show what elements of follow-up visits are recommended. Objectives: The group of patients for whom the structured follow-up systems are intended were children born very preterm (<32 weeks gestation) or full-term born children with severe neonatal complications. Material and methods: The methods for monitoring neurodevelopment include the following: The General Movements Assessment (GMA), the Ages and Stages Questionnaire (ASQ-3), the Bayley Scales of Infant and Toddler Development (BSID-4), and the Parent Report of Children's Abilities-Revised (PARCA-R). Results: The results of follow-up visits should be registered. Conclusions: The benefits of follow-up neuromotor development assessments can be observed at school age and even in adulthood. [ABSTRACT FROM AUTHOR]

Background: Congenital Myasthenic Syndromes (CMS) are rare genetic diseases, which share as a common denominator muscle fatigability due to failure of neuromuscular transmission. A distinctive clinical feature of presynaptic CMS variants caused by defects of the synthesis of acetylcholine is the association with life-threatening episodes of apnea. One of these variants is caused by mutations in the SLC5A7 gene, which encodes the sodium-dependent HC-3 high-affinity choline transporter 1 (CHT1). To our knowledge there are no published cases of this CMS type in Latin America. Case presentation: We present two cases of CHT1-CMS. Both patients were males presenting with repeated episodes of apnea, hypotonia, weakness, ptosis, mild ophthalmoparesis, and bulbar deficit. The first case also presented one isolated seizure, while the second case showed global developmental delay. Both cases, exhibited incomplete improvement with treatment with pyridostigmine. Conclusions: This report emphasizes the broad incidence of CMS with episodic apnea caused by mutations in the SLC5A7 gene and the frequent association of this condition with serious manifestations of central nervous system involvement. [ABSTRACT FROM AUTHOR]

Background: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. Methods: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4–16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. Results: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p =.35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p =.49) or oppositional defiant disorder (7.7%;0%; p =.15). Conclusion: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management. [ABSTRACT FROM AUTHOR]

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings' father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1- S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue. [ABSTRACT FROM AUTHOR]

The time from conception through the first year of life is the most dynamic period in human development. This time period is particularly important for infants born very preterm (< 30 weeks gestation; VPT), as they experience a significant disruption in the normal developmental trajectories and are at heightened risk of experiencing developmental impairments and delays. Variations in the epigenetic landscape during this period may reflect this disruption and shed light on the interrelationships between aging, maturation, and the epigenome. We evaluated how gestational age (GA) and age since conception in neonates [post-menstrual age (PMA)], were related to DNA methylation in buccal cells collected at NICU discharge from VPT infants (n = 538). After adjusting for confounders and applying Bonferroni correction, we identified 2,366 individual CpGs associated with GA and 14,979 individual CpGs associated with PMA, as well as multiple differentially methylated regions. Pathway enrichment analysis identified pathways involved in axonogenesis and regulation of neuron projection development, among many other growth and developmental pathways (FDR q < 0.001). Our findings align with prior work, and also identify numerous novel associations, suggesting that genes important in growth and development, particularly neurodevelopment, are subject to substantial epigenetic changes during early development among children born VPT. [ABSTRACT FROM AUTHOR]

Background: Global developmental delay with speech and behavioral abnormalities (OMIM: 619243) is an autosomal dominant disease caused by variants in TNRC6B gene. Method: We reviewed and summarized clinical manifestations and genotypes in patients previously reported with TNRC6B gene variants. We used several prediction tools to predict pathogenicity and performed minigene assays to verify the function of the synonymous variant affecting RNA splicing. Result: The patient presented with convulsive seizures and developmental delay. WES combined with functional studies diagnosed a child with a synonymous variant in TNRC6B gene. Through minigene assay and Sanger sequencing, we demonstrated that c.3141G > A variant induced exon 7 skipping and the synonymous variant was pathogenic. Conclusion: Synonymous variants do not change the amino acids encoded by the codon, so we usually consider synonymous variants to be benign and ignore their pathogenicity. Minigene assay is a valuable tool to identify the effect of variation on RNA splicing and identify synonymous variants' benign or pathogenic. We showed that the synonymous variant was pathogenic by minigene assay. WES combined with minigene assay establishes a robust basis for genetic counseling and diagnosing diseases. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusions Individuals with intellectual disability, including people with Down syndrome (DS), often exhibit restricted and repetitive behaviours (RRBs). However, RRBs have not been deeply characterised in children and adolescents with DS.The study encompassed a cohort of 151 participants aged 4 to 18 years with DS. RRBs were assessed utilising the Repetitive Behaviour Scale‐Revised. Additionally, data pertaining to cognitive and adaptive functioning, linguistic abilities, sleep patterns and emotional/behavioural issues were gathered.Self‐injurious behaviours were reported less frequently whereas parents most commonly endorsed items related to behaviours associated with the need for sameness and ritualistic behaviours. We observed very few gender differences, whereas some age‐related differences emerged, with adolescents exhibiting higher scores in items related with higher‐level RRBs. The analysis of the association between RRBs and clinical features revealed that RRBs were associated with parent‐reported sleep difficulties, as well as with internalising and externalising problems. We also observed a negative correlation with IQ whereas associations with adaptive skills emerged mainly for lower‐level RRBs, such as motor stereotypies. Finally, RRBs were negatively associated with linguistic abilities, both expressive and receptive.RRBs in children and adolescents with DS are of significant clinical interest due to their associations with various clinical dimensions. Therefore, psychological and neuropsychiatric assessment should include an accurate evaluation of RRBs for young people with DS. [ABSTRACT FROM AUTHOR]

Background: The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. Case presentation: The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4–10 of the CUX1 gene. Conclusions: Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development. [ABSTRACT FROM AUTHOR]