Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

This study evaluated criteria for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Kable et al. (Child Psychiatry Hum Dev 55:426, 2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17 years) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.

Profiles of language and communication abilities in adolescents with fetal alcohol spectrum disorders.

OBJECTIVE: Language and communication are largely understudied among youth with fetal alcohol spectrum disorders (FASD). Findings have been mixed, and have generally focused on more severely affected (i.e., children with FAS alone) or younger children. This study aimed to elucidate the profiles of language (i.e., receptive, expressive, general language) and communication (i.e., functional, social) abilities in adolescents with FASD. METHOD: Participants aged 12-17 years with (AE = 31) and without (CON = 29) prenatal alcohol exposure were included. Receptive and expressive language were measured by the Clinical Evaluation of Language Fundamentals - Fifth Edition (CELF-5). Parents or caregivers completed the Children's Communication Checklist - Second Edition as a subjective measure of general language skills. Functional communication was measured by the Student Functional Assessment of Verbal Reasoning and Executive Strategies and parents or caregivers completed the Social Skills Improvement System Rating Scales as a measure of social communication. Multivariate analysis of variance determined the overall profiles of language and communication and whether they differed between groups. RESULTS: The AE group performed significantly lower than the CON group on receptive language and parent report of general language while groups did not significantly differ on expressive language. Groups did not significantly differ on functional communication while social communication was significantly lower in the AE group. CONCLUSIONS: Results of this study provide important information regarding the overall profile of basic language abilities and higher-level communication skills of adolescents with FASD. Ultimately, improving communication skills of youth with FASD may translate to better overall functioning.

Development and validation of a postnatal risk score that identifies children with prenatal alcohol exposure.

BACKGROUND: This study aimed to develop an efficient and easily calculable risk score that can be used to identify an individual's risk of having been exposed to alcohol prenatally. METHODS: Data for this study were collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, Phases 2 and 3. Two cohorts (ages 5 to 17 years) completed a comprehensive neurobehavioral battery and a standard dysmorphology exam: a development cohort (DC; n = 325) and a comparative cohort (CC; n = 523). Both cohorts included two groups: those with histories of heavy prenatal alcohol exposure (AE-DC, n = 121; AE-CC, n = 177) and a control group that included subjects with minimal or no prenatal alcohol exposure (CON-DC, n = 204; CON-CC, n = 346). Behavioral assessments and physical exam data were combined using regression techniques to derive a risk score indicating the likelihood of prenatal alcohol exposure. Subjects were then divided into two subgroups: (1) low risk and (2) high risk. Chi-square (χ2 ) determined classification accuracy and ROC curves were produced to assess the predictive accuracy. Correlations between risk scores and intelligence quotient and executive function scores were calculated. RESULTS: Subjects were accurately classified in the DC (χ2  = 78.61, p < 0.001) and CC (χ2  = 86.63, p < 0.001). The classification model also performed well in the DC (ROC = 0.835 [SE = 0.024, p < 0.001]) and CC (ROC = 0.786 [SE = 0.021, p < 0.001]). In the AE-CC and CON-CC, there were modest but significant associations between the risk score and executive function (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001) and intelligence quotient (AE-CC: r = -0.20, p = 0.034; CON-CC: r = -0.28, p < 0.001). CONCLUSION(S): The risk score significantly distinguished alcohol-exposed from control subjects and correlated with important cognitive outcomes. It has significant clinical potential and could be easily deployed in clinical settings.

Validity and Reliability of Executive Function Measures in Children With Heavy Prenatal Alcohol Exposure: Correspondence Between Multiple Raters and Laboratory Measures.

