Os objetivos deste estudo foram estimar a prevalência da deficiência intelectual aos 7-8 anos de idade em uma coorte de nascimentos, através de investigação genética clínica e laboratorial e, também, investigar a etiologia da mesma e os fatores associados. Os participantes faziam parte de uma coorte acompanhada desde o nascimento e foram incluídos neste estudo por apresentar, em acompanhamentos anteriores, suspeita de atraso no desenvolvimento segundo o Teste de Rastreamento de Battelle, QI abaixo de 70 segundo a escala WPPSI e/ou problemas no comportamento observados durante entrevista. Das 4231 crianças da Coorte de 2004 de Pelotas, 214 foram selecionadas para a avaliação genética que constou de: anamnese, exame físico e dismorfológico e coleta de sangue e urina quando indicado. Criou-se um banco de dados incluindo variáves desta avaliação e dos acompanhamentos anteriores da Coorte, tais como: variáveis da gestação e do nascimento, sociodemográficas e relativas à saúde e estimulação da criança. Os dados foram processados no pacote estatístico Stata 13.0 e foi utilizada análise de variância (ANOVA). Foi considerada como tendo deficiência intelectual a criança que, além de apresentar um QI abaixo de 70, apresentava também problemas no comportamento adaptativo. Cento e setenta crianças das duzentas e quatorze selecionadas no início do estudo foram diagnosticadas com deficiência intelectual e classificadas em cinco grupos etiológicos. A maior parte das crianças (44,4%) foi classificada como tendo deficiência intelectual devida a causas não-biológicas, ou seja, ligada a fatores ambientais. O segundo maior grupo (16,6%) foi o grupo de crianças com deficiência intelectual genética que incluiu crianças com síndrome de Down, microdeleções e patologias autossômicas dominantes e patologias multifatoriais. A seguir, crianças com sequelas neonatais (13,3%) e deficiência intelectual associada a outras doenças (13,3%), como epilepsia e TDAH. O menor grupo foi o idiopático, constituído por crianças que, mesmo após investigação clínica e laboratorial, permaneceram sem diagnóstico definido. A prevalência de deficiência intelectual foi de 4,5% e a prevalência de deficiência intelectual genética de 0,66%. Apesar de algumas limitações como a identificação e seleção dos casos aos 4 anos para uma avaliação aos 7-8 anos, é importante considerar que, por ser um estudo de base populacional, com alta taxa de acompanhamento (92,0%), isto minimiza o viés de seleção. O fato dos dados serem colhidos no momento ou em um curto intervalo de tempo, considerando os diversos acompanhamentos, minimiza o viés de memória. Fora do mundo desenvolvido, são raros os estudos de coorte que avaliaram deficiência intelectual, seus fatores de risco e sua etiologia. Grande parte destes estudos, mesmo os conduzidos em países de renda alta, avaliaram a prevalência, mas não a etiologia. Os dados sugerem que boa parte destes casos poderia ser prevenida, principalmente considerando uma etiologia não-biológica, caso existissem, além do rastreamento de problemas no desenvolvimento, estratégias de intervenção educacional e de saúde. / The aims of this study were to estimate the prevalence and etiology of intellectual disability at 7-8 years of age in a birth cohort through clinical and laboratory investigation and associated factors. Participants were part of a cohort followed from birth and were included in this study due to suspected developmental delay according to the Battelle Screening Test, IQ below 70 according to WPPSI scale and / or behavior problems observed during the interview in previous follow-ups. Of the 4231 children in the 2004 Pelotas birth cohort, 214 were selected for genetic evaluation which included anamnesis, physical and dysmorphological examination and collection of blood and urine when indicated. A dataset including variables from this evaluation and the previous cohort of follow-ups such as variables of pregnancy and birth, social demographic and health-related and stimulation of the child. Data were analyzed using Stata version 13.0. Analysis of variance (ANOVA) was performed. To be considered as having intellectual disability the child that presenting an IQ below 70 and problems in adaptive behavior. One hundred and seventy children from two hundred fourteen selected at baseline were diagnosed with intellectual disability and they were classified into five etiologic groups. Most children (44.4 %) were classified as having intellectual disability due to no biological causes, i.e., linked to environmental factors. The second largest group (16.6%) was the group of children with genetic intellectual disability which included children with Down syndrome, microdeletions and autosomal dominant and multifactorial diseases. Children with neonatal sequelae accounted for 13.3% and intellectual disability associated with other diseases such as epilepsy and ADHD also accounted for 13.3%. The smallest group was idiopathic composed of children who even after clinical and laboratory investigation remained without a definite diagnosis. The prevalence of intellectual disability was 4.5 % and the prevalence of genetic intellectual disability 0.66 %. Despite some limitations such as the identification and selection of cases to four years for an assessment at 7-8 years it is important to consider that it is a population-based study with high follow-up rate (92.0 %) which minimizes selection and information bias. As data were collected in time or in a short period of time considering the several follow-ups minimize recall bias. Outside the developed world few cohort studies assessed intellectual disabilities, their risk factors and etiology. Most of these studies even those conducted in high-income countries assessed the prevalence but not the etiology. The data suggest that part of these cases could be prevented specially considering the non-biological etiology if there were screening of developmental delay and intervention strategies on health and educational bases.

