Functional myelin in cognition and neurodevelopmental disorders.

In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.

Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders.

Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10-7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10-3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

Clozapine Treatment for Aggressive Behaviors in Youths with Neurodevelopmental Disorders.

Objectives: The aim of this study was to assess effectiveness and tolerability of Clozapine in the treatment of aggression in youth with Neurodevelopmental Disorders. Methods: Patients were consecutively admitted at our third-level university hospital with nationwide catchment from June 2018 to October 2022, and followed up to July 2023. Eligibility criteria were as follows: (1) Autism Spectrum Disorder (ASD) and/or Intellectual Disability/Borderline Cognitive Functioning, (2) behavioral dyscontrol with physical aggression; (3) age range between 8 and 18 years; (4) clinical indication for Clozapine treatment after at least two failed trials with other Second-Generation Antipsychotics (SGAs); (5) availability of an at least 6-month-long follow-up. To evaluate the response to Clozapine, we used the Clinical Global Impressions (CGI) rating scales (Clinical Global Impressions-Severity [CGI-S] and Clinical Global Impressions-Improvement [CGI-I]), the Children's Global Assessment Scale (CGAS), and the Aberrant Behavior Checklist (ABC). Results: Twenty-six children and adolescents (21 boys, age 13.47 ± 2.05 years, follow-up duration 9.77 ± 3.50 months) were included in the analysis. Clinical severity (CGI-S) and functional impairment (Clinical Global Assessment Scale) significantly improved, as well as the ABC Total Score and the scores in several subscales. Sixteen patients (61.54%) were responders (CGI-I ≤2), and 13 (50.00%) displayed remission of aberrant behaviors (ΔABC-Total >35), while response/remission condition was not affected by add-on medications and psychotherapy. Most frequent side effects were increased appetite (50.00%), sialorrhea (38.46%), and increased repetitive behaviors (26.92%). Two patients presented epileptic seizures, while no patients presented leucopoenia. Conclusions: Our results suggest that Clozapine may be helpful in ameliorating treatment-resistant aggression in youth with neurodevelopmental conditions. Possible pharmacological strategies for the management of most frequent side effects are also suggested.

Infant microbes and metabolites point to childhood neurodevelopmental disorders.

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.

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Neurodevelopmental disorders in children have become a significant global public health concern, impacting child health worldwide. In China, the current intervention model for high-risk infants involves early diagnosis and early treatment. However, in recent years, overseas studies have explored novel preventive early intervention strategies for neurodevelopmental disorders in high-risk infants, achieving promising results. This article provides a comprehensive review of the optimal timing, methods, and intervention models of the preventive early intervention strategies for neurodevelopmental disorders in high-risk infants. The aim is to enhance the awareness and knowledge of healthcare professionals regarding preventive early intervention strategies for neurodevelopmental disorders in high-risk infants, facilitate clinical research and application of such interventions in China, and ultimately reduce the incidence of neurodevelopmental disorders in this high-risk population.

Association of congenital heart disease and neurodevelopmental disorders: an observational and Mendelian randomization study.

BACKGROUND: This study aims to thoroughly study the connection between congenital heart disease (CHD) and neurodevelopmental disorders (NDDs) through observational and Mendelian randomization (MR) designs. METHODS: This observational study uses data from the National Survey of Children's Health (2020-2021). Multivariable logistic regression and propensity score matching (PSM) were performed to analyze the association. PSM was used to minimize bias for covariates such as age, race, gender, maternal age, birth weight, concussion or brain injury, preterm birth, cerebral palsy, Down syndrome, and other inherited conditions. In MR analyses, inverse variance-weighted measures, weighted median, and MR-Egger were employed to calculate causal effects. RESULTS: A total of 85,314 children aged 0-17 were analyzed in this study. In regression analysis, CHD (p = 0.04), the current heart condition (p = 0.03), and the severity of current heart condition (p < 0.05) had a suggestive association with speech or language disorders. The severity of current heart condition (p = 0.08) has a potential statistically significant association with attention deficit hyperactivity disorder(ADHD). In PSM samples, ADHD(p = 0.003), intellectual disability(p = 0.012), and speech or language disorders(p < 0.001) were all significantly associated with CHD. The severity of current heart condition (p < 0.001) also had a significant association with autism. MR analysis did not find causality between genetically proxied congenital cardiac malformations and the risk of NDDs. CONCLUSIONS: Our study shows that children with CHD have an increased risk of developing NDDs. Heart conditions currently and severity of current heart conditions were also significantly associated with these NDDs. In the future, we need to try more methods to clarify the causal relationship between CHD and NDDs.

