213 research outputs found
Using genetic findings in autism for the development of new pharmaceutical compounds
No full textRATIONALE:
The main reason for the current lack of effective treatments for the core symptoms of autism is our limited understanding of the biological mechanisms underlying this heterogeneous group of disorders. A primary value of genetic research is enhancing our insight into the biology of autism through the study of identified autism risk genes.
OBJECTIVES:
In the current review we discuss (1) the genes and loci that are associated with autism, (2) how these provide us with essential cues as to what neurobiological mechanisms may be involved, and (3) how these mechanisms may be used as targets for novel treatments. Next, we provide an overview of currently ongoing clinical trials registered at clinicaltrials.gov with a variety of compounds. Finally, we review current approaches used to translate knowledge derived from gene discovery into novel pharmaceutical compounds and discuss their pitfalls and problems.
CONCLUSIONS:
An increasing number of genetic variants associated with autism have been identified. This will generate new ideas about the biological mechanisms involved in autism, which in turn may provide new leads for the development of novel pharmaceutical compounds. To optimize this pipeline of drug discovery, large-scale international collaborations are needed for gene discovery, functional validation of risk genes, and improvement of clinical outcome measures and clinical trial methodology in autism
22q11.2 deletion syndrome
No full text22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness - all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population
Detecting Mood State Differences Through Digital Behavioural Monitoring in Bipolar Disorder
No full textBipolar disorder is a lifelong mental condition with high inter-individual symptom heterogeneity and limitations in subjective mood episode recognition. Traditional mood assessments are susceptible to recall bias, and there are difficulties distinguishing between disease-related changes and normal everyday fluctuations. This emphasizes the need for instruments for objective detection of mood changes. This thesis focuses on a novel approach called passive monitoring and demonstrates the feasibility of using a smartphone application to potentially track behavioural changes in patients with bipolar disorder across different mood states. Preliminary findings include associations between lower activity levels, increased phone use, and reduced social communication with higher levels of depressive symptoms, while higher activity levels and lower number of places visited were associated with manic symptoms. These findings establish the possibilities of behavioural monitoring instruments for objective recognition of mood episodes to potentially facilitate early intervention and prevention.M.Sc
Affective and psychotic reactivity to daily-life stress in adults with 22q11DS: a study using the experience sampling method
No full textBACKGROUND: 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with an increased risk of psychiatric disorders. Vulnerability for psychopathology has been related to an increased reactivity to stress. Here, we examined affective states, perceived stress, affective and psychotic reactivity to various sources of environmental stress using the experience sampling method (ESM), a structured diary technique allowing repeated assessments in the context of daily life. METHODS: Adults with 22q11DS (n = 31; age, 34.1 years) and matched healthy controls (HCs; n = 24; age, 39.9 years) were included. ESM was used to assess affective states, perceived stress, and stress reactivity. Data were analyzed using multilevel regression models. RESULTS: Adults with 22q11DS displayed overall higher levels of negative affect but comparable levels of positive affect compared to HCs. Higher levels of perceived stress were reported by individuals with 22q11DS. Comparable affective and psychotic reactivity in relation to all types of environmental stress was observed between the two groups. CONCLUSION: The results point toward higher levels of negative affect and differences in the perception of daily hassles in 22q11DS but no difference in affective or psychotic reactivity to stress. This study contributes to the growing literature regarding the impact of stress on the development of psychopathology in the 22q11DS population.sponsorship: This work was supported by an ERC consolidator grant to Prof. Inez Myin-Germeys (Grant number: ERC-2012-StG, project 309767 - INTERACT) and the National Institute of Mental Health (Grant number to Prof. Therese van Amelsvoort, Prof. Swillen, and Prof. Vorstman: U01MH101722 - International Consortium on Brain and Behavior in 22q11.2 deletion syndrome; Grant number to Prof. Therese van Amelsvoort: U01MH119740-02). Maude Schneider is supported by an Ambizione grant from the Swiss National Science Foundation (Grant number: PZ00P1_174206). (ERC|ERC-2012-StG, ERC|309767, National Institute of Mental Health|U01MH101722, National Institute of Mental Health|U01MH119740-02, Swiss National Science Foundation|PZ00P1_174206, European Research Council (ERC)|309767)status: Publishe
More than words: The 22q11.2 deletion syndrome as a genetic model for understanding variability in neuropsychiatric symptoms of children with Developmental Language Disorder
No full textDevelopmental Language Disorder (DLD) is a neurodevelopmental disorder affecting approximately 3-7% of children in the general population. In addition to persistent language difficulties, many children with DLD experience symptoms of various neuropsychiatric disorders. However, the relationship between neuropsychiatric symptoms and language difficulties in DLD is insufficiently clear. A better understanding of this relationship, might improve our ability to identify those children with DLD who are most likely to develop neuropsychiatric symptoms and therefore potentially benefit from targeted intervention. The exact cause of DLD remains unknown and varies from child-to-child. Consequently, the relationship between language difficulties and neuropsychiatric symptoms is likely to vary among children with DLD as well. This variability might have prevented previous research to uncover this relationship in the group of children with DLD. Therefore, studying a population of children who all share the same genetic origin could provide an opportunity to identify relationships between language difficulties neuropsychiatric symptoms. This was the approach central to this dissertation. Children with DLD were compared to a group of children with a genetic condition: children with the 22q11.2 deletion syndrome (22q11DS). Similar to DLD, 22q11DS is associated with language difficulties and neuropsychiatric symptoms. However, these difficulties in 22q11DS have a shared cause, consisting of missing a small part of chromosome 22. Results of this dissertation provide new insights on the impact of language difficulties on the occurrence of neuropsychiatric symptoms in 22q11DS. The findings provide leads for future research and clinical care for children with 22q11DS and children with DLD
A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome
No full textRecently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype–phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics
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