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1.  Pupillometry Reveals a Mechanism for the Autism Spectrum Disorder (ASD) Advantage in Visual Tasks 
Scientific Reports  2014;4:4301.
Research on the neural underpinnings of Autism Spectrum Disorder (ASD) has focussed primarily on impairments of social interaction and communication. Less is known though about the second diagnostic criterion of restricted behaviors and interests. Uniquely in this domain, alongside impairments stands an ‘ASD advantage' characterised by superior performance on many visual tasks. We recently found that 2-year-olds with ASD dramatically outperform age-matched, typically developing controls on visual search. Here we use task-evoked, phasic pupil responses – a sensitive, involuntary measure of effort and a biomarker of the locus coeruleus-norepinephrine (LC-NE) system's modulation of attention – to isolate a causal factor: a ‘hyperphasic' LC-NE system compels (here, advantageously) focussed attention. However, this focussed attention in other contexts may contribute to restricted behaviors and interests.
PMCID: PMC3945923  PMID: 24603348
2.  Beyond Autism: A Baby Siblings Research Consortium Study of High-Risk Children at Three Years of Age 
First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD.
Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ).
At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings.
Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children.
PMCID: PMC3625370  PMID: 23452686
ASD; high-risk siblings; outcome; broad autism phenotype
3.  Predicting Mothers’ Reports of Children’s Mental Health Three Years after Hurricane Katrin 
This study explored pathways through which hurricane-related stressors affected the psychological functioning of elementary school aged children who survived Hurricane Katrina. Participants included 184 mothers from the New Orleans area who completed assessments one year pre-disaster (Time 1), and one and three years post-disaster (Time 2 and Time 3, respectively). Mothers rated their children’s behavior problems at Time 3 only (n = 251 children; 53.0% male; Mean age: 10.19 years, SD = 1.68 years). A path analytic model indicated that hurricane-related stressors were associated with increased maternal psychological distress and school mobility in the first post-disaster year, which were associated with higher child internalizing and externalizing symptoms three years post-disaster. Mediation analysis indicated that hurricane-related stressors were associated with child symptoms indirectly, through their impact on maternal psychological distress. Findings underscore the importance of interventions that boost maternal and child mental health and support children through post-disaster school transitions.
PMCID: PMC3587107  PMID: 23471125
natural disasters; elementary school students; low-income families; maternal psychological distress; child behavior problems
4.  Screening Accuracy and Clinical Application of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA) 
PLoS ONE  2013;8(8):e72602.
The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) is a promising questionnaire for the early detection of psychosocial problems in toddlers. The screening accuracy and clinical application were evaluated.
In a community sample of 2-year-olds (N = 2060), screening accuracy of the BITSEA Problem scale was examined regarding a clinical CBCL1.5-5 Total Problem score. For the total population and subgroups by child’s gender and ethnicity Receiver Operating Characteristic (ROC) curves were calculated, and across a range of BITSEA Problem scores, sensitivity, specificity, likelihood ratio’s, diagnostic odds ratio and Youden’s index. Clinical application of the BITSEA was examined by evaluating the relation between the scale scores and the clinical decision of the child health professional.
The area under the ROC curve (95% confidence interval) of the Problem scale was 0.97(0.95–0.98), there were no significant differences between subgroups. The association between clinical decision and BITSEA Problem score (B = 2.5) and Competence score (B = −0.7) was significant (p<0.05).
The results indicate that the BITSEA Problem scale has good discriminative power to differentiate children with and without psychosocial problems. Referred children had less favourable scores compared to children that were not referred. The BITSEA may be helpful in the early detection of psychosocial problems.
PMCID: PMC3758314  PMID: 24023626
5.  Putting Theory to the Test: Modeling a Multidimensional, Developmentally-Based Approach to Preschool Disruptive Behavior 
There is increasing emphasis on dimensional conceptualizations of psychopathology but empirical evidence of their utility is just emerging. In particular, while a range of multidimensional models have been proposed, the relative fit of competing models has rarely been tested. Further, developmental considerations have received scant attention. In this paper, we test a developmentally-based 4-dimension model of disruptive behavior theorized to represent the defining features of disruptive behavior at preschool age: Temper Loss, Noncompliance, Aggression, and Low Concern for Others.