The study reports on analyses of data collected from the Inventory for Client and Agency Planning (ICAP) for 5,859 children with Autism (n = 511), Traumatic Brain Injury (TBI, n = 522), or Mental Retardation (MR, n = 4826) whose legal guardians applied for support services through the Utah Department of Services for People with Disabilities (DSPD). Results indicate that the least to most frequent problem behaviors were (a) destructive to property, (b) hurtful to self, (c) hurtful to others, (d) socially offensive, (e) unusual habits, (f) withdrawal, (g) uncooperative, and (h) disruptive behaviors. The degree of severity varied from problem to problem, with uncooperative behaviors rated as most severe. Males displayed higher frequency and severity for all problem behaviors, except hurtful to self.

This is a report of a descriptive study in which a random sample of fifty out of four hundred returned questionnaires from parents with a mentally retarded child were analyzed. The foci of analysis were: (1) parental attitudes toward the child; (2) the changes experienced by the family as affected by birth order and sex of the mentally retarded child; (3) how the diagnosis was accomplished; and (4) how in their opinion services during this diagnostic period could be improved. The data revealed that: (1) protectiveness toward the child is the predominant parental response; (2) negative changes are probably twice as high with an only child who is retarded; (3) male retardates are somewhat more disruptive than are female; (4) diagnosis must be individualized; however, generalizations which can be made include: understandable language, patience, empathy, and above all honesty.

The purposes of this study were: (1) to compare nine groups of subjects composed of intellectually normal children, mentally retarded adolescents, and mentally retarded adults on a three dimensional concept formation task; (2) to determine the effects of discrimination training on the sortings of the nine groups on the experimental task. The 207 subjects of this study were divided into nine groups. Seven of t he groups, consisting of high average and low average grade 3, superior high average, and low average grade 6, and high and low adolescent retardates were chosen on the bases of school grade level (3, 6, and adolescent retarded) and IQ level (low average, high average, superior, low and high adolescent, and low and high adult retarded) with each group composed of 21 subjects, except the two adolescent groups which were composed of 30 subjects each. The remaining two groups, high and low adult retardates, were chosen on the bases of chronological age (between 20-35) and IQ level (high and low mildly retarded), with both groups composed of 30 subjects. One-third of the subjects in each group were given special discrimination training with the task objects. The experimental task required each subject to place 27 objects in three trays which could be moved back and forth. The trays were stacked one on another vertically but separated by one-sixteenth of one inch. Each tray was divided into nine boxes. The objects were of three kinds: sphere, cube, and tetrahedron; three sizes: 1, 1 1/2, and 1 3/4 inches; and three shades of blue: dark, medium, and light. Each subject was directed to place the objects in the three dimensional matrix as he desired. The discrimination subjects of each group performed the same task, but they received special orientation training with the trays and objects. One task object, a medium sized, medium blue cube was pre-placed in the center box of the middle tray for an anchor point for each subject to use for his sortings. The results of this study indicate the following: The nine diverse groups included in this study did not show statistically significant differences in their grouping of identical color shades, identical forms and identical sizes in the three dimensional matrix when each element The nine groups did not significantly (statistically) differ in their use of the left to right direction in their grouping of identical color, identical form, and identical size horizontally as well as vertically. This lack of significance also applied to the use of the front to back direction in sorting color, form and size differences both horizontally and vertically. Discrimination training did not significantly affect the performance of the nine groups on any of the dimensions measured in this study. Adult and adolescent retarded groups showed noticeable effects from discrimination training by increasing their responses to size likenesses in their horizontal sortings. In general, normal subjects increased their groupings of identical elements more than retarded subjects, hut the findings indicate that IQ and chronological age did not significantly (statistically) affect discrimination training in these nine groups. Neither chronological age nor IQ significantly (statistically) affected the subjects' concrete tendency to place the largest size objects into the top tray which was most accessible for sorting.

