Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder(GAND). Methods: Fifty GAND subjects were evaluated to determine consistentgenotypic/phenotypic features. Immunoprecipitation assays utilizing in vitrotranscription–translation products were used to evaluate GATAD2B missensevariants’ ability to interact with binding partners within the nucleosomeremodeling and deacetylase (NuRD) complex. Results: Subjects had clinical findings that included macrocephaly,hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios,apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified withmultiple variant types (nonsense, truncating frameshift, splice-site variants,deletions, and missense). Seven subjects were identified with missense variantsthat localized within two conserved region domains (CR1 or CR2) of the GATAD2Bprotein. Immunoprecipitation assays revealed several of these missense variantsdisrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions: A consistent GAND phenotype was caused by a range of geneticvariants in GATAD2B that includeloss-of-function and missense subtypes. Missense variants were present inconserved region domains that disrupted assembly of NuRD complex proteins.GAND’s clinical phenotype had substantial clinical overlap with other disordersassociated with the NuRD complex that involve CHD3 and CHD4, with clinicalfeatures of hypotonia, intellectual disability, cardiac defects, childhoodapraxia of speech, and macrocephaly.

Indiana University-Purdue University Indianapolis (IUPUI) / Objective: Nutritional assessment and diagnosis of malnutrition in pediatric patients is dependent on anthropometric measurements. In macrocephalic children, current anthropometric measures may fail to correctly diagnose malnutrition. The purpose of this study is to determine if the measurement of mid-upper arm circumference (MUAC) in pediatric patients with macrocephaly better identifies children at nutritional risk as compared to weight-for-length (WFL) or body mass index (BMI). Methods: A cross-sectional pilot study of children aged 6-36 months with a head circumference 2 SD above the mean was performed. Visual assessment was used as the clinical “gold standard” for presence of malnutrition. MUAC was compared to the WFL or BMI for each child to determine which anthropometric measurement better identified presence of malnutrition. Statistics: Two-way contingency tables were used to summarize the relationships between each pair of assessments of whether a child is malnourished. Agreement between the methods was evaluated using kappa statistics and percent agreement. Analyses were performed using SAS version 9.4 ™ statistical software. Results: Twenty patients were included who met study criteria. The mean head circumference z-score was 2.6. The mean BMI/WFL z-score was 0.9, which would qualify the child as “nourished.” Of the 20 children included in the study, 20% (n=4) appeared visually malnourished on physical exam. BMI/WFL confirmed diagnosis of malnutrition in 75% (n=3) of children. MUAC confirmed diagnosis of malnutrition in 75% (n=3) of children. Diagnosis of malnutrition using BMI/WFL as compared to visual assessment had a non-significant p-value of 0.317. Diagnosis of malnutrition using MUAC as compared to visual assessment had a non-significant p-value of 0.317. With a p-value of >0.5, there is no statistically significant difference between BMI/WFL and MUAC in diagnosis of malnutrition. Conclusion: MUAC did not perform better than BMI/WFL at identifying malnutrition in pediatric macrocephalic patients.

The 16p11.2 copy-number variant (CNV) represents a well-characterized, high-risk factor for autism spectrum disorder that additionally predisposes deletion carriers (16pdel) to increased head circumference, known as macrocephaly. The 16p11.2 CNV consists of 29 known genes, many of which are associated with neurobiological processes relevant for macrocephaly such as cell proliferation and apoptosis, differentiation and cell growth. Our lab’s previous work has demonstrated that induced pluripotent stem cell (iPSC)-derived neurons from 16pdel carriers show altered cellular morphology related to growth, which include increased soma size, total dendritic length and dendritic complexity. However, specific CNV genes responsible for these phenotypes have not been established. Here, we investigate the relationship between three 16p11.2 genes and the observed cellular phenotypes. We differentiated neurons from control iPSC-derived neural progenitor cells (NPCs) and used short hairpin RNA (shRNA) to reduce the expression of these CNV genes: KCTD13, MAPK3 and C16ORF53. We then assessed neuronal morphology by evaluating soma size, total dendritic length and dendritic complexity. We demonstrate that knocking down KCTD13 and C16ORF53 increases soma size and total dendrite length, respectively, similar to that observed in 16pdel iPSC-derived neurons. For this reason, we speculate that these genes may have a role in cell growth and might underlie macrocephaly. Thus, our study investigates genes in the 16p11.2 CNV that contribute to neuronal morphology, which may have a role in influencing brain size.

No description available.

