La Trisomie 21 ou Syndrome de Down, est due à la présence surnuméraire du chromosome 21 humain (Hsa21), le surdosage génétique qui en résulte provoque différents phénotypes. Cette pathologie est la première cause de retard mental. Notre étude vise à savoir si l’aneuploïdie d’un intervalle génétique, encore non étudié, entraîne des modifications dans la mise en place des processus à l’origine des facultés cognitives. Cet intervalle, entre les gènes Cstb et Prmt2 est porté par le chromosome murin 10 (MMU10) au sein d’une portion homologue à la partie télomérique du Hsa21. Pour cela de nouveaux modèles murins ont été créés, Ms4Yah est monosomique et Ts3Yah est trisomique pour cet intervalle. Le but est donc de caractériser les conséquences de l’aneuploïdie sur le fonctionnement des neurones permettant l’encodage des informations, appelé plasticité synaptique à long terme. Nous avons enregistré ce phénomène au niveau de la communication entre le cortex et le striatum, structures impliquées dans les processus mnémoniques, grâce à la technique électrophysiologique de patch clamp en configuration cellule entière. Ces enregistrements sont faits in vitro sur tranches de cerveaux de souris. Les propriétés électrophysiologiques des NETMs ont été caractérisées. La plasticité synaptique corticostriatale à long terme de type glutamatergique a été étudiée avec des protocoles de stimulation spécifiques, appliqués au niveau cortical. Des protocoles de conditionnement à haute et à basse fréquence ont été utilisés. Nous avons observé que l’aneuploïdie portée par les modèles avait une influence sur la mise en place de la plasticité synaptique corticostriatale à long terme qui est différente en fonction du dosage génétique. Ms4Yah met en place une DLT suite au protocole SHF de même que Ts3Yah. Lorsque le protocole SBF est utilisé Ms4Yah met en place une forme de plasticité à court terme contrairement à Ts3Yah qui présente une DLT. L’intervalle étudié ici jouerait donc un rôle dans le phénotype de la Trisomie 21. Certains gènes de l’intervalle semblent être de bons candidats pour expliquer les phénomènes observés, notamment S100b, Pcbp3 et Trmp2. / Trisomy 21 or Down syndrome is due to a third copy of human chromosome 21 (Hsa21) in the genome, this leads to a global genetic overexpression which results on multiple behavioral phenotypes. This pathology is the first and most common cause of mental retardation. Our study aims to understand whether an aneuploidy of a non-studied genetic interval, included in Hsa21, causes changes in processes mediating intellectual abilities. This interval, between Ctsb and Prmt2, is located on murine chromosome 10 (MMU10) within an homologous portion of the Hsa21 telomeric part. Thus, new mouse models have been engineered, Ms4Yah is monosomic and Ts3Yah trisomic for Cstb-Prmt2 interval. Hence, the aim of this project is to characterized aneuploidy consequences on neuronal functions which lead to information encoding, named long term synaptic plasticity. We have recorded this phenomenon within cortex-striatum neuronal connexion, which is involved in mnemonic processes, using whole-cell patch-clamp electrophysiological technique. Records were made in vitro on mouse horizontal brain slice. We characterized METMs electrophysiological properties. Then, glutamatergic corticostriatal long term synaptic plasticity was studied with specific stimulation protocols applied on the cortex. High and low frequency conditioning protocols were used. We observed that aneuploidy of the models influenced corticostriatal long term synaptic plasticity setting which is different according to the genetic dosage. Ms4Yah showed LTD after HFS protocol like Ts3Yah. But when SBF was applied, Ms4Yah shows a short term plasticity form, conversely Ts3Yah shows anew a LTD. The studied interval may play here a role in phenotype of Trisomy 21. Some of the genes comprised in the Ctsb-Prmt2 interval seemed to be good candidates to explain observed phenotypes, namely S100b, Pcbp3 and Trmp2.

