The prevalence of aggression in genetic syndromes: A review

Research into behavioural phenotypes identifies both environmental and organic factors as influencing aggression in children and adults with genetic disorders associated with intellectual disability. However, in contrast to self-injury there is a paucity of research that compares aggression across relevant syndromes. The primary aim of this review is to examine the association between aggression and genetic syndromes by analysis of prevalence studies. The review also examines the literature on the form of the behaviour and influence of environmental factors.Results imply that certain syndrome groups (Cri du Chat, Smith-Magenis, Prader-Willi, Angelman, Cornelia de Lange, and Fragile X syndromes; estimates over 70%) evidence a stronger association with aggression than others (e.g. Williams and Down syndromes; estimates below 15%). However, the strength of association is difficult to quantify due to methodological differences between studies. The results from examining form and environmental influences highlight the importance of phenotype–environment interactions. Research employing group comparison designs is warranted and future work on the assessment and intervention of aggression in genetic syndromes should consider the importance of phenotype–environment interactions.     

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females

Purpose: ARX, the aristaless‐related homeobox gene, is implicated in cerebral, testicular, and pancreatic development. ARX mutations are associated with various forms of epilepsy, developmental delay, and ambiguous genitalia in humans. A mouse model that recapitulates X‐linked lissencephaly with ambiguous genitalia (XLAG) is far from elucidating the substrate for phenotypes that different ARX mutations cause. Moreover, despite phenotypic pleomorphism associated with X‐linked dominant ARX mutations, heterozygous female carriers have not been thoroughly studied. Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome. Methods: Children’s Hospital Boston patient records were retrospectively screened for patients with infantile epileptic encephalopathies who underwent ARX sequencing based on clinical suspicion. Identified families were analyzed for genetic and neuropsychiatric phenomena. Key Findings: The proband was a male with Ohtahara syndrome, ambiguous genitalia, psychomotor delay, and central nervous system dysgenesis due to a novel ARX mutation in exon 5, causing a frameshift in the aristaless domain. Heterozygous females demonstrated neurocognitive/psychiatric phenomena including learning difficulties, anxiety, depression, and schizophrenia. Significance: This is the first reported case of Ohtahara syndrome with abnormal genital and psychomotor development in the setting of this novel ARX mutation in exon 5. Based on the unique phenotype of the proband and on the presence of heterozygous females with neurocognitive/psychiatric ailments, this study describes the potential roles for ARX mutations in epilepsy and neuropsychiatric disease, underscoring the importance of ARX in interneuron development, cerebral electrical activity, cognition, and behavior.     

Parents’ initial concerns about the development of their children later diagnosed with fragile X syndrome

Background Retrospective parental reports have often been used to identify the early characteristics of children later diagnosed with a developmental disorder.

Method We applied this methodology to document 13 parents’ initial concerns about the development of their 17 children later diagnosed with fragile X syndrome (FXS). Parents were additionally asked about when they noticed the emergence of behavioural signs related to FXS.

Results More than half of the parents reported initial concerns prior to the child’s first birthday, and in most cases it was atypical motor behaviours that caused the first concerns. Behavioural signs related to the FXS phenotype were also reported to be perceptible in the first year of the child’s life.

Conclusions Due to limitations of retrospective parental questionnaires, we suggest that other methodologies, such as home video analysis, are needed to complement our understanding of the pathways of developmental disorders with late clinical onsets.     

