No aggression in a 4-year-old boy with an androgen-producing tumour: Case Report

BACKGROUND: The androgen testosterone plays a critical role in many aspects of sexual differentiation. Also, it is thought to induce aggressive behaviours or to play a role in social dominance. CASE PRESENTATION: In this case report a 4-year-old boy is described whose testosterone and dehydroepiandrosterone sulphate (DHEA-S) levels were raised to pubertal levels due to a testosterone producing testis tumour. This provided the unique opportunity to examine the effects of elevated levels of androgens on levels of aggression or on social dominance before the onset of puberty. CONCLUSION: The present case report does not support the hypothesis of a causal relationship between testosterone and aggression or between testosterone and social dominance in young children

Meten van kenmerken van autismespectrumstoornissen in gezinnen: een zoektocht naar informatieve fenotypes

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders defined by impairments in social communication and social interaction and by a restricted and repetitive pattern of behaviour and interests with a strong genetic basis. Finding genetic causes of ASDs has been complicated by both genotypic and phenotypic heterogeneity. To overcome these kinds of problems in psychiatry genetics, the concept of endophenotypes, traits that are thought to be intermediate between genes and phenotype, was introduced. In 2007 this concept was broadened to (genetically) informative phenotypes, with three subtypes, each with specific characteristics and ways in which they can be genetically informative. These phenotypes can be of biological, cognitive or behavioural nature. Criteria that should be met for some of these subtypes are, e.g., that it should segregate with the disorder, that it can be measured reliably, and that is present in unaffected family members at a higher frequency than in the general population. In this doctoral dissertation, we describe different studies that aim at defining candidate informative phenotypes for ASDs, focusing on behavioural characteristics in participants with an ASD and their unaffected relatives. All the analyses were based on datanbsp;in 170 families with at least one childnbsp;an ASD. A series of factor analyses on Developmental, Dimensional and Diagnostic Interview (3di) data from participants with an ASD results in a five dimensions solution (Chapter 2). The presence of these underlying constructs cannot be confirmed on 3di data of their unaffected siblings, and the same conclusion resulted from analyses on Social Responsiveness Scale (SRS) data. Based on these results, we conclude that clinical and research instruments that measure ASD traits result in different underlying symptom dimensions in ASD vs. non-ASD samples, and consequently, scores on separate symptom dimensions based on the clinical phenotype in ASD are not readily applicable as informative phenotypes in non-ASD samples (Chapter 3). Another way of searching for informative phenotypes is by studying whether behavioural characteristics of individuals with an ASD are also present in their unaffected relatives. In Chapter 4 we report about atypical sensory processing in adolescents with an ASD using the Adolescent/Adult Sensory Profile. Their unaffected adolescent siblings show a level of sensation seeking that is intermediate between adolescents with an ASD and general population controls. We conclude that, although more research is definitely needed, Sensation Seeking may be a candidate genetically informative phenotype. In a similar vein, we study quantitative autism traits (QAT) as measured by the Social Responsiveness Scale (SRS) of all participating family members. Based on comparisons of SRS total scores of participants with an ASD, their unaffected family members and general population controls, we demonstrate that fathers of children with an ASD show a higher level of QAT compared to controls (Chapter 5). In Chapter 6 we describe the association of QAT levels between family members. These results corroborate the assortative mating theory and possible intergenerational transmission of QAT from both fathers and mothers to their offspring. Combining our results and those of other studies, we can conclude that QAT measures, e.g., the SRS, may serve as a genetically informative phenotype. In our general discussion, the methodological difficulties about the informative phenotype concept are thoroughly discussed. In short, we propose to use the umbrella term genetically informative phenotype, when studying behavioural characteristics in genetic research, since the use of subtypes leads to discussions about terminology, that may be contra productive for further research. Based on our analyses and results, but also on the questions we came across carrying out our studies, we also highlight important methodological issues for both researchers and clinicians. For ASD family studies, a thorough diagnostic screening of all family members appears to be very important since false allocation to an unaffected status can have major consequence on the results. For clinical practice, many questionnaires and interviews have been developed for screening and diagnostic assessment purposes. We discuss however, that clinicians should be aware that the context in which they are used, e.g., screening vs. diagnostic assessment in a psychiatric context vs. family research, can have great influence on their reliability.Dankwoord Summary - Samenvatting Table of content Chapter 1: General introduction 1. Autism spectrum