Risk of psychiatric neurodevelopmental disorders after meningitis in childhood: a nationwide, population-based cohort study.

BACKGROUND: Few studies have investigated the risk of psychiatric neurodevelopmental disorders (PNDD) after childhood meningitis. METHODS: Nationwide population-based cohort study (Denmark, 1995-2021) of children with positive cerebrospinal fluid for bacteria or enterovirus, stratified on age as young infants (0 to <90 days, n = 637) or older children (≥90 days to <17 years, n = 1,218). We constructed a comparison cohort from the general population (n = 18,550), and cohorts of siblings of participants. As risk estimates of PNDD we calculated age- and sex-adjusted hazard ratios (aHRs) with 95% confidence intervals (95%CI). RESULTS: Children with bacterial meningitis had increased risks of PNDD, especially learning and intellectual developmental disorders (young infants: aHR 4.2, 95%CI: 2.4-7.1; older children: aHR 1.5, 95%CI: 1.0-2.3), attention deficit disorder (ADHD) (young infants: aHR 2.8, 95%CI: 1.5-5.2; older children: 1.4, 95%CI: 0.9-2.2) and redemption of ADHD medication (young infants: aHR 2.2, 95%CI: 1.0-4.7; older children: 1.5, 95%CI: 1.0-2.3). Young infants with bacterial meningitis additionally had increased risks of autism spectrum disorders (aHR 1.9, 95%CI: 0.9-4.1) and behavioural and emotional disorders (aHR 2.0, 95%CI: 1.0-3.9). In young infants, the excess risk of PNDD was especially observed in premature children. Siblings of older children with bacterial meningitis also had increased risks of PNDD. Children with enteroviral meningitis at any age did not have increased risks of PNDD or redemption of ADHD medication. CONCLUSIONS: Bacterial meningitis in childhood is associated with subsequent diagnosis of PNDD, while enteroviral meningitis is not. The association appears to be partly explained by prematurity and familial and socioeconomic factors.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report.

BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

Awareness and Knowledge of Congenital Cytomegalovirus (cCMV) Among Audiologists and Speech-Language Pathologists in Saudi Arabia: A Cross Sectional Survey.

Congenital cytomegalovirus (cCMV) is the most prevalent congenital infection in the world. It can result in various neurodevelopmental disorders, one of which is environmental hearing loss among children. This study aimed to assess the awareness and knowledge of cCMV among audiologists and speech-language pathologists (SLPs) in Saudi Arabia and to seek their perception of it. An online survey was conducted from May to June 2023, targeting participants through social media, and a descriptive and inferential analysis was performed. A total of 107 participants (31 audiologists and 76 SLPs) were enrolled in this study. Awareness about cCMV was significantly higher among audiologists (84%) compared to SLPs (49%) (p-value < 0.001). However, both groups exhibited poor cCMV knowledge, which was revealed by their low mean knowledge scores (6.8/14 for audiologists and 5.7/14 for SLPs). The difference between their mean scores was non-significant (p-value > 0.05). The majority of SLPs and audiologists agreed that it is crucial for them to learn more about cCMV to enrich their professional backgrounds. This study emphasized the necessity for cCMV education for audiologists and SLPs. Increased awareness and knowledge may allow them to be more mindful of cCMV symptoms and therefore provide enhanced service to their pediatric patients.

Evaluation of the Effects of Optokinetic Stimuli and Dual-Task Performance on Vestibulo-Ocular Reflex Function in Children With Attention Deficit and Hyperactivity Disorder.

OBJECTIVES: This study investigated the effects of optokinetic stimuli and dual-task performance on vestibulo-ocular reflex (VOR) function. The study primarily focused on understanding the effects of attention deficit and hyperactivity disorder (ADHD) and its subtypes. STUDY DESIGN: A case-control study. SETTING: Tertiary medical centre. METHODS: Thirty-eight children diagnosed with ADHD and 40 typically developing (TD) children aged 8-18 were included in the study. According to their diagnostic reports, children diagnosed with ADHD were also examined in three subtypes: predominantly inattentive (ADHD-PI), predominantly hyperactive-impulsive (ADHD-HI) and the combined type. Functional head impulse test (fHIT) was applied to all participants in three conditions-with no additional stimulus, optokinetic stimulation and dual-task. Correct responses (CR) were determined for each group, and the conditions were compared. For the dual-task test performance, children were given a counting task. RESULTS: The findings of the study are significant. The CR values obtained from the fHIT tests applied under three different conditions were lower in the ADHD group compared to the control group. CR values for all fHIT conditions and all semicircular canals were lower in the ADHD-PI subtype and higher in the ADHD-HI subtype compared to other subgroups. CONCLUSION: This study has significant practical implications underscoring its relevance. fHIT, when applied with different protocols, can provide valuable information about the vestibular and cognitive states of children with ADHD. These results are particularly significant as the diagnosis of ADHD often relies on subjective interpretations, and fHIT offers a more objective and reliable method of evaluation.