Presynaptic perspective: Axonal transport defects in neurodevelopmental disorders.

Disruption of synapse assembly and maturation leads to a broad spectrum of neurodevelopmental disorders. Presynaptic proteins are largely synthesized in the soma, where they are packaged into precursor vesicles and transported into distal axons to ensure precise assembly and maintenance of presynapses. Due to their morphological features, neurons face challenges in the delivery of presynaptic cargos to nascent boutons. Thus, targeted axonal transport is vital to build functional synapses. A growing number of mutations in genes encoding the transport machinery have been linked to neurodevelopmental disorders. Emerging lines of evidence have started to uncover presynaptic mechanisms underlying axonal transport defects, thus broadening the view of neurodevelopmental disorders beyond postsynaptic mechanisms. In this review, we discuss presynaptic perspectives of neurodevelopmental disorders by focusing on impaired axonal transport and disturbed assembly and maintenance of presynapses. We also discuss potential strategies for restoring axonal transport as an early therapeutic intervention.

Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Interleukin-23 levels in umbilical cord blood are associated with neurodevelopmental trajectories in infancy.

Our previous study, which aimed to understand the early neurodevelopmental trajectories of children with and without neurodevelopmental disorders, identified five classes of early neurodevelopmental trajectories, categorized as high normal, normal, low normal, delayed, and markedly delayed. This investigation involved measurement using the Mullen Scale of Early Learning in a representative sample of Japanese infants followed up from the age of 0 to 2 years (Nishimura et al., 2016). In the present study, we investigated the potential association between cytokine concentrations in umbilical cord serum with any of the five classes of neurodevelopmental trajectories previously assigned, as follows: high normal (N = 85, 13.0%), normal (N = 322, 49.1%), low normal (N = 137, 20.9%), delayed (N = 87, 13.3%), and markedly delayed (N = 25, 3.8%) in infancy. Decreased interleukin (IL)-23 levels in the cord blood were associated with the markedly delayed class, independent of potential confounders (odds ratio, 0.44; 95%confidence interval: 0.26-0.73). Furthermore, IL-23 levels decreased as the developmental trajectory became more delayed, demonstrating that IL-23 plays an important role in development, and is useful for predicting the developmental trajectory at birth.

Trastornos del sueño en niños con epilepsia / Sleep disorders in children with epilepsy

Introducción: Los niños con epilepsia tienen más trastornos del sueño (TS) que la población sana. Es fundamental su diagnóstico, ya que la epilepsia y los TS tienen una relación bidireccional. Objetivo: Determinar la incidencia de TS y malos hábitos de sueño en niños con epilepsia. Método: Estudio transversal de pacientes menores de 18 años con epilepsia sobre TS, mediante la versión española de Sleep Disturbance Scale for Children (SDSC), y sobre hábitos de sueño, mediante cuestionario de elaboración propia. Resultados: La muestra incluyó 153 pacientes. El 84% de la población estudiada presentaba alterado algún aspecto del sueño. Lo más frecuente fueron las alteraciones en la transición sueño-vigilia (53%), en el inicio-mantenimiento del sueño (47,7%) y la somnolencia diurna (44,4%). Un 70% de los padres de los pacientes referían que su hijo «dormía bien», pero en este grupo se detectaron TS hasta en el 75,7%. Muchos de los pacientes tenían hábitos de sueño poco saludables, como dormirse con dispositivos electrónicos (16,3%), precisar presencia familiar para dormirse (39%) o dormir en colecho o cohabitación (23,5 y 30,5%, respectivamente). Aquellos con epilepsias generalizadas, refractarias, crisis nocturnas y discapacidad intelectual presentaron mayor probabilidad de presentar TS. En cambio, los malos hábitos de sueño fueron frecuentes independientemente de las características de la epilepsia. Conclusiones: Los TS y los malos hábitos de sueño son frecuentes en niños con epilepsia. Su tratamiento puede conllevar una mejoría en la calidad de vida del paciente y su familia, así como una mejoría en el pronóstico de la epilepsia.(AU)

