Prevalence, comorbidities, and profiles of neurodevelopmental disorders according to the DSM-5-TR in children aged 6 years old in a European region.

Pediatric central auditory processing disorder (CAPD) is frequently comorbid with other childhood disorders. However, few studies have examined the relationship between commonly used CAPD, language, and cognition tests within the same sample. The present study examined the relationship between diagnostic CAPD tests and "gold standard" measures of language and cognitive ability, the Clinical Evaluation of Language Fundamentals (CELF) and the Wechsler Intelligence Scale for Children (WISC). A retrospective study. Twenty-seven patients referred for CAPD testing who scored average or better on the CELF and low average or better on the WISC were initially included. Seven children who scored below the CELF and/or WISC inclusion criteria were then added to the dataset for a second analysis, yielding a sample size of 34. Participants were administered a CAPD battery that included at least the following three CAPD tests: Frequency Patterns (FP), Dichotic Digits (DD), and Competing Sentences (CS). In addition, they were administered the CELF and WISC. Relationships between scores on CAPD, language (CELF), and cognition (WISC) tests were examined using correlation analysis. DD and FP showed significant correlations with Full Scale Intelligence Quotient, and the DD left ear and the DD interaural difference measures both showed significant correlations with working memory. However, ∼80% or more of the variance in these CAPD tests was unexplained by language and cognition measures. Language and cognition measures were more strongly correlated with each other than were the CAPD tests with any CELF or WISC scale. Additional correlations with the CAPD tests were revealed when patients who scored in the mild-moderate deficit range on the CELF and/or in the borderline low intellectual functioning range on the WISC were included in the analysis. While both the DD and FP tests showed significant correlations with one or more cognition measures, the majority of the variance in these CAPD measures went unexplained by cognition. Unlike DD and FP, the CS test was not correlated with cognition. Additionally, language measures were not significantly correlated with any of the CAPD tests. Our findings emphasize that the outcomes and interpretation of results vary as a function of the subject inclusion criteria that are applied for the CELF and WISC. Including participants with poorer cognition and/or language scores increased the number of significant correlations observed. For this reason, it is important that studies investigating the relationship between CAPD and other domains or disorders report the specific inclusion criteria used for all tests.

Kinematic and kinetic characteristics of graphomotor skills in children with neurodevelopmental disorders: The impact of DCD, ADHD, and ASD traits.

