FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder.

Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss-of-function by disrupting FIBCD1-CS-4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor-related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal-dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.

Gastrointestinal dysfunctions as a risk factor for sleep disorders in children with idiopathic autism spectrum disorder: A retrospective cohort study.

Sleep disorders often co-occur with autism spectrum disorder. They further exacerbate autism spectrum disorder symptoms and interfere with children's and parental quality of life. This study examines whether gastrointestinal dysfunctions increase the odds of having sleep disorders in 610 children with idiopathic autism spectrum disorder, aged 2-18 years, from the Autism Genetic Resource Exchange research program. The adjusted odds ratio for sleep disorder among those with gastrointestinal dysfunctions compared to those without was 1.74 (95% confidence interval: 1.22-2.48). In addition, the odds of having multiple sleep disorder symptoms among children with gastrointestinal dysfunctions, adjusted for age, gender, behavioral problems, bed wetting, current and past supplements, and current and past medications for autism spectrum disorder symptoms were 1.75 (95% confidence interval: 1.10-2.79) compared to children without gastrointestinal dysfunctions. Early detection and treatment of gastrointestinal dysfunctions in autism spectrum disorder may be means to reduce prevalence and severity of sleep problems and improve quality of life and developmental outcomes in this population.

Ostracism and Peer Victimization in Adolescents With and Without Mental Health Diagnoses in a Public Middle School Setting.

To better understand adolescents experiencing peer victimization, ostracism, and emotional health problems, this study aimed to describe a cohort of middle school students identified as having school peer-related social difficulties as 2 groups: those with mental health diagnoses (MHDs; n = 17) and those without diagnoses (n = 8). Participants were administered a test battery to examine communication ability, social responsiveness, social activity, ostracism, victimization, and emotional health. Results showed that adolescents with MHDs, relative to those without, scored significantly lower on measures of communication ability, social responsiveness, and social activity but similarly on measures of victimization, ostracism, and internalizing/externalizing factors. Results suggest that adolescents with and without MHDs can endure ostracism and peer victimization to a similar extent. Because ostracism and victimization have serious morbidity in adolescents, physicians and caregivers must look for signs in all adolescents, irrespective of MHD. Recommendations for appropriate primary care management are discussed.

Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study.

BACKGROUND: Autism spectrum disorder (ASD) is a heterogeneous disorder characterized not only by deficits in communication and social interactions but also a high rate of co-occurring disorders, including metabolic abnormalities, gastrointestinal and sleep disorders, and seizures. Seizures, when present, interfere with cognitive development and are associated with a higher mortality rate in the ASD population. METHODS: To determine the relative prevalence of non-febrile seizures in children with idiopathic ASD from multiplex and simplex families compared with the unaffected siblings in a cohort of 610 children with idiopathic ASD and their 160 unaffected siblings, participating in the Autism Genetic Resource Exchange project, the secondary analysis was performed comparing the life-time prevalence of non-febrile seizures. Statistical models to account for non-independence of observations, inherent with the data from multiplex families, were used in assessing potential confounding effects of age, gender, and history of febrile seizures on odds of having non-febrile seizures. RESULTS: The life-time prevalence of non-febrile seizures was 8.2% among children with ASD and 2.5% among their unaffected siblings. In a logistic regression analysis that adjusted for familial clustering, children with ASD had 5.27 (95%CI: 1.51-18.35) times higher odds of having non-febrile seizures compared to their unaffected siblings. In this comparison, age, presence of gastrointestinal dysfunction, and history of febrile seizures were significantly associated with the prevalence of non-febrile seizures. CONCLUSION: Children with idiopathic ASD are significantly more likely to have non-febrile seizures than their unaffected siblings, suggesting that non-febrile seizures may be ASD-specific. Further studies are needed to determine modifiable risk factors for non-febrile seizures in ASD.

A Rare Recurrent 4q25 Proximal Deletion Not Involving the PITX2 Gene: A Genomic Disorder Distinct from Axenfeld-Rieger Syndrome.

Haploinsufficient microdeletions within chromosome 4q25 are often associated with Axenfeld-Rieger syndrome. A de novo 4q25 deletion, 675 kb proximal to PITX2, has previously been reported once in an adult patient. The patient did not have Axenfeld-Rieger anomaly, but instead had intellectual disability and a complex behavioral phenotype with withdrawn, stereotypic, and ritualistic behavior. Array comparative genome hybridization demonstrated a smaller, overlapping 4q25 deletion in a 2-year-old patient and his mother, both having significant phenotypic overlap with the initially reported patient. All 3 patients have distinct facial features (including mild hypotelorism and subtle mandibular asymmetry), developmental delay, and complex behavioral difficulties. A genotype-phenotype correlation narrows the shared phenotype to a common COL25A1 gene aberration and proposes that the concurrent EGF gene loss has a significant impact on the phenotypic severity. Overall, our patients provide data to support the existence of a novel 4q25 proximal deletion syndrome.