Introduction: Children with epilepsy present greater prevalence of sleep disorders than the general population. Their diagnosis is essential, since epilepsy and sleep disorders have a bidirectional relationship. Objective: Determine the incidence of sleep disorders and poor sleep habits in children with epilepsy. Methods: We conducted a cross-sectional study of patients under 18 years of age with epilepsy, assessing sleep disorders using the Spanish-language version of the Sleep Disturbance Scale for Children (SDSC), and sleep habits using an original questionnaire. Results: The sample included 153 patients. Eighty-four percent of our sample presented some type of sleep alteration. The most frequent alterations were sleep-wake transition disorders (53%), sleep initiation and maintenance disorders (47.7%), and daytime sleepiness (44.4%). In 70% of cases, the patients’ parents reported that their child “slept well,” although sleep disorders were detected in up to 75.7% of these patients. Many patients had poor sleep habits, such as using electronic devices in bed (16.3%), requiring the presence of a family member to fall asleep (39%), or co-sleeping or sharing a room (23.5% and 30.5%, respectively). Those with generalised epilepsy, refractory epilepsy, nocturnal seizures, and intellectual disability were more likely to present sleep disorders. In contrast, poor sleep habits were frequent regardless of seizure characteristics. Conclusions: Sleep disorders and poor sleep habits are common in children with epilepsy. Their treatment can lead to an improvement in the quality of life of the patient and his/her family, as well as an improvement in the prognosis of epilepsy.(AU)

Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.

BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. METHODS: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. RESULTS: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. CONCLUSIONS: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.

The Brain Gene Registry: a data snapshot.

Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.

Not Just a Mood Disorder─Is Depression a Neurodevelopmental, Cognitive Disorder? Focus on Prefronto-Thalamic Circuits.

Depression is one of the most burdensome psychiatric disorders, affecting hundreds of millions of people worldwide. The disease is characterized not only by severe emotional and affective impairments, but also by disturbed vegetative and cognitive functions. Although many candidate mechanisms have been proposed to cause the disease, the pathophysiology of cognitive impairments in depression remains unclear. In this article, we aim to assess the link between cognitive alterations in depression and possible developmental changes in neuronal circuit wiring during critical periods of susceptibility. We review the existing literature and propose a role of serotonin signaling during development in shaping the functional states of prefrontal neuronal circuits and prefronto-thalamic loops. We discuss how early life insults affecting the serotonergic system could be important in the alterations of these local and long-range circuits, thus favoring the emergence of neurodevelopmental disorders, such as depression.

Prenatal and postnatal neuroimmune interactions in neurodevelopmental disorders.

The intricate relationship between immune dysregulation and neurodevelopmental disorders (NDDs) has been observed across the stages of both prenatal and postnatal development. In this Review, we provide a comprehensive overview of various maternal immune conditions, ranging from infections to chronic inflammatory conditions, that impact the neurodevelopment of the fetus during pregnancy. Furthermore, we examine the presence of immunological phenotypes, such as immune-related markers and coexisting immunological disorders, in individuals with NDDs. By delving into these findings, we shed light on the potential underlying mechanisms responsible for the high occurrence of immune dysregulation alongside NDDs. We also discuss current mouse models of NDDs and their contributions to our understanding of the immune mechanisms underlying these diseases. Additionally, we discuss how neuroimmune interactions contribute to shaping the manifestation of neurological phenotypes in individuals with NDDs while also exploring potential avenues for mitigating these effects.

The effectiveness of a dialogical family guidance intervention regarding child treatment response in families with a child with neurodevelopmental disorders.