Background: Talipes equinovarus, also termed club foot, is a congenital deformity of the ankle joint. Despite its prevalence of approximately 1 per 1000 live births, fetal talipes is relatively poorly studied since the introduction of percutaneous tendo Achilles tenotomies. Objectives: To document the associations, outcomes and prognosis of patients with antenatally diagnosed fetal talipes. The study aims to examine the association between, and prevalence of, fetal talipes and other abnormalities, structural and chromosomal, as well as the outcome in relation to postnatal surgery. The accuracy of prenatal ultrasound in diagnosing fetal talipes is also examined. Methods: A retrospective observational study was made of all cases presenting to the Fetal Medicine Unit between 1 January 2009 and 31 December 2014. All the identified cases were analysed to identify isolated talipes, associated abnormalities, and chromosomal abnormalities. The pregnancy outcomes were determined using the Astraia database as well as maternity records. When the outcome resulted in a live infant, these infants were followed up using the files at the referral hospital to determine the treatment method used and the number requiring surgery. Results: There were 155 cases, all referred to the Fetal Medicine Unit. Antenatal data included 75 who had other structural abnormalities and 75 who had isolated talipes. In five of the cases were no sufficient data could be found. Twenty-five cases were lost to follow-up, and 12 cases had no clubfoot at birth. Only one was labelled as having positional clubfoot. There were 91 live births. Of the cases of talipes with associated abnormalities, 21.19% were live births (excluding ENND). All terminations of pregnancy as well as 90.9% of intrauterine fetal deaths were complex talipes, and 94.52% of the cases of isolated talipes were live births. The most common associated abnormalities were of the central nervous system. Seventeen of the live births were lost to follow-up. Of the cases of isolated talipes, 53.19% had tenotomies and Ponseti treatment. The false positive rate of detecting fetal talipes on ultrasound was 7.74%. Conclusion: The study made it evident that complex talipes is associated with a poor pregnancy outcome defined as pregnancy loss, where isolated talipes is usually associated with a good pregnancy outcome. Ultrasound is a good diagnostic tool when diagnosing talipes antenatally but cannot diagnose the severity of the clubfoot. False negatives were not studied. The introduction of tenotomy can make a difference in the outcome of clubfoot in comparison with previous studies where tenotomies were not performed. Medical professionals need to address the importance of counselling, and a multidisciplinary team should be involved in cases involving prenatal counselling.

Syfte: Syftet med denna studie var att utvärdera effekten av stimulerande gomplattor på den orala motoriken hos barn med Downs syndrom. Studien syftar också till att undersöka om behandlingen är kostnadseffektiv.Material och Metod: Studien är en systematisk litteraturstudie enligt PRISMAs kriterier och artiklarna kvalitetsgranskades med hjälp SBU: s handbok. De databaser som användes för litteratursökningen var PubMed, Cochrane Library, Scopus och CINAHL.Resultat: Screeningen av 107 unika artiklar resulterade i 14 relevanta publikationer. Kvaliteten på artiklarna var överlag låg och 9 artiklar bedömdes måttlig risk för bias och 5 artiklar bedömdes ha hög risk för bias. Alla 14 inkluderade artiklar visade en positiv effekt på minst en orofacial variabel men det finns ingen konsensus gällande utvärderingsmetoder för behandling med gomplattor, behandlingstider eller vilka orofaciala variabler som bör undersökas.Slutsats: I denna litteraturgenomgång identifierades ett antal studier, som undersökte effekten av behandling med stimulerande gomplattor. På grund av att artiklarna använde icke standardiserade metoder, hade olika behandlingstider och använde olika variabler för att mäta effekten, kan ingen slutsats dras från dessa studier. Fler RCT studier med större grupper av barn och standardiserade metoder för utvärdering behövs. / Aim: The aim of this study was to evaluate the effect of treatment with stimulating palatal plates on the oral motor function in children with Down syndrome. The study also aims to investigate if the treatment is cost-effective.Material and Method: The study is a systematic review made according to the PRISMA criteria. The articles were quality reviewed using Swedish Agency for Health Technology Assessment and Assessment of Social Services - SBU’s manual. The databases used for the literature search were PubMed, Cochrane Library, Scopus and CINAHL.Result: Screening of 107 unique papers resulted in 14 eligible publications. The quality of the articles was overall low. Nine articles were rated moderate risk of bias and 5 articles were rated high risk of bias. All 14 included articles showed a positive effect in one or more aspects on oral motor function but there is no consensus regarding evaluation methods for treatment with palatal plates, treatment times or which orofacial variables that should be investigated. No meta-analysis was made due to the lack of consensus.Conclusion: This literature review identified a number of studies, which investigated the effect of treatment with stimulating palatal plates. Due to the unstandardized methods, different treatment times, and different orofacial measuring variables, no consensus can be drawn from these studies. More RCT studies with larger groups of children and standardized methods for evaluation are required.

