Allele-specific associations of 5-HTTLPR/rs25531 with ADHD and autism spectrum disorder.

BACKGROUND: The aims of the present study were to examine the association between a common serotonin transporter gene (SLC6A4) polymorphism 5-HTTLPR/rs25531 with severity of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms. METHODS: Mothers and teachers completed a validated DSM-IV-referenced rating scale for ADHD and ASD symptoms in 118 children with ASD. RESULTS: Analyses indicated that children with at least one copy of the S or L(G) allele obtained significantly more severe maternal ratings of hyperactivity (p=0.001; ηp(2)=0.097) and impulsivity (p=0.027; ηp(2)=0.044) but not inattention (p=0.061; ηp(2)=0.032), controlling for ASD severity, than children homozygous for the L(A) allele. Conversely, mothers' ratings indicated that children with L(A)/L(A) genotype had more severe ASD social deficits than S or L(G) allele carriers (p=0.003; ηp(2)=0.081), controlling for ADHD symptom severity. Teachers' ratings though consistent with mothers' ratings of hyperactivity and social deficits were marginally significant (p=0.07/p=0.09). There was some evidence that the magnitude of parent-teacher agreement regarding symptom severity varied as a function of the child's genotype. CONCLUSION: The 5-HTTLPR/rs25531 polymorphism or its correlates may modulate severity of ADHD and ASD symptoms in children with ASD, but in different ways. These tentative, hypothesis-generating findings require replication with larger independent samples.

Comparison of children with autism spectrum disorder with and without schizophrenia spectrum traits: gender, season of birth, and mental health risk factors.

Children with autism spectrum disorder (ASD) with and without co-occurring schizophrenia spectrum traits (SST) were examined for differences in co-occurring psychiatric symptoms, background characteristics, and mental health risk factors. Participating mothers and teachers completed a DSM-IV-referenced rating scale and a background questionnaire (mothers only) describing 147 children (6-12 years) with ASD. There was a clear pattern of group differences in co-occurring psychiatric symptom severity (+SST > SST-) and background characteristics. Children with impairing SST had more mental health risk factors. Girls were more likely to be classified SST according to mothers' ratings. Children born in spring-summer were more likely to be classified non-SST by teachers' ratings. Findings provide tentative evidence that SST may be a useful marker of behavioral heterogeneity within the ASD clinical phenotype.

Depression symptoms in boys with autism spectrum disorder and comparison samples.

This study compares severity of specific depression symptoms in boys with autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), or chronic multiple tic disorder (CMTD) and typically developing boys (Controls). Children were evaluated with parent and teacher versions of the Child Symptom Inventory-4 (CSI-4) and a demographic questionnaire. Mothers' and teachers' ratings generally indicated the most severe symptoms in boys with ASD ± ADHD. Associations of depression with ASD severity and IQ varied considerably for specific symptoms of depression, ASD functional domain, and informant. Findings provide additional support for the differential influence of neurobehavioral syndromes on co-occurring symptom severity and illustrate how more fine-grained analyses of clinical phenotypes may contribute to a better understanding of etiology and current nosology.

Validity of DSM-IV syndromes in preschoolers with autism spectrum disorders.

Behavior and emotional problems are often present in very young children with autism spectrum disorders (ASDs) but their nosology has been the object of scant empirical attention. The objective of this study was to assess the construct validity of select Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined syndromes (ADHD, ODD, Mood disorder) in preschoolers with ASD (N = 229). Parents and teachers completed the Early Childhood Inventory-4, a behavior rating scale based on the DSM-IV, and ratings were submitted to confirmatory factor analysis. Results generally supported the DSM nosology in this population. There was some evidence that parent ratings were associated with better fit indices (e.g. RSMEA = .062) than teachers (e.g. RMSEA = .083). For both raters, fit indices appeared to improve when the ADHD factor was broken into its constituent parts. However, hyperactivity symptoms accounted for little unique additional variance in the model. Findings lend support to the DSM as a conceptual model for behavioral syndromes in preschoolers with ASDs and also reinforce the importance of source-specificity when considering psychiatric disorders in children with ASDs.

