No description available.

Thesis (M.S.)--Boston University

Thesis (M.S.)--Boston University

Background Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A proportion is presumed to be genetic, but this aetiology is buried under the burden of infections and perinatal insults, in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs), are most severely affected by this diagnostic gap, as the rate of actionable findings is highest in DEE-associated genes. This research study investigated the genetic architecture of epilepsy in South African (SA) children clinically diagnosed with DEE, highlighting the clinical utility of informative genetic findings and relevance to precision medicine for DEEs in a resource-constrained setting. Methods A group of 234 genetically naïve SA children with drug-resistant epilepsy and a diagnosis or suspicion of DEE, were recruited between 2016 and 2019. All probands were genetically tested using a DEE gene panel of 71 genes. Of the panel-negative probands, 78 were tested with chromosomal microarray and 20 proband/parent trios underwent exome sequencing. Statistical comparison of electroclinical features in children with and without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results Pathogenic/likely pathogenic (P/LP) variants were identified in 41/234(17.5%) * probands. Of these, 29/234(12.4%) * were sequence variants in epilepsy-associated genes and 12/234(5.1%) * were genomic copy number variants (CNVs). Sixteen variants of uncertain significance (VUS) were detected in 12 patients. Of the 41 children with P/LP variants, 26/234(11%) had variants supporting precision therapy. Multivariate regression modelling highlighted neonatal or infantile-onset seizures with movement abnormalities and attention difficulties as predictive of a positive genetic finding. This, coupled with an emphasis on precision medicine outcomes, was used to propose the pragmatic “Think-Genetics” decision tree for early recognition of a possible genetic aetiology, pragmatic testing, and multidisciplinary consultation. Conclusion The findings presented here emphasise the relevance of an early genetic diagnosis in DEEs and highlight the importance of access to genetic testing. The “Think-Genetics” strategy was designed for early recognition, appropriate interim management, and genetic testing for DEEs in resource constrained settings. The outcomes of this study emphasise the pressing need for augmentation of the local genetic laboratory services, to incorporate gene panels and exome sequencing. *These percentages were rounded off to whole numbers in the published articles included in this thesis (i.e., rounded off to 18%, 12% and 5%, respectively).

No description available.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

But : Le but de ce programme était de décrire et d’expliquer la participation sociale des personnes atteintes de dystrophie myotonique de type 1 (DM1). Méthode : Un échantillon aléatoire de 200 patients atteints de DM1 (phénotype léger (42) ou adulte (158)) a été recruté. La participation et la satisfaction dans la réalisation des habitudes de vie a été évaluée avec la Mesure des Habitudes de Vie (MHAVIE). Les facteurs environnementaux ont été évalués avec la Mesure de la Qualité de l’Environnement. Les facteurs personnels incluant la force musculaire, l’équilibre, la dextérité fine, la fatigue et l’hypersomnolence ont été évalués à l’aide d’instruments standardisés. Résultats : Les participants avec le phénotype adulte ont démontré un niveau de participation significativement inférieur à celui des participants avec le phénotype léger dans 8 des 11 catégories de la MHAVIE. Une restriction de la participation a été rapportée dans les catégories Déplacements, Habitation, Soins personnels, Nutrition, Condition corporelle, Travail, Loisirs, Vie communautaire chez les participants avec le phénotype adulte. La réalisation des habitudes de vie dans la catégorie loisirs était la plus affectée avec 57% des items qui démontraient une restriction de la participation chez 22 à 27% des participants. Les catégories Travail et Loisirs ont eu le plus faible taux de satisfaction. Les prédicteurs d’une atteinte de la participation sociale des quatre domaines les plus touchés soit Habitation, Déplacements, Travail et Loisirs ont été déterminés avec une analyse de régression logistique. Pour les facteurs personnels, la diminution de la force musculaire et une fatigue importante étaient significativement associées à la diminution de la participation sociale. Pour les facteurs environnementaux, la présence d’obstacles liée au support de la famille et l’accès et l’utilisation de la technologie est associée à une plus faible participation. Conclusion : Cette étude a permis de dresser un portrait et de mieux comprendre la participation sociale dans la DM1. Les résultats aideront à mieux définir le processus d’évaluation et la mise en place d’interventions en réadaptation et dans le milieu communautaire. / Objective: To describe and explain social participation of persons with the adult and mild phenotype of myotonic dystrophy type 1 (DM1). Methods: A random sample of 200 subjects with DM1 (42 mild phenotype, 158 adult phenotype). Level of social participation and satisfaction was assessed with the Assessment of Life Habits (LIFE-H). Environmental factors were assessed with the Measure of the Quality of the Environment. Personal Factors were assessed with standardized instruments including Berg Balance Scale, Krupps Fatigue Severity Scale, and Manual Muscle Testing. Results: Participants with the adult phenotype demonstrated significantly lower participation level than those with the mild phenotype on 8 out of the 11 categories of the LIFE-H. Lower levels of accomplishment were reported in Mobility, Housing, Fitness, Nutrition, Personal Care, Employment, Recreation and Community Life categories among the adult phenotypes. The Recreation category was the most affected category with four out of seven items revealing compromised accomplishment among 22% to 27% of individuals. The lowest satisfaction score was observed in the Employment and Recreation categories. The predictors of the most restricted participation domains being Housing, Mobility, Employment and Recreation were determined with a logistic regression analysis. Participants reported disturbed participation in a large proportion (45-61%) for all domains. Lower extremity strength [OR = 15.4 – 5.5; p < 0.05] and higher fatigue [OR = 6.0 – 2.6; p < 0.05] were significantly present in participants with disturbed participation for all domains. For environmental factors, social support [OR = 3.6 – 2.5; p < 0.05] and public services [OR = 2.8 – 2.4; p < 0.05] were significantly perceived as barriers for participants with disturbed participation for most domains. Conclusion: This doctoral program has permited to better understand social participation in DM1. The results will help to elaborate a more comprehensive evaluation scheme and to develop intervention to promote optimal social participation in this population.