Estimativa da frequência da inversão SWBinv-1 entre pais de portadores ds síndrome de Williams-Beuren e pais de filhos normais do Brasil

Pós-graduação em Ciências Biológicas (Genética) - IBB

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

Perceptual grouping and distance estimates in typical and atypical development: comparing performance across perception, drawing and construction tasks

Perceptual grouping is a pre-attentive process which serves to group local elements into global wholes, based on shared properties. One effect of perceptual grouping is to distort the ability to estimate the distance between two elements. In this study, biases in distance estimates, caused by four types of perceptual grouping, were measured across three tasks, a perception, a drawing and a construction task in both typical development (TD: Experiment 1) and in individuals with Williams syndrome (WS: Experiment 2). In Experiment 1, perceptual grouping distorted distance estimates across all three tasks. Interestingly, the effect of grouping by luminance was in the opposite direction to the effects of the remaining grouping types. We relate this to differences in the ability to inhibit perceptual grouping effects on distance estimates. Additive distorting influences were also observed in the drawing and the construction task, which are explained in terms of the points of reference employed in each task. Experiment 2 demonstrated that the above distortion effects are also observed in WS. Given the known deficit in the ability to use perceptual grouping in WS, this suggests a dissociation between the pre-attentive influence of and the attentive deployment of perceptual grouping in WS. The typical distortion in relation to drawing and construction points towards the presence of some typical location coding strategies in WS. The performance of the WS group differed from the TD participants on two counts. First, the pattern of overall distance estimates (averaged across interior and exterior distances) across the four perceptual grouping types, differed between groups. Second, the distorting influence of perceptual grouping was strongest for grouping by shape similarity in WS, which contrasts to a strength in grouping by proximity observed in the TD participants. (c) 2008 Elsevier Inc. All rights reserved.

Language in genetic syndromes and cognitive modularity

In recent years, research into the impact of genetic abnormalities on cognitive development, including language, has become recognized for its potential to make valuable contributions to our understanding of the brain–behaviour relationships underlying language acquisition as well as to understanding the cognitive architecture of the human mind. The publication of Fodor’s ( 1983 ) book The Modularity of Mind has had a profound impact on the study of language and the cognitive architecture of the human mind. Its central claim is that many of the processes involved in comprehension are undertaken by special brain systems termed ‘modules’. This domain specificity of language or modularity has become a fundamental feature that differentiates competing theories and accounts of language acquisition (Fodor 1983 , 1985 ; Levy 1994 ; Karmiloff-Smith 1998 ). However, although the fact that the adult brain is modularized is hardly disputed, there are different views of how brain regions become specialized for specific functions. A question of some interest to theorists is whether the human brain is modularized from the outset (nativist view) or whether these distinct brain regions develop as a result of biological maturation and environmental input (neuroconstructivist view). One source of insight into these issues has been the study of developmental disorders, and in particular genetic syndromes, such as Williams syndrome (WS) and Down syndrome (DS). Because of their uneven profiles characterized by dissociations of different cognitive skills, these syndromes can help us address theoretically significant questions. Investigations into the linguistic and cognitive profiles of individuals with these genetic abnormalities have been used as evidence to advance theoretical views about innate modularity and the cognitive architecture of the human mind. The present chapter will be organized as follows. To begin, two different theoretical proposals in the modularity debate will be presented. Then studies of linguistic abilities in WS and in DS will be reviewed. Here, the emphasis will be mainly on WS due to the fact that theoretical debates have focused primarily on WS, there is a larger body of literature on WS, and DS subjects have typically been used for the purposes of comparison. Finally, the modularity debate will be revisited in light of the literature review of both WS and DS. Conclusions will be drawn regarding the contribution of these two genetic syndromes to the issue of cognitive modularity, and in particular innate modularity.

Later language

The focus of this chapter is language abilities in individuals with Williams syndrome (WS) after the age of 5 years.

Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy

von Walden F, Casagrande V, Ostlund Farrants AK, Nader GA. Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy. Am J Physiol Cell Physiol 302: C1523-C1530, 2012. First published March 7, 2012; doi:10.1152/ajpcell.00460.2011.-The main goal of the present study was to investigate the regulation of ribosomal DNA (rDNA) gene transcription at the onset of skeletal muscle hypertrophy. Mice were subjected to functional overload of the plantaris by bilateral removal of the synergist muscles. Mechanical loading resulted in muscle hypertrophy with an increase in rRNA content. rDNA transcription, as determined by 45S pre-rRNA abundance, paralleled the increase in rRNA content and was consistent with the onset of the hypertrophic response. Increased transcription and protein expression of c-Myc and its downstream polymerase I (Pol I) regulon (POL1RB, TIF-1A, PAF53, TTF1, TAF1C) was also consistent with the increase in rRNA. Similarly, factors involved in rDNA transcription, such as the upstream binding factor and the Williams syndrome transcription factor, were induced by mechanical loading in a corresponding temporal fashion. Chromatin immunoprecipitation revealed that these factors, together with Pol I, were enriched at the rDNA promoter. This, in addition to an increase in histone H3 lysine 9 acetylation, demonstrates that mechanical loading regulates rRNA synthesis by inducing a gene expression program consisting of a Pol I regulon, together with accessory factors involved in transcription and chromatin remodeling at the rDNA promoter. Altogether, these data indicate that transcriptional and epigenetic mechanisms take place in the regulation of ribosome production at the onset of muscle hypertrophy.

Guidelines of Special Care Dentistry in Patients with Chromosomal and Genetic syndromes

Chromosomal and genetic syndromes are frequently associated with dental and cranio-facial alterations. The aim of our study is to identify and describe the dental and craniofacial alterations typical of six genetic and chromosomal syndromes examined. Materials and Methods- A dental visit was performed to 195 patients referred from Sant’Orsola Hospital of Bologna, University of Bologna, to Service of Special Need Dentistry, Dental Clinic, Department of Biomedical and Neuromotor Science, University of Bologna. The patients recruited were 137 females and 58 males, in an age range of 3-49 years (mean age of 13.8±7.4). The total sample consisted of subjects affected with Down Syndrome (n=133), Familiar Hypophosphatemic Ricket (n=10), Muscular Dystrophies (n=12), Noonan Syndrome (n=13), Turner Syndrome (n=17), Williams Syndrome(n=10). A questionnaire regarding detailed medical and dental history, oral health and dietary habits, was filled by parents/caregivers, or patients themselves when possible. The intra-oral and extra-oral examination valued the presence of facial asymmetries, oral habits, dental and skeletal malocclusions, dental formula, dental anomalies, Plaque Index (Silness&LÖe Index), caries prevalence (dmft/DMFT index), gingivitis and periodontal disease, and mucosal lesions. Radiographic examinations (Intraoral radiographies, Orthopanoramic, Skull teleradiography) were executed according to patient’s age and treatment planning. A review of literature about each syndrome and its dental and cranio-facial characteristics and about caries, hygiene status and malocclusion prevalence on syndromic and non-syndromic population was performed. Results - The data of all the patients were collected in the “Data Collection Tables” created for each syndrome. General anamnesis information, oral hygiene habits and dmft/DMFT, PI, malocclusion prevalence were calculated and compared to syndromic and non-syndromic population results found in literature. Discussions and conclusions - Guidelines of Special Care dentistry were indicated for each syndrome, in relation to each syndrome features and individual patient characteristics.

Vesicoureteral reflux and the extracellular matrix connection.

Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes.

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.

Prosodie et Syndrome de Williams : une étude inter-langue

L’objectif de l’étude est de mieux cerner les particularités acoustiques de la prosodie d’enfants porteurs du SW de langue maternelle anglaise et de langue maternelle française. Des productions spontanées ont été recueillies à l’aide de la tâche de narration « Grenouille, où es-tu ? » (Mayer, 1969). La prosodie des enfants SW est comparée à celle de deux groupes typiques, un de même âge chronologique et un de même âge développemental que le groupe avec SW La population se compose de 1. 7 enfants SW de langue française âgés entre 6 ans et 13 ans 7 mois, appariés à deux groupes typiques et 2. 13 enfants SW de langue anglaise âgés entre 6 ans et 13 ans 11 mois, appariés à deux groupes typiques. Notre analyse porte sur un paramètre acoustique de la prosodie des enfants avec SW : la Variation de la Fréquence Fondamentale. Les résultats sont discutés sur les points suivants : 1. les différences et similitudes entre les profils prosodiques des enfants avec SW et des enfants typiques de même âge chronologique ou développemental, en langue anglaise et en langue française, 2. les différences entre les enfants avec SWde langue maternelle anglaise et les enfants avec SWde langue maternelle française et 3. le développement prosodique observé chez les enfants avec SW. (For English abstract see "Additional Information")