La trisomie 21 (t21) est l'anomalie génétique la plus fréquente à l'origine d'une déficience intellectuelle. Bien que la recherche concernant le stéréotype social de la t21 soit limitée, les personnes porteuses de t21, et particulièrement les enfants, semblent être associées à des traits de personnalité tels que « affectueux » et « heureux », les caractéristiques positives l'emportant sur les négatives comme « retardé ». Cependant, ce stéréotype positif coexiste avec des attitudes ambivalentes notamment à propos de l'intégration scolaire de ces enfants. L'objectif principal de cette thèse est d'étudier ce stéréotype au niveau implicite ainsi que l'impact des caractéristiques faciales sur le stéréotype au niveau explicite et implicite. Nos résultats confirment d'une part, un stéréotype social positif explicite dans des échantillons d'étudiants, d'adultes non étudiant et de professionnels du handicap intellectuel. Les visages d'enfants présentant plus de traits faciaux associés à la t21 sont associés à un stéréotype moins positif que ceux en présentant moins. D'autre part, nous mettons en évidence un stéréotype négatif au niveau implicite, même chez les professionnels du handicap. Nous étudions l'influence des variables individuelles sexe, familiarité avec la t21 et théories implicites de l'intelligence sur le stéréotype explicite et implicite. Puis, nous montrons une relation négative entre la typicalité des visages et le jugement sur l'intelligence alors que nous n'observons pas de relation significative entre la typicalité des visages et le niveau cognitif. Nous discutons l'implication de ces résultats sur l'étude du stéréotype et sur les personnes stigmatisées. / Trisomy 21 (t21) or Down syndrome is the most frequent genetic disorder associated with intellectual disability. Although research on the social stereotype toward t21 is very limited, it seems that persons with t21 are typically viewed as “affectionate” and “happy”; with positive personality traits prevailing over the negative ones (e.g., “mentally retarded”). However, this positive stereotype coexists with ambivalent attitudes. The main objective of this study was to investigate the stereotype at the implicit level and the impact of t21 facial features on the stereotype of t21 at the both explicit and implicit levels. Our results confirm, on one hand, a positive social stereotype explicit in samples of young adult students, non-student adults and professional caregivers working with intellectually disabled persons. The positive bias typically found in explicit judgments of children with t21 is smaller for those whose facial features are highly characteristic of this disorder, compared to their counterparts with less distinctive features and to typically developing children. On the other hand, we also show that this bias can coexist with negative evaluations at the implicit level, even among professional caregivers but to a lesser extent. We study the influence of individual variables sex, familiarity with the t21 and implicit theories of intelligence on explicit and implicit stereotypes. Finally, we show a negative relationship between t21 typicality of faces and the judgment of the intelligence as we do not observe a significant relationship between typicality and the cognitive level. We discuss the implications of these results.