Background：There has been a lack of prevalence estimates of DSM-5 mental disorders in child populations at the national level worldwide. Little is known about the disease burden of child mental disorders. Taiwan’s National Epidemiological Study of Child Mental Disorders (TNESCMD) was designed to address these research gap. This study reported the methodology of the TNESCMD and the lifetime and six-month prevalence of mental disorders according to the DSM-5 diagnostic criteria in Taiwanese children. I further compared the prevalence and estimated disease burden from the TNESCMD with Taiwan National Health Insurance Research Database (TNHIRD). Methods: The TNESCMD used stratified cluster sampling to select 69 schools in Taiwan resulting in a nationally representative sample. Among all 10118 eligible children selected via our sampling method, 9560 (94.4%) children, 6846 (67.6%) parents, and 9759 (96.3%) teachers participated in this study and completed the questionnaires. Among them, 4816 children in grades 3 (n=1352), 5 (n=1297), and 7 (n=2167) further underwent face-to-face psychiatric interviews using the Kiddie-Schedule for Affective Disorders and Schizophrenia-Epidemiological (K-SADS-E) version, modified for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Clinical questionnaires for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), emotional and behavioral problems included the Chinese version of the Swanson, Nolan, and Pelham IV scale, Social Responsiveness Scale, and Child Behavior Checklist were used to examine the convergent and divergent validity with K-SADS-E. Risk factor analysis for mental disorders included sex, age, urban/rural and community income. 1,389,372 participants aged 8 to 14 were randomly selected from the 2016 TNHIRD claims dataset. The disease burden was calculated regarding years lived with disability (YLDs) with adjustment for comorbidity. YLDs and their 95% uncertainty intervals (UI) were reported. A rates ratio (RR) was reported to depict the strength of YLDs difference between TNESCMD and TNHIRD. Results: The K-SADS-E showed satisfactory inter-rater reliability (prevalence adjusted bias adjusted kappa = .80-1.00) among eight interviewers. The diagnoses of K-SADS-E demonstrated good convergent and divergent validity with most corresponding clinical questionnaires. The weighted lifetime and 6-month prevalence rates for overall mental disorders were 32.3% and 25.8%, respectively. The most prevalent mental disorders (lifetime, 6-month) were anxiety disorders (15.1%, 13.5%) and ADHD (10.5%, 9.0%), followed by sleep disorders, tic disorder, oppositional defiant disorder, and ASD. New DSM-5 mental disorders, avoidant/restrictive food intake disorder and disruptive mood dysregulation disorder, were also found with current low prevalence (<1%). Boys were more likely to have neurodevelopmental disorders and disruptive and impulse-control, and conduct disorders, whereas girls were more likely to develop anxiety disorders, depressive disorder and anorexia nervosa. Depressive disorder and suicide-related problems were more prevalent in Grade 7 children. The participants living in urban areas and low socioeconomic communities had increased risks for mental disorders. The overall YLD from all mental disorders in the TNESCMD was 5.24 times (95% UI: 4.15-6.70) more than that in TNHIRD, with the lowest and highest YLDs RR for autism spectrum disorder (ASD; RR: 2.24 and 95% UI: 1.28-3.93) and anxiety disorders (RR: 351.00 and 95% UI: 175.05-703.80), respectively. Unlike ADHD and ASD, the total proportions explained by anxiety disorders and conduct disorder/oppositional defiant disorder were significantly lower in TNHIRD than those in the TNESCMD and Global Burden of Disease 2016. Conclusions: Our findings suggest that the Mandarin version of the K-SADS-E for DSM-5 is a reliable and valid instrument for diagnosing child and adolescent mental disorders based on DSM-5. Similar to the DSM-IV prevalence rates reported in Western countries, indicate that DSM-5 mental disorders are common in the Taiwanese child population. The comparatively higher estimate of the disease burden of mental disorders in children from community-based setting might provide the preparation of future financial resource allocation, development and management of medical service, and human resource for mental health care in the clinic-based settings. For disorders with a significant difference in disease burden between the community-based and clinic-based settings, they may need more mental health promotion and prevention.

Background. Children diagnosed with attention deficit hyperactivity disorder (ADHD) often encounter motor co-ordination difficulties. Little has been documented about the prevalence of comorbid ADHD and developmental co-ordination disorder (DCD), both in South Africa (SA) and globally. Objective. The purpose of the study was to establish the prevalence and demographics of comorbid ADHD and DCD at 5 sites located within 3 districts of KwaZulu-Natal Province, SA. Methods. A descriptive observational study was undertaken of 151 children aged 8 - 9 years, both male and female, from 4 population groups. The children were clinically diagnosed with ADHD and were receiving remedial education. Children with any other conditions and/or receiving occupational therapy, physiotherapy and/or psychotherapy were excluded. The Conners' Teacher Rating Scale, the DCD Questionnaire and the Movement Assessment Battery for Children were administered to confirm comorbid ADHD and DCD. Results. A 74% prevalence of comorbid ADHD and DCD was identified, with a male-to-female ratio of 2:1. The combined subtype of ADHD was most commonly associated with comorbid DCD. Conclusion. From the relatively high prevalence figures, it appears that an association between ADHD and DCD exists. Children with ADHD should therefore be assessed for motor skills deficiency and offered appropriate interventions.