Cross-cultural gene− environment interactions in depression,post-traumatic stress disorder,and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia

Abstract

Despite increased attention to global mental health, psychiatric genetic research has been dominated by studies in high-income countries, especially with populations of European descent. The objective of this study was to assess single nucleotide polymorphisms (SNPs) in the FKBP5 gene in a population living in South Asia. Among adults in Nepal, depression was assessed with the Beck Depression Inventory (BDI), post-traumatic stress disorder (PTSD) with the PTSD Checklist-Civilian Version (PCL-C), and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). FKBP5 SNPs were genotyped for 682 participants. Cortisol awakening response (CAR) was assessed in a subsample of 118 participants over 3 days. The FKBP5 tag-SNP rs9296158 showed a main effect on depressive symptoms (p = 0.03). Interaction of rs9296158 and childhood maltreatment predicted adult depressive symptoms (p = 0.02) but not PTSD. Childhood maltreatment associated with endocrine response in individuals homozygous for the A allele, demonstrated by a negative CAR and overall hypocortisolaemia in the rs9296158 AA genotype and childhood maltreatment group (p < 0.001). This study replicated findings related to FKBP5 and depression but not PTSD. Gene–environment studies should take differences in prevalence and cultural significance of phenotypes and exposures into account when interpreting cross-cultural findings.     

Adolescent toluene exposure produces enduring social and cognitive deficits in mice: An animal model of solvent-induced psychosis

Abstract

Objectives. Abuse of toluene-containing volatile solvents by adolescents is a significant public health problem. The present study characterized the long-term behavioural and neurochemical consequences of toluene exposure during adolescence. Methods. Male NMRI mice received one injection per day of either toluene (600 mg/kg) or corn oil during postnatal days (PN) 35–37 and (750 mg/kg) during PN38–39 and PN42–46. A variety of psychiatric disorder-relevant behavioural tests were examined at PN56–P84. Results. The toluene-exposed mice were significantly deficient in the social interaction test, nesting behaviour, social dominance tube test, and novel objective recognition test. However, toluene exposure did not affect locomotor activity and behavioural profiles in the forced swimming test, tail suspension test, emergence test and elevated plus maze. Neurochemically, the turnover rates of dopamine in the prefrontal cortex, striatum and nucleus accumbens were reduced in toluene-treated mice. Conclusions. Adolescent toluene exposure leads to social deficits and cognitive impairment at adulthood as well as neurochemical dysfunction in mice, which correlate with the symptoms observed in patients suffering from solvent-induced psychosis. These findings highlight the need for understanding the effects of solvent abuse on the developing nervous system and reveal an animal model suitable for research into pathophysiology of neurological and psychiatric consequences of solvent abuse.     

Young patients’ views about provided psychiatric care

Background: Psychiatric illness is common among young adults, but there are only a few studies examining their views about the care they receive. There is a paradigm shift towards person-centred care and, therefore, a need for patients’ perspectives in the development of clinical guidelines. Aim: The aim of this study was to examine the views about provided psychiatric care in a group of young adult psychiatric patients.

Method: This study was part of a larger study. Patients between the ages of 19–29 years old (n?=?127) diagnosed with bipolar disorder, borderline personality disorder, and/or attention deficit hyperactivity disorder were interviewed. Participants answered open-ended questions concerning their views about provided psychiatric care in six different areas.

Result: The results were categorized into six themes: (1) Wish for better diagnostic assessments, (2) Dissatisfaction with treatment, (3) Inadequate information, (4) Lack of professional attitude, (5) Feeling abandoned, and (6) Satisfaction with care.

Conclusion: Young psychiatric patients expressed a need for improvement of services that, if implemented, could make psychiatric care more person-centred.     

Parental reports on early language and motor milestones in fragile X syndrome with and without autism spectrum disorders

Objective: This study examined features of early language and motor milestones in children with fragile X syndrome (FXS) and contrasted these features with a diagnosis of Autism Spectrum Disorder (ASD) later in life in these children.

Methods: We retrospectively examined parental report of age of onset for walking and first words for primarily boys with FXS, both with ASD (FXS?+?ASD) and FXS-only. The diagnosis of ASD was established by DSM-IV criteria, which were complemented by the ADOS. The age of onset was analyzed as a continuous and categorical variable, which were compared to the upper limit of typically developing children.

Results: Individuals with FXS-only are more delayed in the onset of first words than first walks. The finding represents a pattern suggesting a continuum as robustly demonstrated in individuals with FXS?+?ASD vs. FXS-only.