BACKGROUND: Rating scales are designed to complement traditional performance-based measures, and both can provide useful information about the functioning of youth with histories of prenatal alcohol exposure. Few studies, however, have compared ratings from multiple informants or the relationship between these subjective rating scale scores and the objective results from laboratory performance-based scales. METHODS: The current study addressed both of these questions in 3 study groups: children with histories of prenatal alcohol exposure (n = 47), attention-deficit/hyperactivity disorder (ADHD; n = 41), and typically developing controls (CON; n = 73). All subjects completed a standardized neuropsychological test battery, including laboratory measures of executive functioning and a self-report measure of executive function behaviors. Parents and teachers completed corresponding rating scales of executive function behaviors for each subject. This study assessed the relationship between these behavior rating scales and corresponding neuropsychological tests, and interrater agreement among the multiple informants. RESULTS: Weak correlations were found between the rating scales and laboratory measures, indicating poor convergent validity for the behavior rating scale. Interrater reliability was found but it differed by group. Agreement was found between parent and teacher ratings for children with prenatal alcohol exposure, whereas teacher-child agreement was found for those with ADHD. CONCLUSIONS: Findings from this study indicate that behavior ratings can be used to supplement laboratory measures but may not be measuring cognitive abilities regardless of whether a clinical diagnosis is present. A multimethod approach should be used when measuring skills in this domain. This was one of the first studies to examine cross-informant agreement in a sample of children with prenatal alcohol exposure. Further research is necessary to understand why interrater agreement differed for children with prenatal alcohol exposure and those with ADHD.

Cross-Sectional Analysis of Spatial Working Memory Development in Children with Histories of Heavy Prenatal Alcohol Exposure.

BACKGROUND: In children with prenatal alcohol exposure, spatial working memory is affected and brain regions important for spatial working memory performance exhibit atypical neurodevelopment. We therefore hypothesized that children with prenatal alcohol exposure may also have atypical development of spatial working memory ability. METHODS: We examined the relation between spatial working memory and age using a cross-sectional developmental trajectory approach in youth with and without histories of heavy prenatal alcohol exposure. The Cambridge Neuropsychological Test Automated Battery Spatial Working Memory subtest was administered to children 5.0 to 16.9 years old. RESULTS: While the controls and children with prenatal alcohol exposure showed similar performance at younger ages, larger group differences were observed in older children. This effect was replicated in a separate sample. CONCLUSIONS: The atypical brain development that has previously been reported in children with heavy prenatal alcohol exposure may have clinically relevant implications for cognitive development; however, longitudinal cognitive analyses are needed.

Executive and Social Functioning Across Development in Children and Adolescents With Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is linked to a variety of neurodevelopmental challenges, including social functioning (SF) and executive functioning (EF) deficits. These deficits present differently across developmental stages from preschool age to adolescence. METHODS: The post hoc analyses described here were conducted on data from 83 preschool-age children with PAE (early childhood group; ages 2.5 to 5.0) and 95 adolescents (49 with PAE, 46 controls; ages 8 to 16). Each child completed EF tasks as part of several prior studies. Parents completed social and communication inventories about their child's abilities. Thirty-three participants from the early childhood group returned for a 4-year follow-up and completed both SF and EF measures. RESULTS: Both the early childhood and adolescent groups with PAE showed deficits in SF and EF. There was a relationship between SF and EF within the adolescent PAE group that was not present in the adolescent control group or the early childhood PAE group. However, at the 4-year follow-up (Mage  = 8.45), participants originally in the early childhood PAE group also demonstrated this relationship. CONCLUSIONS: These findings support previous research on EF/SF deficits in adolescents with PAE while also addressing a gap in the literature concerning early childhood research on this topic. Additionally, these findings suggest that the relationship between EF and SF deficits may strengthen throughout development. This line of research highlights potential sensitive periods for SF and EF training in children with PAE and suggests that fetal alcohol spectrum disorders programs consider targeting EF training as a component of social skill interventions.

Para-limbic Structural Abnormalities Are Associated With Internalizing Symptoms in Children With Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. METHODS: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images. RESULTS: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. CONCLUSIONS: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE.

Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure.

In utero alcohol exposure can disrupt the development of the fetal brain and result in a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). This paper provides a comprehensive review of the cognitive and behavioral outcomes of prenatal alcohol exposure, including domains of general intelligence, executive functioning, language development, learning and memory, adaptive functioning, academic performance, and concurrent psychopathology. In addition, the current status of the neurobehavioral profile of FASD and its potential as a diagnostic tool will be discussed.

Relation Between Oppositional/Conduct Behaviors and Executive Function Among Youth with Histories of Heavy Prenatal Alcohol Exposure.