Duzentas amostras de DNA obtidas de voluntários brasileiros não aparentados foram triadas para SNPs em uma região de 4079 pares de bases do gene PLAC4 através de reação em cadeia da polimerase (PCR) - utilizando o kit Taq Platinum DNA polymerase (Invitrogen, USA) ciclada em termociclador Eppendorf Mastercycle Gradient (Eppendorf, Germany); e posterior sequenciamento - utilizando o kit Big Dye Terminator Cycle Sequencing v3.1 (Applied Biosystems, USA) corrida em sequenciador ABI 3100 DNA Sequencer (Applied Biosystems, USA). Sete fragmentos foram amplificados utilizando pares de iniciadores desenhados com o auxílio do programa Primer 3 baseado em uma sequência do gene PLAC4 obtida do GenBank. Dez SNPs com taxa de heterozigozidade superior a 25% foram identificados, localizados em seis dos sete fragmentos estudados, que fazem a cobertura de 93% da população brasileira. Um painel combinando estes 10 SNPs apresenta potencial utilidade clínica em um teste pré-natal não invasivo da síndrome de Down fetal baseado na abordagem SNP/mRNA / Two hundred DNA samples obtained from unrelated Brazilian individuals were screened for SNPs in a region of 4079 bp of the exon of PLAC4 gene by polymerase chain reaction (PCR) - using Taq Platinum DNA polymerase kit (Invitrogen, USA) cycled on Eppendorf Mastercycle Gradient thermocycle (Eppendorf, Germany); and subsequent sequencing using Big Dye Terminator Cycle Sequencing v3.1 kit (Applied Biosystems, USA) on ABI 3100 DNA Sequencer (Applied Biosystems, USA). Seven fragments were amplified using primer pairs designed by primer 3 software based on PLAC4 sequence obtained from GenBank. Ten SNPs with heterozigosity rate above 25% were identified, located in six of the seven fragments studied, that covers up to 93% of Brazilian population. A panel combining this 10 SNPs show potential utility in clinical setting for a noninvasive prenatal diagnostic test for Down syndrome based in the SNP/mRNA approach

Duzentas amostras de DNA obtidas de voluntários brasileiros não aparentados foram triadas para SNPs em uma região de 4079 pares de bases do gene PLAC4 através de reação em cadeia da polimerase (PCR) - utilizando o kit Taq Platinum DNA polymerase (Invitrogen, USA) ciclada em termociclador Eppendorf Mastercycle Gradient (Eppendorf, Germany); e posterior sequenciamento - utilizando o kit Big Dye Terminator Cycle Sequencing v3.1 (Applied Biosystems, USA) corrida em sequenciador ABI 3100 DNA Sequencer (Applied Biosystems, USA). Sete fragmentos foram amplificados utilizando pares de iniciadores desenhados com o auxílio do programa Primer 3 baseado em uma sequência do gene PLAC4 obtida do GenBank. Dez SNPs com taxa de heterozigozidade superior a 25% foram identificados, localizados em seis dos sete fragmentos estudados, que fazem a cobertura de 93% da população brasileira. Um painel combinando estes 10 SNPs apresenta potencial utilidade clínica em um teste pré-natal não invasivo da síndrome de Down fetal baseado na abordagem SNP/mRNA / Two hundred DNA samples obtained from unrelated Brazilian individuals were screened for SNPs in a region of 4079 bp of the exon of PLAC4 gene by polymerase chain reaction (PCR) - using Taq Platinum DNA polymerase kit (Invitrogen, USA) cycled on Eppendorf Mastercycle Gradient thermocycle (Eppendorf, Germany); and subsequent sequencing using Big Dye Terminator Cycle Sequencing v3.1 kit (Applied Biosystems, USA) on ABI 3100 DNA Sequencer (Applied Biosystems, USA). Seven fragments were amplified using primer pairs designed by primer 3 software based on PLAC4 sequence obtained from GenBank. Ten SNPs with heterozigosity rate above 25% were identified, located in six of the seven fragments studied, that covers up to 93% of Brazilian population. A panel combining this 10 SNPs show potential utility in clinical setting for a noninvasive prenatal diagnostic test for Down syndrome based in the SNP/mRNA approach