In the study by Khalifa et al. in this issue of Acta Paediatrica 1, levels of the excitatory neurotransmitter glutamate were analysed in a clinical sample of young children aged 3–10 years with autism spectrum disorders (ASD). The 30 children were randomly selected from the ASD Outpatient Clinic at the Abou El-Reesh Hospitals, Cairo University and compared to 30 randomly selected controls, without any mental disorders or major medical illnesses, whose siblings were attending another outpatient clinic at the hospital. The prevalence of ASD has been the subject of many studies, and, as the authors report, many of which have reported a dramatic increase during the last decade. A Swedish study 2 reported that considerably fewer ASD symptoms now seemed to be required for a clinical diagnosis of ASD, particularly after the preschool years. These findings suggest that increases in ASD diagnoses could be partly due to how ASD is diagnosed. The increased level of serum glutamate that was found by Khalifa et al. 1 is interesting and in line with other studies of serum glutamate in children with autism that they refer to and has clinical and further research implications. As the authors point out, glutamate is one of the major excitatory neurotransmitters in the human brain and plays a significant role in brain development, cell migration, synapse induction and cell differentiation. It is also involved in a wide range of neural and cognitive functions, such as learning and memory. Although glutamate does not cross the blood–brain barrier readily, levels of glutamate in blood and cerebrospinal fluid have been positively correlated in humans, suggesting that peripheral glutamate levels can reflect the glutamate level in the brain 3. In an early study (1992) 4, the concentration of glutamate, but of no other amino acid, was markedly elevated in the cerebrospinal fluid of patients with Rett syndrome, a genetic disorder characterised by the loss of functions and in many cases a period with autistic features. Attempts to understand the pathobiology of the glutamatergic system have led to new investigational treatments for ASD. The potential implications of modulating the glutamatergic system while treating ASD, by using specific drugs that affect glutamatergic receptors, have been explored in preclinical and clinical studies. These have specifically targeted the NMDA receptors (agonists and antagonists), the AMPA/kainate receptors (antagonists) and metabotropic glutamate receptor 5 (mGluR5) (antagonists) and other mechanisms in the glutamatergic system 5. However, despite the potentially encouraging preliminary findings of clinical trials using glutamate, there are several limitations. These are mainly associated with the fact that ASD is a very heterogeneous disorder with many potential aetiologies, including those where a glutamatergic dysfunction might not play a key role in the pathophysiology 5. There is a growing interest in this area, and studies have indicated an imbalance in excitatory (glutamatergic) and inhibitory γ-aminobutyric acid (GABAergic) neurotransmission in ASD 1. Although GABA is best known as an inhibitory neurotransmitter, it can be either inhibitory or excitatory, depending on intraneuronal (Cl−), which is modulated by two isoforms of the cation-Cl− cotransporter family. These are NKCC1, an isoform of the Na+-K+-2Cl− cotransporter, and KCC2, an isoform of the K+-Cl− cotransporter. NKCC1 transports Cl−, along with Na+ and K+, into the neuron, which increases (Cl−) leading to depolarisation (excitatory state) on the opening of Cl− channels, such as GABA-A receptors. KCC2 transports Cl−, along with K+, out of the neuron, which decreases (Cl−) leading to hyperpolarisation (inhibitory state) with Cl− channel opening 6. NKCC1 is widely distributed throughout the body and is also found in neurons 6. Normally, adult neurons have low intracellular chloride levels underlying the GABAergic inhibitory drive. In contrast, there are high chloride levels and concomitant excitatory GABA actions in a wide range of pathological conditions. Reducing GABAergic inhibition produces neuronal hyperexcitability, and can lead to deleterious neurological and psychiatric sequelae, including ASD 7. These observations have raised considerable interest in the development of pharmacological treatments that restore physiological (Cl−) levels and GABAergic inhibition in pathological conditions 7, 8. Based on animal studies of autism, revealing that the NKCC1 chloride-importer inhibitor bumetanide restores physiological chloride levels and enhances GABAergic inhibition, clinical treatment studies have been performed and published by a French group from 2010 onwards 7, 8. In 2017, this group published a double-blind, randomised, placebo-controlled, multisite study that assessed the efficacy, safety, pharmacokinetics and the optimal dose of bumetanide in children and adolescents with ASD, including Asperger's syndrome 7. The study group consisted of 88 children and adolescents aged 2–18 years, and the treatment period was 3 months. The findings showed that bumetanide improved core symptoms of ASD and presented a favourable benefit/risk ratio, particularly when 1.0 mg of bumetanide was administered twice daily. The frequency and incidence of adverse events were directly correlated with the bumetanide dose 7. Another study was carried out by the French group based on findings that constraining eye contact leads to an exaggerated increase in amygdala activation in ASD. Functional magnetic resonance imaging and eye tracking were performed on adolescents and young adults with high-functioning ASD before and after bumetanide. This revealed that bumetanide normalised the amygdala activation levels during constrained eye contact with dynamic emotional face stimuli. In addition, eye-tracking data revealed that bumetanide increased the time spent in spontaneous eye gaze during a free-viewing mode of the same face stimuli. The data support the excitatory/inhibitory dysfunction hypothesis for ASD and indicate that bumetanide may improve specific aspects of social processing in ASD 9. The results from the bumetanide studies are interesting and promising and should be followed up by further, large double-blind placebo-controlled trials in patients with ASD. It would be preferable if these included different aetiologically and clinically defined subgroups, for example ASD with coexisting intellectual disability, attention-deficit hyperactivity disorder, epilepsy and those with other coexisting developmental disorders. If possible, these should include approaches to monitor the molecular mechanisms of medication responses. Along with data from a meta-analysis, Khalifa et al. 1 discussed the potential role of glutamate as a biomarker of ASD but underscored that larger sample studies are needed to verify whether it can be used for early detection of autism. However, since the findings of higher glutamate levels seem to be prevalent in many central nervous system disorders, it would be necessary to base any diagnosis of ASD on a full clinical neurodevelopmental assessment, including evaluation of the ASD symptom criteria. Autism spectrum disorder is a highly heterogeneous neurodevelopmental disorder, with regard to its aetiology and clinical presentation 10, and most patients with ASD have at least one coexisting neurodevelopmental or neuropsychiatric disorder. These include intellectual disability, attention-deficit hyperactivity disorder, developmental language disorder, anxiety disorders, tic disorders, obsessive-compulsive disorder, feeding, sleeping and eating disorder, motor coordination disorder, epilepsy and, or, other types of specific problems, including mood dysregulation, sensory abnormalities and self-harm behaviour. An important challenge for future research is to explore the extent to which glutamatergic and GABAergic imbalance underlies specific subsets of patients with ASD. The studies to date are encouraging and support possible and promising pharmacological treatment options to improve functioning in individuals with ASD by targeting the glutamatergic and GABAergic systems. The author has no conflict of interests to report.