Model testing was conducted in two independent samples of preschoolers: Clinically-Enriched (N=336) and Epidemiologic (N=532). Tau-equivalent confirmatory factor analyses were used to test the fit of the Developmental Model relative to 3 leading competing models (DSM ODD/CD Model, “Callous” Model and an “Irritable/Headstrong/Hurtful” Model). Reliability of the 4 dimensions was also tested. Validity of the dimensions was tested by predicting multi-informant, multi-method ratings of disruptive behavior and impairment, and incremental utility relative to DSM symptoms.
In both samples, the Developmental Model demonstrated a superior fit compared to the competing models within the full sample, and across key demographic sub-groups. Validity was also demonstrated, including incremental utility relative to DSM-IV disruptive behavior symptoms.
Critical next steps for achieving scientific consensus about the optimal dimensional model of disruptive behavior and its clinical application are discussed.
PMCID: PMC3674547  PMID: 22632619
disruptive behavior; developmental psychopathology; dimensional; early childhood; preschool behavior problems
6.  Defining the developmental parameters of temper loss in early childhood: implications for developmental psychopathology 
Temper modulation problems are both a hallmark of early childhood and a common mental health concern. Thus, characterizing specific behavioral manifestations of temper loss along a dimension from normative misbehaviors to clinically significant problems is an important step toward identifying clinical thresholds.
Parent-reported patterns of temper loss were delineated in a diverse community sample of preschoolers (n = 1,490). A developmentally sensitive questionnaire, the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), was used to assess temper loss in terms of tantrum features and anger regulation. Specific aims were: (a) document the normative distribution of temper loss in preschoolers from normative misbehaviors to clinically concerning temper loss behaviors, and test for sociodemographic differences; (b) use Item Response Theory (IRT) to model a Temper Loss dimension; and (c) examine associations of temper loss and concurrent emotional and behavioral problems.
Across sociodemographic subgroups, a unidimensional Temper Loss model fit the data well. Nearly all (83.7%) preschoolers had tantrums sometimes but only 8.6% had daily tantrums. Normative misbehaviors occurred more frequently than clinically concerning temper loss behaviors. Milder behaviors tended to reflect frustration in expectable contexts, whereas clinically concerning problem indicators were unpredictable, prolonged, and/or destructive. In multivariate models, Temper Loss was associated with emotional and behavioral problems.
Parent reports on a developmentally informed questionnaire, administered to a large and diverse sample, distinguished normative and problematic manifestations of preschool temper loss. A developmental, dimensional approach shows promise for elucidating the boundaries between normative early childhood temper loss and emergent psychopathology.
PMCID: PMC3633202  PMID: 22928674
Developmental psychopathology; temper tantrums; disruptive behavior; preschool psychopathology; dimensional
7.  Parsing the Effects Violence Exposure in Early Childhood: Modeling Developmental Pathways 
Objective To prospectively examine pathways from early childhood violence exposure and trauma-related symptoms to school-age emotional health. Methods A longitudinal, birth cohort (N = 437) was assessed with parent reports of lifetime violence exposure and trauma-related symptoms at 3 years of age and later, internalizing and externalizing symptoms, and social competence at school age. Results Early family and neighborhood violence correlated significantly with early trauma-related symptoms and also significantly predicted school-age internalizing and externalizing symptoms and poorer competence, independent of sociodemographic risk and past-year violence exposure. Longitudinal pathways were significantly mediated by arousal and avoidance symptoms at 3 years of age, which increased risk for clinically significant emotional problems and lower competence at school age (adjusted odds ratios = 3.1–6.1, p < 0.01). Conclusions Trauma-related symptoms may mediate developmental pathways from early violence exposure to later emotional health. Interventions that prevent or reduce early trauma-related symptoms may ameliorate the long-term deleterious impact of violence exposure.
PMCID: PMC3263769  PMID: 21903730
longitudinal; post-traumatic stress; preschool; trauma; violence
8.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study 
Pediatrics  2011;128(3):e488-e495.
The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.
A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.
A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.
The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.
PMCID: PMC3164092  PMID: 21844053
autism; recurrence; sibling risk
9.  Toddlers with Autism Spectrum Disorder are more successful at visual search than typically developing toddlers 
Developmental science  2011;14(5):980-988.
