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Autism spectrum disorder (ASD) encompasses a broad range of neurodevelopmental disorders, with two core symptoms: deficits in social communication, and restrictive interests and repetitive behaviors. Genetics is thought to play a large role in ASD and currently there are hundreds of associated genes. We first studied the thousand and one amino acid kinase gene (TAOK2), which plays an important role in neurodevelopment. We found that loss of TAOK2 causes deficits in neuron development and activity, leading to morphological changes in various mouse brain regions and ASD-related behaviors. We studied the impact of de novo mutations identified in TAOK2, which caused aberrant neuron dendritic arborization and formation of synapses. To elucidate how TAOK2 regulates neuron development we used a proximity-labeling proteomics technique (BioID) to identify its protein-protein interaction (PPI) network. We applied this same methodology to a total of 41 ASD-risk genes and observed multiple convergent biological processes, including the less-studied mitochondrial and metabolic pathways. ASD-risk genes, including TAOK2, associated with mitochondrial proteins were found to have altered cellular respiration. The shared ASD-risk gene PPI network enriched for other ASD-risk genes and was used to group genes based on their shared PPI networks. These gene groups showed correlation between the clinical behavior scores of individuals that had mutations within the distinct gene groups. Lastly, we identified changes in the PPI networks of multiple ASD-risk genes through BioID, which we validated with various functional assays. In summary, we developed a proximity-labeling proteomics method that identified multiple convergent biological pathways associated with ASD. Studying the function of TAOK2 revealed multiple disease-relevant pathologies associated with the disorder, however proximity labeling has the potential to categorize multiple ASD-risk genes and elucidate their shared signaling pathways, which together, can advance the development of robust treatments for ASD. / Thesis / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) is a group of brain disorders that affect more than 1% of children. Genetic variants are thought to cause ASD pathology, however there are currently hundreds of genes that have not been studied. We studied how disruption of one of those genes, TAOK2, alters brain development in mice and identified TAOK2 variants in multiple children with ASD. We then used BioID to find the shared disease-related mechanisms between multiple ASD-risk genes, and found that mitochondrial function and activity were connected to many of these genes. We showed that BioID can be used to study the effect of mutations in multiple ASD-risk genes simultaneously. Last, we could group children with ASD with similar behavior test scores based on the shared mechanisms of ASD-risk genes. Together our findings could be used to advance the development of robust treatments or new diagnostic tools for ASD.

Bakgrund: Aktivitetsbalans är en subjektiv upplevelse som innefattar rätt mängd och rätt variation mellan aktiviteter. Att ha ett barn med NPF kan ha effekter på hur familjens vardagsrutiner utformas samt påverka föräldrarnas val och planering av aktiviteter. Syfte: Undersöka aktivitetsbalans hos föräldrar till barn med neuropsykiatrisk funktionsnedsättning, NPF, i åldrarna 6–12 år. Metod: En kvantitativ enkätstudie genomfördes. Webbenkäten utformades enligt Occupational Balance Questionnaire (OBQ) och varje fråga på ordinalskalenivå kompletterades med ett fritextsvar. Vid analys av data tillämpades en kvantitativ bearbetning och en kvalitativ innehållsanalys. I studien deltog 194 föräldrar. Resultat: Föräldrarna skattade sin aktivitetsbalans övervägande lågt. Resultatet visade även att det fanns en signifikant skillnad mellan föräldrarnas arbetssituation och antal barn med NPF. Däremot visade resultatet ingen signifikant skillnad om föräldrarna var sammanboende/gifta eller ensamstående. I studiens innehållsanalys identifierades tre kategorier: Omstrukturering av vardagen, Förälderns kontakt med samhällsinsatser och Den förändrade rollen som förälder. Slutsats: Föräldrarna har en genomgående låg aktivitetsbalans. För att bemöta föräldrarnas behov av stöd bör arbetsterapeuter utgå från ett helhetsperspektiv på familjen i arbetet med barn med NPF. / Background: Occupational balance is a subjective experience that includes the right amount and the right variation between activities. Having a child with NDD can have effects on how the family's everyday routines are organized and affect the parents' choice and planning of activities. Aim: Exploring occupational balance in parents to children with neurodevelopmental disorder, NDD, ages 6-12 years. Method: A quantitative survey was conducted. The web survey was designed according to the Occupational Balance Questionnaire (OBQ) and each question at the ordinal scale level was supplemented with a free text response. When analyzing data, a quantitative processing and a qualitative content analysis were applied. The study had 194 parents participating. Result: Parents estimated their occupational balance predominantly low. The result also showed that there was a significant difference between the parents' work situation and the number of children with NDD. However, the result showed no significant difference if the parents were cohabiting / married or single. In the study's content analysis three categories were identified: Restructuring of everyday life, Parent's contact with social support and The changed role as a parent. Conclusion: The parents have a consistently low occupational balance. To address the parents' need for support, occupational therapists should proceed a holistic perspective on the family in the work with children with NDD.

