Equinoterapia en niñas con síndrome de Rett

El presente estudio tiene como objetivo principal la valoración de los beneficios que la equinoterapia tiene en niñas afectadas con síndrome de Rett, y se llevará a cabo en un centro hípico que reúna las condiciones e instalaciones necesarias para poder realizar las sesiones de tratamiento. Será un estudio cualitativo y transversal, en el que participarán tanto fisioterapeutas expertos en el ámbito de la equinoterapia como niñas con síndrome de Rett que estén siendo tratadas con ella. Mediante entrevistas semiestructuradas de respuesta abierta a los profesionales y a los familiares cercanos de las niñas, se podrá recopilar la información necesaria para la elaboración de los resultados finales. La utilización de la equinoterapia debería ser una útil herramienta más de la que pudiera disponer la medicina y, concretamente, la fisioterapia para el tratamiento de los trastornos neurológicos o de muchos otros. Las posibles limitaciones de este estudio pueden ser la falta de niñas que cumplan los requisitos necesarios para participar en el proyecto, debido a que el síndrome de Rett es una enfermedad minoritaria.

Sindrome de Rett

Neste Projecto de Investigação proponho abordar questões relacionadas com o Síndrome de Rett, pois é uma temática pouco estudada e consequentemente, a bibliografia é escassa. Tendo um grande interesse pela Deficiência Mental e sabendo que há muitas coisas, e algumas muito boas, pretendo com este estudo saber mais acerca das necessidades e das competências da criança com Síndrome de Rett. A experiência profissional, por opção própria e consciente, relaciona-se com crianças portadoras de deficiências. Os profissionais que trabalham nesta área gostam do que fazem, do qual os professores de Ensino Especial e, por isso, há o intuito de ter possibilidades em compreender todas as vontades e desejos, alegrias e tristezas, conforto e desconforto que as nossas crianças nos comunicam, muitas vezes com um simples olhar. Sabemos que podemos trabalhar juntos, de mãos dadas, para que isso aconteça, como dizia Carl Sandburg: "Enquanto há vida, há esperança". É emocionante quando nos encontramos a caminho de novas descobertas que nos tragam respostas às nossas questões e à esperança de tratamentos que ajudarão as crianças com Síndrome de Rett. Nas palavras de Eleanor Roosevelt, “nunca duvide que o comprometimento de um pequeno grupo de pessoas dedicadas possa mudar o mundo. Na verdade é a única coisa que pode”. Flocos de neve são uma das coisas mais frágeis da natureza... mas veja só o que eles podem fazer quando se juntam! Por outro lado pretende-se planear Programas de Intervenção apropriados. Com base nestes pressupostos aceitei o desafio e encaro o tema pelo que tem de novidade e, aprofundar os conhecimentos na área da deficiência mental. O Projecto encontra-se organizado em duas partes. Na primeira parte, proceder-se-á à análise da literatura onde se fará a apresentação da problemática e dos conceitos fundamentais do trabalho. Tentar-se-á fazer uma abordagem a vários aspectos que se consideram de grande importância para a compreensão desta deficiência. Assim, nesta parte I caracterizar-se-á o Síndrome de Rett, analisar-se-ão as suas causas, o diagnóstico e medidas de intervenção médica, terapêutica, educativa, pedagógica, psicológica e social. Parte II, apresentar-se-á o objecto de estudo, de acordo com a pergunta de partida. Especificar-se-ão as hipóteses teóricas que estão na base desta pesquisa e as respectivas variáveis dependentes e independentes que visarão estabelecer elos de ligação causa e efeito. Apresentar-se-á os instrumentos de pesquisa e os aspectos metodológicos respeitantes ao estudo de uma criança com Síndrome de Rett sobre a qual serão colhidos dados para a elaboração deste trabalho. Surgem as considerações finais e conclusão onde se colocarão questões e pistas sobre a importância do conhecimento das dificuldades e competências adquiridas pela criança para a elaboração de um Projecto de Intervenção. Faz-se também referência à bibliografia consultada para recolha de dados necessários à realização deste estudo. Os anexos constarão de um glossário.

