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MSc (Med), Child Health Neurodevelopment, Faculty of Health Sciences, University of the Witwatersrand / Background The early identification of developmental disorders facilitates early intervention, improving childhood outcomes. Parent-administered questionnaires have been recommended for this purpose. The PEDS COMBINED, which includes the Parents Evaluation of Developmental Status (PEDS) and PEDS Developmental Milestones (PEDS:DM), and the Ages and Stages Questionnaire (ASQ) are parent-administered questionnaires with good psychometric properties. It has not been determined if they identify the same infants at-risk for developmental delays however. It is also not know how South African paediatricians monitor childhood development. Objective To compare the ASQ, PEDS COMBINED and South African paediatricians’ subjective assessment (PSA) of neonatal intensive care graduates at 6-months corrected age. To identify trends in developmental screening practices, including the knowledge and use of parentadministered screening tools, in a diverse group of paediatricans working in Gauteng, South Africa. Methods Developmental screening and referral practices of paediatricians were ascertained by analysis of a short questionnaire sent to participating paediatricians. Concordance between the questionnaires and PSA was determined using the kappa coefficient (κ) and Test of Symmetry (κ ≤ 0.4 indicating poor agreement; κ ≥ 0.75 indicating excellent agreement). Results Concordance between the ASQ and PEDS COMBINED was 90.7% (κ = 0.82, ρ = 0.05). The PSA showed poor concordance with both PEDS COMBINED and ASQ (κ = 0.28, ρ = 0.03 and κ= 0.26, ρ = 0.01 respectively). The ASQ and PEDS COMBINED identified 40% and 42% of the cohort with developmental concerns and the PSA identified 6%. Only 13% of paediatricians used specific guidelines for developmental assessment and none used, or could name any parent-administered questionnaire. Conclusion There is excellent agreement between the ASQ and PEDS COMBINED in identifying the same children with developmental concerns. Paediatricians identified significantly fewer infants and showed statistically significant poor agreement with both questionnaires. Most paediatricians in Gauteng, South Africa are not using standardized screening tools to detect developmental delay and have poor knowledge regarding these tools.

After a review of the literature on Pivotal Response Treatment (PRT) in young children with developmental delays, less was known on its effects on challenging behavior and functional communication in preschool age children receiving services in a traditional public school. A multiple baseline design across three participants was used to evaluate the effects of PRT on the functional communication of three preschool students with developmental delays. Based on a functional analysis, we also observed the effects of PRT on challenging behavior. A visual analysis of the data revealed a functional relation between PRT and functional communication and provided promising evidence regarding the effectiveness of function aligned mands in reducing problem behavior. Brief surveys and interviews revealed that the intervention was feasible and effective based on staff and family reports. This research study adds to the evidence supporting the use of the intervention and expands on the knowledge base surrounding function aligned communication. Implications for research and practice are discussed.

Laws and legislation related to early childhood and special education have shaped the field and impacted the need for early intervention services, but the outcomes of those services both academically and socially at the forefront. Children with developmental delays today are eligible for school services beginning at birth across the country, the new challenging is determining the impact of services on the social and academic outcomes. Many children with developmental delays are served in inclusive early intervention classrooms. A need for developmentally appropriate quality mathematics instruction exists to prepare students to meet the demands of a global economy; students must demonstrate mastery of core subjects, such as mathematics, along with skills in information and communication technology (Partnership for 21st Century Skills, 2009). To promote mathematics achievement technology should be infused in instruction. Data were collected through a variety of sources including: student records review, TEMA-3 test scores, researcher‘s observation field notes, transcripts from student exit interviews, teacher interviews pre and post data collection, and parent questionnaires. The data were analyzed using Atlas-ti and was triangulated from the various data sources. Inter-observer agreement was obtained for all the results. Researcher observations occurred for 19 days in a pre-kindergarten inclusive classroom. The data were analyzed to identify themes for the four individual cases as well as two overarching themes as it related to the investigation of utilizing handheld technology for mathematics instruction in an early childhood education setting.