Children with alcohol-related neurodevelopmental disorder or attention deficit/hyperactivity disorder differ on neuropsychological tasks and measures of eye movement control. M.Sc. Thesis, Queen’s University, Kingston, Ontario, Canada, January 2010. Background: Alcohol-related neurodevelopmental disorder (ARND) accounts for the majority of diagnoses associated with prenatal alcohol exposure. Unfortunately, ARND frequently poses a significant clinical challenge as these patients lack the visible physical characteristics associated with alcohol teratogenicity. Moreover, the cognitive and behavioural disabilities are complex and overlap with those of attention deficit/hyperactivity disorder (ADHD). Furthermore, co-morbid ADHD is prevalent in children with prenatal alcohol exposure. While early and accurate diagnosis provides the best prognosis for those affected, there is a lack of tools for differential diagnosis between these two disorders. The goal of this study was to test the hypothesis that children with ARND exhibit different performance from children with ADHD on computer-based neuropsychological tests and eye movement tasks. Methods: Our study group was composed of 42 children with ARND and 31 children with ADHD aged 8-15 years, male and female. Children completed four tasks selected from the Cambridge Neuropsychological Test Automated Battery (CANTAB®) that provided measures of attention, planning, strategy and spatial working memory. Subjects also performed pro- and anti-saccade tasks, and eye movements were recorded using a mobile eye-tracking system. Results: Children with ARND demonstrated elevated decision times on a visual matching test of attention and longer response times on a task of spatial working memory, although the two groups had similar errors scores. Also, compared to children with ADHD, children with ARND had greater anticipatory errors in both the pro- and anti-saccade tasks. Conclusion: This study demonstrates that there are measurable differences in executive function and eye movement control between children with ARND or ADHD. Greater deficits in visuospatial processing in ARND may underlie these differences. These findings demonstrate that the neurobehavioural phenotypes of children with ARND or ADHD have distinct features, which may be accounted for by differences in the patterns of brain injury underlying these two disorders. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-01-15 15:15:47.738

Chromatin remodeling complexes modulate DNA accessibility permitting neuronal progenitor cells to proliferate and differentiate to form the mammalian neocortex. In the case of BPTF (Bromodomain PHD transcription Factor), the major subunit of a chromatin remodelling complex called NURF (Nucleosome Remodelling Factor), mutations leading to its haploinsufficiency have been linked to cause a recently annotated human neurodevelopmental disorder called NEDDFL (Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies). Patients with this syndrome are mainly characterized with microcephaly and intellectual disability. We conditionally knockout (cKO) the Bptf gene during neocortical neurogenesis to analyze its role during embryonic and postnatal brain development. The Bptf cKO animals reveal significant forebrain hypoplasia. During cortical neurogenesis, the Bptf cKO mice show a reduction in intermediate neuronal progenitor (INP) cells, an increase in apoptosis as well as a prolonged cell cycle within proliferating progenitors. Similarly, the postmitotic pyramidal neurons of the Bptf cKO mice contained lower levels of Ctip2 and Foxp1. Lastly, our RNA-seq analysis delineated gene pathways deregulated by Bptf removal, which are involved in neurogenesis and neuronal differentiation. Our results indicate that Bptf is critical for murine telencephalon neurogenesis. The hypoplasia demonstrated in the mouse model can resemble the microcephaly displayed by the human NEDDFL patients, highlighting the relevance of chromatin remodelling complexes during intricate neural developmental processes.

