1. Auyeung B, Taylor K, Hackett G, Baron-Cohen S. {{Foetal testosterone and autistic traits in 18 to 24-month-old children}}. {Mol Autism};1(1):11.
ABSTRACT: BACKGROUND: Autism spectrum conditions have been characterised as an extreme presentation of certain male-typical psychological traits. In addition, several studies have established a link between prenatal exposure to testosterone and cognitive sex differences in later life, and one study found that foetal testosterone (FT) is positively correlated to autistic traits in 6 to 10 year-old children. In this study, we tested whether FT is positively correlated with autistic traits in toddlers aged 18-24 months. METHODS: Levels of FT were analysed in amniotic fluid and compared with autistic traits, measured using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in 129 typically developing toddlers aged between 18 and 24 months (mean +/- SD 19.25 +/- 1.52 months). RESULTS: Sex differences were observed in Q-CHAT scores, with boys scoring significantly higher (indicating more autistic traits) than girls. In addition, we confirmed a significant positive relationship between FT levels and autistic traits. CONCLUSIONS: The current findings in children between 18 and 24 months of age are consistent with observations in older children showing a positive association between elevated FT levels and autistic traits. Given that sex steroid-related gene variations are associated with autistic traits in adults, this new finding suggests that the brain basis of autistic traits may reflect individual differences in prenatal androgens and androgen-related genes. The consistency of findings in early childhood, later childhood and adulthood suggests that this is a robust association.
2. Bent S, Bertoglio K, Ashwood P, Bostrom A, Hendren RL. {{A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder}}. {J Autism Dev Disord} (Aug 4)
We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3-8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (+/-4.8) points in the omega-3 group compared to 0.3 (+/-7.2) points in the placebo group (p = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects.
3. Buxbaum JD, Baron-Cohen S. {{Molecular Autism: accelerating and integrating research into neurodevelopmental conditions}}. {Mol Autism};1(1):1.
4. Cannon DS, Miller JS, Robison RJ, Villalobos ME, Wahmhoff NK, Allen-Brady K, McMahon WM, Coon H. {{Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders}}. {Mol Autism};1(1):3.
ABSTRACT: BACKGROUND: It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD) would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that ‘insistence on sameness’ (IS) and ‘repetitive sensory-motor actions’ (RSMA) are two factors within the ASD ‘repetitive and stereotyped behavior’ domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales. METHODS: A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC) method that allows for multilocus linkage analysis on large extended pedigrees. RESULTS: Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod) 3.42) and for RSMA at 15q13.1-q14 (recessive model hlod 3.93). We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled. CONCLUSIONS: The finding that IS and RSMA are linked to different regions that only partially overlap regions previously identified with ASD as the phenotype supports the value of including multiple, narrowly defined phenotypes in ASD genetic research. Further, we replicated previous reports indicating that RSMA is more strongly associated than IS with measures of ASD severity.
5. Carayol J, Schellenberg GD, Tores F, Hager J, Ziegler A, Dawson G. {{Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk}}. {Mol Autism};1(1):4.
ABSTRACT: BACKGROUND: Autism is a complex disorder characterized by deficits involving communication, social interaction, and repetitive and restrictive patterns of behavior. Twin studies have shown that autism is strongly heritable, suggesting a strong genetic component. In other disease states with a complex etiology, such as type 2 diabetes, cancer and cardiovascular disease, combined analysis of multiple genetic variants in a genetic score has helped to identify individuals at high risk of disease. Genetic scores are designed to test for association of genetic markers with disease. METHOD: The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population. RESULTS: In both samples, odds ratios (ORs) increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49). The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59). CONCLUSIONS: These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk.
6. Charnsil C. {{Efficacy of Atomoxetine in Children With Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study}}. {J Atten Disord} (Aug 4)
Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the Aberrant Behavior Checklist (ABC) to rate ADHD symptoms at baseline, week 6, and week 10. The Clinical Global Impression-Improvement (CGI-I) scale was used as secondary outcome to assess the overall improvement of the children’s development at week 10. Results: A total of 12 children participated in this study. Although CGI-I scores showed improvement at week 10, the ABC hyperactivity subscale did not show a significant improvement of the ADHD symptoms at baseline (M = 33.89) compared to those at week 10 (M = 31.78, p = .62). Conclusion: Atomoxetine did not benefit children with severe autistic disorder who have ADHD symptoms. (J. of Att. Dis. 2010; XX(X) 1-XX).
7. Coon H, Villalobos ME, Robison RJ, Camp NJ, Cannon DS, Allen-Brady K, Miller JS, McMahon WM. {{Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees}}. {Mol Autism};1(1):8.