Le développement de la prosodie dans le syndrome de Williams et le syndrome de Down chez des enfants de langue anglaise

The aim of the present study is to investigate the developmental profile of three aspects of prosody function, i.e. affect, focus and turn-endings in children with Williams and in those with Down’s syndrome compared to typically developing English speaking children. The tasks used were part of the computer-based battery, Profiling Elements of Prosody for Speech Communication (Peppe, McCann & Gibon, 2003). Cross-sectional developmental trajectories linking chronological and non-verbal mental age and affects and turn-ending functions of prosody were constructed. The results showed an atypical profile in both clinical populations. More interestingly, the profiles were atypical for different reasons, suggesting multiple and possibly different developmental pathways to the acquisition of prosody in these two populations.

Fluorescent in situ hybridization (FISH) as a diagnostic tool for Williams-Beuren syndrome

Fluorescent in situ hybridization (FISH) with commercial probes covering the elastin gene (ELN) was used to determine the frequency of the 7q11.23 deletion in 18 children clinically diagnosed with Williams-Beuren syndrome (WBS). A de novo deletion was detected in 15 of the children (83%). Diagnostic investigation for WBS started late in childhood (median = 5.8 years). All the children showed facial features typical of the syndrome, mental retardation and developmental delay. Over-friendliness was observed in the majority of cases. Clinodactyly of the 5th finger (n = 13), cardiovascular disease (n = 9), loquacity (n = 9), low birthweight (n = 8), and failure to thrive (n = 9) were observed only in those children with the deletion. Respiratory problems (n = 9), though not previously reported in the literature, was a common finding in the group studied. Our results confirmed that FISH is useful in identifying 7q11.23 deletions in cases of WBS. Clinical manifestations were more evident in the deletion-positive children.

Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a genetic disorder characterized by physical and intellectual developmental delay, associated with congenital heart disease and facial dysmorphism. WBS is caused by a microdeletion on chromosome 7 (7q11.23), which encompasses the elastin (ELN) gene and about 27 other genes. The gold standard for WBS laboratory diagnosis is FISH (fluorescence in situ hybridization), which is very costly. As a possible alternative, we investigated the accuracy of three clinical diagnostic scoring systems in 250 patients with WBS diagnosed by FISH. We concluded that all three systems could be used for the clinical diagnosis of WBS, but they all gave a low percentage of false-positive (6.0-9.2%) and false-negative (0.8-4.0%) results. Therefore, their use should be associated with FISH testing. © FUNPEC-RP.

Copy number variation in Williams-Beuren syndrome: suitable diagnostic strategy for developing countries

Abstract Background Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis (SVAS), mental retardation, and overfriendliness comprise typical symptoms of WBS. Although fluorescence in situ hybridization (FISH) is considered the gold standard technique, the microsatellite DNA markers and multiplex ligation-dependent probe amplification (MLPA) could be used for to confirm the diagnosis of WBS. Results We have evaluated a total cohort of 88 patients with a suspicion clinical diagnosis of WBS using a collection of five markers (D7S1870, D7S489, D7S613, D7S2476, and D7S489_A) and a commercial MLPA kit (P029). The microdeletion was present in 64 (72.7%) patients and absent in 24 (27.3%) patients. The parental origin of deletion was maternal in 36 of 64 patients (56.3%) paternal in 28 of 64 patients (43.7%). The deletion size was 1.55 Mb in 57 of 64 patients (89.1%) and 1.84 Mb in 7 of 64 patients (10.9%). The results were concordant using both techniques, except for four patients whose microsatellite markers were uninformative. There were no clinical differences in relation to either the size or parental origin of the deletion. Conclusion MLPA was considered a faster and more economical method in a single assay, whereas the microsatellite markers could determine both the size and parental origin of the deletion in WBS. The microsatellite marker and MLPA techniques are effective in deletion detection in WBS, and both methods provide a useful diagnostic strategy mainly for developing countries.