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.

The Sjögren-Larsson syndrome (SLS) is a genetically determined syndrome with autosomal recessive inheritance originally and comprehensively described from Sweden. It is characterized by the three cardinal signs congenital ichthyosis, spastic di- or tetraplegia and mental retardation.The present investigation covers all 35 SLS patients alive in Sweden in 1978 and the genetic study all 58 SLS patients born in Sweden in 1886-1977. Forty-five of these were bom in a restricted area in the northeast of Sweden and five more had ancestors from this area. This concentration is probably the result of a founder effect — transmission of the SLS gene mutation from early immigrants to this area — followed by little migration to and from this area. Ancestors of SLS patients have been traced back to an early immigrant to this area in the 14th century.The mean yearly incidences of SLS per 100.000 newborn during the years 1901-1977 were 0.6 in the whole of Sweden, 10.2 in the county of Västerbotten and 2.7 in the county of Norrbotten. The corresponding prevalence figures for SLS on 31 December 1978 were 0.4, 8.3 and 2.6 per 100.000 in these areas, respectively.The ichthyosis in the SLS was found to be congenital in the true sense of the word, as it was always seen at birth. The characteristic skin findings indicate that the use of replicas in ichthyotic patients may be a good complement to the clinical and histopathological examinations.All SLS patients had mental retardation and spastic di- or tetraplegia. The first observation of these symptoms was made between the age of 4 and 30 months.Small white glistening dots located in the ocular fundus were noted in all 30 SLS patients examined in this respect and seem to be pathognomonic for SLS.The fatty acid patterns of plasma phospholipids, cholesteryl esters, triglycerides and free fatty acids in SLS patients were examined. The results suggest that SLS is possibly a disorder of fatty acid metabolism leading to an altered composition of polyunsaturated fatty acids due to a disturbance in the A6-desaturation of essential fatty acids. / <p>Some photos have been censored.</p><p>En del foton har blivit censurerade.</p> / digitalisering@umu

No description available.

Since its discovery in 1984, psychological investigators have continued to explore the Flynn Effect, the phenomenon of consistent and secular IQ gains within industrialized nations approximating 0.3 points per year. The most contentious debate within this field of research surrounds the purported cause of the Effect, and yet the research literature lacks a synthesis of the leading causal theories and the evidence supporting them. The principal hypothesized causal mechanisms – psychometric artifact, educational intervention, environmental changes, nutrition, genetics, gene-environment interaction model, medical improvements, and the multiplicity hypothesis – are reviewed and analyzed within the larger breadth of Flynn Effect scholarly literature. Flynn Effect causal investigation has not yielded any decisive results, and the unproductive postulation of causal theories has recently stagnated, so researchers must accept a necessary shift in the focus of their research toward a more collaborative and holistic understanding of the Effect in order to effectively determine its causes. Extensive social implications of the Effect within the scopes of special education and judicial policy necessitate the expedited revitalization of Flynn Effect research such that contemporary society may be better able to appropriately incorporate the Effect into public policy.

Hos barn med utvecklingsstörning och autism är kontrollen över blåsan och tarmen försenad i varierande grad. Syfte: Att utvärdera hur föräldrars upplevelse av sitt barns förmåga gällande toalettbesök samt blås- ochtarmkontroll har förändrats sedan avslutad föräldracirkel. Metod: Deskriptiv studie. Enkäter till samtliga föräldrar (n=64) som deltagit i föräldracirkeln vid Habiliteringen för barn ochvuxna i Uppsala län, åren 2002-2010. Svarsfrekvensen var 27 av 64 (42 %). Enkäten innehöll femton slutna frågor rörande barnens förmågor, två frågor omföräldrarnas behållning samt två öppna frågor om vad som var bra respektive saknades. Huvudresultat: Majoriteten av föräldrarna upplever att barnens förmågor har blivit bättre vad gäller toalettbesök, bortsett från förmågan att torka sig ordentligt efter att ha bajsat. Majoriteten av föräldrarna upplever även en förbättring av barnets förmågor vid blås- och tarmkontroll. En stor del av föräldrarna anser att föräldracirkeln gett dem stöd samt att de kunnat omvandla de råd de fått. Det som föräldrarna uppskattade med föräldracirkeln var bland annat informationen, verktygen, kunskapen samt möjligheten till utbyte av erfarenheter. Det föräldrarna däremot saknade var uppföljning och utvärdering. Vissa uttryckte ett behov av mer tid för diskussion samt individanpassat stöd. Det fanns även föräldrar som upplevde att föräldracirkeln inte gav dem vare sig stöd eller hjälp. Slutsats: Idag ger föräldracirkeln positiva upplevelser för majoriteten av deltagarna. Detta i sig ger föräldracirkeln ett värde. Det finns dock delar i utformningen som bör förbättras för att tillmötesgå fler föräldrars behov. / The bladder and bowel control is delayed in different extent in children with mental retardation and autism. Aim: To evaluate how parents experience if their child’s ability, regarding toileting and bladder and bowel control, has changed since the end of parental study circle. Method: Descriptive study. Questionnaires were sent to all parents (n=64) who participated in the parental study circle organized by the Habilitation centre in Uppsala, during 2002-2010. Fifteen closed questions concerning children's abilities, two questions on the parents’ benefits, and two open questions about what was good and was missing. The respond rate was 27 of 64 (42 %). Primary results: After the parental study circle the majority of parents feel that their children’s abilities have improved in terms of toileting, apart from the ability to wipe themselves properly after defecation. The majority of parents also experience an improvement in the child's abilities regarding the bladder and bowel control. Many parents believed that the parental study circle gave them support and that they could apply the advice they received. The parents appreciated the information, tools, knowledge and opportunity to exchange experiences. The parents, however, missed follow-up and evaluation. Some expressed a need for more time for discussion and individual support. There were also parents who felt that the parental study circle had not given them support or assistance. Conclusion: Today the parental study circle was experienced positively by the majority of the participants. This in itself gives the parental study circle a value. However, there are some parts that could be improved to meet the needs of parents.