Association of DRD4 polymorphism with severity of oppositional defiant disorder, separation anxiety disorder and repetitive behaviors in children with autism spectrum disorder.

The objective was to examine whether a common polymorphism in the dopamine D4 receptor gene (DRD4) might be a potential biomarker for behavioral variation within the autism spectrum disorder clinical phenotype. Children (N=66) were evaluated with a validated mother- and teacher-completed DSM-IV-referenced rating scale. Partial eta-squared (ηp(2) ) was used to gauge the magnitude of group differences: 0.01-0.06=small, 0.06-0.14=moderate and >0.14=large. Children who were 7-repeat allele carriers had more severe oppositional defiant disorder behaviors according to mothers' (ηp(2)=0.10) and teachers' (ηp(2)=0.06) ratings than noncarriers, but the latter was marginally significant (P=0.07). Children who were 7-repeat allele carriers also obtained more severe maternal ratings of tics (ηp(2)=0.07) and obsessions-compulsions (ηp(2)=0.08). Findings for maternal ratings of separation anxiety were marginally significant (P=0.08, ηp(2) =0.05). Analyses of combined DRD4 and dopamine transporter gene (DAT1) genotypes approached significance (P=0.05) for teachers' ratings of oppositional behavior and mothers' ratings of tics. DRD4 allelic variation may be a prognostic biomarker for challenging behaviors in children with autism spectrum disorder, but these exploratory findings remain tentative pending replication with larger independent samples.

Parent-child DRD4 genotype as a potential biomarker for oppositional, anxiety, and repetitive behaviors in children with autism spectrum disorder.

The primary objective of the present study was to examine whether a combination of parent-child DRD4 genotypes results in more informative biomarkers of oppositional, separation anxiety, and repetitive behaviors in children with autism spectrum disorder (ASD). Based on prior research indicating the 7-repeat allele as a potential risk variant, participants were sorted into one of four combinations of parent-child genotypes. Owing to the possibility of parent-of-origin effects, analyses were conducted separately for mother-child (MC) and father-child (FC) dyads. Mothers completed a validated DSM-IV-referenced rating scale. Partial eta-squared (ηp(2)) was used to determine the magnitude of group differences: 0.01-0.06=small, 0.06-0.14=moderate, and >0.14=large. Analyses indicated that children in MC dyads with matched genotypes had the least (7-/7-) and most (7+/7+) severe mother-rated oppositional-defiant (ηp(2)=0.11) and separation anxiety (ηp(2)=0.19) symptoms. Conversely, youths in FC dyads with matched genotypes had the least (7-/7-) and most (7+/7+) severe obsessive-compulsive behaviors (ηp(2)=0.19) and tics (ηp(2)=0.18). Youths whose parents were both noncarriers had less severe tics than peers with at least one parental carrier, and the effect size was large (ηp(2)=0.16). There was little evidence that noncarrier children were rated more severely by mothers who were carriers versus noncarriers. Transmission Disequilibrium Test analyses provided preliminary evidence for undertransmission of the 2-repeat allele in youths with more severe tics (p=0.02). Parent genotype may be helpful in constructing prognostic biomarkers for behavioral disturbances in ASD; however, findings are tentative pending replication with larger, independent samples.

Anxiety symptoms in boys with autism spectrum disorder, attention-deficit hyperactivity disorder, or chronic multiple tic disorder and community controls.

We compared symptoms of generalized anxiety disorder (GAD) and separation anxiety disorder (SAD) in 5 groups of boys with neurobehavioral syndromes: attention-deficit/hyperactivity disorder (ADHD) plus autism spectrum disorder (ASD), ADHD plus chronic multiple tic disorder (CMTD), ASD only, ADHD only, and community Controls. Anxiety symptoms were assessed using parent and teacher versions of a DSM-IV-referenced rating scale. All three groups of boys with co-morbid ADHD evidenced more severe anxiety than Controls. Group differences in anxiety varied as a function of symptom, disorder, informant, and co-morbidity supporting the notion that co-morbid neurobehavioral syndromes differentially impact clinical features of co-occurring anxiety symptoms. Findings also suggest that GAD and SAD are phenomenologically unique, even in children with ASD. Implications for nosology are discussed.

