Anxiety in children and youth: Part 1-Diagnosis.

Anxiety disorders are the most common mental health concerns affecting Canadian children and adolescents. The Canadian Paediatric Society has developed two position statements that summarize current evidence regarding the diagnosis and management of anxiety disorders. Both statements offer evidence-informed guidance to support paediatric health care providers (HCPs) making decisions around the care of children and adolescents with these conditions. The objectives of Part 1, which focuses on assessment and diagnosis, are to: (1) review the epidemiology and clinical characteristics of anxiety disorders and (2) describe a process for assessment of anxiety disorders. Specific topics are reviewed, including prevalence, differential diagnosis, co-occurring conditions, and the process of assessment. Approaches are offered for standardized screening, history-taking, and observation. Associated features and indicators that distinguish anxiety disorders from developmentally appropriate fears, worries, and anxious feelings are considered. Note that when the word 'parent' (singular or plural) is used, it includes any primary caregiver and every configuration of family.

Delayed diagnosis of avoidant/restrictive food intake disorder and autism spectrum disorder in a 14-year-old boy.

Psychiatric comorbidities are common among individuals with ARFID and may contribute to a failure to establish an accurate diagnosis, delayed diagnosis, and poor long-term prognosis, especially among children and adolescents.

DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders.

Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.

Serotonin system gene variants and regional brain volume differences in pediatric OCD.

Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.

Glutamate Genetics in Obsessive-Compulsive Disorder: A Review.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is common and debilitating with patients exhibiting persistent intrusive thoughts (obsessions), repetitive ritualistic behaviours (compulsions) and anxiety. While it is known that OCD is highly heritable, the specific genetic risk factors for OCD are still largely unknown. The etiology of OCD has also not been fully elucidated but there is growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical (CSTC) circuitry plays a role in its pathogenesis. METHODS: We conducted a focused review of recent literature on the role of glutamate genes in OCD. RESULTS: There have been several recent discoveries in the SAPAP (DLGAP) family, SLC1A1, and GRIN/GRIK families of proteins related to OCD. CONCLUSION: There is growing evidence supporting a role for genetic variation leading to dysfunctional glutamate signaling in OCD. Based on this new evidence we hypothesize that sustained glutamatergic neurotransmission in key areas of the brain may be contributing to the etiology of OCD.

OBJECTIF: Le trouble obsessionnel-compulsif (TOC) est commun et débilitant chez les patients qui présentent des pensées intrusives (obsessions) persistantes, des comportements rituels répétitifs (compulsions) et de l'anxiété. Bien que l'on sache que le TOC est fortement héréditaire, les facteurs de risque génétique spécifiques du TOC sont encore largement inconnus. L'étiologie du TOC n'a pas non plus été encore pleinement élucidée, mais il apparaît de plus en plus que le glutamate qui signale une dysfonction dans le circuit cortico-striatal-thalamo-cortical (CSTC) joue un rôle dans sa pathogenèse. MÉTHODES: Nous avons mené une revue ciblée de la littérature récente sur le rôle des gènes du glutamate dans le TOC. RÉSULTATS: Il y a eu plusieurs découvertes récentes dans la famille SAPAP (DLGAP), les familles de protéines SLC1A1, et GRIN/GRIK liées au TOC. CONCLUSION: Les preuves s'accumulent à l'appui du rôle d'une variation génétique menant à un signal dysfonctionnel du glutamate dans le TOC. Selon ces nouvelles preuves, nous émettons l'hypothèse que la neurotransmission glutamatergique soutenue dans les principales régions du cerveau peut contribuer à l'étiologie du TOC.

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. METHODS: We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. RESULTS: We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 × 10-03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. CONCLUSIONS: Our findings suggest that rare CNVs may contribute to the etiology of OCD.

Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C.

BACKGROUND: A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. RESULTS: Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP. CONCLUSIONS: We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.

Assessment of methylation level prediction accuracy in methyl-DNA immunoprecipitation and sodium bisulfite based microarray platforms.

In this study, we verified the accuracy of two array methods--methylated DNA immunoprecipitation coupled with CpG island microarrays (MeDIP-CGI-arrays) and sodium bisulfite conversion based microarrays (BC-arrays)--in predicting regional methylation levels as measured by pyrosequencing of bisulfite converted DNA (BC-pyrosequencing). To test the accuracy of these methods we used the Agilent Human CpG island and the Illumina HumanMethylation27 microarrays respectively, and compared microarray outputs to the data from targeted BC-pyrosequencing assays from several genomic regions of corresponding samples. We observed relatively high correlation with BC-pyrosequencing data for both array platforms, R = 0.87 for BC-Array and R = 0.79 for MeDIP-CGI array. However, MeDIP-CGI array were less reliable in predicting intermediate levels of DNA methylation. Several bioinformatics strategies, to ameliorate the performance of the MeDIP-CGI-Arrays did not improve the correlation with BC-pyrosequencing data. The high scalability, low cost and simpler analysis of BC-arrays, together with the recent extended coverage may make them a more versatile methylation analysis tool.