disorders 1.1. Classification and clinical picture 1.2. Epidemiology 1.3. Aetiology 1.3.1. Twin and family studies 1.3.2. Genetics of ASDs 1.3.3. Environmental factors contributing to ASDs 1.3.4. Estimation of recurrence risk 1.3.5. Solutions to overcome the heterogeneity in research 1.4. Informative phenotypes 1.4.1. History of the concept 1.4.2. Component phenotype 1.4.3. Intermediate phenotype 1.4.4. Covariate 1.4.5. Difficulties in the search for informative phenotypes 1.5. Broad autism phenotype 1.6. Quantitative autism traits in the general population 1.7. Conclusion 2. Aims of this PhD research 2.1. To search for candidate informative phenotypes for ASD 2.1.1. Social and communicative reciprocity 2.1.2. Constructs underlying the categorical ASD phenotype 2.1.3. Symptoms of sensory hyper- and/or hyposensitivity 2.2. To search for patterns of familial transmission of QAT in ASD families 2.3. To define individual and familial characteristics that influence both the presence and transmission of these traits 2.3.1. Gender 2.3.2. Relation to the child with an ASD 2.3.3. Type of family: simplex vs. multiplex 3. Methodology of the PhD research 3.1. Ethical approval 3.2. Participants 3.3. Instruments and procedures 3.3.1. Sensory Profile (SP) and Adult and Adolescent Sensory Profile 3.3.2. Developmental, Dimensional and Diagnostic Interview 3.3.3. Other procedures References Chapter 2: The underlying symptom structure of autism spectrum disorders: A factor analytic approach using the Developmental, Dimensional and Diagnostic Interview Abstract 1. Introduction 2. Methods 2.1. Participants 2.2. Instruments 2.3. Statistical analyses 3. Results 3.1. Confirmatory factor analyses 3.2. Exploratory factor analyses 4. Discussion 5. Conclusion Acknowledgements References Chapter 3: No replication of the autism spectrum disorder symptom structure in unaffected siblings Abstract 1. Introduction 2. Methods 3. Results 4. Additional analyses and results 5. Conclusion References Chapter 4: Atypical sensory processing in adolescents with an autism spectrum disorder and their non-affected siblings Abstract 1. Introduction 2. Methods 2.1. Sample 2.1.1. Participants with an ASD and siblings 2.1.2. Controls 2.1.3. Total sample 2.2. Measures 2.2.1. Adolescent/Adult Sensory Profile (AASP) 2.2.2. Developmental, Dimensional and Diagnostic Interview (3di) 2.2.3. Social Responsiveness Scale (SRS) 2.3. Statistical analyses 3. Results 4. Discussion 4.1. Limitations 4.2. Clinical Implications 5. Conclusion Acknowledgements References Chapter 5: Quantitative autism traits in first degree relatives: Evidence for the broader autism phenotype in fathers, but not in mothers and siblings Abstract 1. Introduction 1.1. Aims of the study 2. Methods 2.1. Research population 2.1.1. Children with an ASD, their siblings and parents 2.1.2. General population controls 2.1.3. Adults with an ASD 2.1.4. Total sample 2.2. Instruments 2.2.1. Social Responsiveness Scale (SRS) 2.2.2. Developmental, Dimensional and Diagnostic Interview (3di) 2.3. Statistical analysis 3. Results 3.1. Children 3.2. Adults 4. Discussion 4.1. Children 4.2. Adults 4.3. Limitations 5. Conclusion Acknowledgements References Chapter 6: Measuring quantitative autism traits in families: Informant effect or intergenerational transmission? Abstract 1. Introduction 2. Methods 2.1. Participants 2.2. Instruments 2.2.1. Social Responsiveness Scale (SRS) 2.3. Statistical analyses 3. Results 3.1. Do mother, father and teacher reports yield similar SRS ratings for children? 3.2. Do self- and other-reports yield similar SRS ratings for adults? 3.3. How are parental and offspring QAT related in ASD families, while accounting for possible informant effects? 4. Discussion 4.1. Inter-informant agreement in children 4.2. Inter-informant agreement in adults 4.3. Relatedness of parental and offspring QAT in families, accounting for informant effects 4.4. Limitations 5. Conclusion Acknowledgments References Chapter 7: General discussion 1. Background and research goals 2. Answers to our research questions 2.1. Candidate informative phenotypes? 2.1.1. A milder expression of ASD traits: evidence for the Broader Autism Phenotype in fathers but not in mothers and siblings 2.1.2. Constructs underlying the categorical ASD phenotype 2.1.3. Symptoms of sensory hyper- and/or hyposensitivity: Sensation Seeking as a candidate informative phenotype. 2.2. Familial transmission of QAT? 2.3. Patient and family characteristics that influence both the presence and transmission of the possible informative phenotypes presented earlier 2.3.1. Influence on the BAP in unaffected family members 2.3.2. Influence on atypical sensory processing in unaffected family members 2.3.3. Influence on familial transmission of QAT 2.4. Building an interesting database of well phenotyped ASD families for further research 2.5. Conclusions 2.6. Discussion 3. Reflections about methodology: limitations to our (and other) studies 3.1. Participants: who do we include? 3.1.1. ASD: who is affected and who is not? 3.1.2. Simplex or Multiplex? 3.1.3. Research sample reflecting the full spectrum? 3.2. Diagnostic instruments: what do we (want to) measure? 3.2.1. Questionnaires 3.2.2. Interviews 3.2.3. Direct observations 4. Recommendations for future research 5. Reflections for clinicians 5.1. Diagnostic assessment 5.2. Diagnostic stability 5.3. Broader Autism Phenotype? 5.4. Recurrence risk and intergenerational transmission References Appendix A: list of publications based on the dataset gathered during this PhD research Curriculum vitae & publicationsstatus: publishe