ABSTRACT: BACKGROUND: Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability. METHODS: We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees. RESULTS: When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19. CONCLUSIONS: The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.
8. Jepson B, Granpeesheh D, Tarbox J, Olive ML, Stott C, Braud S, Yoo JH, Wakefield A, Allen MS. {{Controlled Evaluation of the Effects of Hyperbaric Oxygen Therapy on the Behavior of 16 Children with Autism Spectrum Disorders}}. {J Autism Dev Disord} (Aug 3)
Hyperbaric oxygen therapy (HBOT) has been used to treat individuals with autism. However, few studies of its effectiveness have been completed. The current study examined the effects of 40 HBOT sessions at 24% oxygen at 1.3 ATA on 11 topographies of directly observed behavior. Five replications of multiple baselines were completed across a total of 16 participants with autism spectrum disorders. No consistent effects were observed across any group or within any individual participant, demonstrating that HBOT was not an effective treatment for the participants in this study. This study represents the first relatively large-scale controlled study evaluating the effects of HBOT at the level of the individual participant, on a wide array of behaviors.
9. Leu RM, Beyderman L, Botzolakis EJ, Surdyka K, Wang L, Malow BA. {{Relation of Melatonin to Sleep Architecture in Children with Autism}}. {J Autism Dev Disord} (Aug 4)
Children with autism often suffer from sleep disturbances, and compared to age-matched controls, have decreased melatonin levels, as indicated by urine levels of the primary melatonin metabolite, 6-sulfatoxymelatonin (6-SM). We therefore investigated the relationship between 6-SM levels and sleep architecture in children with autism spectrum disorders (ASD). Twenty-three children, aged 4-10 years, completed two nights of polysomnography and one overnight urine collection for measurement of urinary 6-SM excretion rate. Parents completed the Children’s Sleep Habits Questionnaire. We found that higher urinary 6-SM excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime sleepiness. The results warrant further examination to examine the effects of supplemental melatonin on sleep architecture and daytime sleepiness.
10. Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H. {{The Genetics of Autism Spectrum Disorders and Related Neuropsychiatric Disorders in Childhood}}. {Am J Psychiatry} (Aug 4)
Objective: Autism spectrum disorders are considered to be among the most heritable mental disorders, a notion based on surprisingly sparse data from small clinical studies. Population-based studies of the heritability of other neuro-psychiatric disorders and comorbidities among them have also been sparse. The authors sought to address both of these issues. Method: Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2000 (N=10,895) were interviewed regarding autism spectrum disorders and associated conditions (response rate, 80%). Concordance rates and structural equation modeling were used for evaluating causes for familial aggregation and overlap between conditions. Results: Monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention defcit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder. Genetic effects accounted for 80% (95% CI=29-91) of the variation in liability for autism spectrum disorders, 79% (95% CI=61-88) for ADHD, 70% (95% CI=35-83) for developmental coordination disorder, and 56% (95% CI=37-68) for tic disorder. Among monozygotic co-twins of children with autism spectrum disorders, the probability of having a diagnosis of ADHD was 44%, compared with 15% for dizygotic co-twins. Differences in cross-disorder effects between monozygotic and dizygotic twins were observed for most other comorbidities, and substantial proportions of the genetic variance for autism spectrum disorders was shared with each of the other disorders. Conclusions: Different neuropsychiatric disorders seem to have a common genetic etiology, suggesting caution in the use of diagnostic entities and proband status in efforts to uncover genes predisposing to autism spectrum disorders.
11. McInnes LA, Nakamine A, Pilorge M, Brandt T, Jimenez Gonzalez P, Fallas M, Manghi ER, Edelmann L, Glessner J, Hakonarson H, Betancur C, Buxbaum JD. {{A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region}}. {Mol Autism};1(1):5.
ABSTRACT: BACKGROUND: The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. METHODS: We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. RESULTS: Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. CONCLUSIONS: From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.
12. Mosconi MW, Kay M, D’Cruz AM, Guter S, Kapur K, Macmillan C, Stanford LD, Sweeney JA. {{Neurobehavioral abnormalities in first-degree relatives of individuals with autism}}. {Arch Gen Psychiatry} (Aug);67(8):830-840.