Glutamate transporter gene (SLC1A1) single nucleotide polymorphism (rs301430) and repetitive behaviors and anxiety in children with autism spectrum disorder.

Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene (SLC1A1) with severity of repetitive behaviors (obsessive-compulsive behaviors, tics) and anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children with autism spectrum disorder. Although analyses were not significant for repetitive behaviors, youths homozygous for the high expressing C allele had more severe anxiety than carriers of the T allele. Allelic variation in SLC1A1 may be a biomarker for or modifier of anxiety symptom severity in children with ASD, but study findings are best conceptualized as tentative pending replication with larger independent samples.

Relative clinical utility of three Child Symptom Inventory-4 scoring algorithms for differentiating children with autism spectrum disorder vs. attention-deficit hyperactivity disorder.

OBJECTIVE: The present study compared three separate Child Symptom Inventory-4 (CSI-4) scoring algorithms for differentiating children with autism spectrum disorder (ASD) from youngsters with attention-deficit/hyperactivity disorder (ADHD). METHOD: Parents/teachers completed the CSI-4, a DSM-IV-referenced rating scale, for 6 to 12-year-old clinical referrals with ASD (N = 186) and ADHD (N = 251). Algorithms were based on either all CSI-4 items (forward logistic regressions) or the 12 DSM-IV symptoms of pervasive developmental disorder (PDD) included in the CSI-4. RESULTS: ROC analyses indicated generally good to excellent values for area under the curve, sensitivity, specificity, and positive predictive power. Algorithms for parent ratings were superior to teacher ratings. The algorithm based solely on PDD symptoms evidenced the greatest generalizability. CONCLUSION: Although algorithms generated from regression analyses produced greater clinical utility for specific samples, the PDD-based algorithm resulted in greater stability across samples.

Deconstructing the PDD clinical phenotype: internal validity of the DSM-IV.

BACKGROUND: Empirical studies of the structure of autism symptoms have challenged the three-domain model of impairment currently characterizing pervasive developmental disorders (PDD). The objective of this study was to assess the internal validity of the DSM as a conceptual model for describing PDD, while paying particular attention to certain subject characteristics. METHODS: Parents and teachers completed a DSM-IV-referenced rating scale for 3- to 12-year-old clinic referrals with a PDD (n = 730). Ratings were submitted to confirmatory factor analysis and different models were assessed for fit. RESULTS: Measures of fit indicated that the three-factor solution based on the DSM was superior to other models. Most indices of fit were acceptable, but showed room for improvement. Fit indices varied according to the rater (parent or teacher), child's age (preschool versus school aged), PDD subtype (autism, Asperger's, pervasive developmental disorder not otherwise specified (PDDNOS)), and IQ. CONCLUSIONS: More research needs to be done before discarding current classification systems. Subject characteristics, modality of assessment, and procedural variations in statistical analyses impact conclusions about the structure of PDD symptoms.

Association of COMT (Val158Met) and BDNF (Val66Met) gene polymorphisms with anxiety, ADHD and tics in children with autism spectrum disorder.

The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (etap (2) = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, etap (2) = 0.10) and teacher-rated tics (p = 0.04; etap (2) = 0.07). There was also evidence of a possible interaction (p = 0.02, etap (2) = 0.09) of BDNF genotype with DAT1 3' VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples.

Oppositional defiant and conduct disorder behaviors in boys with autism spectrum disorder with and without attention-deficit hyperactivity disorder versus several comparison samples.