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In this study, we have used genetic, cell biological and transcriptomic methods in the nematode C. elegans as a model to examine the impact of glucose supplementation during development. We show that a glucose-supplemented diet slows the rate of developmental progression (termed "glucose-induced developmental delay" or GIDD) and induces the mitochondrial unfolded protein response (UPRmt) in wild-type animals. Mutation in the insulin receptor daf-2 confers resistance to GIDD and UPRmt in a daf-16-dependent manner. We hypothesized that daf-2(e1370) animals alter their metabolism to manage excess glucose. To test this, we used RNA-sequencing which revealed that the transcriptomic profiles of glucose-supplemented wildtype and daf-2(e1370) animals are distinct. From this, we identified a set of 27 genes which are both exclusively upregulated in daf-2(e1370) animals fed a glucose-supplemented diet and regulated by daf-16, including a fatty acid desaturase (fat-5), and two insulin-like peptides (ins-16 and ins-35). Mutation of any of these genes suppresses the resistance of daf-2(e1370) to GIDD. Additionally, double mutation of ins-16 and ins-35 in a daf-2(e1370) background results in an increase in constitutive dauer formation which is suppressed by glucose supplementation. Further investigation of the insulin-like peptides revealed that ins-16 mutation in a wild-type background results in upregulation of ins-35 and DAF-16 nuclear translocation regardless of diet; however, unlike daf-2(e1370), this translocation is not associated with resistance to GIDD. Taken together, these data suggest that glucose-supplemented daf-2(e1370) animals maintain developmental trajectory in part through upregulation of specific insulin-like peptide genes and fatty acid desaturation and contribute to a deeper understanding of the mechanisms underlying the resistance of daf-2(e1370) animals to GIDD. We also showed another fascinating aspect of GIDD: it becomes more pronounced in subsequent generations exposed to a glucose-supplemented diet, suggesting that the parental glucose diet has an impact on the developmental progression of their offspring.

Orientador: Danilo Moretti-Ferreira / Resumo: As ACs são alterações visíveis nos cromossomos, classificadas como numéricas e estruturais. Atualmente o grande desafio da genética clínica é classificar e associar a relevância clínica dos desequilíbrios genéticos ao fenótipo dos portadores. O trabalho tem como objetivo principal caracterizar desequilíbrio genômico sem diagnóstico sindrômico previamente descritos pelas técnicas de citogenética clássica, molecular visando apurar os pontos de quebras e genes inseridos na região cromossômica alterada por meio da citogenômica em estudos de casos. Foram feitas análises por citogenética (bandamento GTG), citogenética molecular (FISH) e citogenômica (array-CGH) em três pacientes com malformações congênitas não-sindrômicas para definição diagnóstica e maior conhecimento sobre a correlação genótipo-fenótipo. Foram redigidos estudos de casos de três pacientes portadores de MCs, atraso do desenvolvimento e deficiência intelectual. O primeiro copilado de caso trata-se de paciente do sexo feminino com anomalias esqueléticas, deficiência intelectual e atraso do desenvolvimento. O cariótipo da paciente é 46,XX[11]/47,XX,+mar[9]. A análise de array-CGH revelou dois ganhos/duplicações nas bandas cromossômicas 6p11.2q12 (10.335 Mb de tamanho) e 6q14.1q14.3 (10.765 Mb de tamanho). Por meio da técnica da FISH e os resultados do array-CGH a região duplicada 6q14.1q14.3 encontra-se inserida em um cromossomo marcador, oriundo do cromossomo 6. Os sinais clínicos descritos na paciente foram semelhan... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The ACs are visible changes in the chromosomes, classified as numerical and structural. Currently the great challenge of clinical genetics is to classify and associate the clinical relevance of genetic imbalances with the phenotype of the carriers. The main objective of this work is to characterize genomic imbalance without syndromic diagnosis previously described by the classical and molecular cytogenetic techniques, in order to determine the breakpoints and genes inserted in the chromosomal region altered by cytogenetics in case studies. Cytogenetics (GTG banding), molecular cytogenetics (FISH) and cytogenetics (array-CGH) were performed in three patients with non-syndromic congenital malformations for diagnostic definition and greater knowledge on genotype-phenotype correlation. Case studies of three patients with MCs, developmental delay and intellectual disability were written. The first case file is a female patient with skeletal anomalies, intellectual disability and developmental delay. The patient's karyotype is 46, XX [11] / 47, XX, + sea [9]. The array-CGH analysis revealed two gains / doublings in the chromosomal bands 6p11.2q12 (10,335 Mb in size) and 6q14.1q14.3 (10,765 Mb in size). Through the FISH technique and the results of the array-CGH the duplicate region 6q14.1q14.3 is inserted in a chromosome marker, coming from chromosome 6. The clinical signs described in the patient were similar to other patients with duplication of the region 6q14. The genes PGM3, M... (Complete abstract click electronic access below) / Mestre