BACKGROUND: Youth with heavy prenatal alcohol exposure have high rates of behavioral concerns and psychopathology, including increased oppositional and conduct behaviors. The relation between those concerns and executive function (EF) deficits is unknown. We investigated the association of oppositional and conduct behavior and EF in adolescents to inform targeted intervention. METHODS: Subjects (N = 267) ages 10 to 17 years comprised 3 groups: alcohol-exposed with oppositional/conduct behaviors (AE+), alcohol-exposed without oppositional/conduct behaviors (AE-), and controls (CON). Group differences on direct neuropsychological (Delis-Kaplan Executive Function System [D-KEFS]) and indirect parent-report (Behavior Rating Inventory of Executive Function [BRIEF]) EF measures were tested with multivariate analysis of covariances, followed by univariate analysis of variances and pairwise comparisons. The contribution of attention-deficit/hyperactivity disorder (ADHD) within the AE groups was assessed in secondary analyses. RESULTS: On the D-KEFS, there was an omnibus main effect of group, with significant main effects on 3 of 6 variables (CON>AE+, AE-). Within the AE groups, ADHD did not alter the results. On the BRIEF, there was an omnibus significant main effect of group, with significant main effects on all scales (CON

Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders.

BACKGROUND: Since the 1970s, a range of facial, neurostructural, and neurocognitive adverse effects have been shown to be associated with prenatal alcohol exposure. Typically, these effects are studied individually and not in combination. Our objective is to improve the understanding of the teratogenic effects of prenatal alcohol exposure by simultaneously considering face-brain morphology and neurocognitive measures. METHODS: Participants were categorized as control (n = 47), fetal alcohol syndrome (FAS, n = 22), or heavily exposed (HE) prenatally, but not eligible for a FAS diagnosis (HE, n = 50). Structural brain MRI images and high-resolution 3D facial images were analyzed using dense surface models of features of the face and surface shape of the corpus callosum (CC) and caudate nucleus (CN). Asymmetry of the CN was evaluated for correlations with neurocognitive measures. RESULTS: (i) Facial growth delineations for FAS, HE, and controls are replicated for the CN and the CC. (ii) Concordance of clinical diagnosis and face-based control-FAS discrimination improves when the latter is combined with specific brain regions. In particular, midline facial regions discriminate better when combined with a midsagittal profile of the CC. (iii) A subset of HE individuals was identified with FAS-like CN dysmorphism. The average of this HE subset was FAS-like in its facial dysmorphism. (iv) Right-left asymmetry found in the CNs of controls is not apparent for FAS, is diminished for HE, and correlates with neurocognitive measures in the combined FAS and HE population. CONCLUSIONS: Shape analysis which combines facial regions with the CN, and with the CC, better identify those with FAS. CN asymmetry was reduced for FAS compared to controls and is strongly associated with general cognitive ability, verbal learning, and recall in those with prenatal alcohol exposure. This study further extends the brain-behavior relationships known to be vulnerable to alcohol teratogenesis.

Executive Functioning Correlates With Communication Ability in Youth With Histories of Heavy Prenatal Alcohol Exposure.

OBJECTIVES: Caregivers of youth with heavy prenatal alcohol exposure report impaired communication, which can significantly impact quality of life. Using data collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we examined whether cognitive variables predict communication ability of youth with histories of heavy prenatal alcohol exposure. METHODS: Subjects (ages 10-16 years) comprised two groups: adolescents with heavy prenatal alcohol exposure (AE) and non-exposed controls (CON). Selected measures of executive function (NEPSY, Delis-Kaplan Executive Function System), working memory (CANTAB), and language were tested in the child, while parents completed communication ratings (Vineland Adaptive Behavior Scales - Second Edition). Separate multiple regression analyses determined which cognitive domains predicted communication ability. A final, global model of communication comprised the three cognitive models. RESULTS: Spatial Working Memory and Inhibition significantly contributed to communication ability across groups. Twenty Questions performance related to communication ability in the CON group only while Word Generation performance related to communication ability in the AE group only. Effects remained significant in the global model, with the exception of Spatial Working Memory. CONCLUSIONS: Both groups displayed a relation between communication and Spatial Working Memory and Inhibition. Stronger communication ability related to stronger verbal fluency in the AE group and Twenty Questions performance in the CON group. These findings suggest that alcohol-exposed adolescents may rely more heavily on learned verbal storage or fluency for daily communication while non-exposed adolescents may rely more heavily on abstract thinking and verbal efficiency. Interventions aimed at aspects of executive function may be most effective at improving communication ability of these individuals. (JINS, 2018, 24, 1026-1037).