BACKGROUND: Children with neurodevelopmental disorders (NDD) can have emotional and behavioral symptoms affecting not only the child, but the whole family. Since family members have a strong impact on each other, studies highlight the need to offer effective family interventions to strengthen the wellbeing of the family. The aim of the current study is to clarify whether there is a difference between parents` opinions regarding their child`s emotional and behavioral condition immediately after Dialogical Family Guidance (DFG) has ended and after a three and six month follow-up. METHOD: Fifty families with a child with NDD were randomized into two groups. Group 1 received DFG with an immediate starting point, and Group 2 received DFG after a three-month waiting period. Parent experiences of treatment response regarding their children`s emotional and behavioral symptoms were estimated before and after DFG using the parent version of the Strengths and Difficulties Questionnaire (SDQ-p) at baseline, and after three and six months. Additionally, comparisons between boys and girls, and the age of the child were analyzed. RESULTS: The total difficulties score between Group 1 and Group 2 showed no difference immediately after DFG, or after three months. Regarding subdomains boys had more peer problems than girls, and at baseline, children between 3 and 6 years appeared to have more conduct problems than children between 7 and 13 years. Subdomain prosocial behavior increased statistically significantly during the study period in Group 1. Other SDQ-p subdomains remained constant in both groups between baseline and three and six month follow-up. CONCLUSIONS: The result does not show any differences between parents` opinions regarding their child immediately after or three months after DFG regarding SDQ-p total difficulties scores in either group. The difference between younger and older children regarding conduct problems at baseline, and the difference between boys and girls regarding peer problems is worth paying attention to in the clinical setting. Because of the small sample, it is not possible to draw relevant conclusions regarding the intervention`s effect regarding the child`s mental health dimensions, gender, or age. Nevertheless, Dialogical family Guidance represents one intervention that can be used. TRIAL REGISTRATION: ClinicalTrials.gov NCT04892992 (retrospectively registered May 18th 2021).

Neurodevelopmental Disorders Including Autism Spectrum Disorder and Intellectual Disability as a Risk Factor for Delayed Diagnosis of Catatonia.

OBJECTIVE: Catatonia is a distinct and severe medical syndrome comprising motor, somatic, and psychiatric symptoms that is reported in upwards of 17% of young patients with autism spectrum disorders. Clinical experience indicates catatonia is often under-recognized in this clinical population. Here we characterize the clinical presentation of catatonia in patients with and without neurodevelopmental disorders (NDDs) including autism, including the time from symptom onset to diagnosis of catatonia. METHOD: Retrospective chart review of electronic medical records at a large, academic pediatric medical center identified 113 pediatric and young adult patients with a charted history of catatonia, as identified by an encounter diagnosis or problem list entry between September 2017 and September 2021. Workup, treatments, and diagnoses (psychiatric, neurodevelopmental, and genetic) were identified. RESULTS: We observed a clear and substantial delay in identification of catatonia in those with NDDs (diagnosis after 330 days for those without psychosis) compared with neurotypical patients (∼16 days). Psychiatry involvement was associated with shorter delays. CONCLUSION: Intellectual disability and autism are risk factors for significantly delayed diagnosis of catatonia. It is unknown whether delayed diagnosis contributes to the difficulty in treating catatonia in this patient population or whether the treatment difficulties relate instead to differential and ongoing biological mechanisms and underlying encephalopathy. Overall, these findings highlight the importance of increased recognition of catatonia symptoms in patients with NDDs and suggest early referral to psychiatric specialists may shorten the delay to diagnosis.

Complex interplay of neurodevelopmental disorders (NDDs), fractures, and osteoporosis: a mendelian randomization study.

BACKGROUND: Neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Tourette Syndrome (TS), have been extensively studied for their multifaceted impacts on social and emotional well-being. Recently, there has been growing interest in their potential relationship with fracture risks in adulthood. This study aims to explore the associations between these disorders and fracture rates, in order to facilitate better prevention and treatment. METHODS: Employing a novel approach, this study utilized Mendelian randomization (MR) analysis to investigate the complex interplay between ADHD, ASD, TS, and fractures. The MR framework, leveraging extensive genomic datasets, facilitated a systematic examination of potential causal relationships and genetic predispositions. RESULTS: The findings unveil intriguing bidirectional causal links between ADHD, ASD, and specific types of fractures. Notably, ADHD is identified as a risk factor for fractures, with pronounced associations in various anatomical regions, including the skull, trunk, and lower limbs. Conversely, individuals with specific fractures, notably those affecting the femur and lumbar spine, exhibit an increased genetic predisposition to ADHD and ASD. In this research, no correlation was found between TS and fractures, or osteoporosis.These results provide a genetic perspective on the complex relationships between NDDs and fractures, emphasizing the importance of early diagnosis, intervention, and a holistic approach to healthcare. CONCLUSION: This research sheds new light on the intricate connections between NDDs and fractures, offering valuable insights into potential risk factors and causal links. The bidirectional causal relationships between ADHD, ASD, and specific fractures highlight the need for comprehensive clinical approaches that consider both NDDs and physical well-being.