Background: Autism and other neurodevelopmental disorders (NDD) are common in low- and middle-income countries (LMIC). However, services to address the needs of this group in LMIC are almost non-existent. The World Health Organization (WHO) developed the Caregiver Skills Training (CST) programme to be suitable for delivery in diverse global contexts. Ethiopia, the country of focus in this study, has a largely rural population and a lack of specialist service providers. Additional contextual challenges, including poverty, low literacy, limited access to healthcare and a lack of specialist child mental health services, may undermine the delivery of CST in this setting. This thesis, therefore, seeks to explore the acceptability and feasibility of non-specialist delivery of the WHO-CST from the perspective of providers and caregivers in rural Ethiopia. Methods: In Chapter one, a general literature review of neurodevelopmental disability and caregiver skills training is presented, with a focus on sub-Saharan Africa, to help contextualise the main qualitative study, outlined in chapter two. In-depth interviews were conducted with caregivers (n=19) who were all participants in two rural pilot studies of the WHO-CST programme. In addition, three focus group interviews were conducted with non-specialist facilitators (n=8), who facilitated the CST programme in two rural pilot tests. Data were analysed using the framework approach. Results: Findings were mapped onto the three framework themes created for this analysis: 1) Programme content: caregivers and facilitators uniformly indicated that the adapted programme addressed a need and was relevant for their context; caregivers emphasised how the programme helped them understand their child's problems and improve their skills to support their children; facilitators highlighted having acquired new knowledge and skills relating to NDD; 2) Programme facilitation: caregiver responses suggested that programme facilitation by non-specialists was acceptable; non-specialist facilitators emphasised the importance of support and supervision for the facilitators and simplification and modification of some concepts, such as the concept of play, and 3) CST training approach and delivery: participants indicated that the training modalities, including home visits and group training, were acceptable and feasible in the local context. Conclusions: This study suggested that, with some contextually appropriate modifications of programme content and delivery and continuing supervision of facilitators, the WHO-CST programme facilitated by non-specialists would be acceptable and feasible in rural Ethiopia. Results from this study may be useful to fine-tune the implementation of non-specialist delivery of the CST programme in Ethiopia, as well as other LMIC.

Editorial on the Research Topic. Obesogenic Environmental Conditions Affect Neurodevelopment and Neurodegeneration

Neurodevelopmental disorders (NDD) refer to conditions that can be present during a child’s early developmental period, and are typically characterized by challenges in a child’s personal, social, academic, or occupational functioning. Autism spectrum disorder (ASD) is an example of NDD, impacting 1 in 66 children in Canada. While interventions vary across this heterogeneous group of impairments, everyday functioning is an important outcome to families. However, this concept of functioning needs further examination with respect to whether and how it is incorporated within the instruments and concepts used in family-centred services (FCS), and how this is understood by parents. This thesis is composed of two studies: a narrative review identifying function-focused measures published in the literature for children with NDD; and a qualitative study examining how parents of children with ASD perceive their child’s abilities in relation to family-centred services. Fourteen clinical measures were described in the review based on how they utilized the International Classification of Functioning, Disability, and Health (ICF) to describe child functioning. In the qualitative study, five themes (Parenting Approaches, Accepting My Child, Managing Child’s Challenges, Doing the Right Thing for My Child, and “The Disability Tag”) were identified as influential factors that can affect how parents perceive their child’s abilities and functioning. As the cultural shift within interventions for children with NDD continue to move beyond the historically prominent deficit-focused lens, and towards the integration of neurodiverse abilities, this study enables us to understand better how concepts of function-focused care are operationalized in family-centred services and intervention systems. / Thesis / Master of Science Rehabilitation Science (MSc) / To support the shift in health care that focuses on the abilities of children with neurodevelopmental disorders (NDD) rather than their ‘problems’ or ‘deficits,’ we need to further understand how family-centred services (FCS) can better fit this change in thinking. This thesis explores paediatric health care focused on addressing ‘everyday abilities’ for children with NDD in research and clinical practice over two studies. Study #1 reviews some of the current ways that everyday functioning is measured in paediatric health care, examining 14 clinical tools developed for children with NDD. Study #2 reports key patterns that describe the experiences of parents of children with autism, in regards to how they think about their child’s abilities, and the care their child receives. Overall, this thesis studied new ways that we can explore the abilities of children with NDD in FCS, specifically concerning how parents and clinicians describe and measure functioning.