BackgroundIn response to COVID-19, there has been increasing momentum in telehealth development and delivery. To assess the anticipated exponential growth in telehealth, it is important to accurately capture how telehealth has been used in specific mental health fields prior to the pandemic.ObjectiveThis systematic review aimed to highlight how telehealth has been used with clinical samples in the neurodevelopmental field, including patients with neurodevelopmental disorders (NDDs), their families, and health care professionals. To identify which technologies show the greatest potential for implementation into health services, we evaluated technologies for effectiveness, economic impact, and readiness for clinical adoption.MethodsA systematic search of literature was undertaken in April 2018 and updated until December 2019, by using the Medline, Web of Science, Scopus, CINAHL Plus, EMBASE, and PsycInfo databases. Extracted data included the type of technology, how the technology was used (ie, assessment, treatment, and monitoring), participant characteristics, reported outcomes and authors’ views on clinical effectiveness, user impact (ie, feasibility and acceptability), economic impact, and readiness for clinic adoption. A quality review of the research was performed in accordance with the Oxford Centre for Evidence-Based Medicine Levels of Evidence.ResultsA total of 42 studies met the inclusion criteria. These studies included participants and family members with autism spectrum disorders (21/42, 50%), attention deficit hyperactivity disorders (8/42, 19%), attention deficit hyperactivity or autism spectrum disorders (3/42, 7%), communication disorders (7/42, 17%), and tic disorders (2/42, 5%). The focus of most studies (33/42, 79%) was on treatment, rather than assessment (4/42, 10%) or monitoring (5/42, 12%). Telehealth services demonstrated promise for being clinically effective, predominantly in relation to diagnosing and monitoring NDDs. In terms of NDD treatment, telehealth services were usually equivalent to control groups. There was some evidence of positive user and economic impacts, including increased service delivery efficiency (eg, increased treatment availability and decreased waiting times). However, these factors were not widely recorded across the studies. Telehealth was demonstrated to be cost-effective in the few studies that considered cost-effectiveness. Study quality varied, as many studies had small sample sizes and inadequate control groups. Of the 42 studies, only 11 (26%) were randomized controlled trials, 12 (29%) were case studies or case series, 6 (14%) were qualitative studies, and 5 (12%) were noncomparative trials.ConclusionsTelehealth has the potential to increase treatment availability, decrease diagnosis waiting times, and aid in NDD monitoring. Further research with more robust and adequately powered study designs that consider cost-effectiveness and increased efficiency is needed. This systematic review highlights the extent of telehealth technology use prior to the COVID-19 pandemic and the movement for investing in remote access to treatments.Trial RegistrationPROSPERO International Prospective Register of Systematic Reviews CRD42018091156; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018091156