The underlying symptom structure of autism spectrum disorders: A factor analytic approach using the Developmental, Dimensional and Diagnostic Interview

© 2014 Elsevier Ltd. Several studies have focused on the underlying symptom structure of Autism Spectrum Disorders (ASD), but results have been equivocal. We performed a confirmatory factor analysis on data of the Developmental, Dimensional and Diagnostic Interview of 275 participants with ASD between 3 and 23 years of age, aimed at strengthening the empirical evidence of previously published factor structure solutions using the same instrument. As none of these hypothesised models fitted our data, an exploratory factor analysis was undertaken. Results pointed towards a five factor model. A 'Restricted and Repetitive Behaviour and Interest' factor could be separated from 'Shaking and Nodding', 'Emotional Reciprocity' and two other factors that both represented deficits in social interaction and communication. Although not completely confirming, our results are generally in favour of the present DSM-5 criteria. By showing that the items did not fully segregate according to theoretically postulated subdomains, we offer a possible explanation for the heterogeneity in proposed factor structures for ASD.publisher: Elsevier articletitle: The underlying symptom structure of autism spectrum disorders: A factor analytic approach using the developmental, dimensional and diagnostic interview journaltitle: Research in Autism Spectrum Disorders articlelink: http://dx.doi.org/10.1016/j.rasd.2014.11.002 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.status: publishe

Measuring quantitative autism traits in families: Informant effect or intergenerational transmission?