Work, leisure and retirement are fundamental aspects of life for individuals with an intellectual disability, just as with the general population. Many educational efforts have taught knowledge and skills to persons with an intellectual disability to improve their functioning in the work and leisure domains. More recently, retirement concerns have become particularly salient because so many individuals now live much longer. The present study looked at using a conceptual approach to improve education in these three domains. It employed the principles that instruction works much better when it proceeds from an individual=s existing concepts and that instruction should teach useful concepts that an individual can apply to improve his or her real world functioning. This conceptual approach has not been used much with the education of persons with an intellectual disability. In Study 1, sixty adults with an intellectual disability were interviewed to determine their existing concepts of work, leisure and retirement and their work and leisure histories. Most had solid concepts of work and leisure, but with some gaps, particularly in notions of volunteer work and occupational status. Most reported satisfactory work and leisure lives. Most had a relatively poor concept of retirement at best and had done little or no retirement planning. These data suggested some key targets for an educational program to improve their knowledge and functioning in these domains. In Study 2, these data were used to develop an instructional program that focussed on gaps in knowledge of volunteer work, banking, budgeting and participation in satisfying leisure activities and in retirement planning. This instructional program was delivered over eight weeks to a class consisting of nine adults with an intellectual disability, with some success. This general conceptual approach can be usefully applied to teaching in other important domains with persons with an intellectual disability. They can be taught key concepts which they can use to live their lives more purposely and independently.

<p>Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders.</p><p>In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene <i>ZDHHC15 </i>in a patient with severe mental retardation. Subsequent experiments revealed loss of <i>ZDHHC15</i> transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.</p>

Chromosomal abnormalities are defined as changes in the chromosome structure and fall in one of two categories. The first category is numerical alterations while the second category consists of structural abnormalities. Structural chromosomal abnormalities do not always interrupt genes in order to cause disease. They can also affect gene expression by separating a gene and its promoter element from distant regulatory elements. We have used characterisation of structural chromosomal abnormalities to identify the genetic bases for several congenital disorders. In papers I-III, we have applied molecular characterisation of chromosomal translocations in order to identify candidate genes involved in mental retardation, hypospadias and anal malformation and premature ovarian failure. In paper I, we localised the chromosome X translocation breakpoint in a t(X;15) to be in the immediate proximity of the gene ZDHHC15 in a patient with severe mental retardation. Subsequent experiments revealed loss of ZDHHC15 transcription in the patient which suggests this gene to be involved in the aetiology of the patient’s phenotype. In paper II, we show that a balanced translocation between chromosomes 6 and 17 in a patient with urogential malformation disrupts 2 genes, one at each translocation breakpoint. We also identified a fusion-gene as a result of the translocation. Our hypethesis is that the translocation together with its molecular consequences is important for the phenotype in the patient. Similarly, in paper III, we have used molecular characterisation of the breakpoints in a balanced translocation between chromosomes X and 11 in order to localise candidate genes in ovarian function. Our results indicate a number of genes affected by the translocation. In paper IV, we have used array-based comparative genomic hybridisation (array-CGH) in order to investigate a cohort of autistic sib-pairs for submicroscopic chromosomal alterations. We have identified several novel duplications and one novel deletion with strong association with autism.

The mechanisms that govern the repression of 5-HT1A receptor gene expression mediated by a novel mental retardation gene, Freud-1, were examined in HEK293 and SKNSH cells. This study provides a possible mechanism of 5-HT1A receptor gene regulation by Freud-1, which, to mediate its action, recruits Swi/Snf and Sin3A/histone deacetylase (HDAC) complexes in non-neuronal HEK293 cells and Swi/Snf only in neuronal, 5-HT1A receptor-expressing SKNSH cells. Thus, Freud-1 has a dual mechanism of repression depending on cell type: HDAC dependent in HEK293 cells and HDAC independent in SKNSH cells. In addition, I present evidence that Freud-1 is not sumoylated at its consensus sumoylation sites and I present the lipid binding properties of Freud-1 and Freud-1 mutants.

False confessions are a leading cause of wrongful convictions. Defendants under the age of 18 or who have mental retardation are at a high risk of making false confessions. Participants read a short synopsis of a hypothetical robbery and trial. They then answered several questions as jurors. The age (16 years or 32 years) and intelligence in terms of IQ (68 or 102) of the defendant were manipulated. Results suggest there was no effect of age or intelligence on verdict or confidence that the confession was true. There was an effect of age and intelligence on guilt confidence such that defendants are less confident of a guilty verdict when the defendant is a juvenile or has mental retardation than when the defendant is an adult or of average intelligence. Punishment of younger defendants was more lenient than punishment of adult defendants. Confessions made by defendants with mental retardation were perceived as less reliable than confessions made by defendants of average intelligence, but there was no effect of intelligence on punishment.

The mechanisms that govern the repression of 5-HT1A receptor gene expression mediated by a novel mental retardation gene, Freud-1, were examined in HEK293 and SKNSH cells. This study provides a possible mechanism of 5-HT1A receptor gene regulation by Freud-1, which, to mediate its action, recruits Swi/Snf and Sin3A/histone deacetylase (HDAC) complexes in non-neuronal HEK293 cells and Swi/Snf only in neuronal, 5-HT1A receptor-expressing SKNSH cells. Thus, Freud-1 has a dual mechanism of repression depending on cell type: HDAC dependent in HEK293 cells and HDAC independent in SKNSH cells. In addition, I present evidence that Freud-1 is not sumoylated at its consensus sumoylation sites and I present the lipid binding properties of Freud-1 and Freud-1 mutants.