Conclusion: Our results support validity of FXS?+?ASD co-morbidity as a distinct phenotype in individuals with FXS.     

The genetic blueprint of major depressive disorder: Contributions of imaging genetics studies

Abstract

Objectives. To review neuroimaging intermediate phenotypes of MDD and their relation to genetic risk variants. Methods. A systematic literature search of peer-reviewed English language articels using PubMed (www.pubmed.org) was performed. Results. Comprehensive evidence on the influence of serotonergic genes (SLC6A4, HTR1A, MAOA, TPH2) and BDNF on the following neural intermediate phenotypes is displayed: amygdala reactivity, coupling of amygdala-anterior cingulate cortex (ACC) activity, ACC volume, hippocampal volume and serotonin receptor 1A (5-HT1A) binding potential (BP). Conclusions. Intermediate phenotypes may bridge the gap between genotype and phenotype by reducing the impreciseness of psychiatric phenotypes and yield more insights into the underlying biology.     

Subtypes in 22q11.2 deletion syndrome associated with behaviour and neurofacial morphology

22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among adults with 22q11DS (～25–30% vs. ～1% in the general population). The purpose of this study was to investigate whether subtypes exist among people with 22q11DS, with a similar phenotype and an increased risk of developing mental health problems. Physical, cognitive and behavioural data from 50 children and adolescents with 22q11DS were included in a k-means cluster analysis. Two distinct phenotypes were identified: Type-1 presented with a more severe phenotype including significantly impaired verbal memory, lower intellectual and academic ability, as well as statistically significant reduced total brain volume. In addition, we identified a trend effect for reduced temporal grey matter. Type-1 also presented with autism-spectrum traits, whereas Type-2 could be described as having more 22q11DS-typical face morphology, being predominately affected by executive function deficits, but otherwise being relatively high functioning with regard to cognition and behaviour. The confirmation of well-defined subtypes in 22q11DS can lead to better prognostic information enabling early identification of people with 22q11DS at high risk of psychiatric disorders. The identification of subtypes in a group of people with a relatively homogenous genetic deletion such as 22q11DS is also valuable to understand clinical outcomes.     

Genome-wide association study of behavioural and psychiatric features in human prion disease

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10⁻⁵) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.     

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders

Objectives: Exposure-based cognitive behavioural therapy (eCBT) is an effective treatment for anxiety disorders. Response varies between individuals. Gene expression integrates genetic and environmental influences. We analysed the effect of gene expression and genetic markers separately and together on treatment response.

Methods: Adult participants (n?≤?181) diagnosed with panic disorder or a specific phobia underwent eCBT as part of standard care. Percentage decrease in the Clinical Global Impression severity rating was assessed across treatment, and between baseline and a 6-month follow-up. Associations with treatment response were assessed using expression data from 3,233 probes, and expression profiles clustered in a data- and literature-driven manner. A total of 3,343,497 genetic variants were used to predict treatment response alone and combined in polygenic risk scores. Genotype and expression data were combined in expression quantitative trait loci (eQTL) analyses.

Results:Expression levels were not associated with either treatment phenotype in any analysis. A total of 1,492 eQTLs were identified with q?Conclusions: We assessed gene expression alone and alongside genetic variants. No associations with treatment outcome were identified. Future studies require larger sample sizes to discover associations.     

The role of voltage‐gated calcium channels in neurotransmitter phenotype specification: Coexpression and functional analysis in Xenopus laevis