Children diagnosed with auditory processing disorders (APD) experience difficulties in auditory functioning and with memory, attention, language, and reading tasks. However, it is not clear whether the behavioral characteristics of these children are distinctive from the behavioral characteristics of children diagnosed with a different developmental disorder, such as specific language impairment (SLI), dyslexia, attention-deficit hyperactivity disorder (ADHD), learning disorder (LD), or autism spectrum disorder. This study describes the performance of children diagnosed with APD, SLI, dyslexia, ADHD, and LD to different outcome measurements. The aim of this study was to determine (1) which characteristics of APD overlap with the characteristics of children with SLI, dyslexia, ADHD, LD, or autism spectrum disorder; and (2) if there are characteristics that distinguish children diagnosed with APD from children diagnosed with other developmental disorders. A systematic review. Six electronic databases (Pubmed, CINAHL, Eric, PsychINFO, Communication & Mass Media Complete, and EMBASE) were searched to find peer-reviewed studies from 1954 to May 2015. The authors included studies reporting behaviors and performance of children with (suspected) APD and children diagnosed with a different developmental disorder (SLI, Dyslexia, ADHD, and LD). Two researchers identified and screened the studies independently. Methodological quality of the included studies was assessed with the American Speech-Language-Hearing Association's levels-of-evidence scheme. In total, 13 studies of which the methodological quality was moderate were included in this systematic review. In five studies, the performance of children diagnosed with APD was compared with the performance of children diagnosed with SLI: in two with children diagnosed with dyslexia, one with children diagnosed with ADHD, and in another one with children diagnosed with LD. Ten of the studies included children who met the criteria for more than one diagnosis. In four studies, there was a comparison made between the performances of children with comorbid disorders. There were no studies found in which the performance of children diagnosed with APD was compared with the performance of children diagnosed with autism spectrum disorder. Children diagnosed with APD broadly share the same characteristics as children diagnosed with other developmental disorders, with only minor differences between them. Differences were determined with the auditory and visual Duration Pattern Test, the Children's Auditory Processing Performance Scale questionnaire, and the subtests of the Listening in Spatialized Noise-Sentences test, in which noise is spatially separated from target sentences. However, these differences are not consistent between studies and are not found in comparison to all groups of children with other developmental disorders. Children diagnosed with APD perform equally to children diagnosed with SLI, dyslexia, ADHD, and LD on tests of intelligence, memory or attention, and language tests. Only small differences between groups were found for sensory and perceptual functioning tasks (auditory and visual). In addition, children diagnosed with dyslexia performed poorer in reading tasks compared with children diagnosed with APD. The result is possibly confounded by poor quality of the research studies and the low quality of the used outcome measures. More research with higher scientific rigor is required to better understand the differences and similarities in children with various neurodevelopmental disorders.

Advances in Our Understanding of Genetic Risk Factors for Autism Spectrum Disorders