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Die psychomotorische Entwicklungsstörung (neurodevelopmental disorder, Abkürzung: NDD) bezeichnet eine Gruppe von Erkrankungen, die auf Störungen des sich entwickelnden Gehirns und/oder des Zentralnervensystems pränatal bzw. in den ersten Lebensjahren zurückzuführen ist. Die Ursachen sind aufgrund der zeitlichen und räumlichen Komplexität der kindlichen Entwicklung vielfältig und sowohl auf exogene, genetische als auch (noch) unbekannte Ursachen zurückzuführen. Bisher konnten mehr als 1000 Gene, die im Zusammenhang mit kindlicher Entwicklung stehen, identifiziert werden. Doch trotz enormen Entwicklungen diagnostischer Möglichkeiten in den letzten Jahren, insbesondere im Bereich der Exom- und Genomsequenzierung, bleiben viele Fälle wegen einer großen genetischen Heterogenität und häufig unspezifischem Phänotyp ungeklärt. Man geht derzeit davon aus, dass nach wie vor tausende Gene unbekannt sind. Ziel der vorliegenden Arbeit ist die Identifizierung und Charakterisierung neuer bisher unbekannter NDD-Gene. Die Durchführung dieser Arbeit erfolgte mittels (in der Mehrheit Trio-) Exomsequenzierung von 130 Patient:innen mit NDD in Einzelfallanalysen. In einem ersten Schritt wurden alle Patient:innen individuell auf Varianten in bereits bekannten NDD-Genen untersucht. Bei 31 Fällen konnte eine solche Variante identifiziert, systematisch klassifiziert und der Phänotyp mit bereits beschriebenen Symptomen verglichen werden. In einem nächsten Schritt wurden die übrigen 99 Patient:innen hinsichtlich sogenannter Kandidatengene analysiert. Diese wurden anhand Expressionsmuster, Funktion, in silico Analysen, Literaturrecherche und Assoziation mit anderen neurologischen Krankheitsbildern ausgewählt und mithilfe eines Kandidatengen-Scoring-Tools standardisiert und systematisch priorisiert. In Austausch und Kooperation mit anderen Wissenschaftler:innen weltweit wurden ausgewählte Kandidatengene anschließend mittels funktioneller Analysen auf ihre Pathogenität hin untersucht. Von den insgesamt 99 Patient:innen konnten so in 48 Fällen insgesamt 60 Kandidatengene eruiert werden, von denen mittlerweile drei (POU3F3, MADD und TAOK1) publiziert wurden und für weitere drei (UNC13C, GABRA2 und NARS) funktionelle Analysen durchgeführt werden und kurz vor der Publikation stehen. Es zeigte sich, dass sich Einzelfallanalysen, die auf den ersten Blick vor allem nach zeitintensiver und kleinschrittiger Arbeit aussehen, im Vergleich zu großen rein statistischen Kohortenstudien als sehr ertragreich erweisen. Die bisher größte statistische Kohortenstudie, die über 30.000 Fälle umschloss, führte zur Identifizierung von 49 (0,15% der Fälle) neuen NDD-Genen. Hiergegen konnten beispielsweise in der hier vorliegenden Arbeit mit einer Kohorte von 130 Fällen schon mindestens drei (2,3% der Fälle) neue Krankheitsbilder beschrieben werden und weitere werden folgen. Somit stellt dies einen vielversprechenden Ansatz (min. 2,3% vs. 0,15%) zur Identifizierung von neuen NDD-Genen dar. Darüber hinaus zeichnete sich ab, dass das Kandidatengen-Scoring-Tool als geeignetes Werkzeug zur systematischen und standardisierten Priorisierung von Kandidatengenen genutzt werden kann, um eine Fokussierung auf Kandidatengene zu ermöglichen, die mit größerer Wahrscheinlichkeit krankheitsverursachend sind. So konnte beispielsweise dem Kandidatengen UNC13C, das eine maßgebliche Rolle beim molekularen und/oder positionellen „Superpriming“ spielt, trotz einer Kohortengröße von bisher nur vier Patient:innen weltweit, eine relevante Bedeutung zugeschrieben werden, was weiterführende Untersuchungen mittels funktioneller Analysen zur Sicherung der potenziellen Pathogenität ermöglichte.:1. Einleitung 1.1. Genetische Erkrankungen 1.2. Psychomotorische Entwicklungsstörung 1.2.1. Exogene Ursachen von NDD 1.2.2. Genetische Ursachen von NDD 1.2.3. Relevanz der Identifizierung von NDD-Genen 1.3. Strategien zur Identifizierung von neuen NDD-Genen 2. Ziel der Arbeit 3. Untersuchungskollektiv, Materialien und Methoden 3.1. Untersuchungskollektiv 3.2. Methoden 3.2.1. DNA-Isolierung 3.2.2. Next Generation Sequencing-Technologien 3.2.3. Filterungsschritte mit VARVIS und weitere Beurteilung 3.2.4. Systematische Klassifikation von Varianten 3.2.5. Kandidatengen-Scoring 3.2.6. Genematcher 4. Ergebnisse 4.1. Exomsequenzierung von 130 Fällen mit NDD 4.2. Mutationen in bereits beschriebenen NDD-Genen 4.3. Varianten in neuen NDD-Kandidatengenen 4.4. UNC13C-Varianten in vier Patient:innen mit NDD 4.4.1. Phänotypische Beschreibung der Patient:innen 4.4.2. Neurozelluläre Grundlagen von UNC13C 4.4.3. Molekulare Modellierung der Varianten 5. Diskussion 5.1. Identifizierung der genetischen Ursachen von NDD mittels NGS 5.1.1. Vergleich Einzelfallanalysen vs. Große Kohortenstudien 5.1.2. Identifizierung von Mutationen in bereits bekannten Genen für NDD 5.1.3. Identifizierung und Priorisierung von Mutationen in neuen NDD-Genen 5.2. UNC13C als Kandidatengen für NDD 5.3. Ausblick 6. Zusammenfassung 7. Verzeichnis 7.1. Abbildungsverzeichnis 7.2. Tabellenverzeichnis 8. Referenzen 8.1. Webreferenzen 8.2. Literaturverzeichnis 9. Anhang 10. Selbstständigkeitserklärung 11. Lebenslauf 12. Mitarbeit an Veröffentlichungen 13. Danksagung