La place du Dépistage Prénatal Non Invasif (DPNI) n’est pas encore clairement définie dans le dépistage prénatal de la trisomie 21 en France. Nos objectifs étaient d’évaluer la compréhension, les connaissances, et l’attitude de professionnels de santé et de patientes concernant le DPNI.Une étude prospective multicentrique par questionnaire auprès de patientes enceintes et de professionnels de santé a été menée dans différents hôpitaux français entre février 2014 et juillet 2015.Sur les 260 questionnaires recueillis chez les professionnels, le score moyen de connaissances était 5,38±2,83(sur 10)et 92,7%(n=241) avaient une attitude favorable face au DPNI. En analyse multivariée, les facteurs associés à un bon niveau de connaissances étaient la profession de gynécologue ou de conseiller en génétique, l’âge<30 ans, le fait de travailler à l’hôpital ou en cabinet et le fait de suivre>50 grossesses par an.Sur les 380 questionnaires de patientes, le score moyen de connaissances était faible 2,20±1,88(sur 10) et 89,9%(n=328) avaient une attitude favorable face au DPNI. En analyse multivariée, les facteurs associés à un bon niveau de connaissances chez les patientes étaient l’âge maternel et le fait de consulter en secteur privé.Le niveau de connaissances des professionnels et des patientes sur le DPNI est faible. La plupart des patientes ne peuvent pas formuler de consentement éclairé. Toutefois, la plupart des professionnels et des patientes sont très en faveur de ce test. La généralisation du DPNI dans le dépistage de la trisomie 21 implique un important programme de formation des professionnels afin qu'ils délivrent une information prénatale de qualité et non directive. / The place of Non Invasive Prenatal Testing(NIPT) is not clearly established for prenatal screening for Down syndrome in France. Our objectives were to assess the understanding, knowledge of, and attitudes towards NIPT in French patients and healthcare providers.A prospective multicenter study was performed in several French hospital centers between February 2014 and July 2015. A survey was administered to pregnant patients and to healthcare professionals.A total of 260 questionnaires were completed by healthcare providers. The average knowledge score was 5,38±2,83(out of a possible 10). In multivariate analysis, the characteristics associated with satisfactory knowledge were: profession as obstetrician or genetic counsellor, age<30 years, working in hospital or in doctor’s office, more than 50 pregnancies followed per year. Among professionals, 92,7%n=241) had a favorable attitude towards NIPT.We collected 380 questionnaires from pregnant women. The average knowledge score was very low: 2,20±1,88(out of 10). In multivariate analysis, the two significant characteristics associated with satisfactory knowledge was maternal age and having prenatal care in private practice. Among patients, 89,9%(n=328) had a favorable attitude towards NIPT.The level of knowledge of NIPT of healthcare professionals and patients is low. Many patients can not provide informed consent. However most professionals and patients are in favor of the use of this test. The input of NIPT in prenatal screening for trisomy 21 requires a considerable teaching program for healthcare providers so they can give balanced pretest information and non-directive counselling.