Plaisted, O’Riordan and colleagues (Plaisted, O’Riordan & Baron-Cohen, 1998; O’Riordan, 2004) showed that school-age children and adults with Autism Spectrum Disorder (ASD) are faster at finding targets in certain types of visual search tasks than typical controls. Currently though, there is very little known about the visual search skills of very young children (1–3-year-olds) – both typically developing or with ASD. We used an eye-tracker to measure looking behavior, providing fine-grained measures of visual search in 2.5-year-old toddlers with and without ASD (this representing the age by which many children may first receive a diagnosis of ASD). Importantly, our paradigm required no verbal instructions or feedback, making the task appropriate for toddlers who are pre- or nonverbal. We found that toddlers with ASD were more successful at finding the target than typically developing, age-matched controls. Further, our paradigm allowed us to estimate the number of items scrutinized per trial, revealing that for large set size conjunctive search, toddlers with ASD scrutinized as many as twice the number of items as typically developing toddlers, in the same amount of time.
PMCID: PMC3177163  PMID: 21884314
10.  Reliability and Validity of the Dutch Version of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA) 
PLoS ONE  2012;7(6):e38762.
The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) is a relatively new and short (42-item) questionnaire that measures psychosocial problems in toddlers and consists of a Problem and a Competence scale. In this study the reliability and validity of the Dutch version of the BITSEA were examined for the whole group and for gender and ethnicity subgroups.
Parents of 7140 two-year-old children were invited in the study, of which 3170 (44.4%) parents completed the BITSEA. For evaluation of the score distribution, the presence of floor/ceiling effects was determined. The internal consistency (Cronbach's alpha) was evaluated and in subsamples the test-retest, parent-childcare provider interrater reliability and concurrent validity with regard to the Child Behavioral Checklist (CBCL). Discriminative validity was evaluated by comparing scores of parents that worry and parents that do not worry about their child's development.
The BITSEA showed no floor or ceiling effects. Psychometric properties of the BITSEA Problem and Competence scale were respectively: Cronbach's alphas were 0.76 and 0.63. Test-retest correlations were 0.75 and 0.61. Interrater reliability correlations were 0.30 and 0.17. Concurrent validity was as hypothesised. The BITSEA was able to discriminate between parents that worry about their child and parents that do not worry. The psychometric properties of the BITSEA were comparable across gender and ethnic background.
The results in this large-scale study of a diverse sample support the reliability and validity of the BITSEA Problem scale. The BITSEA Competence scale needs further study. The performance of the BITSEA appears to be similar in subgroups by gender and ethnic background.
PMCID: PMC3371000  PMID: 22715411
11.  Autism Spectrum Disorders in Young Children 
PMCID: PMC3166636  PMID: 19486843
Autism; Young children; Early diagnosis; Early intervention; Family
12.  Prevalence of DSM-IV Disorder in a Representative, Healthy Birth Cohort at School Entry: Sociodemographic Risks and Social Adaptation 
The aims of this paper are as follows: to present past-year prevalence data for DSM-IV disorders in the early elementary school years; to examine the impact of impairment criteria on prevalence estimates; to examine the relation of sociodemographic and psychosocial risk factors to disorders; and to explore associations between ”internalizing” and ”externalizing” disorders and social competence and family burden as further validation of the impairing nature of these disorders.
As part of a longitudinal representative population study of children born healthy between July 1995 and September 1997 in the New Haven–Meriden Standard Metropolitan Statistical Area of the 1990 Census (n = 1,329), parents of a subsample enriched for child psychopathology (n = 442; 77.6% response rate, 69.5% of eligible sample) were interviewed in the child's kindergarten or first-grade year with the Diagnostic Interview Schedule for Children, Version IV (DISC-IV). Parents were surveyed about sociodemographic and psychosocial characteristics, and both parents and teachers were surveyed about social competence.
Approximately one in five (21.6 %) children met criteria for psychiatric disorder(s) with impairment. Sociodemographic and psychosocial correlates included persistent poverty beginning in early childhood, limited parental education, low family expressiveness, stressful life events, and violence exposure. Finally, diagnostic status was significantly associated with poorer social competence and family burden.
That approximately one in five children evidenced a psychiatric disorder with impairment during the transition to formal schooling highlights the importance of integrating psychiatric epidemiological and developmental approaches to inform conversations about school readiness and intervention planning.
PMCID: PMC3166638  PMID: 20610138
child psychiatric disorders; prevalence; social competence; family burden; impairment
13.  Evaluation of an early detection tool for social-emotional and behavioral problems in toddlers: The Brief Infant Toddler Social and Emotional Assessment - A cluster randomized trial 
BMC Public Health  2011;11:494.
The prevalence of social-emotional and behavioral problems is estimated to be 8 to 9% among preschool children. Effective early detection tools are needed to promote the provision of adequate care at an early stage. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) was developed for this purpose. This study evaluates the effectiveness of the BITSEA to enhance social-emotional and behavioral health of preschool children.