Academic Difficulties in Children with Prenatal Alcohol Exposure: Presence, Profile, and Neural Correlates.

BACKGROUND: Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. METHODS: Children (8 to 16 years) were assessed using the WIAT-II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure (n = 67) and controls (n = 61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample (n = 42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. RESULTS: The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group × academic domain interaction (p < 0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol-exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. CONCLUSIONS: Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children.

A Decision Tree to Identify Children Affected by Prenatal Alcohol Exposure.

OBJECTIVE: To develop and validate a hierarchical decision tree model that combines neurobehavioral and physical measures to identify children affected by prenatal alcohol exposure even when facial dysmorphology is not present. STUDY DESIGN: Data were collected as part of a multisite study across the US. The model was developed after we evaluated more than 1000 neurobehavioral and dysmorphology variables collected from 434 children (8-16 years of age) with prenatal alcohol exposure, with and without fetal alcohol syndrome, and nonexposed control subjects, with and without other clinically-relevant behavioral or cognitive concerns. The model subsequently was validated in an independent sample of 454 children in 2 age ranges (5-7 years or 10-16 years). In all analyses, the discriminatory ability of each model step was tested with logistic regression. Classification accuracies and positive and negative predictive values were calculated. RESULTS: The model consisted of variables from 4 measures (2 parent questionnaires, an IQ score, and a physical examination). Overall accuracy rates for both the development and validation samples met or exceeded our goal of 80% overall accuracy. CONCLUSIONS: The decision tree model distinguished children affected by prenatal alcohol exposure from nonexposed control subjects, including those with other behavioral concerns or conditions. Improving identification of this population will streamline access to clinical services, including multidisciplinary evaluation and treatment.

The Influence of Extrinsic Reinforcement on Children with Heavy Prenatal Alcohol Exposure.

BACKGROUND: Prenatal alcohol exposure affects inhibitory control and other aspects of attention and executive function. However, the efficacy of extrinsic reinforcement on these behaviors has not been tested. METHODS: Alcohol-exposed children (AE; n = 34), children with attention-deficit/hyperactivity disorder (ADHD; n = 23), and controls (CON; n = 31) completed a flanker task with 4 reward conditions (no reward, reward, reward+occasional response cost, equal probability of reward+response cost). Inhibitory control was tested in the no reward conditions using a 3(group) × 2(flanker type) ANCOVA. Response to reinforcement was tested using 3(group) × 4(reward condition) × 4(flanker type) analysis of covariance (ANCOVA). Response time (RT) and accuracy were tested independently. RESULTS: Groups did not differ on demographic variables. The flanker task was successful in taxing interference control, an aspect of executive attention (i.e., responses to incongruent stimuli were slower than to congruent stimuli) and the AE group demonstrated impaired executive control over the other groups. Overall, the AE group had significantly slower RTs compared to the CON and ADHD groups, which did not differ. However, reinforcement improved RT in all groups. While occasional response cost had the greatest benefit in the CON group, the type of reinforcement did not differentially affect the AE and ADHD groups. Accuracy across reward conditions did not differ by group, but was dependent on flanker type and reward condition. CONCLUSIONS: Alcohol-exposed children, but not children with ADHD, had impaired interference control in comparison with controls, supporting a differential neurobehavioral profile in these 2 groups. Both clinical groups were equally affected by introduction of reinforcement, although the type of reinforcement did not differentially affect performance as it did in the control group, suggesting that reward or response cost could be used interchangeably to result in the same benefit.

Neurobehavioral Deficits Consistent Across Age and Sex in Youth with Prenatal Alcohol Exposure.