BACKGROUND: It has long been accepted that the environment we experience can impact our well-being; throughout recorded history, the greatest prevalence and severity of disease has been experienced by marginalized and underserved populations. However, the translation of such nontangible influences into biological changes in our health has been elusive until the recent advent of epigenetic studies. Modifications outside of the genome play a critical role in regulating transcription as well as subsequent gene expression without altering DNA sequencing by controlling the accessibility of the DNA for interaction with key initiation proteins and enzymes. These modifications, which include DNA methylation, histone acetylation, and small noncoding microRNA regulation, have increasingly been found to have a fluid, adaptive response to experiences throughout life. Based on the literature supporting societal stressors negatively impacting neurologic outcome, as well as elucidating an association between epigenetic changes and adverse neurologic outcome, we hypothesize that alterations in CpG methylation sites associated with socioeconomic adversity will also be correlated with the incidence of Neurodevelopmental Disorders. METHODS: 889 of the 1,506 neonates initially recruited from 14 medical centers throughout the United States at their time of birth qualified to participate in this study. Placental samples were taken immediately following delivery and neonatal blood samples were taken within the first month of life. Children that survived were followed at 2 years old and 10 years old to evaluate for the presence of four possible Neurodevelopmental Disorders: cognitive impairment, Cerebral Palsy, Autism Spectrum Disorder, and epilepsy. Taking this data as well as demographic information into consideration, the entire cohort included in this study was first evaluated for aberrant methylation levels at 33 CpG sites previously associated with socioeconomic adversity to analyze the degree of significant correlation between altered methylation status and Neurodevelopmental Disorder prevalence. A secondary Epigenome-Wide Association Study was conducted for each of our 889 participants to pinpoint significant changes in CpG methylation in order to evaluate the relationship between altered methylation of particular genes and incidence of Neurodevelopmental Disorders. Taking the previous finding that cognitive impairment imposes a greater burden on both the individual and society than non-cognitive impairment into consideration, both analyses were categorized based on this measure of impairment severity: No Impairment, Non-Cognitive Impairment (diagnosed with Cerebral Palsy, Autism Spectrum Disorder, and/or epilepsy without cognitive deficit), and Cognitive Impairment (cognitive deficit with or without other neurodevelopmental disorders present). RESULTS: Primary analysis of the 33 CpG sites previously associated with socioeconomic adversity did not reveal any significant associations with Non-Cognitive or Cognitive Impairment. However, cg15519318 and cg10613063 (located in the PCCB gene) were marginally associated with Non-Cognitive Impairment while cg02765535 (located in the NTN4 gene) was marginally associated with Cognitive Impairment. Secondary analysis of the entire epigenome found 4 CpG sites significantly associated with Non-Cognitive Impairment (cg07322235, cg13592565, cg13723879, and cg24387818) as well as 4 CpG sites significantly associated with Cognitive Impairment (cg23081580, cg14134658, cg00762003, and cg08546514). DISCUSSION: We were not able to define a significant relationship between the CpG methylation sites related to socioeconomic adversity and adverse neurodevelopmental outcomes. This could stem from several causes, including insufficient power as well as limiting our evaluation of the extensive list of environmental influences to the four measures of societal stress focused on in this study (low educational attainment, single relationship status, public health insurance, and receiving supplemental nutrition assistance). Investigating the epigenome for differential methylation that was significantly associated with the incidence of Neurodevelopmental Disorders identified CpGs associated with several important genes, including genes coding for Neuregulin-3 (NRG3) and Premature Ovarian Failure Actin Binding Protein 1B (POF1B) region with Non-Cognitive Impairment as well as genes coding for Six-Transmembrane Epithelial Antigen of Prostate 2 Metalloreductase (STEAP2), Ly1 Antibody Reactive (LYAR), 1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3), and Ninein-like protein (NINL) with Cognitive Impairment.

Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the underlying determinants of these reductions have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND). Using magnetic resonance imaging scans from 121 participants (57 ARND and 64 controls) aged 8 to 16 years, cortical morphology was analyzed. Results revealed the ARND group had reduced cortical grey matter volumes, but did not differ from controls in cortical thickness. Rather, the cortical abnormalities reflected reductions in global surface area, local surface area reductions in the right occipital-temporal area and right superior temporal gyrus, as well as reduced gyrification. A significant interaction between sex and group was observed, with females showing greater reductions than males in cortical volume and surface area. Results suggest that ARND is characterized by global reductions in cortical surface area and gyrification and females are more vulnerable than males to the teratogenic effects of alcohol.

Individuals exposed to alcohol in utero have reduced cortical grey matter volumes. However, the underlying determinants of these reductions have not been investigated exclusively in alcohol-related neurodevelopmental disorder (ARND). Using magnetic resonance imaging scans from 121 participants (57 ARND and 64 controls) aged 8 to 16 years, cortical morphology was analyzed. Results revealed the ARND group had reduced cortical grey matter volumes, but did not differ from controls in cortical thickness. Rather, the cortical abnormalities reflected reductions in global surface area, local surface area reductions in the right occipital-temporal area and right superior temporal gyrus, as well as reduced gyrification. A significant interaction between sex and group was observed, with females showing greater reductions than males in cortical volume and surface area. Results suggest that ARND is characterized by global reductions in cortical surface area and gyrification and females are more vulnerable than males to the teratogenic effects of alcohol.