Background: Individuals with neurodevelopmental disorders are unemployed or underemployed at staggering rates. Employment for this population is impacted by many factors, including contextual issues. This review was conducted to enhance understanding of contextual factors influencing employment procurement for individuals with neurodevelopmental disorders. Methodology: The Arksey and O’Malley scoping review framework was utilized to examine five databases and sources of grey literature regarding the contextual factors influencing employment procurement for individuals with neurodevelopmental disorders. Articles were analyzed using the International Classification of Functioning, Disability and Health criteria for Contextual Factors, including both Environmental and Personal Factors. Results: The findings from 41 articles indicate that Contextual Factors, Environmental Factors and Personal Factors influence employment procurement by creating both barriers and facilitators to obtaining employment for individuals with neurodevelopmental disorders. Conclusion: A focus on contextual factors that impact individuals with neurodevelopmental disorders may provide further insight into the facilitators and barriers influencing employment outcomes. Further research should aim to understand the strength of relationships and to expand the use and application of the International Classification of Functioning, Disability and Health’s biopsychosocial framework. This research can aid in promoting the employment outcomes for individuals with neurodevelopmental disorders. / Thesis / Master of Science (MSc)

Neurodevelopmental disorders (NDD) refer to a group of conditions resulting from disturbances of the developing brain with a typical onset in childhood before puberty. Genetic causes make up a large part of developmental delays, which is why genetic examinations play a decisive role in the clarification of the causes of NDD. Due to the development of Next Generation Sequencing (NGS) and the increased use of genome-wide analyses in recent years, it has become clear that a large proportion of cases are due to rare, monogenic alterations in each case. Meanwhile, 1534 genes have been currently associated with NDD. Nevertheless, half of the evaluated cases remain without a valid diagnosis. However, this is a prerequisite for personalized support and the estimation of the development prognosis, as well as the differentiated assessment of the risk of recurrence for family members. To decipher the genetics of NDD, I systematically analyzed the exome sequences of 104 individuals with NDD and their relatives (see Figure 2). In 10 of the 104 cases, I was able to find variants in already known genes that partially explain the phenotype. I intensively evaluated all the cases for new candidate genes and identified 89 candidate genes in 58 individuals (see Supplementary, Table S1). In the remaining 46 individuals, no candidate gene could be identified. I then scored the candidate genes to prioritize them regarding the probability of being true NDD genes. From the detailed analysis of a relatively small cohort of NDD individuals (n=104) and the resulting 89 candidate genes, a total of 9 research collaborations have emerged (see Table 1). Of the candidate genes with further research in AutoCasC, six are in my top 20 candidate genes, which is a good indication of the efficiency of this systematic approach on deciphering the genetics of NDD. Studies on the candidate genes SKOR2, HCN2, SP9, CCDC66, and TANC1 are currently being worked on by collaborators worldwide and we could add our clinical and genetic data (see Table 1). Further, I was more substantially involved in the identification of the candidate gene ATP2B1, subsequently studied functionally, and published in the American Journal of Human Genetics (IF 11,0) with me as coauthor as a novel NDD gene, and the ongoing research on a genotype-phenotype correlation with functional lines of evidence of NDD-individuals with variants in DOCK4. Furthermore, I have led the efforts for the genes RIPPLY2 and PABPC1. I was able to describe three individuals from two families with compound-heterozygous variants in RIPPLY2 in two sisters and a homozygous nonsense variant in an 8-year-old boy. All individuals had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of spondylocostal dysostosis 6 (SCDO6) including scoliosis, mild facial asymmetry, spinal spasticity, and hemivertebrae. At this time, RIPPLY2 was only associated as a candidate gene with SCDO6 and had only been described in a small cohort of seven individuals from five families in two publications. I could confirm that bi-allelic variants in RIPPLY2 cause congenital cervical spine malformation in spondylocostal dysostosis type 6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum as a first author in a publication published in Clinical Genetics (IF 4,4). In the study on PABPC1, I describe four individuals with an overlapping phenotype of