Abstract This paper is based on the study of a special education teacher who tutoring a particular child in a kindergarten, evaluating the effects of the case of its social abilities and cognitive abilities learning after a tutoring service. The study object is a heavy degree of retarded child with the age of five years and five months old. This paper is to apply the method of quality case study, starting from the evaluation of the basic ability of the case to involve in a four times of social abilities learning program and tutoring, for one year of period. It is to make an essential record in detail of the social abilities in the process of the cognitive abilities learning and performance, and to re-evaluate the result and its effects of the case situation after the itinerant teaching service. This study found : (A) A good improvement in the social abilities of the case, by means of the tutoring and a four-times social teaching program, especially of the interaction with its peer group , and also with a good progress in the adaptability to the environment, but not showing the eminent result in the interaction with adults. (B) A good improvement in the cognitive abilities learning, with the increasing of the time length in the concentration about the aspects of seeing, listening, and playing, a good progress in the cognition of self-conception, and basic skills of learning in writing, reading. The case has gradually developed a reading habit. As to the numeric conception and memory shows little progress, but not found in the improvement of the logic thinking.

The purpose of this study was to look at the genotoxic and cytotoxic effects of benzo-á-pyrene (BáP), a chemical mutagen that is present in cigarette smoke, on the insulin-like growth factor-I (IGF-I) gene. Women who smoke during pregnancy are more likely to have a growth-restricted baby. We hypothesized that BáP exerts its effects through genotoxic and cytotoxic avenues. The cytotoxicity is manifested by chromosomal abnormalities and a decrease in the rate of cell division. The genotoxicity is manifested by changes in certain genes known to be important in mammalian fetal development such as IGF-I. IGF-I is implicated in intrauterine growth restriction (IUGR), a problem that greatly increases the risk of perinatal morbidity and mortality. To futher understand the mechanism by which BáP influences the normal growth and development of human placental cells, human placental trophoblast cells from an established immortalized cell line were utilized. Cells were cultured in appropriate media, starved (using starvation "Serum Free Medium"), and treated with two doses of BáP, 1µM (dose 1) and 5µM (dose 2). Chromosomes were prepared for cytogenetic analysis and visualized using light microscopy after Giemsa staining. Chromosomal aberrations were identified and the rate of cell division was determined through the analysis of the mitotic index for treated cells compared to a control group. To further understand the influence of BáP on the IGF-I gene expression level, RNA was extracted from control and treated cells, from which cDNA was synthesized and used for further analysis using polymerized chain reaction (PCR). The PCR results were used to better understand the genotoxicity of BáP, while chromosomal aberration analysis was used to determine the cytotoxic effects of BáP on human placental cells. Our results indicate that many chromosomal abnormalities were present in the treated groups compared to the control group. In addition, there was a significant decrease in the mitotic index of the BáP-treated cells (MI=0.3%) verses the control group (MI=0.93%), p value 0.0447. Through the PCR assay, we speculate that there is a dose-related response to BáP of the IGF-I RNA expression level, with low levels in the treated groups compared to the control group. We conclude from these results that BáP influences placental cells at both the gene and chromosome level. It also affects the cell cycle of human placental cells. It is known that smoking is deleterious for fetal development. We believe that the current study brings us closer to understanding the mechanism by which smoking can lead to fetal growth restriction.