Calcium activity has been implicated in many neurodevelopmental events, including the specification of neurotransmitter phenotypes. Higher levels of calcium activity lead to an increased number of inhibitory neural phenotypes, whereas lower levels of calcium activity lead to excitatory neural phenotypes. Voltage‐gated calcium channels (VGCCs) allow for rapid calcium entry and are expressed during early neural stages, making them likely regulators of activity‐dependent neurotransmitter phenotype specification. To test this hypothesis, multiplex fluorescent in situ hybridization was used to characterize the coexpression of eight VGCC α1 subunits with the excitatory and inhibitory neural markers xVGlut1 and xVIAAT in Xenopus laevis embryos. VGCC coexpression was higher with xVGlut1 than xVIAAT, especially in the hindbrain, spinal cord, and cranial nerves. Calcium activity was also analyzed on a single‐cell level, and spike frequency was correlated with the expression of VGCC α1 subunits in cell culture. Cells expressing Ca_v2.1 and Ca_v2.2 displayed increased calcium spiking compared with cells not expressing this marker. The VGCC antagonist diltiazem and agonist (?)BayK 8644 were used to manipulate calcium activity. Diltiazem exposure increased the number of glutamatergic cells and decreased the number of γ‐aminobutyric acid (GABA)ergic cells, whereas (?)BayK 8644 exposure decreased the number of glutamatergic cells without having an effect on the number of GABAergic cells. Given that the expression and functional manipulation of VGCCs are correlated with neurotransmitter phenotype in some, but not all, experiments, VGCCs likely act in combination with a variety of other signaling factors to determine neuronal phenotype specification. J. Comp. Neurol. 522:2518–2531, 2014. © 2014 Wiley Periodicals, Inc.     

Resting state vagal tone in attention deficit (hyperactivity) disorder: A meta-analysis

Objectives: To quantify evidence on resting-state vagal activity in patients with attention deficit hyperactivity disorder (ADHD) relative to controls using meta-analysis.

Methods: Three electronic databases (PubMed, PsycINFO, CINAHL Plus) were reviewed to identify studies. Studies reporting on any measure of short-term, vagally mediated heart rate variability during resting state in clinically diagnosed ADHD patients as well as non-ADHD healthy controls were eligible for inclusion.

Results: Eight studies reporting on 587 participants met inclusion criteria. Random-effect meta-analysis revealed no significant main effect comparing individuals with ADHD (n?=?317) and healthy controls (n?=?270) (Hedges’ g?=?0.06, 95% CI: 0.18–0.29, Z?=?0.48, P?=?0.63; k?=?8). Sub-group analysis showed consistent results among studies in adults (k?=?2) and children (k?=?6) with ADHD.

Conclusions: Unlike a variety of internalising psychiatric disorders, ADHD is not associated with altered short-term measures of resting-state vagal tone.     

Online priming of agent and patient thematic roles and related verbs in younger and older adults

Background: Online priming studies have found that verbs (e.g., arrest) provide immediate access to typical agents (e.g., policeman) and patients (e.g., criminal) by generating expectancies from a verb to its related thematic roles and vice versa. These findings have contributed significantly to theories of thematic roles. However, these investigations and theoretical implications have been limited to young adults. Investigating verb–thematic role processing in older adults is important for understanding the semantic system in normal ageing, which aids in assessment, characterisation, and treatment of disorders that affect semantic processing in older adults.

Aims: The current study investigates verb–thematic role priming in young adults and extends the investigation to older adults. It was predicted that both groups would show priming effects but that the older adult group would have slower reaction times overall.

Methods & Procedures: Using a lexical decision task with a short stimulus onset asynchrony (250 ms), the current study investigated bidirectional agent–verb and patient–verb priming of younger and older adults.

Outcomes & Results: Consistent with our predictions, the younger participants exhibited bidirectional priming for agent–verb pairs and patient–verb pairs in the participant and item analyses. The older adults also showed priming for patient–verb pairs, but unexpectedly they did not exhibit priming for agent–verb pairs. Reaction times for the older participants were slower than the reaction times for the younger participants in all conditions.

Conclusions: Neither participant nor methodological factors readily explain the unexpected results. Theoretical explanations for the findings are explored.     

Age-related differences in the associations among at-risk drinking,alcohol use disorder,and psychological distress across the adult lifespan: a nationwide representative study in South Korea

Purpose

To investigate age-related differences in the relationships among at-risk alcohol consumption, alcohol use disorder (AUD), and psychological distress with a special focus on older adults.