Intellectual disability (ID) affects approximately 1-3% of the population and is defined as having an IQ below 70 as well as a significant limitation in adaptive behavior. The implementation of chromosomal microarrays (CMA) into the field of clinical genetics has revolutionized the ability to find genetic aberrations responsible for different genetic disorders. Importantly. these technologies have allowed several new microdeletion and microduplication aberrations to be identified that otherwise would have escaped detection using more conventional methods. Finding the genetic etiology of a syndrome and its association to the phenotype is paramount to better health care, provision of tailored therapy, presymptomatic screening, accurate prognosis, recurrence risk evaluation and in some cases prenatal testing. Despite the plethora of new information available, there are still a number of clinical and genetic features we do not fully understand. The aim of this work was to identify regions and syndromes associated with ID by CMA analysis and to make a detailed clinical description of the affected patients’ phenotype. In paper I we studied the 22q11.2 duplication syndrome and presented two familial cases with a description of both their genotype and phenotype. Additionally, 36 cases harboring the duplication were reviewed to further delineate the phenotype of the syndrome. In paper II, we revealed two unrelated patients with a deletion at 6q14.1-q15 and a distinct phenotype. Together with one previously reported patient our study suggests that a novel, clinically recognizable microdeletion syndrome exists in these patients. In paper III the phenotype and genotype of six unrelated patients with partially overlapping microdeletions at 10p12.31-p11.21 were described. Taken together with a previously reported patient we propose that these findings represent a new contiguous gene syndrome. In paper IV, two sisters; one presenting with two tandem interstitial duplications and the other a large deletion over the same region (6q13-q16) were reported. The reason for the CNVs was a maternal de novo translocation. This is the first case describing the genotype and phenotype of this duplicated region at 6q13-q16. In conclusion, four different genetic aberrations involved in the etiology of ID and their corresponding phenotypes and candidate genes have been characterized.

Early intervention services are important in obtaining better outcomes for infants with a developmental delay or a condition that may result in a delay. In Florida, a primary resource for providing these services is the Early Steps Program. This study analyzed the Early Steps referral process to identify barriers to prompt access. The guiding hypothesis was if differences exist in key outcomes of the referral process, then these differences may reveal where improvements can be made. Improving access to early intervention should produce better outcomes and reduce the costs of services required later by addressing developmental concerns earlier. The dataset included records for 10,688 infants referred to the Hillsborough County Early Steps Program between 2006 and 2009. Two measures (age at referral and time to IFSP) represented points within the referral process where delays could be quantified. Age at referral is a measure of how long it takes for a delay to be identified and the infant referred for evaluation. The time from the referral to the date an IFSP is created provides a measure of the delay in beginning services. Delays in obtaining a referral were associated with being referred by a family member, the referral code Developmental Delay At Risk and barrier codes Child/Family Issues and No Show/Unsuccessful Contact. Delays in completing the IFSP were related to being younger at referral, being referred by one of the sources that made less frequent referrals to Early Steps, an eligibility determination related to behavior concerns, maternal education that stopped at grade 8 or below and being Black.