Novel CDKL5 targets identified in human iPSC-derived neurons.

CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism.

BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Sleep Disturbances and Co-sleeping in Italian Children and Adolescents with Autism Spectrum Disorder.

The current study aimed (1) to provide an analysis of the frequency and prevalence of sleep disturbances in a large Italian sample of children and adolescents with ASD, detecting specific predictors of the presence/absence of sleep disorders, (2) to examine the phenomenon of co-sleeping within a subgroup of participants with ASD. A total of 242 children and adolescents with ASD (194 males, mean age 5.03 ± 3.15 years) were included. After the diagnostic procedure, caregivers were requested to complete the Sleep Disturbance Scale for Children (SDSC) to assess sleep disorders among participants. The presence of co-sleeping was investigated in a subgroup of 146 children and adolescents with ASD. An elevated or clinically relevant global score for sleep disorders (≥ 60) was found in 33% of participants. The most prevalent sleep disorder in our group was related to difficulties with sleep onset and sleep maintenance (~ 41% of cases). Sleep disturbances were predicted by higher intelligence quotient (IQ)/developmental quotient (DQ), increased internalizing problems, and elevated parental stress. The subgroup of participants engaged in co-sleeping (N = 87) were younger and had lower IQ/DQ scores, reduced adaptive functioning, and diminished psychological wellbeing than the non-co-sleeping group. Our findings are consistent with the current literature highlighting that insomnia is the most widespread sleep problem associated with ASD. The relationship between IQ/DQ and sleep alterations is a crucial topic that deserves additional research. Future studies should assess sleep by objective measures such as EEG topography to better understand the mechanisms underlying sleep alterations in this neurodevelopmental disorder.

POLR3B de novo variants are a rare cause of infantile myoclonic epilepsy.

PURPOSE: To report on a new phenotype in a patient carrying a novel, undescribed de novo variant in POLR3B, affected by generalized myoclonic epilepsy and neurodevelopmental disorder, without neuropathy. It is known that biallelic pathogenic variants in POLR3B cause hypomyelinating leukodystrophy-8, and heterozygous de novo variants are described in association to a phenotype characterized by predominantly demyelinating sensory-motor peripheral neuropathy, ataxia, spasticity, intellectual disability and epilepsy, in which the peripheral neuropathy is often the main clinical presentation. METHODS: We collected clinical, electrophysiological and neuroimaging data from the affected subject and performed a Trio-Clinical Exome Sequencing. RESULTS: We detected a de novo novel heterozygous missense variant c.1132A>G in POLR3B (NM_018082.6) that was considered as likely pathogenic following ACMG criteria. We also consulted our custom genomic database of a total of 1485 patients that were genetically analysed from 2018 for epilepsy, and found no other de novo variants in the POLR3B gene. CONCLUSION: We hypothesize a possible genotype-phenotype correlation, particularly regarding epilepsy. We also provide a review of the literature about the previously described POLR3B heterozygous patients, with particular attention to the epileptic phenotype, underlining the association between POLR3B and early onset myoclonic epilepsy, which can represent the main manifestation of the disease at its onset.

Diverse clinical presentation of SPTBN1 variants: Complex versus primary attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10-5) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.

Splice-switching antisense oligonucleotides for pediatric neurological disorders.

Pediatric neurological disorders are frequently devastating and present unmet needs for effective medicine. The successful treatment of spinal muscular atrophy with splice-switching antisense oligonucleotides (SSO) indicates a feasible path to targeting neurological disorders by redirecting pre-mRNA splicing. One direct outcome is the development of SSOs to treat haploinsufficient disorders by targeting naturally occurring non-productive splice isoforms. The development of personalized SSO treatment further inspired the therapeutic exploration of rare diseases. This review will discuss the recent advances that utilize SSOs to treat pediatric neurological disorders.

Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders.

There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis. Affected individuals in six out of eight families (75%) carried homozygous variants that met ACMG criteria for being pathogenic (in the genes ADGRG1, METTL23, SPG11) or likely pathogenic (in the genes GPAA1, MFN2, SGSH). The remaining two families had homozygous candidate variants in the genes (AP4M1 and FAM126A) associated with phenotypes consistent with their clinical presentations, but the variants did not meet the criteria for pathogenicity and were hence classified as variants of unknown significance. Notably, the variants in ADGRG1, AP4M1, FAM126A, and SGSH did not have prior reports in the literature, demonstrating the importance of including diverse populations in genomic studies. We provide clinical phenotyping along with analyses of ES data that support the utility of ES in making accurate molecular diagnoses in these patients, as well as in unearthing novel variants in known disease-causing genes in underrepresented populations from LMIC.

