Heterogeneity in Autism Spectrum Disorders

176 Pages·2016·3.57 MB·English

Heterogeneity in Autism Spectrum Disorders:
Clarifying Core and eo-occurring Characteristics,
Correlates and Course.
Martinus Lambertus Jacobus Marie Eussen

Heterogeneity in Autism Spectrum Disorders:
Clarifying Core and eo-occurring Characteristics,
Correlates and Course.
Heterogeniteit bij autismespectrumstoornissen:
op zoek naar de sa men hang tussen kernsymptomen, comorbide symp
tomen, onderliggende kenmerken en beloop
Proefschrift
Ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de rector magnificus
Prof. Dr. H.A.P. Pols
en volgens het besluit van het College voor Promoties
De open bare verdediging zal plaatsvinden op
vrijdag 4 september 2015 om 11.30 uur
door
Martin us Lambertus Jacobus Marie Eussen
geboren te Geleen
Erasmus University Rotterdam
PROMOTIECOMMISSIE
Promotor: Prof. dr. F.C. Verhulst
Overige leden: Prof. dr. C. Rieffe
Prof. dr. F. Verheij
Dr.T. White
eo-promotor: Dr. K. Greaves-Lord
CONTENTS
Chapter 1 General introduction. 7
Chapter 2 Profiles of core autistic symptoms and relations with 23
eo-occurring internalizing and externalizing problems
Submitted for publication.
Chapter 3 The association of quality of social relations, symptom 35
severity and intelligence with anxiety in children with
Autism Spectrum Disorders
Autism, 2013, 17(6), 723-735.
Chapter4 Formal Thought Disorder in Autism Spectrum Disorder 51
predicts future symptom-severity, but not psychosis
prodrome. European Child and Adolescent Psychiatry,
2015 Feb;24(2):163-72.
Chapter 5 Childhood facial recognition predicts adolescent 71
symptom severity in Autism Spectrum Disorders.
Autism Research, Doi: 10.1 002/aur.1443.
Chapter 6 Superior disembedding performance in childhood 91
predicts adolescent severity of repetitive behaviors:
a seven years follow-up of individuals with autism
spectrum disorder. Accepted Autism Research.
Chapter 7 General Discussion. 109
ChapterS References 127
Summary 145
Samenvatting 151
CV 157
Portfolio and Publications 159
Dankwoord 171

Chapter 1
General introduction

19
General Introduction
INTRODUCTION
Short background, general aims
The general aim of the current thesis is to contribute to the clarification of the het
erogeneity within Autism Spectrum Disorder (ASD). ASD is a heterogeneous disor
der at the phenotypicallevel, but also at the endophenotypical and the genotypical
level (Waterhouse, 2011).
The phenotype can be defined as the composite of all observable characteristics
of an individual. At the phenotypical level, ASD is characterized by a broad range
and variation in the core symptoms of social interaction problems, communication
problems and repetitive behaviors and restricted interests (Hus, Pickles, Cook et
al., 2007). Besides that, individuals with ASD show a large variation in the levels of
eo-occurring psychiatric symptoms, like anxiety, attention problems, externalizing
behavior and this results in an overlap between ASD and other disorders (Leyfer,
Folstein, Bacalman et al., 2006; De Bruin, Ferdinand, Meester et al., 2007; Simonoff,
Pickles, Charman et al., 2008).
The genotype can be defined as the sum total of genes, transmitted from parent
to offspring. At the level of the genotype, heterogeneity in ASD is caused in the
first place by the presence of multiple gene variants, each exerting a small effect
on the phenotype (Rutter & Thapar, 2014; Jeste & Geschwind, 2014). Copy number
variations (CNV) constitute a second source of genetic heterogeneity in ASD. CNV's
are unique for each person; 70% of CNV's in ASD concern de novo mutations and
CNV's result in milder or more severe symptoms (Jeste & Geschwind, 2014). Single
Nucleotide Polymorfisms (SNP) constitute a third source of genetic heterogeneity
and from Genome Wide Association Studies (GWAS) we know that SNP's in ASD are
not only located in the coding regions (exons) of genes, but also in the noncoding
or regulatory regions (introns) (Abrahams & Geschwind, 2008; Waterhouse, 2011;
Rutter & Thapar, 2014.
Endophenotypes (or intermediate phenotypes or vulnerability markers) can be
defined as internal, not directly observable characteristics, which can be detected
by biochemical tests, brain imaging or neuropsychological tests. The concept of
endophenotypes was introduced in order to bridge the gap between the consider
able genetic and phenotypical variability (Gottesman & Gould, 2003). Positioned
between the genetic disposition of the individual and the phenotype, endopheno
types were considered to offer a gateway to clarify the complex interplay of genetic
factors and life experiences that finally give rise to the phenotype (Gottesman &
Gould, 2003; Persico & Sacco, 2014). At present, many different endophenotypes for
ASD have been proposed, most of which show insufficient specificity and sensitivity
l
10 Chapter 1
(Persico & Sacco, 2014) and hence the level of endophenotypes is also characterized
by heterogeneity.
In this introduction, first general aspects of ASD and sources of phenotypical
heterogeneity within ASD will be discussed. Next, as a frame of interpretation,
general aspects of endophenotypes will be described, and subsequently, particular
neuropsychological and social cognitive endophenotypes in ASD relevant for this
thesis will be addressed in more detail. Finally, the research questions and sample in
the chapters of this thesis will be discussed and an overall outline will be provided.
General aspects of ASD
As for the definition of ASD, both the Diagnostic Statistical Manual (DSM)-IV-TR (APA,
2000) classification will be described-because it was used in this thesis- as well as
the classification according to DSM 5 (APA, 2013), because it incorporates important
changes compared to DSM-IV-TR based on insights from research findings.
In the current DSM 5 (APA, 2013), ASD is defined as a neurodevelopmental disor
der with persistent deficits across multiple social contexts on two domains of symp
toms: 'social communication & social interaction' (SCI) and 'restricted, repetitive
patterns of behaviour, interests, or activities' (RRBI). The term neurodevelopmental
implicates that symptoms are present early in live, that these same symptoms exert
their infiuence upon further development and that altered brain processes govern
this atypical development. As a consequence, the symptoms of ASD should be pres
ent in early childhood during the second year of life (12-24 months of age), but they
may not fully manifest themselves until social demands exceed limited capacities
(APA, 2013) or they may be seen earlier than 12 months if developmental delays are
severe.
In the DSM-IV-TR the overarching category of Pervasive Developmental Disorder
(POD) was introduced and this overarching category included multiple classifica
tions, ranging from the classification of Autistic Disorder (AD) with strict criteria and
severe symptoms on each ofthe symptom domains, to categories with more lenient
criteria. The categories of Asperger's Syndrome (AS) and Pervasive Developmental
Disorder -Not Otherwise Specified (POD-NOS) were characterized by more lenient
criteria, i.e. less symptoms on the different domains (APA, 2000). The presumed
category of AS in DSM-IV-TR differed from AD in its relatively normal language
development, in the high level of cognitive functioning and in the relatively mild
communication impairment (APA, 2000; Toth & King, 2008). The classification of
POD-NOS in DSM-IV-TR could be applied to a child who showed symptoms within
all three domains of ASD, but did not reach the threshold for a full diagnosis of AD,
or to a child who only showed symptoms above threshold in one or two domains of
ASD (APA, 2000; Happe & Ronald, 2008). Thus, children with POD-NOS constituted a