CONTEXT: Studying sensorimotor and neurocognitive impairments in unaffected family members of individuals with autism may help identify familial pathophysiological mechanisms associated with the disorder. OBJECTIVE: To determine whether atypical sensorimotor or neurocognitive characteristics associated with autism are present in first-degree relatives of individuals with autism. DESIGN: Case-control comparison of neurobehavioral functions. SETTING: University medical center. PARTICIPANTS: Fifty-seven first-degree relatives of individuals with autism and 40 age-, sex-, and IQ-matched healthy control participants (aged 8-54 years). MAIN OUTCOME MEASURES: Oculomotor tests of sensorimotor responses (saccades and smooth pursuit); procedural learning and response inhibition; neuropsychological tests of motor, memory, and executive functions; and psychological measures of social behavior, communication skills, and obsessive-compulsive behaviors. RESULTS: On eye movement testing, family members demonstrated saccadic hypometria, reduced steady-state pursuit gain, and a higher rate of voluntary response inhibition errors relative to controls. They also showed lateralized deficits in procedural learning and open-loop pursuit gain (initial 100 milliseconds of pursuit) and increased variability in the accuracy of large-amplitude saccades that were confined to rightward movements. In neuropsychological studies, only executive functions were impaired relative to those of controls. Family members reported more communication abnormalities and obsessive-compulsive behaviors than controls. Deficits across oculomotor, neuropsychological, and psychological domains were relatively independent from one another. CONCLUSIONS: Family members of individuals with autism demonstrate oculomotor abnormalities implicating pontocerebellar and frontostriatal circuits and left-lateralized alterations of frontotemporal circuitry and striatum. The left-lateralized alterations have not been identified in other neuropsychiatric disorders and are of interest given atypical brain lateralization and language development associated with the disorder. Similar oculomotor deficits have been reported in individuals with autism, suggesting that they may be familial and useful for studies of neurophysiological and genetic mechanisms in autism.
13. Muscarella LA, Guarnieri V, Sacco R, Curatolo P, Manzi B, Alessandrelli R, Giana G, Militerni R, Bravaccio C, Lenti C, Saccani M, Schneider C, Melmed R, D’Agruma L, Persico AM. {{Candidate gene study of HOXB1 in autism spectrum disorder}}. {Mol Autism};1(1):9.
ABSTRACT: BACKGROUND: HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. METHODS: Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. RESULTS: We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)chi2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01). CONCLUSIONS: HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.
14. Parmeggiani A, Barcia G, Posar A, Raimondi E, Santucci M, Scaduto MC. {{Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders}}. {Brain Dev} (Aug 4)
The occurrence of epilepsy in autism is variable; nevertheless, EEG paroxysmal abnormalities (PA) are frequently recorded in patients with autism, although the influence of epilepsy and/or EEG PA on the autistic regression has not been clarified yet. We examine a large sample of 345 inpatients with autism, divided into three groups: (1) patients without epilepsy and EEG PA; (2) patients with EEG PA but no seizures; (3) patients with epilepsy including febrile convulsions. The prevalence of epilepsy (24.9%) and EEG PA (45.5%) was higher than that reported in the general population. The significant differences among the three groups concerned autistic regression (comparison between groups 1 and 2, p<0.05; comparison between groups 1 and 3, p<0.01), cerebral lesions (comparison between groups 1 and 2, p<0.05; between groups 1 and 3, p<0.001), and symptomatic autism (comparison between groups 1 and 2 as much as comparison between groups 1 and 3, p<0.001), which were prevalent in groups 2 and 3; while severe/profound mental retardation was more frequent in group 3 compared to group 1 (p<0.01). Focal epilepsy (43.0%) and febrile convulsions (33.7%) were frequent in the third group with epilepsy. EEG PA were mainly localized in temporal and central areas (31.4%). Only 2.6% of patients had subcontinuous/continuous EEG PA during sleep. Seizures and EEG PA were not related to autistic regression. EEG PA occurred mainly in childhood, while epilepsy tended to occur (p<0.001) as age increased. The age at onset of seizures had two peaks: between 0 and 5 and between 10 and 15years with no difference between idiopathic and symptomatic cases. In 58.5% of subjects aged 20years, epilepsy including febrile seizures occurred at some point of their lives, while cases with only EEG PA were less frequent (9.7%). The relationship among autism, EEG PA and epilepsy should be clarified and investigated. In autism, seizures and EEG PA could represent an epiphenomenon of a cerebral dysfunction independent of apparent lesions.
15. Sasanfar R, Haddad SA, Tolouei A, Ghadami M, Yu D, Santangelo SL. {{Paternal age increases the risk for autism in an Iranian population sample}}. {Mol Autism};1(1):2.
ABSTRACT: BACKGROUND: Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent. METHODS: In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data. RESULTS: There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age. CONCLUSIONS: This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.