Wentz et al. (1) sought to investigate the prevalence of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD), in children recruited from a university outpatient clinic specializing in severe obesity. The authors also compared body mass index (BMI) and metabolic profile among the 76 children recruited. The results indicated that one-third of children (31.6%) recruited had at least one neurodevelopmental disorder. Girls diagnosed with ADHD/ASD had a higher BMI index compared with girls with no neurodevelopmental disorder. Moreover, nearly one-fifth of parents screened positive for ADHD which could complicate adherence to treatment regimens in obesity units. Interestingly, the finding that neurodevelopmental disorders are “highly over-represented” in children with obesity coincides with recent research implicating a role for air pollution in the etiology of these disorders. Fluegge (2) recently published a review outlining the possible role of environmental exposure to the air pollutant nitrous oxide (N2O) in the etiology of a range of neurodevelopmental disorders, including ADHD and ASD. The review of the N2O toxicity literature posits several mechanisms that may be responsible for this effect. First, subanalgesic N2O targets the reversible inhibition of the α7 nicotinic acetylcholine receptor (α7nAChR), a receptor widely found in the CNS and involved in long-term memory as well as food intake behavior. The α7nAChR has been shown to be downregulated in the subcutaneous adipose tissue and isolated mature adipocytes of human subjects with obesity, and a lifestyle intervention not only rescued this downregulation but also facilitated weight loss in these subjects (3). N2O is also an NMDA receptor antagonist, and central activation of the NMDA receptor may exert potent metabolic effects through a brain-liver axis to reduce glucose production (4), suggesting that chronic exposure to environmental N2O may challenge an endogenous protective mechanism against metabolic dysfunction. Furthermore, low-dose N2O exposure is also characterized by the endogenous release of the opioid peptide dynorphin, which acts upon its cognate opioid receptor, the kappa opioid receptor (KOR). Interestingly, Czyzyk et al. (5) reported that central activation of KOR may play an integral role in the metabolic adaptation to a high-energy diet in mice. KOR-knockout mice experienced improved glycemic control and a reduction in triglyceride synthesis in the liver, while wild-type mice experienced increases in body weight. The authors concluded that KOR activation may play a permissive role in the development of an obesogenic phenotype under conditions of a high-energy diet. Importantly, these endogenous pathways may have direct roles in facilitating adverse psychiatric and metabolic outcomes, potentially linking the finding that neurodevelopmental disorders are “highly over-represented” in obesity. Parents who are affected by similar conditions may lack the discipline to enforce strict dietary controls in their children with obesity, and this may further compound obesogenic risk profiles. Therefore, more attention should be paid to environmental air pollutants, like N2O, that may play a role in onset of neurodevelopmental disorders and accompanying metabolic co-morbid conditions, like obesity.

To investigate prevalence of neurodevelopmental disorders in children with obesity and to compare body mass index (BMI) and metabolic profile in the children. Seventy-six children (37 girls, 39 boys) were consecutively recruited from a university outpatient clinic specialized in severe obesity. Neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD) were assessed using interviews and questionnaires. Neurodevelopmental diagnoses were collected retrospectively in medical records. BMI ranged between 1.9 and 5.9 SDS and age between 5.1 and 16.5 years. In 13.2% and 18.4% ASD and ADHD was assigned, respectively. In addition, 25% screened positive for DCD, 31.6% had at least one neurodevelopmental disorder, and 18.4% had a parent who screened positive for adult ADHD. Girls with ASD/ADHD had higher BMI SDS than girls without neurodevelopmental disorder (P = 0.006). One third of children with obesity referred to specialist centers have a neurodevelopmental disorder including deviant motor skills, and these problems may deteriorate weight status. One fifth of the parents exhibit ADHD symptomatology which could partly explain the poor adherence by some families in obesity units. Future obesity therapy could benefit from incorporating a neurodevelopmental treatment approach.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8–12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders.

BackgroundPrevious studies examined the associations of gestational diabetes mellitus (GDM) with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the associations between GDM and other neurodevelopmental disorders (NDDs), such as the common speech/language disorder (SLD) and developmental coordination disorder (DCD), are rarely studied and whether the associations vary by race/ethnicity remains unknown. ObjectiveTo examine the associations of GDM with individual NDDs in young offspring and investigate whether the associations varied by race/ethnicity. Study DesignThis retrospective cohort study (Glucose in Relation to Women and Babies’ Health [GrownB]) included 14,480 mother-offspring pairs in a large medical center in the United States (US) from 3/1/2013 to 8/31/2021. We ascertained GDM using the validated International Classification of Disease (ICD) codes (ICD-9: 648.8x; ICD-10: O24.4x), and identified NDDs (SLD, DCD, ASD, and other NDDs [ADHD, behavioral disorder, intellectual disability, and learning difficulty]) and their combinations using validated algorithms. We compared the hazard of NDDs during the entire follow-up period between offspring born to mothers with and without GDM using multivariable Cox regression models. ResultsAmong all mothers, 19.9% were Asians, 21.8% were Hispanics, 41.0% were non-Hispanic Whites, and 17.3% were other/unknown race/ethnicity. During the median follow-up of 3.5 years (range: 1.0-6.3 years) after birth, 8.7% of offspring developed at least one NDD. GDM was associated with a higher risk of SLD (adjusted hazard ratio: 1.59 [95% confidence interval, 1.07, 2.35]), DCD (2.36 [1.37, 4.04]), ASD (3.16 [1.36, 7.37]), other NDDs (3.12 [1.51, 6.47]), any NDD (1.86 [1.36, 2.53]), combination of SLD and ASD (3.79 [1.35, 10.61]), and combination of SLD and DCD (4.22 [1.69, 10.51]) among offspring born to non-Hispanic White mothers. No associations between GDM and any NDDs or their combinations were observed among offspring born to mothers of other racial/ethnic groups. ConclusionsWe observed an elevated risk of NDDs in young offspring born to non-Hispanic White mothers with GDM, but not among other racial/ethnic groups.