Un nombre significatif d’enfants autistes ont une macrocéphalie. Malgré plusieurs études du périmètre crânien en autisme, peu d’études ont été faites sur des adultes. Aussi, les références actuelles en périmètre crânien (PC) adulte datent d’environ 20 ans. Les objectifs de cette étude étaient de construire une échelle de référence du PC adulte, et de comparer les taux de macrocéphalie entre un groupe d’adultes autistes et un groupe d’adultes neurotypiques. Dans cette étude, 221 sujets masculins adultes étaient recrutés de différents milieux afin de déterminer le meilleur modèle prédictif du PC et de construire l’échelle de référence. La hauteur et le poids étaient mesurés pour chaque participant afin de déterminer leur influence sur les dimensions crâniennes. Pour la partie comparative, 30 autistes et 36 sujets neurotypiques, tous adultes, étaient recrutés à partir de la base de données du laboratoire de recherche. Pour l’échelle de référence, les résultats démontraient des corrélations positives entre le PC avec la hauteur et le poids. Après analyse, la corrélation conjointe de la hauteur et du poids sur le PC a été déterminée comme étant le modèle qui offre les résultats les plus significatifs dans la prédiction du PC. Pour la partie comparative, les taux de macrocéphalie atteignaient 10,00% chez les autistes contre 2,56% chez les neurotypiques selon la formule de régression linéaire obtenue du modèle. Cependant le test d’exactitude de Fisher n’a révélé aucune différence significative entre les 2 groupes. Mes résultats suggèrent qu’il est nécessaire de considérer la hauteur et le poids en construisant une référence du PC et que, même en utilisant la nouvelle référence, les taux de macrocéphalie demeurent plus élevés chez les autistes adultes que chez les adultes neurotypiques en dépit de l’absence de différences significatives. / A significant proportion of autistic children have macrocephaly. Despite numerous head circumference studies in autism, few studies in adults exist. Also, current adult head circumference (HC) references are around 20 years old. The purposes of this study were to construct an adult head measurement reference chart, and to compare macrocephaly rates between a group of autistic adults and a group of typically developing adults. In this study, 221 male adults were recruited from various settings in order to determine the best predictive model for HC and to construct the reference chart. Height and weight were measured for each participant in order to evaluate their influence on head dimensions. For the comparison part, 30 autistic and 36 typically developing adult subjects were recruited from within the research lab’s database. For the reference chart, results showed positive correlations between HC, and both height and weight. After analysis, the combined influence of both height and weight on HC size has was determined to be the model showing most significant results in predicting HC. For the comparison part, macrocephaly rates reached 10.00% in the autistic group against 2.56% in the control group according to the linear regression formula obtained from the model. However, the Fisher’s exact test revealed no significant difference in macrocephaly rates between both groups. My results suggest the necessity of considering both height and weight when constructing a head circumference reference chart and that, even using a new reference, macrocephaly rates remain higher than normal in autistic adults although not significantly different enough from the typically developing adults.

Cette thèse examine l'impact de la mondialisation sur l'urbanisation de Beyrouth, capitale pensée a la fois comme métropole au sein du Liban et ville–monde à l’échelle internationale. Longtemps, les discours sur la Ville Globale, ont porté principalement sur les villes du Premier Monde. Une littérature postcoloniale plus récente sur Beyrouth et le monde arabe a élargi le discours de la mondialisation pour inclure le « tiers-monde », les pays en voie de développement et plus particulièrement les villes du Proche-Orient et du bassin méditerranée. Ainsi, cette ouverture a permis de relier l'urbanisation contemporaine avec les diverses formes prises par la modernité. L’objectif de cette recherche est de proposer une lecture de l’urbanisation de Beyrouth depuis la fin du XIXème siècle en mettant en lumière la place centrale prise par les interactions, souvent contradictoires, entre logiques spatiales endogènes et exogènes dans l’explication de ce processus. La méthodologie repose sur quatre approches complémentaires (cartes mentales, entretiens auprès d’experts, analyse critique et historique de la planification urbaine étatique de Beyrouth, géopolitique de l’enseignement supérieur) permettant l’analyse de la restructuration et de la différenciation de la région métropolitaine de Beyrouth et du littoral. La spécificité géographique de Beyrouth contribue à nuancer les tendances à la mondialisation du phénomène urbain dans les espaces dits en voie de développement. Trois étapes de la croissance et de la structuration urbaine se dégage : la centralisation de la période coloniale, la décentralisation liée à la période de l'indépendance et de la guerre civile, la fragmentation enfin lors de la période dite de la « post guerre ». Ce processus inscrit dans le temps long, s’accélère au cours de la dernière période. La « Mondiapolisation » de Beyrouth signifie à la fois l’insertion de Beyrouth dans un modèle monde de l’urbanisation et l’affirmation de valeurs métropolitaines. / This dissertation investigates the impact of globalization on the urbanization of Beirut, a city perceived, on the one hand, as a capital metropolis in the heart of Lebanon and, on the other hand, as an international world-city. The literature on global cities has mainly tackled the cities of the developed world despite the fact that more recent postcolonial literature about Beirut and the Arab world has expanded the discourse of globalization to include the “third-world,” the under-developed countries, and particularly the cities of the Near-East and the mediterranean basin. The objective is to provide an explanation of the urbanization of Beirut, and to try to apply this corpus in order to assess the evolution of Beirut since the end of the nineteenth century. The methodology examines the restructuration and the differentiation of Beirut’s metropolitan area and its coastline as one whole carrying the highest level of urbanization. It is based on four complementary approaches: the mental image of the metropolitan area of Beirut as perceived by its inhabitants, semi-directive interviews to complete the representations and widen the scope of the initial claim, a spatio–chronological reading of the official discourses of urban planning at the different periods of development of contemporary Beirut, and the choice of spatial indicators among which the spatial distribution of universities as a reflection of the geopolitical differentiation of Lebanon and the intersection of endogenous and exogenous factors. In conclusion, the geographical specificity of Beirut reveals the nuances of globalization trends of the urban phenomenon in the so-called under-development spaces. Three stages of growth and urban structure are identified : centralization, corresponding to the colonial period, decentralization, to the period of independence and civil war, and fragmentation, to the period known as "post-war" Beirut. We call this long-term process the "Globapolization" of Beirut.

No description available.