We compared disruptive behaviors in boys with either autism spectrum disorder (ASD) plus ADHD (n = 74), chronic multiple tic disorder plus ADHD (n = 47), ADHD Only (n = 59), or ASD Only (n = 107). Children were evaluated with parent and teacher versions of the Child Symptom Inventory-4 including parent- (n = 168) and teacher-rated (n = 173) community controls. Parents rated children in the three ADHD groups comparably for each symptom of oppositional defiant disorder (ODD) and conduct disorder. Teacher ratings indicated that the ASD + ADHD group evidenced a unique pattern of ODD symptom severity, differentiating them from the other ADHD groups, and from the ASD Only group. The clinical features of ASD appear to influence co-morbid, DSM-IV-defined ODD, with implications for nosology.

Comparative study of children with ADHD only, autism spectrum disorder + ADHD, and chronic multiple tic disorder + ADHD.

OBJECTIVE: Identification of differences among children with ADHD only, autism spectrum disorder (ASD)+ADHD, and chronic multiple tic disorder (CMTD)+ADHD may lead to better understanding of clinical phenotypes. METHOD: Children were evaluated using the parent- and teacher-completed questionnaires. RESULTS: All three groups were highly similar in severity of oppositional defiant disorder and conduct disorder symptoms; however, the ASD+ADHD group generally exhibited the most severe anxiety, although the CMTD+ADHD group had the most severe generalized anxiety. The two comorbid groups had the most involved medical histories and the greatest likelihood of a family history of psychopathology. CONCLUSION: Groups differed in clinically meaningful ways, and the apparent association between tics and anxiety may explain in part the elevated levels of anxiety in both comorbid groups. Collectively, results suggest that ADHD may be better conceptualized as a family of interrelated syndromes defined in part by comorbid conditions and that continued research is clearly warranted.

Validation of DSM-IV model of psychiatric syndromes in children with autism spectrum disorders.

The objective of this study was to assess the internal construct validity of the DSM-IV as a conceptual model for characterizing behavioral syndromes in children with ASD. Parent and teachers completed the Child Symptom Inventory-4, a DSM-IV-referenced rating scale, for 6-to-12 year old clinic referrals with an ASD (N = 498). Ratings were submitted to confirmatory factor analysis and models were assessed for fit. Results were also compared to those obtained for a sample of non-ASD psychiatric outpatient school-age children. Fit indices ranged from acceptable to good for the ASD samples and compared well to those obtained in typically developing children. Findings lend support to the notion that DSM-IV syndromes may be an appropriate conceptual model for characterizing psychopathology in ASD.

Association of a monoamine oxidase-a gene promoter polymorphism with ADHD and anxiety in boys with autism spectrum disorder.

The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned comparisons indicated that children with the 4- versus 3-repeat allele had significantly (p < 05) more severe parent-rated ADHD inattention and impulsivity, and more severe teacher-rated symptoms of generalized anxiety. Our results support a growing body of research indicating that concomitant behavioral disturbances in children with ASD warrant consideration as clinical phenotypes, but replication with independent samples is necessary to confirm this preliminary finding.

Pregnancy-specific stress, prenatal health behaviors, and birth outcomes.

OBJECTIVE: Stress in pregnancy predicts earlier birth and lower birth weight. The authors investigated whether pregnancy-specific stress contributes uniquely to birth outcomes compared with general stress, and whether prenatal health behaviors explain this association. DESIGN: Three structured prenatal interviews (N = 279) assessing state anxiety, perceived stress, life events, pregnancy-specific stress, and health behaviors. MAIN OUTCOME MEASURES: Gestational age at delivery, birth weight, preterm delivery (<37 weeks), and low birth weight (<2,500 g). RESULTS: A latent pregnancy-specific stress factor predicted birth outcomes better than latent factors representing state anxiety, perceived stress, or life event stress, and than a latent factor constructed from all stress measures. Controlling for obstetric risk, pregnancy-specific stress was associated with smoking, caffeine consumption, and unhealthy eating, and inversely associated with healthy eating, vitamin use, exercise, and gestational age at delivery. Cigarette smoking predicted lower birth weight. Clinically-defined birth outcomes were predicted by cigarette smoking and pregnancy-specific stress. CONCLUSION: Pregnancy-specific stress contributed directly to preterm delivery and indirectly to low birth weight through its association with smoking. Pregnancy-specific stress may be a more powerful contributor to birth outcomes than general stress.