Background/Objectives: Autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS) are neurodevelopmental disorders (NDDs) with overlapping symptoms, suggesting a partially shared genetic origin. This study investigates the prevalence of connective tissue-related conditions in individuals with ASD, ADHD, or TS. Methods: A questionnaire was administered to families of 120 individuals with ASD, ADHD, or TS, collecting sociodemographic data and examining 10 types of disorders affecting various organs and systems. Statistical analyses were performed using STATA 16.0, with the significance level set at 5%. Results: Among the 120 patients, 48 had ASD, 36 had ADHD, and 36 had TS. Flat feet were significantly more common in individuals with ASD (52.1%; OR 7.20; p < 0.001), ADHD (52.8%; OR 6.73; p = 0.001), and TS (38.9%; OR 3.70; p = 0.034) compared to controls (13.6%). Hypersensitivity was more frequent in individuals with ASD (56.3%; OR 5.90; p = 0.001), ADHD (50.0%; OR 4.11; p = 0.011), and TS (58.3%; OR 5.35; p = 0.003) compared to controls (18.2%). Myopia and ptosis were more common in ADHD (30.6%). There was a possible trend towards orthodontic device use in TS (OR 3.20; p = 0.076). Flat feet and hypersensitivity were also common in fathers (31.0% and 36.4%, respectively), mothers (31.0% and 15.2%), and patients (43.8% and 55%). Conclusions: The findings of this study highlight the significant associations between ASD, ADHD, and TS and specific physical symptoms, such as flat feet, sensory hypersensitivity, and other connective tissue-related manifestations. The familial prevalence of these symptoms suggests a potential genetic underpinning, further supporting the hypothesis of shared aetiological pathways. These insights underscore the need for interdisciplinary research to explore the mechanisms linking neurodevelopmental and connective tissue disorders, aiming to improve diagnosis and management strategies.

Noonan syndrome (NS) is a RASopathy, a group of genetic disorders caused by alterations in the RAS/MAPK signalling pathway, and is associated with brain-related disorders, including intellectual developmental disorder (IDD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), epilepsy, and depression and anxiety. However, estimates of prior prevalence vary widely. The aim of this systematic review and meta-analysis was to estimate the prevalence of brain-related disorders (i.e., IDD, ASD, ADHD, epilepsy, and depression and anxiety) in NS. A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted from inception to July 2025. Studies that estimated the prevalence of IDD, ASD, ADHD, epilepsy, and depression and anxiety in the population with NS were included. Genotype was considered when possible. Random-effects meta-analyses of prevalence, expressed as proportions (0-1) and their 95% confidence intervals (95% CI), were performed. Twenty-one studies were included in the systematic review, while 20 were included in the meta-analysis. The IDD prevalence was 0.23 (95% CI: 0.12, 0.35), the ASD prevalence was 0.11 (95% CI: 0.05, 0.17); the ADHD prevalence was 0.31 (95% CI: 0.22, 0.41); the epilepsy prevalence was 0.09 (95% CI: 0.03, 0.15) and the depression and anxiety prevalence was 0.23 (95% CI: 0.08, 0.39). There was hardly any genotype-specific data, particularly for minor mutations. NS is strongly associated with brain-related disorders, which reinforces the need for early and periodic screening in this population. Furthermore, genotype-phenotype correlation studies are required, as there is currently little evidence in this area. What is Known: • Noonan syndrome is a RASopathy characterised by short stature, heart disease and brain-related disorders. • Brain-related disorders include intellectual developmental disorder (IDD), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), among others. What is New: • IDD, ASD and ADHD were estimated to affect 23%, 11% and 31% of individuals, respectively. This is higher than the prevalence in the general population. • The prevalence of seizure disorders and emotional disorders was also high, although the evidence was more limited.

How to advance the understanding of multimorbidity in neurodevelopmental disorders using longitudinal research?