16. Sousa I, Clark TG, Holt R, Pagnamenta AT, Mulder EJ, Minderaa RB, Bailey AJ, Battaglia A, Klauck SM, Poustka F, Monaco AP. {{Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry}}. {Mol Autism};1(1):7.
ABSTRACT: BACKGROUND: Autism spectrum disorders (ASDs) are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR) proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes – LRRTM1 (2p), LRRTM3 (10q), LRRN1 (3p) and LRRN3 (7q) – in order to identify common genetic risk factors underlying ASDs. METHODS: In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls. RESULTS: Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3. CONCLUSIONS: Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.
17. Vanvuchelen M, Roeyers H, De Weerdt W. {{Imitation Assessment and Its Utility to the Diagnosis of Autism: Evidence from Consecutive Clinical Preschool Referrals for Suspected Autism}}. {J Autism Dev Disord} (Aug 4)
The present study sought to examine imitation difficulties as a risk factor for autism. Imitation aptitude was examined in 86 preschoolers suspected of autism (1.9-4.5 years) using the Preschool Imitation and Praxis Scale (PIPS). Differences between imitation, language, motor age-equivalents and nonverbal mental age were used to predict the diagnosis of autism. Multidisciplinary team diagnoses and ADOS-G classifications were used to differentiate children with autism spectrum disorders and non-spectrum developmental disorders. Two factors were found to be significantly associated with autism using simple logistic regression analyses: procedural imitation delay and receptive language delay. In a multivariable setting, only procedural imitation delay remained a significant predictor of autism. Results are new to the literature and require replications.
18. Wheelwright S, Auyeung B, Allison C, Baron-Cohen S. {{Defining the broader, medium and narrow autism phenotype among parents using the Autism Spectrum Quotient (AQ)}}. {Mol Autism};1(1):10.
ABSTRACT: BACKGROUND: The Autism Spectrum Quotient (AQ) is a self-report questionnaire for quantifying autistic traits. This study tests whether the AQ can differentiate between parents of children with an autism spectrum condition (ASC) and control parents. In this paper, the use of the AQ to define the broader, medium and narrow autism phenotypes (BAP, MAP, NAP) is reported, and the proportion of parents with each phenotype is compared between the two groups. METHODS: A sample of 571 fathers and 1429 mothers of children with an ASC completed the AQ, along with 349 fathers and 658 mothers of developing typically children. RESULTS: Both mothers and fathers of the diagnosed children scored higher than the control parents on total AQ score and on four out of five of the subscales. Additionally, there were more parents of diagnosed children with a BAP, MAP or NAP. CONCLUSIONS: The AQ provides an efficient method for quantifying where an individual lies along the dimension of autistic traits, and extends the notion of a broader phenotype among first-degree relatives of those with ASC. The AQ is likely to have many applications, including population and clinical screening, and stratification in genetic studies.
19. Williams K, Wheeler DM, Silove N, Hazell P. {{Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD)}}. {Cochrane Database Syst Rev};8:CD004677.
BACKGROUND: Autism spectrum disorders (ASD) are characterised by abnormalities in social interaction and communication skills, as well as stereotypic behaviours and restricted activities and interests. Selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of co-morbidity associated with ASD such as depression, anxiety and obsessive-compulsive behaviours. OBJECTIVES: To determine if treatment with an SSRI: 1. improves the core features of autism (social interaction, communication and behavioural problems); 2. improves other non-core aspects of behaviour or function such as self-injurious behaviour; 3. improves the quality of life of children and their carers; 4. has short and long term effects on outcome; 5. causes harms. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 4), MEDLINE ( December 2009), EMBASE (December 2009), CINAHL (December 2009), PsycINFO (December 2009) and ERIC (December 2009), without language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any dose of oral SSRI compared with placebo, in participants with autism spectrum disorders. Trials must have included at least one standardised outcome measure. DATA COLLECTION AND ANALYSIS: Two authors independently selected and appraised studies for inclusion and risk of bias. All data were continuous. Meta-analysis, where possible, used a random-effects model. MAIN RESULTS: Seven RCTs with a total of 271 participants were included. Four SSRIs were evaluated: fluoxetine (two studies), fluvoxamine (two studies), fenfluramine (two studies) and citalopram (one study). Five studies included only children and two studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence of participants. Seventeen different outcome measures were reported. Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive behaviour (OCB), different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis. One large, high quality study in children showed no evidence of positive effect of citalopram. Two small studies in adults showed positive outcomes for CGI and OCB; one study showed improvements in aggression and another in anxiety. AUTHORS’ CONCLUSIONS: There is no evidence of effect of SSRIs in children and emerging evidence of harm. There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear.