Methods and Design
A cluster randomized controlled trial is set up in youth health care centers in the larger Rotterdam area in the Netherlands, to evaluate the BITSEA. The 31 youth health care centers are randomly allocated to either the control group or the intervention group. The intervention group uses the scores on the BITSEA and cut-off points to evaluate a child's social-emotional and behavioral health and to decide whether or not the child should be referred. The control group provides care as usual, which involves administering a questionnaire that structures the conversation between child health professionals and parents. At a one year follow-up measurement the social-emotional and behavioral health of all children included in the study population will be evaluated.
It is hypothesized that better results will be found, in terms of social-emotional and behavioral health in the intervention group, compared to the control group, due to more adequate early detection, referral and more appropriate and timely care.
Trial registration
Current Controlled Trials NTR2035
PMCID: PMC3146861  PMID: 21702936
14.  Exposure to potentially traumatic events in early childhood: differential links to emergent psychopathology 
To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children.
Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family violence and non-interpersonal events) and recent stressful life events were assessed with the Preschool Age Psychiatric Assessment (PAPA) and Child Life Events Scale. Child psychiatric symptoms and disorders were assessed with parent-reports in the PAPA, a comprehensive, developmentally sensitive interview. Sociodemographic risk, parental anxiety and depressive symptoms (Center for Epidemiologic Studies Depression, Beck Anxiety Inventory), and child developmental level (Mullen Scales of Early Learning) also were assessed.
Violence exposure was broadly associated with psychiatric status in the areas of depression, separation anxiety, posttraumatic stress, and conduct problems, whereas potentially traumatic non-interpersonal exposure was associated with phobic anxiety. The majority of the associations between violence exposure and preschoolers’ symptoms were significant even when other key factors, including economic disadvantage and parental mood and anxiety symptoms, were controlled statistically. However, parental depressive/anxious symptoms may have partially or fully mediated the relationships between violence exposure and depressive and conduct symptoms.
Evidence of robust associations between violence exposure and early childhood internalizing and externalizing disorders and symptoms highlights the need for longitudinal prospective research concerning neurodevelopmental mechanisms and pathways. Findings underscore the relevance of assessing trauma exposure, particularly interpersonal violence, to identify young children at risk.
PMCID: PMC3106304  PMID: 20840502
Early childhood; symptoms; disorders; posttraumatic stress; violence; contextual risk
15.  Social-Emotional Screening Status in Early Childhood Predicts Elementary School Outcomes 
Pediatrics  2008;121(5):957-962.
The goal was to examine whether children who screen positive for social-emotional/behavioral problems at 12 to 36 months of age are at elevated risk for social-emotional/behavioral problems in early elementary school.
The sample studied (N = 1004) comprised an ethnically (33.3% minority) and socioeconomically (17.8% living in poverty and 11.3% living in borderline poverty) diverse, healthy, birth cohort from a metropolitan region of the northeastern United States. When children were 12 to 36 months of age (mean age: 23.8 months; SD: 7.1 months), parents completed the Brief Infant-Toddler Social and Emotional Assessment and questions concerning their level of worry about their child’s behavior, emotions, and social development. When children were in early elementary school (mean age: 6.0 years; SD: 0.4 years), parents completed the Child Behavior Checklist and teachers completed the Teacher Report Form regarding behavioral problems. In a subsample (n = 389), parents reported child psychiatric status.
Brief Infant-Toddler Social and Emotional Assessment screen status and parental worry were associated significantly with school-age symptoms and psychiatric disorders. In multivariate analyses that included Brief Infant-Toddler Social and Emotional Assessment status and parental worry, Brief Infant-Toddler Social and Emotional Assessment scores significantly predicted all school-age problems, whereas worry predicted only parent reports with the Child Behavior Checklist. Children with of-concern scores on the problem scale of the Brief Infant-Toddler Social and Emotional Assessment were at increased risk for parent-reported subclinical/clinical levels of problems and for psychiatric disorders. Low competence scores predicted later teacher-reported subclinical/clinical problems and parent-reported disorders. Worry predicted parent-reported subclinical/clinical problems. Moreover, the Brief Infant-Toddler Social and Emotional Assessment identified 49.0% of children who exhibited subclinical/clinical symptoms according to teachers and 67.9% of children who later met the criteria for a psychiatric disorder.
Screening with a standardized tool in early childhood has the potential to identify the majority of children who exhibit significant emotional/behavioral problems in early elementary school.
