Self-harm as the first presentation of attention deficit hyperactivity disorder in adolescents.

BACKGROUND: Self-harm (SH) in adolescence has previously been shown to significantly overlap with both attention deficit hyperactivity disorder (ADHD) and emotional dysregulation (ED). Our objective as such was to investigate the relationship between self-harm and ADHD in our population and consider its clinical relevance. METHODS: This case series analysis examined 124 presentations of SH in 13- to 17 year-olds to Accident and Emergency Departments in South West London (97F:27M). Strength and Difficulties Questionnaires (SDQs) were used to screen for ADHD/hyperactivity and ED, and scores were compared with reference data obtained from Meltzer et al. (1999, International Review of Psychiatry (Abingdon, England), 15, 185). RESULTS: Mean SDQ ADHD/hyperactivity scores were significantly higher in our SH sample compared to reference data (p < .0001). Furthermore, significantly greater ED scores were found in our sample compared with the control reference data. CONCLUSION: Our findings contribute to the evidence for an important link between ADHD and clinical presentations of SH and suggest there to be value in screening girls presenting to A&E with self-harm for ADHD. We speculate that ED plays a role in the evolution of SH in dysregulated ADHD. We recommend that clinicians assessing adolescents have self-harmed to be aware of possible ADHD symptoms and screen as appropriate; however, future research examining the temporal association between ADHD, emotional dysregulation and self-harm is required to establish causal direction.

Synaptic, transcriptional and chromatin genes disrupted in autism.

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions.

BACKGROUND: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. METHODS: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). RESULTS: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10(-7); OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). CONCLUSIONS: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis.

BACKGROUND: Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. AIMS: To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). METHOD: Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD-ASD (n = 16) and healthy controls (n = 78). RESULTS: Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures. CONCLUSIONS: Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.

Diagnosing autism spectrum disorder in community settings using the Development and Well-Being Assessment: validation in a UK population-based twin sample.

BACKGROUND: Increasing numbers of people are being referred for the assessment of autism spectrum disorder (ASD). The NICE (UK) and the American Academy of Pediatrics recommend gathering a developmental history using a tool that operationalises ICD/DSM criteria. However, the best-established diagnostic interview instruments are time consuming, costly and rarely used outside national specialist centres. What is needed is a brief, cost-effective measure validated in community settings. We tested the Development and Well-Being Assessment (DAWBA) for diagnosing ASD in a sample of children/adolescents representative of those presenting in community mental health settings. METHODS: A general population sample of twins (TEDS) was screened and 276 adolescents were selected as at low (CAST score < 12; n = 164) or high risk for ASD (CAST score ≥ 15 and/or parent reported that ASD suspected/previously diagnosed; n = 112). Parents completed the ASD module of the DAWBA interview by telephone or online. Families were visited at home: the ADI-R and autism diagnostic observation schedule (ADOS) were completed to allow a best-estimate research diagnosis of ASD to be made. RESULTS: Development and Well-Being Assessment ASD symptom scores correlated highly with ADI-R algorithm scores (ρ = .82, p < .001). Good sensitivity (0.88) and specificity (0.85) were achieved using DAWBA computerised algorithms. Clinician review of responses to DAWBA questions minimally changed sensitivity (0.86) and specificity (0.87). Positive (0.82-0.95) and negative (0.90) predictive values were high. Eighty-six per cent of children were correctly classified. Performance was improved by using it in conjunction with the ADOS. CONCLUSIONS: The DAWBA is a brief structured interview that showed good sensitivity and specificity in this general population sample. It requires little training, is easy to administer (online or by interview) and diagnosis is aided by an algorithm. It holds promise as a tool for assisting with assessment in community settings and may help services implement the recommendations made by NICE and the American Academy of Pediatrics regarding diagnosis of young people on the autism spectrum.

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

Rare deletions at the neurexin 3 locus in autism spectrum disorder.

The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

The effect of age on DNA concentration from whole saliva: implications for the standard isolation method.

OBJECTIVES: Adequate quantity and quality of the DNA isolated from saliva samples are crucial for ensuring successful genotyping rates in genetic studies. However, there is little information about these issues when saliva samples are collected from children. The objectives of this study were to assess whether there are differences in DNA quality or quantity isolated from saliva samples of children at different ages and adolescents compared to adults and, if so, to establish a modified protocol to improve and standardize DNA isolation from saliva samples of children. METHODS: Saliva samples were collected with Oragene DNA Sample Collection Kit from 41 healthy subjects including children of different ages, adolescents, and adults. Quantity and quality of isolated DNA were determined spectrophotometrically. RESULTS: DNA concentration and age were positively correlated (r = 0.676, P < 0.001). A high percentage of samples from children below 12 years yielded DNA concentrations <100 ng/µL and DNA quality a260/a280 ratios of <1.8. Modifying the standard DNA isolation method raised DNA quantity and quality in these critical samples. CONCLUSIONS: Age determines, at least in part, the high variability observed in the concentration of DNA isolated from saliva samples. This fact should be taken into account for a better standardization of the DNA isolation to ensure DNA banking in large-scale genetic studies involving children.

Plasma, oral fluid, and whole-blood distribution of antipsychotics and metabolites in clinical samples.