Development of a genotyping microarray for Usher syndrome

BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

Bases moleculares del síndrome de Rett, una mirada actual

El síndrome de Rett (SR) es un trastorno del neurodesarrollo que afecta casi exclusivamente a niñas y cursa secundariamente con autismo. Es poco frecuente y consta de 5 formas clínicas, una clásica y el resto atípicas que comprometen de manera general la habilidad manual, el lenguaje y la motricidad amplia unida a la aparición de estereotipias y epilepsia precoz. Con el objetivo de actualizar la información sobre SR, se aplicaron los descriptores de búsqueda Síndrome de Rett, genes y «Síndrome de Rett», «Rett Syndrome gene», «Rett Syndrome», «Rett Syndrome gene therapy» y «Rett Syndrome review». Se investigó en los archivos digitales PubMed, Hinari, SCIELO y Medline, y se consultaron los sitios web OMIM, ORPHANET, GeneMap, Genetests, Proteins y Gene, entre otros. Entre 1.348 artículos se seleccionaron 42, los cuales reportan 3 genes causantes del síndrome: MECP2, CDKL5y FOXG. El gen MECP2 está mutado en el 80% de los pacientes con SR clásico así como en el 40% de los afectados con alguna de sus formas atípicas. El SR con epilepsia precoz y la variante congénita se deben fundamentalmente a variaciones en los genes CDKL5 y FOXG1 respectivamente.

Clinical utility of amyloid PET imaging in the differential diagnosis of atypical dementias and its impact on caregivers

La maladie d’Alzheimer (MA) se caractérise pathologiquement par l’accumulation de plaques amyloïde dans le cerveau. La tomographie par émission de positrons (TEP) permet d’imager les plaques amyloïde in vivo. Le but de ce projet est d’évaluer le rôle de la TEP amyloïde dans le processus diagnostique de la MA dans des cas de démences atypiques. Le deuxième but de ce projet est de déterminer l’impact de la révélation d’un diagnostic plus certain chez les proches aidants. 28 patients sans diagnostic malgré une investigation exhaustive ont été sélectionnées et imagées avec le traceur amyloïde 18F-NAV4694 (âge 59,3 ans, é-t. 5,8; MMSE 21.4, é-t 6.0). Les neurologues référents documentaient par la suite tout changement de niveau de certitude, de diagnostic, de traitement et/ou de prise en charge. Les proches aidants consentants ont été rencontrés subséquemment, et un questionnaire avec une échelle de Likert a été utilisé afin de documenter l’impact de l’imagerie leur perception de la maladie. Notre cohorte a été également divisée entre amyloïde positifs (14/28) et négatifs (14/28). Un changement de diagnostic a lieu dans 9/28 cas (32,1% :17.8% ont changé de MA à non-MA, 14,3% de non-MA à MA). Il y avait une augmentation significative (p<0,05) de 44% dans la certitude du neurologue suite à cet examen. Un changement de prise en charge a été obtenu dans 20/28 (71,4%) des cas. Bien que non significatifs statistiquement, un impact favorable sur les proches-aidants a été noté. Cette étude suggère que l’imagerie amyloïde a un rôle bénéfique dans les cas de démences atypiques n’ayant pu être élucidés avec les techniques d’investigations actuellement recommandées. De plus, le processus a été perçu positivement par les proches aidants, notamment en encourageant du temps de qualité avec leurs personnes chères. Ceci illustre un rôle prometteur des biomarqueurs, qui sont de plus en plus explorés.

Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development

MeCP2 plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription. In spite of MeCP2`s ubiquitous expression, its functions have always been considered in the context of brain physiology. In this study, we demonstrate that alterations of the normal pattern of expression of MeCP2 in cardiac and skeletal tissues are detrimental for normal development. Overexpression of MeCP2 in the mouse heart leads to embryonic lethality with cardiac septum hypertrophy and dysregulated expression of MeCP2 in skeletal tissue produces severe malformations. We further show that MeCP2`s expression in the heart is developmentally regulated; further suggesting that it plays a key role in regulating transcriptional programs in non-neural tissues.

Community introduction of practice parameters for autistic spectrum disorders: Advancing early recognition.