Autism spectrum disorders (ASD) have a high degree of heritability, but there is still much debate about specific causal genes and pathways. To gain insight into patterns of transmission, research has focused on the relatedness of quantitative autism traits (QAT) between family members, mostly using questionnaires. Yet, different kinds of bias may influence research results. In this paper, we focus on possible informant effects and, taking these into account, on possible intergenerational transmission of QAT. This study used multiple informant data retrieved via the Social Responsiveness Scale from 170 families with at least one member with ASD. Using intraclass correlations (ICCs) and mixed model analyses, we investigated inter-informant agreement and differences between parent and teacher reports on children and between self- and other-reports on adults. Using structural equation modelling (SEM), we investigated the relatedness of QAT between family members in ASD families. Parent-teacher agreement about social responsiveness was poor, especially for children with ASD, though agreement between parents was moderate to strong for affected and unaffected children. Agreement between self- and other-report in adult men was good, but only moderate in women. Agreement did not differ between adults with and without ASD. While accounting for informant effects, our SEM results corroborated the assortative mating theory and the intergenerational transmission of QAT from both fathers and mothers to their offspring.status: publishe

Quantitative autism traits in first degree relatives: Evidence for the broader autism phenotype in fathers, but not in mothers and siblings

Autism spectrum disorder (ASD) symptoms are present in unaffected relatives and individuals from the general population. Results are inconclusive, however, on whether unaffected relatives have higher levels of quantitative autism traits (QAT) or not. This might be due to differences in research populations, because behavioral data and molecular genetic research suggest that the genetic etiology of ASD is different in multiplex and simplex families. We compared 117 unaffected siblings and 276 parents of at least one child with ASD with 280 children and 595 adults from the general population on the presence of QAT using the Social Responsiveness Scale (SRS). Mean SRS scores for siblings, control children, parents and control adults were 25.4, 26.6, 33.7 and 32.9. Fathers of children with ASD showed significantly higher levels of QAT than controls, but siblings and mothers did not. We could not detect a statistically significant difference in SRS scores between relatives from simplex and multiplex families. These results do not support the theory of differential (genetic) etiology in multiplex and simplex families and suggest that a carried genetic risk is generally not expressed phenotypically in most relatives, except in fathers.status: publishe

DISC1 duplication in two brothers with autism and mild mental retardation

We describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family.status: publishe

Platelet studies in autism spectrum disorder patients and first-degree relatives

Platelets have been proven to be a useful cellular model to study some neuropathologies, due to the overlapping biological features between neurons and platelets as granule secreting cells. Altered platelet dense granule morphology was previously reported in three autism spectrum disorder (ASD) patients with chromosomal translocations that disrupted ASD candidate genes NBEA, SCAMP5, and AMYSIN, but a systematic analysis of platelet function in ASD is lacking in contrast to numerous reports of elevated serotonin levels in platelets and blood as potential biomarker for ASD.status: publishe

Additional file 2: Figure S1. of Platelet studies in autism spectrum disorder patients and first-degree relatives

Platelet activation pathways investigated in this study. Platelet aggregation with the strong agonist arachidonic acid (AA) stimulates platelets via the formation of thromboxane A2 (TxA2) by the enzyme COX1 to finally active the G protein-coupled thromboxane receptor that will result in calcium efflux and the release of alpha (α) and dense (δ) granules. A high dose of AA does not require platelet secretion for full platelet activation. Activation with the weak agonist epinephrine (EPI) will partially stimulate platelets via the adrenergic receptor but will require platelet δ granule secretion (with the release of ADP and TxA2) to obtain full platelet activation. Platelet ATP secretion from δ granules was measured after platelet activation with collagen and ADP that stimulate different pathways to result in the release of ATP from dense granules that was measured using a lumino-aggregometer. Serotonin was measured in plasma after isolation of platelets by centrifugation. It is known that serotonin can active it G protein-coupled receptor but it is a weak agonist that is not able to induce platelet aggregation without stimulation with another agonist. Normal plasma concentrations of serotonin are unable to result in full platelet aggregation. Additional file 2: Figure S2 Platelet aggregation with arachidonic acid. Platelet aggregation in response to 1 mM AA in 159 ASD patients, 103 siblings, 186 parents, and 41 adult controls measured in platelet-rich plasma. Graphs indicating means and 95 % CI value. (PDF 97 kb

Additional file 1: Table S1. of Platelet studies in autism spectrum disorder patients and first-degree relatives

Criteria leading to exclusion of individuals in the platelet study. (DOC 33 kb