Patterns of Gesture Use in Adolescents With Autism Spectrum Disorder.

PURPOSE: The purpose of this study was to examine patterns of spontaneous gesture use in a sample of adolescents with autism spectrum disorder (ASD). METHOD: Thirty-five adolescents with ASD ages 11 to 16 years participated (mean age = 13.51 years; 29 boys, 6 girls). Participants' spontaneous speech and gestures produced during a narrative task were later coded from videotape. Parents were also asked to complete questionnaires to quantify adolescents' general communication ability and autism severity. RESULTS: No significant subgroup differences were apparent between adolescents who did not gesture versus those who produced at least 1 gesture in general communication ability and autism severity. Subanalyses including only adolescents who produced gesture indicated a statistically significant negative association between gesture rate and general communication ability, specifically speech and syntax subscale scores. Adolescents who gestured produced higher proportions of iconic gestures and used gesture mostly to add information to speech. CONCLUSIONS: The findings relate spontaneous gesture use to underlying strengths and weaknesses in adolescents' speech and syntactical language development. More research examining cospeech gesture in fluent speakers with ASD is needed.

A Few Close Friends: The Pediatrician's Role in the Management of Social Skills Deficits in Adolescent Children.

Pediatricians must recognize and respond to adolescents with social skills deficits because they are at heightened risk for mental health disorders, peer victimization, and social isolation. The aim of this project was to describe a group of adolescent children at the time of enrollment into social skills treatment. Ninety participants with neurodevelopmental weaknesses or disorders, to include high-functioning autism spectrum disorder, participated. Results showed that adolescents referred for social skills deficits had communication weaknesses and concerns in everyday social reciprocal behavior. They rarely hosted get-togethers with same-aged peers and were not often invited by same-aged peers to get-togethers. Twenty-nine percent of participants reported that they were victims of bullying, and more than half of participants reported clinically significant ostracism experiences. Results are discussed in terms of the pediatrician's role in the prevention, identification, and treatment of social skills deficits in light of recent research showing brain neuroplasticity extending into adolescence.

An intragenic deletion of the gene MNAT1 in a family with pectus deformities.

Pectus carinatum and excavatum have multiple genetic associations. We report on a novel association of these deformities in a 34-month-old male and his father, likely due to a small intragenic deletion of MNAT1 (ménage a trois 1 gene). Both individuals share a deletion of MNAT1 located at 14q23.1 and an interstitial duplication of CHRNA7 located at 15q13.3. Deletion of MNAT1 has been associated with connective tissue abnormalities and is likely the etiology of the malformations, whereas the duplication of CHNRA7 is unlikely related due to the lack of association with any such connective tissue abnormalities.

Bullying and ostracism experiences in children with special health care needs.

OBJECTIVE: Bullying experiences are becoming increasingly common in children and can have devastating consequences. Ostracism threatens a child's need for self-esteem, sense of belonging, sense of control, and meaningful existence. Recent literature suggests that children with special health care needs may be at risk for these negative events and consequences. This study compares bullying and ostracism experiences in children with and without various special health care needs. METHODS: Participants aged 8 to 17 years completed questionnaires during a routine primary care or subspecialty clinic visit. Children with learning disabilities (N = 34), attention deficit or hyperactivity disorder (N = 100), autism spectrum disorders (N = 32), behavioral or mental health disorders (N = 33), and cystic fibrosis (CF, N = 22) were compared with 73 control children with no diagnosis on Reynolds' Bully-Victimization Scale scores and a 15-item pilot ostracism scale. RESULTS: Compared with the control group, children in the learning disabilities, autism spectrum disorders, and attention deficit or hyperactivity disorder groups exhibited significant victimization scores on the Bully-Victimization Scale, whereas the behavioral or mental health disorders group had increased mean victimization scores. The learning disabilities group also reported clinically significant bullying. The CF group did not report involvement as bullies or victims. All children with special health care needs groups had increased mean frequency of threats to basic needs related to ostracism, and children with attention deficit or hyperactivity disorder and autism spectrum disorders were at higher risk for ostracism experiences. CONCLUSION: Children with special health care needs may be at higher risk for bullying, victimization, and ostracism. Further research is needed to explore this relationship, especially as it relates to child adjustment. Children with special health care needs should be asked about bullying and ostracism experiences and potential effects as part of mental health screening.