OBJECTIVES: Within a strong interdisciplinary framework, improvement in the quality of care for children with autistic spectrum disorders through a 2 year implementation program of Practice Parameters, aimed principally at improving early detection and intervention. METHOD: We developed Practice Parameters (PPs) for Pervasive Developmental Disorders and circulated the PPs to all child and adolescent psychiatrists practicing in the region. RESULTS: PP development and parallel information strategies resulted in a significant decrease of 1.5 years in the mean-age-at-diagnosis. However, further analysis indicated that improvement was only transient. CONCLUSION: Despite the encouraging improvement in mean-age-at-diagnosis 2 years after PP implementation, other indicators showed a failure to maintain the improvements. A systematic screening program would be the most reliable method to reinforce the PPs.

Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. © 2012 Wiley Periodicals, Inc.

Mécanismes moléculaires impliqués dans la régulation de l’acide polysialique (PSA) dans le néocortex visuel des souris durant la maturation des synapses GABAergiques

Le fonctionnement du cortex cérébral nécessite l’action coordonnée de deux des sous-types majeurs de neurones, soient les neurones à projections glutamatergiques et les interneurones GABAergiques. Les interneurones GABAergiques ne constituent que 20 à 30% des cellules corticales par rapport au grand nombre de neurones glutamatergiques. Leur rôle est toutefois prépondérant puisqu’ils modulent fortement la dynamique et la plasticité des réseaux néocorticaux. Il n’est donc pas surprenant que les altérations de développement des circuits GABAergiques soient associées à plusieurs maladies du cerveau, incluant l’épilepsie, le syndrome de Rett et la schizophrénie. La compréhension des mécanismes moléculaires régissant le développement des circuits GABAergiques est une étape essentielle menant vers une meilleure compréhension de la façon dont les anormalités se produisent. Conséquemment, nous nous intéressons au rôle de l’acide polysialique (PSA) dans le développement des synapses GABAergiques. PSA est un homopolymère de chaînons polysialylés en α-2,8, et est exclusivement lié à la molécule d’adhésion aux cellules neuronales (NCAM) dans les cerveaux de mammifères. PSA est impliqué dans plusieurs processus développementaux, y compris la formation et la plasticité des synapses glutamatergiques, mais son rôle dans les réseaux GABAergiques reste à préciser. Les données générées dans le laboratoire du Dr. Di Cristo démontrent que PSA est fortement exprimé post- natalement dans le néocortex des rongeurs, que son abondance diminue au cours du développement, et, faits importants, que son expression dépend de l’activité visuelle i et est inversement corrélée à la maturation des synapses GABAergiques. La présente propose de caractériser les mécanismes moléculaires régulant l’expression de PSA dans le néocortex visuel de la souris. Les enzymes polysialyltransférases ST8SiaII (STX) et ST8SiaIV (PST) sont responsables de la formation de la chaîne de PSA sur NCAM. En contrôlant ainsi la quantité de PSA sur NCAM, ils influenceraient le développement des synapses GABAergiques. Mon projet consiste à déterminer comment l’expression des polysialyltransférases est régulée dans le néocortex visuel des souris durant la période post-natale; ces données sont à la fois inconnues, et cruciales. Nous utilisons un système de cultures organotypiques dont la maturation des synapses GABAergiques est comparable au modèle in vivo. L’analyse de l’expression génique par qPCR a démontré que l’expression des polysialyltransférases diminue au cours du développement; une baisse majeure corrélant avec l’ouverture des yeux chez la souris. Nous avons de plus illustré pour la première fois que l’expression de STX, et non celle de PST, est activité-dépendante, et que ce processus requiert l’activation du récepteur NMDA, une augmentation du niveau de calcium intracellulaire et la protéine kinase C (PKC). Ces données démontrent que STX est l’enzyme régulant préférentiellement le niveau de PSA sur NCAM au cours de la période post-natale dans le cortex visuel des souris. Des données préliminaires d’un second volet de notre investigation suggèrent que l’acétylation des histones et la méthylation de l’ADN pourraient également contribuer à la régulation de la transcription de cette enzyme durant le développement. Plus d’investigations seront toutefois nécessaires afin de confirmer cette hypothèse. En somme, la connaissance des mécanismes par lesquels l’expression des ii polysialyltransférases est modulée est essentielle à la compréhension du processus de maturation des synapses GABAergiques. Ceci permettrait de moduler pharmacologiquement l’expression de ces enzymes; la sur-expression de STX et/ou PST pourrait produire une plus grande quantité de PSA, déstabiliser les synapses GABAergiques, et conséquemment, ré-induire la plasticité cérébrale.