Methods

We used a nationwide cross-sectional study of a representative sample of community-dwelling adults from the Korean Epidemiologic Catchment Area study for psychiatric disorders conducted by door-to-door interviews. The Korean version of the Composite International Diagnostic Interview was applied. Subjects were categorized into four age groups: young-to-middle-aged (20–54 years), near-old (55–64 years), early-old (65–74 years), and late-old (≥ 75 years). The associations among at-risk drinking, alcohol use disorder, and psychological distress were examined according to age groups.

Results

Among a total of 5102 individuals, half of them drank alcohol in the previous year, of whom 20.5% were at-risk drinkers (≥ 100 g/week). Older people were less often diagnosed with AUD than young-to-middle-aged adults with a similar degree of at-risk drinking. They were less likely to meet the DSM-5 AUD criteria in terms of social and vocational role disruption or creation of a physically hazardous situation. However, at-risk drinking showed a stronger association with subjective psychological distress in older adults, particularly in the near-old group (adjusted odds ratio 1.82, 95% confidence interval 1.09–3.03; p = 0.023).

Conclusions

These findings indicate the importance of screening for mental health problems in older adults, especially near-old adults, who drink more than 100 g of alcohol per week even when they do not satisfy the criteria for a diagnosis of AUD.

     

Examining reports of mental health in adults with Williams syndrome

Prior research suggests that individuals with Williams syndrome (WS) have a disposition towards anxiety. Information regarding this is typically derived from parents and carers. The perspectives of the individuals with WS are rarely included in research of this nature. We examined the mental health of 19 adults with WS using explicit (psychiatric interview) and implicit (modified Stroop task) measures and compared informant (parents/carers) and respondent (adults with WS) reports of psychiatric symptoms. Informants and respondents both reported more symptoms of anxiety (n = 7-9) than depression (n = 2). Strong positive correlations were found between informant and respondent reports of symptoms of mental health problems. Compared to informants, respondents reported significantly more symptoms overall and somewhat more symptoms of anxiety. Results from the Stroop task indicated that the adults with WS were more vigilant to anxiety-related words than to depression-related words. The adults with WS provided reliable information regarding their mental health, thus providing further evidence that anxiety is part of the behavioural phenotype of the syndrome.     

An Xp; Yq translocation causing a novel contiguous gene syndrome in brothers with generalized epilepsy, ichthyosis, and attention deficits

PURPOSE: We describe two brothers with generalized epilepsy, attention deficits, congenital ichthyosis, and Leri-Weill dyschondrosteosis who harbor an unusual Xp; Yq translocation chromosome, resulting in a novel contiguous gene syndrome because of deletion of genes from the distal short arm of the X chromosome. METHODS: Physical examination, neuropsychologic testing, EEG, and neuroimaging studies were performed. Because of their unusual phenotype, karyotyping, fluorescence in situ hybridization, and further molecular analyses were carried out to refine the break points of the underlying unbalanced sex chromosome rearrangement. RESULTS: The subjects had generalized epilepsy, X-linked ichthyosis, Madelung deformities, mesomelia, normal intelligence, and attention deficits. The brothers' karyotype was unbalanced; they inherited a maternal derivative X chromosome. Deleted distal Xp genes included short-stature homeobox on the X chromosome (SHOX), aryl sulfatase E (ARSE), variably charged X-chromosome mRNA gene A (VCX-A), and steroid sulfatase (STS). The final karyotype was 46,Y,der(X)t(X; Y)(p22.3; q11.2).ish der(X) (DXZ1+, KAL+, STS-, SHOX-) mat. CONCLUSIONS: Loss of distal contiguous Xp genes resulted in a syndrome comprising bony deformities, ichthyosis, attention problems, and generalized epilepsy. Candidate epilepsy genes within the deleted segment, such as ASMT, a gene involved in the final synthesis of melatonin, are discussed. Cytogenetic analyses should be included in the clinical evaluation of patients with generalized epilepsy and complex phenotypes.