<p>Down syndrome (DS) is a genetic disorder that results from triplication of human chromosome 21 (Hsa21) and occurs in around 1 in 1000 live births. All individuals with DS present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences between males and females with DS suggest a sexual dimorphism in how trisomy affects skeletal deficits associated with trisomy 21 (Ts21). Previous investigations of skeletal abnormalities in DS have varied methodology, sample sizes and ages making the underlying causes of deficits uncertain. Mouse models of DS were used to characterize skeletal abnormalities, but the genetic and developmental origin remain unidentified. Over-expression <i>Dyrk1a</i>, found on Hsa21 and mouse chromosome 16 (Mmu16) has been linked to cognitive deficits and skeletal deficiencies. Dp1Tyb mice contain three copies of all of the genes on Mmu16 that are homologous to Hsa21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb at 6 weeks 16 weeks showed distinctive abnormalities in BMD, trabecular architecture, and reduced bone strength over time that occur generally through an interaction between sex and genotype. Increased gene dosage and sexual dimorphism in Dp1Tyb mice revealed distinct phenotypes in bone formation and resorption. To assess how <i>Dyrk1a</i> influences the activity and function of osteoblasts Ts65Dn female trisomic mice, female mice with a floxed <i>Dyrk1a</i> gene (Ts65Dn, <i>Dyrk1a</i>^fl/+) were be bred to <i>Osx1</i>-GFP::Cre+ mice to generate Ts65Dn animals with a reduced copy of <i>Dyrk1a </i>in mature osteoblast cells. Female Ts65Dn,<i>Dyrk1a^+/+/+</i>and Ts65Dn,<i>Dyrk1a^+/+/-</i>displayed significant defects in both trabecular architecture and cortical geometry. Ultimate force was reduced in trisomic animals, suggesting whole bone and tissue level properties are not adversely affected by trisomy. Reduction of <i>Dyrk1a</i> functional copy number in female mice did not improve skeletal deficits in an otherwise trisomic animal. <i>Dyrk1a </i>may not alter osteoblast cellular activity in an autonomous manner in trisomic female mice. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of the skeleton in DS mice, potentially paving the way for identification of the causal dosage-sensitive genes in both male and female animals. </p>

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Ce mémoire examine la pratique du dépistage prénatal et du diagnostic prénatal (désormais les tests prénataux ) en deux temps. D’abord, et après une brève mise en contexte, je présente une analyse des facteurs qui ont influencé la mise en place du Programme québécois de dépistage prénatal de la trisomie 21 (PQDPT21). En me basant sur la littérature gouvernementale, je démontre comment un ensemble de pressions politiques, éthiques et sociales a mené à l’impératif d’PQDPT21. Ensuite, je présente une revue de la recherche qualitative à propos de l’expérience de poursuivre une grossesse affectée par l’aneuploïdie fœtale, y compris la trisomie 21. Les principaux résultats de cette revue suggèrent que la ‘rhétorique’ du choix n’est pas toujours démontrée lorsque les parents amènent à terme un fœtus diagnostiqué avec aneuploïdie. Ensuite, je discuterai de l’ensemble de ces travaux selon le concept foucaldien de biopolitique, où les normes et la normalisation agissent sur la régulation politique et sociale. En conclusion, des recommandations pour la recherche et la pratique sont proposées, principalement la nécessité de documenter l’expérience vécue des personnes qui participent aux tests prénataux et d’intégrer ces constatations dans les décisions politiques et dans l’éducation des professionnels de la santé. / This thesis examines the practice of prenatal screening and prenatal diagnosis (henceforth “prenatal testing”) from two angles. Firstly, following a brief introduction to provide context, I present a framework analysis of the factors that influenced the implementation of the Trisomy 21 Prenatal Screening Program of Québec (T21PSPQ). Using governmental literature, I demonstrate how a combination of political, ethical and social pressures led to the imperative of the T21PSPQ. I then present a scoping review of primary empirical qualitative research regarding the experiences of continuing a pregnancy affected by fetal aneuploidy, including trisomy 21. The main findings of this review suggest the ‘rhetoric’ of choice is not always demonstrated in cases where prospective parents bring to term a fetus diagnosed with aneuploidy. The results of this work are then discussed through the Foucauldian concept of biopolitics, where norms and normalization are the principal forms of social and political regulation. Finally, recommendations for research and practice are offered, mainly the need to document the lived experience of those participating in prenatal testing and to incorporate those findings into policy making and into education for health care professionals.