Molecular and Cytogenetic Analyses on Brazilian Youths with Pervasive Developmental Disorders

The Pervasive Developmental Disorders (PDDs) constitute a group of behavioral and neurobiological impairment conditions whose main features are delayed communicative and cognitive development. Genetic factors are reportedly associated with PDDs and particular genetic abnormalities are frequently found in specific diagnostic subgroups such as the autism spectrum disorders. This study evaluated cytogenetic and molecular parameters in 30 youths with autism or other PDDs. The fragile X syndrome was the most common genetic abnormality detected, presented by 1 patient with autism and 1 patient with PPD not-otherwise specified (PPD-NOS). One girl with PDD-NOS was found to have tetrasomy for the 15q11-q13 region, and one patient with autism exhibited in 2/100 metaphases an inv(7)(p15q36), thus suggesting a mosaicism 46,XX/46,XX,inv(7)(p15q36) or representing a coincidental finding. The high frequency of chromosomopathies support the hypothesis that PDDs may develop as a consequence to chromosomal abnormalities and justify the cytogenetic and molecular assessment in all patients with PDDs for establishment of diagnosis.

Kinin-B2 Receptor Activity Determines the Differentiation Fate of Neural Stem Cells

Bradykinin is not only important for inflammation and blood pressure regulation, but also involved in neuromodulation and neuroprotection. Here we describe novel functions for bradykinin and the kinin-B2 receptor (B2BkR) in differentiation of neural stem cells. In the presence of the B2BkR antagonist HOE-140 during rat neurosphere differentiation, neuron-specific beta 3-tubulin and enolase expression was reduced together with an increase in glial protein expression, indicating that bradykinin- induced receptor activity contributes to neurogenesis. In agreement, HOE-140 affected in the same way expression levels of neural markers during neural differentiation of murine P19 and human iPS cells. Kinin-B1 receptor agonists and antagonists did not affect expression levels of neural markers, suggesting that bradykinin-mediated effects are exclusively mediated via B2BkR. Neurogenesis was augmented by bradykinin in the middle and late stages of the differentiation process. Chronic treatment with HOE-140 diminished eNOS and nNOS as well as M1-M4 muscarinic receptor expression and also affected purinergic receptor expression and activity. Neurogenesis, gliogenesis, and neural migration were altered during differentiation of neurospheres isolated from B2BkR knock-out mice. Whole mount in situ hybridization revealed the presence of B2BkR mRNA throughout the nervous system in mouse embryos, and less beta 3-tubulin and more glial proteins were expressed in developing and adult B2BkR knock-out mice brains. As a underlying transcriptional mechanism for neural fate determination, HOE-140 induced up-regulation of Notch1 and Stat3 gene expression. Because pharmacological treatments did not affect cell viability and proliferation, we conclude that bradykinin-induced signaling provides a switch for neural fate determination and specification of neurotransmitter receptor expression.

Child and adolescent psychiatric genetics

The current status of child and adolescent psychiatric genetics appears promising in light of the initiation of genome-wide association studies (GWAS) for diverse polygenic disorders and the molecular elucidation of monogenic Rett syndrome, for which recent functional studies provide hope for pharmacological treatment strategies. Within the last 50 years, tremendous progress has been made in linking genetic variation to behavioral phenotypes and psychiatric disorders. We summarize the major findings of the Human Genome Project and dwell on largely unsuccessful candidate gene and linkage studies. GWAS for the first time offer the possibility to detect single nucleotide polymorphisms and copy number variants without a priori hypotheses as to their molecular etiology. At the same time it is becoming increasingly clear that very large sample sizes are required in order to enable genome wide significant findings, thus necessitating further large-scaled ascertainment schemes for the successful elucidation of the molecular genetics of childhood and adolescent psychiatric disorders. We conclude by reflecting on different scenarios for future research into the molecular basis of early onset psychiatric disorders. This review represents the introductory article of this special issue of the European Child and Adolescent Psychiatry.

Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings.

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.