Short communication: catechol-O-methyltransferase allelic variation in relation to psychological and hormonal indices of stress in children and adolescents with chromosome 22q11.2 deletion syndrome (22q11.2DS).

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a developmental disorder with high rates of anxiety and psychosis. Catechol-O-methyltransferase (COMT) regulates epinephrine (E), norepinephrine (NE), and dopamine (DA) and is implicated in both anxiety and psychotic disorders. The aim of this study was to determine how COMT variation relates to psychological anxiety and associated stress physiology responsiveness to better understand symptom heterogeneity in people with 22q11.2DS. We examined COMT allelic variation in relation to anxiety and hypothalamic-pituitary-adrenocortical (HPA) and sympathetic-adrenomedullary (SAM) hormonal stress indicators in 30 children and adolescents with 22q11.2DS. Contrary to expectation, individuals with the higher activity COMTval allele had higher anxiety levels versus those with the low activity (COMTmet) allele (p = 0.021; Glass' Δ = 0.69). Anxiety was not correlated with salivary cortisol (CORT) or alpha-amylase (sAA) in either group. Groups did not differ in CORT levels (p = 0.58), but the COMTmet group had higher sAA (p = 0.026; Glass' Δ = 0.67, uncorrected) suggesting greater SAM reactivity but not HPA activity. This suggests that COMT allelic variation may contribute to differences in acute SAM but not slower HPA stress reactivity in those with 22q11.2DS.

Trends in fetal alcohol spectrum disorder research: A bibliometric review of original articles published between 2000 and 2023.

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability globally. International organizations have highlighted an urgent need for improved prevention, diagnosis, and support. However, the evidence base needed to inform this is thought to be limited. We conducted two complementary reviews to (i) describe trends in the volume and characteristics of original FASD research articles (Review 1) and (ii) compare the volume of published research on FASD to that of other neurodevelopmental disorders (Review 2). In Review 1, we systematically searched MEDLINE, Embase, CINAHL and PsycInfo for original studies with FASD terms in the title, published between 2000 and 2023. We summarised study characteristics including the article topic(s), sample population, country of origin, and publication year using quantitative content analysis and time-series plots. A total of 854 studies were eligible. Studies showed a relative focus on diagnosis and screening, compared to prevention and intervention. FASD research originated from 31 countries, however most countries (68%) had fewer than 10 articles published over the 23-year review period. In Review 2, we searched PubMed for records published between 2000 and 2023 with FASD, autism, or attention-deficit-hyperactivity disorder (ADHD) terms in the title. We compared the volume of records for these conditions using descriptive statistics and time-series plots. Of the 64,069 records retrieved, 2% were for FASD, compared to 60% for autism and 38% for ADHD. FASD remains considerably under-researched. While there has been an increase in the number of original FASD research articles published annually over time, this is much lower than expected compared to publication trends for other neurodevelopmental conditions, and the wider scientific literature. Further research is needed to understand the impact of FASD across the lifespan, to inform evidence-based policy and support, and to advance progress in strength-based, stigma-reducing approaches to FASD research and practice.

Predicting emotional consequences of disorganization among adults with neurodevelopmental disorders: a structural equation model.

PURPOSE: Previous studies exhibited differences in sensory processing, motor coordination, metacognitive executive functions (EF-MI), and sleep quality among adults with neurodevelopmental disorders (NDD). This study aims to find relationships between those abilities and organization-in-time, focusing on emotional responses after decreased organization abilities. MATERIALS AND METHODS: This is a secondary data analysis of a larger sample from three previous studies conducted in one laboratory. Data were collected from 290 adults; 149 with NDD and 141 sex- and age- (20-50 years) matched controls completed the Adolescent/Adult Sensory Profile, Adult Developmental Coordination Disorder, Adults Behavioral Rating Inventory of Executive Functions, Mini Sleep, and Time Organization and Participation questionnaires. Structural equation model (SEM) analysed relationships and variable prediction. RESULTS: Significant between-group differences were found for all variables; SEM indicated similar paths in both groups. Sensory processing affected EF-MI and sleep quality and significantly correlated with motor coordination, affecting EF-MI; EF-MI affected organization-in-time. Sleep quality significantly affected organization-in-time, affecting emotional responses. CONCLUSIONS: Sensory, motor, EF, and sleep differences were associated with decreased organization-in-time abilities of adults with NDD, adversely affecting their emotional well-being. Early detection of such differences and targeted interventions may improve daily functioning and life quality and prevent negative emotional implications.

