Cognitive, Behavioral, and Adaptive Functioning in Fragile X and Non-Fragile X Retarded Men

The cognitive, behavioral, and adaptive functioning of 12 men with fragile X syndrome (aged 23 to 62 years) was systematically assessed and compared to two matched groups of retarded men without fragile X syndrome residing at the same institution. The fragile X group was largely indistinguishable from the comparison groups on the cognitive, behavioral, and adaptive measures. Fragile X patients were, however, significantly more likely to have achieved levels of adaptive functioning commensurate with their intellectual abilities. Fragile X subjects who had similarly affected siblings emerged as significantly higher-functioning in all areas than Fragile X subjects who did not have affected siblings. These findings are discussed with respect to future research

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy

Visuo-spatial cognition in Williams syndrome: Reviewing and accounting for the strengths and weaknesses in performance

Individuals with Williams syndrome typically show relatively poor visuo-spatial abilities in comparison to stronger verbal skills. However, individuals' level of performance is not consistent across all visuo-spatial tasks. The studies assessing visuo-spatial functioning in Williams syndrome are critically reviewed, in order to provide a clear pattern of the relative difficulty of these tasks. This prompts a possible explanation of the variability in performance seen which focuses on the processing demands of some of these tasks. Individuals with Williams syndrome show an atypical processing style on tests of construction, which does not affect tests of perception

Temper outbursts in Lowe syndrome:Characteristics, sequence, environmental context and comparison to Prader–Willi syndrome

Background: There is limited research into the nature and aetiology of temper outbursts in people with intellectual disabilities. In this study, we describe the phenomenology and environmental context of temper outbursts in Lowe syndrome, a rare genetic syndrome in which outbursts are purportedly frequent. Method: A temper outburst interview (TOI) was conducted with caregivers of seventeen individuals with Lowe syndrome to generate an account of the behavioural sequence, common antecedents and consequences of temper outbursts, and to enable comparisons with similar work on Prader–Willi syndrome. Results: Outbursts in Lowe syndrome were frequently triggered by thwarted goaldirected behaviour and were associated with high levels of physical aggression and property destruction. Conclusions: Form and sequence of outbursts showed similarities to Prader–Willi syndrome and to behaviours reported in literature on typically developing children. The results highlight the importance of considering shared aetiology as well as syndrome‐specific pathways in the development of outbursts

Uncommon genetic syndromes and narrative production - Case Studies with Williams, Smith-Magenis and Prader- Willi Syndromes

This study compares narrative production among three syndromes with genetic microdeletions: Williams syndrome (WS), Smith-Magenis syndrome (SMS), and Prader-Willi syndrome (PWS), characterized by intellectual disabilities and relatively spared language abilities. Our objective is to study the quality of narrative production in the context of a common intellectual disability. To elicit a narrative production, the task Frog! Where Are You was used. Then, structure, process, and content of the narrative process were analysed in the three genetic disorders:WS (n52), SMS (n52), and PWS (n52). Data show evidence of an overall low narrative quality in these syndromes, despite a high variability within different measures of narrative production. Results support the hypothesis that narrative is a highly complex cognitive process and that, in a context of intellectual disability, there is no evidence of particular ‘hypernarrativity’ in these syndromes.This research was supported by the grants FEDER –

Family coordination in families who have a child with autism spectrum disorder

Little is known about the interactions of families where there is a child with autism spectrum disorder (ASD). The present study applies the Lausanne Trilogue Play (LTP) to explore both its applicability to this population as well as to assess resources and areas of deficit in these families. The sample consisted of 68 families with a child with ASD, and 43 families with a typically developing (TD) child. With respect to the global score for family coordination there were several negative correlations: the more severe the symptoms (based on the child’s ADOS score), the more family coordination was dysfunctional. This correlation was particularly high when parents had to play together with the child. In the parts in which only one of the parents played actively with the child, while the other was simply present, some families did achieve scores in the functional range, despite the child’s symptom severity. The outcomes are discussed in terms of their clinical implications both for assessment and for interventio

