Purpose Angelman Syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromo... more Purpose Angelman Syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD) or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are reported frequently in clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. Methods Prospective cohort study of 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the Bone Health Index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication (ASM) use, mobility, BMI, and onset of puberty. Results Children with AS had a mean BHI of -1.77 SD...
While many neuroimaging studies have investigated the neurobiological basis of attention deficit ... more While many neuroimaging studies have investigated the neurobiological basis of attention deficit hyperactivity disorder (ADHD), few have studied the neurobiology of attention problems in the general population. The ability to pay attention falls along a continuum within the population, with children with ADHD at one extreme of the spectrum and, therefore, a dimensional perspective of evaluating attention problems has an added value to the existing literature. Our goal was to investigate the relationship between cortical thickness and inattention and hyperactivity symptoms in a large population of young children. This study is embedded within the Generation R Study and includes 6- to 8-year-old children (n = 444) with parent-reported attention and hyperactivity measures and high-resolution structural imaging data. We investigated the relationship between cortical thickness across the entire brain and the Child Behavior Checklist Attention Deficit Hyperactivity Problems score. We foun...
ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogen... more ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation.MethodsWe assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non...
The following full text is a publisher's version. For additional information about this publ... more The following full text is a publisher's version. For additional information about this publication click this link.
The development of brain structure and function shows large inter-individual variation. The exten... more The development of brain structure and function shows large inter-individual variation. The extent to which this variation is due to genetic or environmental influences has been investigated in twin studies using structural and func-tional Magnetic Resonance Imaging (MRI). The current re-view presents an overview of twin studies using MRI in children, adults and elderly, and focuses on cross-sectional and longitudinal designs. The majority of the investigated brain measures are heritable to a large extent (60–80 %), although spatial differences in heritability are observed as well. Cross-sectional studies suggest that heritability estimates slightly increase from childhood to adulthood. Long-term longitudinal studies are better suited to study developmental changes in heritability, but these studies are limited. Results so far suggest that the heritability of change over time is relatively low or absent, but more studies are needed to confirm these findings. Compared to brain struct...
This thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity pr... more This thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity problems in the general population. The notion that child psychopathology might be better described within a dimensional framework, rather than with clearly defined diagnostic categories, has recently gained support. Despite this, the majority of studies are still performed in clinical samples of children with attention-deficit/hyperactivity disorder (ADHD). By studying the neurobiology (neuroimaging and genetics) and neuropsychology of attention-deficit/hyperactivity problems in the general population, this thesis extends previous work in clinical samples to the full range of problems in the general population.
markdownabstractThis thesis focuses on the neurobiology and neuropsychology of attention-deficit/... more markdownabstractThis thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity problems in the general population. The notion that child psychopathology might be better described within a dimensional framework, rather than with clearly defined diagnostic categories, has recently gained support. Despite this, the majority of studies are still performed in clinical samples of children with attention-deficit/hyperactivity disorder (ADHD). By studying the neurobiology (neuroimaging and genetics) and neuropsychology of attention-deficit/hyperactivity problems in the general population, this thesis extends previous work in clinical samples to the full range of problems in the general population.
Purpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitiv... more Purpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. Methods We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. Results Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population....
ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve in... more ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4–17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5–10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.ResultsThirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect −5.6 IQ points, 95% confidence interval −12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questio...
Purpose Angelman Syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromo... more Purpose Angelman Syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD) or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are reported frequently in clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. Methods Prospective cohort study of 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the Bone Health Index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication (ASM) use, mobility, BMI, and onset of puberty. Results Children with AS had a mean BHI of -1.77 SD...
While many neuroimaging studies have investigated the neurobiological basis of attention deficit ... more While many neuroimaging studies have investigated the neurobiological basis of attention deficit hyperactivity disorder (ADHD), few have studied the neurobiology of attention problems in the general population. The ability to pay attention falls along a continuum within the population, with children with ADHD at one extreme of the spectrum and, therefore, a dimensional perspective of evaluating attention problems has an added value to the existing literature. Our goal was to investigate the relationship between cortical thickness and inattention and hyperactivity symptoms in a large population of young children. This study is embedded within the Generation R Study and includes 6- to 8-year-old children (n = 444) with parent-reported attention and hyperactivity measures and high-resolution structural imaging data. We investigated the relationship between cortical thickness across the entire brain and the Child Behavior Checklist Attention Deficit Hyperactivity Problems score. We foun...
ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogen... more ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation.MethodsWe assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non...
The following full text is a publisher's version. For additional information about this publ... more The following full text is a publisher's version. For additional information about this publication click this link.
The development of brain structure and function shows large inter-individual variation. The exten... more The development of brain structure and function shows large inter-individual variation. The extent to which this variation is due to genetic or environmental influences has been investigated in twin studies using structural and func-tional Magnetic Resonance Imaging (MRI). The current re-view presents an overview of twin studies using MRI in children, adults and elderly, and focuses on cross-sectional and longitudinal designs. The majority of the investigated brain measures are heritable to a large extent (60–80 %), although spatial differences in heritability are observed as well. Cross-sectional studies suggest that heritability estimates slightly increase from childhood to adulthood. Long-term longitudinal studies are better suited to study developmental changes in heritability, but these studies are limited. Results so far suggest that the heritability of change over time is relatively low or absent, but more studies are needed to confirm these findings. Compared to brain struct...
This thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity pr... more This thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity problems in the general population. The notion that child psychopathology might be better described within a dimensional framework, rather than with clearly defined diagnostic categories, has recently gained support. Despite this, the majority of studies are still performed in clinical samples of children with attention-deficit/hyperactivity disorder (ADHD). By studying the neurobiology (neuroimaging and genetics) and neuropsychology of attention-deficit/hyperactivity problems in the general population, this thesis extends previous work in clinical samples to the full range of problems in the general population.
markdownabstractThis thesis focuses on the neurobiology and neuropsychology of attention-deficit/... more markdownabstractThis thesis focuses on the neurobiology and neuropsychology of attention-deficit/hyperactivity problems in the general population. The notion that child psychopathology might be better described within a dimensional framework, rather than with clearly defined diagnostic categories, has recently gained support. Despite this, the majority of studies are still performed in clinical samples of children with attention-deficit/hyperactivity disorder (ADHD). By studying the neurobiology (neuroimaging and genetics) and neuropsychology of attention-deficit/hyperactivity problems in the general population, this thesis extends previous work in clinical samples to the full range of problems in the general population.
Purpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitiv... more Purpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. Methods We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. Results Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population....
ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve in... more ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4–17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5–10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.ResultsThirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect −5.6 IQ points, 95% confidence interval −12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questio...
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