developmental delay, expressive speech delay, autistic features, and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms are seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to mRNA metabolism-related proteins such as PAIP2. Co-immunoprecipitation confirmed this as it demonstrated a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. The wild type Pabpc1 could rescue this disturbance, while three of the four variants did not. Together with partners from the Central South University in Changsha, China, I was able to propose that pathogenic missense variants in the PABP-domain of PABPC1 lead to a novel form of developmental disorder and published my work in Genetics in Medicine (IF 8,9). Through this, I demonstrated that systematic trio exome analysis and identification and characterization of candidate genes followed by prioritizing the genes based on systematic scoring and by building international cooperation to gather further individuals, describe the phenotypes, and prove that the pathogenicity of the variants is an excellent way to decipher the genetics of NDD. With this approach, I was able to describe PABPC1 as a novel NDD-gene and confirm the association between RIPPLY2 and SCDO6. Moreover, I contributed as a co-author to the publication of ATP2B1 as a novel NDD-gene and to the ongoing research on SKOR2, SP9, HCN2, CCDC66, TANC1, and DOCK4. More might follow in the future. The continuation of this research in genetic diagnostics is important for creating personalized support and prevention programs for individuals with neurodevelopmental delays, to be able to estimate the developmental prognosis, and to be able to assess the recurrence risk of other family members in a more differentiated way.:1 Introduction 1.1 Genetics of neurodevelopmental disorders 1.2 Identification of neurodevelopmental delay genes 1.3 Assessment of candidate genes 1.4 Rationale 1.5 Results 1.5.1 Identification of neurodevelopmental delay genes 1.5.2 Scoring of the identified candidate genes 1.5.3 Candidate genes under further research 2 Publications 2.1 Congenital cervical spine malformation due to bi-allelic RIPPLY2 variants in spondylocostal dysostosis type 6 2.2 De novo variants in the PABP-domain of PABPC1 lead to developmental delay 3 Summary 4 References 5 Internet resources 6 Supplementary 7 Presentation of personal scientific contribution 8 Declaration of Authorship

Mental health problems are increasing in Swedish adolescents and mortality rates are higher in this age group than among younger. 10-20% of all adolescents suffer from a chronic medical condition (CC). Few protective factors (PF) and clustering of health-risk behaviours (HRB) are frequent among adolescents with CCs. One of the most common CC in Swedish adolescents is type 1 diabetes mellitus (T1DM). Metabolic control often deteriorates during adolescence, especially in girls. Poor metabolic control is associated with increased risk for long-term complications, of which cognitive problems are common. However, the implication of cognitive/executive problems in patients with T1DM has not been sufficiently studied. Neither has the impact of neurodevelopmental problems (NDP), such as ADHD, on HRB in adolescents with CCs been analysed. Methods: In paper I and II the questionnaire ”Life and Health in Youth” was distributed to all students in year nine and year two of the upper secondary school in the county of Sörmland, 2008 (n=5771) and 2011 (n=5550). Adolescents with CCs were compared to healthy peers with regard to PFs and HRBs. In paper III, the ”Five to Fifteen” questionnaire was used in 175 paediatric patients with T1DM. Patients with indications of NDPs were compared with patients without such problems with regard to metabolic control. In paper IV, the BRIEF questionnaire and the ADHD Rating Scale as well as data from the Swedish Childhood Diabetes Registry was used in 241 adolescents with T1DM. Patients with indications of executive problems were compared with patients without such problems with regard to diabetes control. Results: CCs were associated with few PFs and clustered HRBs. The combination of CCs and low numbers of PFs was found to be associated with an increased risk of clustered HRBs. In the presence of coexisting ADHD the pattern of few PFs and clustering of HRBs was aggravated. ADHD was more common among adolescents with other CCs. Definite memory and learning problems as well as mild executive problems were associated with poor metabolic control, especially among adolescents. Executive problems were also associated with many outpatient visits and low physical activity. Girls with T1DM tended to self-report executive problems to a larger extent than boys, while parents more often reported these problems in boys. Conclusion: Knowledge about factors influencing treatment adherence and life in general is essential in the work with chronically ill adolescents. Focus must be put on enhancing PFs in order to avoid HRBs. Identification of coexisting NDPs, such as ADHD, is crucial, since such problems can adversely influence treatment adherence, HRBs and school achievements