PMCID: PMC3088107  PMID: 18450899
screening; medical home; behavioral problems; Brief Infant-Toddler Social and Emotional Assessment; parental concern
16.  A Replication of the Autism Diagnostic Observation Schedule (ADOS) Revised Algorithms 
To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282).
Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment.
Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified.
Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.
PMCID: PMC3057666  PMID: 18434924
autism; pervasive developmental disorders not otherwise specified; Autism Diagnostic Observation Schedule; diagnosis
17.  Persistence of Maternal Depressive Symptoms throughout the Early Years of Childhood 
Journal of Women's Health  2009;18(5):637-645.
The purpose of these analyses was to examine the persistence and predictors of elevated depressive symptoms in 884 women over their children's preschool years.
Depressive symptoms in women with young children are surprisingly consistent throughout their children's preschool years. Of the 82.6% of women without elevated depressive symptoms at the initial assessment (study child was 11–42 months of age), 82.4% remained without symptoms over two follow-up assessments. Of 17.4% of women with elevated symptoms at baseline, 35.6% had elevated symptoms at one of the two follow-ups, and 27.4% had elevated symptoms at both follow-ups. Persistently elevated depressive symptoms were related to low education, high levels of anxiety, high parenting distress, and low levels of emotional support at baseline.
Women who report symptoms of depression when their children are young are highly likely to continue to report such symptoms. These results support the need to screen for elevated depressive symptoms at varying intervals depending on prior screening results and for screening in locations where women most at risk routinely visit, such as well-child clinics. Further, these results point to the need for a system to identify and manage this common treatable condition because these elevated symptoms continue throughout their children's preschool years for a substantial portion of women.
PMCID: PMC2858294  PMID: 19445615
18.  Clinical Assessment and Management of Toddlers With Suspected Autism Spectrum Disorder: Insights From Studies of High-Risk Infants 
Pediatrics  2009;123(5):1383-1391.
With increased public awareness of the early signs and recent American Academy of Pediatrics recommendations that all 18- and 24-month-olds be screened for autism spectrum disorders, there is an increasing need for diagnostic assessment of very young children. However, unique challenges exist in applying current diagnostic guidelines for autism spectrum disorders to children under the age of 2 years. In this article, we address challenges related to early detection, diagnosis, and treatment of autism spectrum disorders in this age group. We provide a comprehensive review of findings from recent studies on the early development of children with autism spectrum disorders, summarizing current knowledge on early signs of autism spectrum disorders, the screening properties of early detection tools, and current best practice for diagnostic assessment of autism spectrum disorders before 2 years of age. We also outline principles of effective intervention for children under the age of 2 with suspected/confirmed autism spectrum disorders. It is hoped that ongoing studies will provide an even stronger foundation for evidence-based diagnostic and intervention approaches for this critically important age group.
PMCID: PMC2833286  PMID: 19403506
autism; early detection; toddlers; longitudinal studies; child development
19.  A Comparative Analysis of Well-Being and Coping among Mothers of Toddlers and Mothers of Adolescents with ASD 
The present study examined the impact of autism symptoms and coping strategies on the well-being of mothers of children with ASD. The sample consisted of 153 mothers of toddlers and 201 mothers of adolescents drawn from two ongoing, longitudinal studies of families of individuals with ASD. For mothers of toddlers, lower levels of emotion-focused coping and higher levels of problem-focused coping were generally associated with better maternal well-being, regardless of the level of child symptomatology. For mothers of adolescents, coping often acted as a buffer when autism symptoms were high. Although there was evidence of maternal distress in both groups, the presence of significant buffering effects reflects adaptation in the face of stress, particularly for mothers of adolescents.
PMCID: PMC2831472  PMID: 17924181
coping; autism symptoms; maternal well-being; toddlers; adolescents
20.  A Neuroligin-4 Missense Mutation Associated With Autism Impairs Neuroligin-4 Folding and ER Export 
Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4; gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations, and the limited information about the affected patients and the functional consequences of their mutations, cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino acid substitution in NL4 (R87W). This substitution was absent from the brothers’ asymptomatic parents, suggesting that it arose in the maternal germline. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W-substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell-surface. As a result, the R87W-substitution inactivated the synapse-formation activity of NL4, and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism.
PMCID: PMC2777970  PMID: 19726642
Neuroligin; autism spectrum disorder; protein misfolding; synaptic transmission; synapse; behavior

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