Journal of Neurodevelopmental Disorders最新文献

Background: Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment.

Methods: We longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using the Repetitive Behavior Scale - Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs.

Results: Results identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs.

Conclusions: Findings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels, which has important implications for early and targeted interventions.

Introduction: Rett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT.

Methods: This is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression.

Results: Data were available for 365 individuals with RTT [median (range) age 17.8 (2.9-51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores.

Conclusion: Except for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.

Background: Recent studies have suggested an increasing prevalence of intellectual disability diagnoses in some countries. Our aim was to describe the trend in the prevalence of intellectual disability diagnoses in Sweden and explore whether associated sociodemographic and perinatal factors can explain changes in the prevalence.

Methods: We used a register-based nationwide cohort of residents in Sweden born between 2001 and 2011. We calculated the prevalence of intellectual disability diagnoses by age 10 for each birth cohort and the prevalence ratios in relation to the baseline year 2011, overall and by severity of intellectual disability, and comorbidity of autism and attention-deficit/hyperactivity disorder. The prevalence ratios were stratified and adjusted for associated sociodemographic and perinatal factors.

Results: Among 1,096,800 individuals, 8,577 were diagnosed with intellectual disability by age 10. Among these, 3,949 (46%) and 2,768 (32%) were also diagnosed with autism and attention-deficit/hyperactivity disorder, respectively, and 4% were diagnosed with profound, 8% severe, 20% moderate, 52% mild, and 16% other/unspecific intellectual disability. The recorded age-10 prevalence of intellectual disability diagnoses increased from 0.64% (95% confidence interval 0.59-0.69%) in 2011 to 1.00% (0.94-1.06%) in 2021, corresponding to an annual prevalence ratio of 1.04 (1.04-1.05). The increase was, however, restricted to mild, moderate, and other/unspecific intellectual disability diagnoses, while the trends for profound and severe intellectual disability diagnoses were stable. The increasing trend was perhaps less pronounced among females and children with diagnosed attention-deficit/hyperactivity disorder, but independent of the co-occurrence of autism. The prevalence ratios did not change with stratification or adjustment for other associated demographic and perinatal factors.

Conclusion: The recorded prevalence of diagnosed mild and moderate intellectual disability among 10-year-olds in Sweden has increased over the recent decade. This increase could not be explained by changes in associated sociodemographic or perinatal factors, including birth weight, gestational age, and parental age, migration status, and education at the child's birth. The increase instead may be due to changes in diagnostic practices in Sweden over time.

Background: Do different genetic disorders impart different psychiatric risk profiles? This question has major implications for biological and translational aspects of psychiatry, but has been difficult to tackle given limited access to shared batteries of fine-grained clinical data across genetic disorders.

Methods: Using a new suite of generalizable analytic approaches, we examine gold-standard diagnostic ratings, scores on 66 dimensional measures of psychopathology, and measures of cognition and functioning in two different sex chromosome aneuploidies (SCAs)-Klinefelter (XXY/KS) and XYY syndrome (n = 102 and 64 vs. n = 74 and 60 matched XY controls, total n = 300). We focus on SCAs for their high collective prevalence, informativeness regarding differential X- vs. Y-chromosome effects, and potential relevance for normative sex differences.

Results: We show that XXY/KS elevates rates for most psychiatric diagnoses as previously reported for XYY, but disproportionately so for anxiety disorders. Fine-mapping across all 66 traits provides a detailed profile of psychopathology in XXY/KS which is strongly correlated with that of XYY (r = .75 across traits) and robust to ascertainment biases, but reveals: (i) a greater penetrance of XYY than KS/XXY for most traits except mood/anxiety problems, and (ii) a disproportionate impact of XYY vs. XXY/KS on social problems. XXY/KS and XYY showed a similar coupling of psychopathology with adaptive function and caregiver strain, but not IQ.

Conclusions: This work provides new tools for deep-phenotypic comparisons of genetic disorders in psychiatry and uses these to detail unique and shared effects of the X- and Y-chromosome on human behavior.

Background: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD).

Objectives: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels.

Methods: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC.

Results: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001).

Conclusions: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Background: Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD.

Methods: The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children.

Results: The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016).

Conclusions: The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development.

Background: Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion.

Methods: Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2-4 and 8-12 years) participated in a low-level stress task whilst wearing a wireless electrocardiogram. Children's negative emotional expressions (facial, vocal, bodily) were coded following standardized protocols. Alexithymia traits were assessed using the Children's Alexithymia Measure with school-aged children only. Data analyses involved ANOVAs, correlations, and sensitivity analyses.

Results: There were no group differences in physiological arousal (heart rate) or in communicative expressions of stress to the stress task. For TD preschoolers, physiological arousal during the stress task was associated with vocal expressions and for TD school-aged children, they were associated with facial and bodily expressions. By contrast, for children on the autism spectrum, physiological arousal during the stress tasks was not associated with communicative expressions across age groups.

Conclusions: Our findings suggest that children on the autism spectrum might experience emotional disconcordance, in that their physiological arousal does not align with their communicative expressions. Therefore, the internally experienced stress of children on the autism spectrum may be inadvertently missed by teachers and caregivers and, consequently, learning opportunities for teaching emotional communication and regulation may be also missed. Our results support the use of wearable biosensors to facilitate such interventions in children on the autism spectrum.