TPH2 polymorphisms and expression in Prader-Willi syndrome subjects with differing genetic subtypes

Prader-Willi syndrome (PWS) is a genetic imprinting disease that causes developmental and behavioral disturbances resulting from loss of expression of genes from the paternal chromosome 15q11-q13 region. In about 70% of subjects, this portion of the paternal chromosome is deleted, while 25% have two copies of the maternal chromosome 15, or uniparental maternal disomy (UPD; the remaining subjects have imprinting center defects. There are several documented physical and behavioral differences between the two major PWS genetic subtypes (deletion and UPD) indicating the genetic subtype plays a role in clinical presentation. Serotonin is known to be disturbed in PWS and affects both eating behavior and compulsion, which are reported to be abnormal in PWS. We investigated the tryptophan hydroxylase gene (TPH2), the rate-limiting enzyme in the production of brain serotonin, by analyzing three different TPH2 gene polymorphisms, transcript expression, and correlation with PWS genetic subtype. DNA and RNA from lymphoblastoid cell lines derived from 12 PWS and 12 comparison subjects were used for the determination of genetic subtype, TPH2 polymorphisms and quantitative RT-PCR analysis. A similar frequency of TPH2 polymorphisms was seen in the PWS and comparison subjects with PWS deletion subjects showing increased expression with one or more TPH2 polymorphism. Both PWS deletion and PWS UPD subjects had significantly lower TPH2 expression than control subjects and PWS deletion subjects had significantly lower TPH2 expression compared with PWS UPD subjects. PWS subjects with 15q11-q13 deletions had lower TPH2 expression compared with PWS UPD or control subjects, requiring replication and further studies to identify the cause including identification of disturbed gene interactions resulting from the deletion process

Social functioning and behaviour in Mucopolysaccharidosis IH [Hurlers Syndrome]

Background: Mucopolysaccharidosis type IH (MPS-IH) [Hurlers Syndrome] is a developmental genetic disorder characterised by severe physical symptoms and cognitive decline. This study aimed to investigate the behavioural phenotype of MPS-IH treated by haematopoietic cell transplantation, focusing on social functioning and sleep. Parental stress was also measured. Methods: Participants were 22 children with MPS-IH (mean age 9 years 1 month), of whom 10 were male (45%). Parents completed the Social Responsiveness Scale (SRS), Child Behaviour Checklist (CBCL), Children’s Sleep Habit Questionnaire and Parent Stress Index, Short Form (PSI-SF). Results: Twenty-three per cent of children with MPS-IH scored in the severe range of the SRS, suggesting significant difficulties in social functioning. Children with MPS-IH were more than 30 times more likely to receive scores in the severe range than typically developing children. Thirty-six per cent scored in the mild-to-moderate range, suggesting milder, but marked, difficulties in social interaction. Although children with MPS-IH did not show significantly higher rates of internalising, externalising or total behaviour problems than the normative sample, they received scores that were significantly higher on social, thought and attention problems and rule-breaking behaviour, and all the competence areas of the CBCL. Parents of children with MPS-IH did not score significantly higher on parental stress than parents in a normative sample. Conclusions: Parents of children with MPS-IH rate their children as having problems with social functioning and various areas of competence more frequently than previously thought, with implications for clinical support

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

Anxiety Disorders in Williams Syndrome Contrasted with Intellectual Disability and the General Population: A Systematic Review and Meta-Analysis

Individuals with specific genetic syndromes associated with intellectual disability (ID), such as Williams syndrome (WS), are at increased risk for developing anxiety disorders. A systematic literature review identified sixteen WS papers that could generate pooled prevalence estimates of anxiety disorders for WS. A meta-analysis compared these estimates with prevalence estimates for the heterogeneous ID population and the general population. Estimated rates of anxiety disorders in WS were high. WS individuals were four times more likely to experience anxiety than individuals with ID, and the risk was also heightened compared to the general population. The results provide further evidence of an unusual profile of high anxiety in WS