BACKGROUND: Oral fluid provides a noninvasive method of sample collection. The aim of this study was to obtain oral fluid, plasma, and whole blood from patients prescribed amisulpride, aripiprazole, clozapine, quetiapine, risperidone, or sulpiride and to measure plasma:whole blood and plasma:oral fluid analyte distribution. METHODS: Matched oral fluid, plasma and whole-blood samples were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: There were 101 sets of samples from 90 (56 male, 34 female) patients (nine prescribed 2 antipsychotics, and one 3). There were ≤ 5 samples for aripiprazole, amisulpride, and sulpiride. There was a good relationship between the plasma and hemolyzed whole-blood concentrations (R > 0.95), with plasma:whole-blood ratios varying between 0.7 (amisulpride) and 1.8 (aripiprazole). Amisulpride plasma and oral fluid concentrations were similar, whereas aripiprazole and dehydroaripiprazole oral fluid concentrations were approximately 8% of those in the plasma, reflecting the weak and strong plasma protein binding of these compounds, respectively. For the other analytes, plasma concentrations were 2-4 times higher than oral fluid concentrations. In general, there was a poor relationship (R = 0.3-0.7) between the plasma and oral fluid concentrations, possibly due to intrapatient saliva pH variation during sample collection. CONCLUSIONS: This work shows that hemolyzed whole-blood samples can be used for therapeutic drug monitoring purposes for the analytes of interest, provided that the plasma:whole-blood ratio is taken into account when interpreting results. For aripiprazole and dehydroaripiprazole, measurements in oral fluid will probably not be feasible. However, the relationship between plasma and oral fluid concentration for amisulpride, clozapine (and norclozapine), quetiapine (and possibly quetiapine metabolites), and risperidone/9-hydroxyrisperidone shows potential for oral fluid analysis.

Design and construction of custom-made neoprene thumb carpo-metacarpal orthosis with thermoplastic stabilization for first carpo-metacarpal joint osteoarthritis.

Individuals with first carpo-metacarpal (CMC) osteoarthritis (OA) often experience pain and difficulty with functional activities. Thus, designing orthotics to improve function and decrease pain is common practice. These therapists designed an orthosis using a combination of neoprene and thermoplastic materials to create a soft orthosis that provides support to the first CMC joint - Victoria Priganc, PhD, OTR, CHT, CLT.

Pathway mapping as a tool to address police use of force in behavioral health crisis.

Police use of force is a significant problem in many communities, particularly related to episodes of behavioral health crisis where police are called to respond. Fragmentation of the behavioral health care system creates a revolving door where many residents with behavioral health challenges cycle in and out of the system, often accessing services via the 9-1-1 emergency system during a crisis episode. This work leverages ethnographic and participatory techniques to build a pathway map in order to represent and characterize the behavioral health crisis system in metropolitan Phoenix, Arizona, United States. Map findings illustrate that many nominally existing connections are functionally distant when viewed through the lens of a clinical handoff. The resulting pathway map can be used as a planning and confirmatory tool for community members, practitioners, and policymakers to address challenges in behavioral health and public safety.

Double-Blind, Sham-Controlled Randomized Trial Testing the Efficacy of fMRI Neurofeedback on Clinical and Cognitive Measures in Children With ADHD.

OBJECTIVE: Functional MRI neurofeedback (fMRI-NF) could potentially be a novel, safe nonpharmacological treatment for attention deficit hyperactivity disorder (ADHD). A proof-of-concept randomized controlled trial of fMRI-NF of the right inferior frontal cortex (rIFC), compared to an active control condition, showed promising improvement of ADHD symptoms (albeit in both groups) and in brain function. However, comparison with a placebo condition in a larger trial is required to test efficacy. METHODS: This double-blind, sham-controlled randomized controlled trial tested the effectiveness and efficacy of fMRI-NF of the rIFC on symptoms and executive functions in 88 boys with ADHD (44 each in the active and sham arms). To investigate treatment-related changes, groups were compared at the posttreatment and 6-month follow-up assessments, controlling for baseline scores, age, and medication status. The primary outcome measure was posttreatment score on the ADHD Rating Scale (ADHD-RS). RESULTS: No significant group differences were found on the ADHD-RS. Both groups showed similar decreases in other clinical and cognitive measures, except for a significantly greater decrease in irritability and improvement in motor inhibition in sham relative to active fMRI-NF at the posttreatment assessment, covarying for baseline. There were no significant side effects or adverse events. The active relative to the sham fMRI-NF group showed enhanced activation in rIFC and other frontal and temporo-occipital-cerebellar self-regulation areas. However, there was no progressive rIFC upregulation, correlation with ADHD-RS scores, or transfer of learning. CONCLUSIONS: Contrary to the hypothesis, the study findings do not suggest that fMRI-NF of the rIFC is effective in improving clinical symptoms or cognition in boys with ADHD.

Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min-1]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.

No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.

The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.

OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.

Maturation of limbic regions in Asperger syndrome: a preliminary study using proton magnetic resonance spectroscopy and structural magnetic resonance imaging.

People with autistic spectrum disorders (ASD, including Asperger syndrome) may have developmental abnormalities in the amygdala-hippocampal complex (AHC). However, in vivo, age-related comparisons of both volume and neuronal integrity of the AHC have not yet been carried out in people with Asperger syndrome (AS) versus controls. We compared structure and metabolic activity of the right AHC of 22 individuals with AS and 22 healthy controls aged 10-50 years and examined the effects of age between groups. We used structural magnetic resonance imaging (sMRI) to measure the volume of the AHC, and magnetic resonance spectroscopy ((1)H-MRS) to measure concentrations of N-acetyl aspartate (NAA), creatine+phosphocreatine (Cr+PCr), myo-inositol (mI) and choline (Cho). The bulk volume of the amygdala and the hippocampus did not differ significantly between groups, but there was a significant difference in the effect of age on the hippocampus in controls. Compared with controls, young (but not older) people with AS had a significantly higher AHC concentration of NAA and a significantly higher NAA/Cr ratio. People with AS, but not controls, had a significant age-related reduction in NAA and the NAA/Cr ratio. Also, in people with AS, but not controls, there was a significant relationship between concentrations of choline and age so that choline concentrations reduced with age. We therefore suggest that people with AS have significant differences in neuronal and lipid membrane integrity and maturation of the AHC.