BACKGROUND: Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children. METHODS: Subjects were 407 youth with prenatal alcohol exposure (n = 192) and controls (n = 215). Two age groups (child [5 to 7 years] or adolescent [10 to 16 years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history) × 2 (sex) × 2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses. RESULTS: No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females. CONCLUSIONS: Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains.

Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE): Proposed DSM-5 Diagnosis.

Over the past 40 years, a significant body of animal and human research has documented the teratogenic effects of prenatal alcohol exposure (PAE). Neurobehavioral Disorder associated with PAE is proposed as a new clarifying term, intended to encompass the neurodevelopmental and mental health symptoms associated with PAE. Defining this disorder is a necessary step to adequately characterize these symptoms and allow clinical assessment not possible using existing physically-based diagnostic schemes. Without appropriate diagnostic guidelines, affected individuals are frequently misdiagnosed and treated inappropriately (often to their considerable detriment) by mental health, educational, and criminal justice systems. Three core areas of deficits identified from the available research, including neurocognitive, self-regulation, and adaptive functioning impairments, are discussed and information regarding associated features and disorders, prevalence, course, familial patterns, differential diagnosis, and treatment of the proposed disorder are also provided.

Volume changes and brain-behavior relationships in white matter and subcortical gray matter in children with prenatal alcohol exposure.

Children with prenatal alcohol exposure (PAE) may have cognitive, behavioral and brain abnormalities. Here, we compare rates of white matter and subcortical gray matter volume change in PAE and control children, and examine relationships between annual volume change and arithmetic ability, behavior, and executive function. Participants (n = 75 PAE/64 control; age: 7.1-15.9 years) each received two structural magnetic resonance scans, ~2 years apart. Assessments included Wechsler Intelligence Scale for Children (WISC-IV), the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function. Subcortical white and gray volumes were extracted for each hemisphere. Group volume differences were tested using false discovery rate (q < 0.05). Analyses examined group-by-age interactions and group-score interactions for correlations between change in volume and raw behavioral scores. Results showed that subjects with PAE had smaller volumes than control subjects across the brain. Significant group-score interactions were found in temporal and parietal regions for WISC arithmetic scores and in frontal and parietal regions for behavioral measures. Poorer cognitive/ behavioral outcomes were associated with larger volume increases in PAE, while control subjects generally showed no significant correlations. In contrast with previous results demonstrating different trajectories of cortical volume change in PAE, our results show similar rates of subcortical volume growth in subjects with PAE and control subjects. We also demonstrate abnormal brain-behavior relationships in subjects with PAE, suggesting different use of brain resources. Our results are encouraging in that, due to the stable volume differences, there may be an extended window of opportunity for intervention in children with PAE.

Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q.

PURPOSE: Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder. METHODS: In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization. RESULTS: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein. CONCLUSION: Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.

Effects of prenatal alcohol exposure and attention-deficit/hyperactivity disorder on adaptive functioning.

BACKGROUND: Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) are associated with adaptive behavior deficits. This study examined the interaction between these 2 factors on parent ratings of adaptive behavior. METHODS: As part of a multisite study, primary caregivers of 317 children (8 to 16 years, M = 12.38) completed the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Four groups of subjects were included: children with prenatal alcohol exposure with ADHD (AE+, n = 82), children with prenatal alcohol exposure without ADHD (AE-, n = 34), children with ADHD (ADHD, n = 71), and control children (CON, n = 130). VABS-II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [AE]) × 2 (ADHD diagnosis) between-subjects analyses of covariance. RESULTS: There were significant main effects of AE (p < 0.001) and ADHD (p < 0.001) on all VABS-II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication, F(1, 308) = 7.49, p = 0.007, partial η(2) = 0.024, but not Daily Living Skills or Socialization domains (ps > 0.27). Follow-up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects (ADHD vs. CON) than exposed subjects (AE+ vs. AE-), and the effects of alcohol exposure were stronger in subjects without ADHD (AE- vs. CON) than in subjects with ADHD (AE+ vs. ADHD) CONCLUSION: As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these 2 factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broaden our understanding of how ADHD exacerbates behavioral outcomes in this population.