Neurodevelopmental disorders (NDD) emerging early in development affect lifelong well-being, and personal, social, academic, and occupational function.Adults with NDD may experience reduced quality of life due to ineffective time organization and life management.Ineffective time organization and consequence negative emotional responses are tied with deficient sensory processing, motor coordination, metacognitive executive function abilities, and sleep quality.Early diagnosis of such deficiencies following by targeted intervention may enhance daily functioning, reduce emotional challenges, and improve overall life outcomes.

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties.

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

Regional Disparities in Growth Patterns of Children with Cerebral Palsy: A Comparative Analysis of Saudi Arabian, UK, and US Data.

AIM: In order to understand the global variations in the growth trajectories of cerebral palsy patients, this study aimed to compare the growth patterns of cerebral palsy patients in Saudi Arabi with United States and United Kingdom counterparts. METHOD: Anthropometric data from 107 participants with cerebral palsy in Saudi Arabia were collected, including age, gender, cerebral palsy type, Gross Motor Function Classification System level, birth weight, weight at assessment, height at assessment, body mass index, and head circumference at assessment. RESULTS: This study found discrepancies between the growth patterns of Saudi Arabian children with cerebral palsy and United Kingdom and the United States growth charts, particularly among those with severe cerebral palsy. Significant differences were observed in weight, height, and body mass index z-scores when comparing Saudi Arabian data with the United kingdom and United States reference data. INTERPRETATION: These findings emphasize the importance of validating growth charts across different populations to ensure accurate monitoring and clinical management of children with cerebral palsy. Additionally, this study highlights the need for region-specific growth references to better address the diverse needs of individuals with cerebral palsy worldwide.

Association between Motor Skills, Occupational Performance, and Mental Health in Japanese Children with Neurodevelopmental Disorders: A Cross-Sectional Correlational Study.

BACKGROUND: Motor skills have been linked to executive functions (EFs) in children with developmental coordination disorder (DCD). However, the traits of other neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder and autism spectrum disorder, remain overlooked. Therefore, this study explored the association between motor skills, occupational performance, and mental health in older kindergarten children with DCD and other NDDs. Overall, 95 participants aged 5-6 years were included in this study and divided into four groups: DCD traits (DCD-t), DCD-t + NDD traits (DCD-t + NDD-t), NDD-t-only, and typically developing children. Motor skills, EFs, and mental health were assessed using the DCD Questionnaire (DCDQ-J) and Movement Assessment Battery for Children-Second Edition, School Assessment of Motor and Process Skills (S-AMPS), and the Strengths and Difficulties Questionnaire (SDQ), respectively. The DCD-t + NDD-t group exhibited a strong correlation between the S-AMPS motor skill score and the DCDQ-J fine motor skill score (r = 0.88, p < 0.001) and between the total DCDQ-J score and the SDQ Total Difficulties Score (r = -0.94, p < 0.001). The findings indicate that children with DCD-t and NDD-t are more likely to experience EF and mental health problems than those with DCD-t only.

tubg1 Somatic Mutants Show Tubulinopathy-Associated Neurodevelopmental Phenotypes in a Zebrafish Model.

Development of the multilayered cerebral cortex relies on precise orchestration of neurogenesis, neuronal migration, and differentiation, processes tightly regulated by microtubule dynamics. Mutations in tubulin superfamily genes have been associated with tubulinopathies, encompassing a spectrum of cortical malformations including microcephaly and lissencephaly. Here, we focus on γ-tubulin, a pivotal regulator of microtubule nucleation encoded by TUBG1. We investigate its role in brain development using a zebrafish model with somatic tubg1 mutation, recapitulating features of TUBG1-associated tubulinopathies in patients and mouse disease models. We demonstrate that γ-tubulin deficiency disrupts neurogenesis and brain development, mirroring microcephaly phenotypes. Furthermore, we uncover a novel potential regulatory link between γ-tubulin and canonical Wnt/ß-catenin signaling, with γ-tubulin deficiency impairing Wnt activity. Our findings provide insights into the pathogenesis of cortical defects and suggest that γ-tubulin could be a potential target for further research in neurodevelopmental disorders, although challenges such as mode of action, specificity, and potential side effects must be addressed.

Clinical characteristics, longitudinal adaptive functioning, and association with electroencephalogram activity in PPP2R5D-related neurodevelopmental disorder.

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.