1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders.

This study assessed metabolic functioning of regional brain areas to address whether there is a neurometabolic profile reflecting the underlying neuropathology in individuals with autism spectrum disorders, and if varied profiles correlate with the clinical subtypes. Thirteen children (7-16 years) with autism spectrum disorders and 8 typically developing children were compared on (1)H-magnetic resonance spectroscopy data collected from hippocampus-amygdala and cerebellar regions. The autism spectrum disorder group had significantly lower N-acetyl-aspartate/creatine ratios bilaterally in the hippocampus-amygdala but not cerebellum, whereas myo-inositol/creatine was significantly increased in all measured regions. Choline/creatine was also significantly elevated in the left hippocampus-amygdala and cerebellar regions of children with autism spectrum disorder. Comparisons within the autism spectrum disorder group when clinically subdivided by history of speech delay revealed significant metabolic ratio differences. Magnetic resonance spectroscopy can provide important information regarding abnormal brain metabolism and clinical classification in autism spectrum disorders.

Predictors of psychiatric symptoms in children with an autism spectrum disorder.

This study examined mental health risk/protective factors for DSM-IV psychiatric symptoms in children with an autism spectrum disorder (ASD) and their contribution to functioning separate from ASD symptom severity. Mothers/teachers completed measures of risk/protection and social, adaptive, and school functioning in 6- to 12-year-olds with a diagnosed ASD (N = 238). Bivariate correlations and simultaneous regression analyses indicated a unique pattern of predictors for attention-deficit/hyperactivity disorder, aggression, anxiety, and depression symptoms. Moreover, psychiatric symptoms differentially predicted social and school performance. Findings indicate that co-occurring psychiatric symptoms and their associated mental health risk/protective factors may have important clinical implications and generally support a biopsychosocial model of psychopathology in children with an ASD that appears to share many similarities with models for non ASD children.

Screening for autism spectrum disorder with the Early Childhood Inventory-4.

OBJECTIVE: The early identification of children with autism spectrum disorders (ASDs) is critical for the remediation of developmental deficits. This study examined the clinical utility of ASD scoring algorithms for the Early Childhood Inventory-4 (ECI-4), a DSM-IV-referenced rating scale, as a practical solution for screening 3- to 5-year-old children for ASD in medical and public school settings. METHODS: Parents/teachers completed the ECI-4 for 3- to 5-year-old clinic referrals with an ASD (n = 196) or non-ASD psychiatric (n = 135) diagnosis. Children attending early childhood (i.e., day care, preschool, Head Start) programs were also rated by their parents (n = 507) and teachers (n = 407). RESULTS: Stepwise logistic regression was used to generate ASD scoring algorithms for the ECI-4. Receiver operating characteristic analyses generally indicated high levels of sensitivity/specificity for recommended ASD cutoff scores for parent (clinic: 0.96/0.80; preschool: 0.92/0.96) and teacher (clinic: 0.81/0.79; preschool: 0.97/0.92) ratings. CONCLUSION: Findings indicate that the ECI-4 shows promise as a clinically useful screening measure for ASD in clinic-referred and preschool children.

Oppositional defiant disorder as a clinical phenotype in children with autism spectrum disorder.

To examine the validity of oppositional defiant disorder (ODD) as a clinical phenotype distinct from attention-deficit hyperactivity disorder (ADHD), parents and teachers completed a DSM-IV-referenced rating scale and a background questionnaire for 608 children (ages 3-12 years) with autism spectrum disorder (ASD). The ASD sample was separated into four groups: ODD, ADHD, ODD + ADHD, and neither (NONE). Comparison samples were non-ASD clinic (n = 326) and community (n > 800) controls. In the ASD sample, all three ODD/ADHD groups were clearly differentiated from the NONE group, and the ODD + ADHD group had the most severe co-occurring symptoms, medication use, and environmental disadvantage. There were few differences between ASD + ODD and ASD + ADHD groups. Findings for ASD and control samples were similar, supporting overlapping mechanisms in the pathogenesis of ODD.