Childhood-onset Psychosis Research Articles

Fetal Gene Regulatory Gene Deletions are Associated with Poor Cognition and Altered Cortical Morphology in Schizophrenia and Community-Based Samples.

Schizophrenia spectrum disorders (SSDs) are characterized by substantial clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for SSDs; however, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. The current study examined associations between borderline intellectual functioning or childhood-onset psychosis, known risk CNVs, and burden of deletions affecting genes in 18 previously validated neurodevelopmental gene-sets in 618 SSD individuals. CNV associations were assessed for replication in 235 SSD relatives and 583 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Known SSD- and neurodevelopmental disorder (NDD)-risk CNVs were associated with borderline intellectual functioning in SSD cases (odds ratios (OR) = 7.09 and 4.57, respectively); NDD-risk deletions were nominally associated with childhood-onset psychosis (OR = 4.34). Furthermore, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline intellectual functioning across SSD cases and non-cases (OR = 2.58), with partial replication in the ABCD cohort. Exploratory analyses of cortical morphology showed associations between fetal gene regulatory gene deletions and altered gray matter volume and cortical thickness across cohorts. Results highlight contributions of known risk CNVs to phenotypic variability in SSD and the utility of a neurodevelopmental framework for identifying mechanisms that influence phenotypic variability in SSDs, as well as the broader population, with implications for personalized medicine approaches to care.

Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis

To identify genes underlying childhood onset psychosis. Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors. We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder. This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.

Developmental and symptom profiles in early-onset psychosis

Psychotic disorders in children are more heterogeneous than is captured by categorical diagnoses. In a new cohort of children and adolescents, we evaluated the relationships among age at onset (AAO), clinical symptoms and developmental impairments. Patients with schizophrenia and other “spectrum” psychotic diagnoses (N = 88; AAO 6–17, mean 12.6) were evaluated with diagnostic interviews, a new clinical scale (Lifetime Dimensions of Psychosis Scale-Child and Adolescent), and neuropsychological and medical evaluations. Key findings were replicated in an adult cohort of 2420 cases, including 127 with retrospective AAO<13. Factor and cluster analyses were carried out to identify clinical profiles. Five clinical factors were identified in each cohort: Positive, Bizarre Positive, Negative/Formal Thought Disorder, Depression and Mania. Earlier AAO predicted severity of bizarre positive symptoms in children and of bizarre and other symptoms in adults. Four clinical clusters in the child cohort were characterized by: more severe bizarre positive symptoms (N = 31); negative symptoms (N = 15); premorbid autism spectrum features and developmental delay (N = 12); and depressive symptoms with heterogeneous diagnoses and mild positive/negative symptoms (N = 25). Previous factor-analytic studies of childhood psychosis did not specifically consider bizarre positive symptoms. Here, bizarre positive symptoms emerged as clinical markers of severe, childhood-onset psychosis similar to adult schizophrenia. The four clusters are clinically meaningful and useful for treatment planning and potentially for biological research. Childhood-onset cases are rare and thus difficult to study, but additional, larger cohorts may be useful in dissecting the biological and developmental heterogeneity of psychotic disorders.

2.3 Childhood-Onset Psychosis and Typical Development: Insights From Neuroimaging Studies

2.3 Childhood-Onset Psychosis and Typical Development: Insights From Neuroimaging Studies

A 12 year chart review of childhood and adolescent onset psychosis at a Nigerian tertiary mental health facility

Objectives: To review the profile of children and adolescents presenting with psychosis at a specialist mental health facility, and to compare childhood with adolescent onset psychosis.Method: Hospital records of all children and adolescents over a 12-year period (1999–2010) were perused to identify those falling under the categories of psychotic disorders. Clinical, socio-demographic, obstetric, and developmental information was extracted.Results: Mean age of the children ((n = 409)) was 15.9 years, with 8.1% aged 12 years or less. The most frequent diagnoses were schizophrenia (40.8%), brief psychotic disorder (25.9%), mood disorder with psychosis (15.2%), and organic psychosis (7.8%). Family history of mental illness was reported among 22.5%. Subjects with childhood onset were significantly less likely than those with adolescent onset to have a family history of mental illness (p = 0.016), more likely to report maternal illness during pregnancy (p = 0.005) and illness during infancy (p = 0.010), and more likely to have a diagnosis of psychotic disorder due to another general medical condition (p < 0.001).Conclusion: The study suggests that antenatal/obstetric factors and illness during infancy may be particularly relevant in psychosis of childhood onset. Family history of mental illness may however be of greater relevance in adolescent onset psychosis.

Neuropsychological functioning in childhood-onset psychosis and attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) and childhood-onset psychosis (COP) are chronic, heterogeneous disorders with symptoms that frequently co-occur, but the etiology of their comorbidity is unknown. Studies of each disorder indicate that both ADHD and COP are associated with a range of neuropsychological weaknesses, but few neuropsychological studies have directly compared groups with ADHD and COP. Groups with ADHD only (32 F, 48 M), COP only (5 F, 5 M), ADHD + COP (9 F, 21 M), and a control group with neither disorder (25 F, 44 M) completed a neuropsychological battery that included measures of verbal working memory, response inhibition, response speed and variability, and selective attention. All three clinical groups exhibited significantly lower performance versus the control group on all neuropsychological measures, whereas the only significant difference between the clinical groups was a significantly larger weakness in verbal working memory in the groups with COP. The frequent co-occurrence between COP and ADHD may reflect shared neuropsychological weaknesses that are most pronounced on measures of working memory and response variability.

A comparison of adolescent- and adult-onset first-episode, non-affective psychosis: 2-year follow-up

This study aimed to compare 2-year outcome among individuals with early-onset (EO; <18 years) versus adult-onset (AO) first-episode, non-affective psychosis. We compared clinical and treatment characteristics of 43 EO and 189 AO patients 2 years after their inclusion in a clinical epidemiologic population-based cohort study of first-episode psychosis. Outcome variables included symptom severity, remission status, drug abuse, treatment utilization, cognition and social functioning. At baseline, EO patients were more symptomatically compromised. However, these initial baseline differences were no longer significant at the 2-year follow-up. This study challenges the findings of a larger and older literature base consisting primarily of non-comparative studies concluding that teenage onset indicates a poor outcome. Our results indicate that adolescent-onset and adult-onset psychosis have similar prognostic trajectories, although both may predict a qualitatively different course from childhood-onset psychosis.

Brief Report: No Association Between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

Whereas Dysbindin is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. (J Autism Dev Disord 35:831-838, 2005) reported an association between Dysbindin and PMA in US-Caucasian individuals with childhood-onset psychosis. In a sample of 222 adult-onset schizophrenia inpatients from Germany, we could not detect an association between PMA and 36 SNPs in Dysbindin. Our results suggest that genetic variation in Dysbindin may not contribute to the schizophrenia phenotype with an onset beyond childhood. Further studies including even larger samples and more SNPs may be warranted to clarify the relationship between Dysbindin and PMA.

Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

Straub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009-.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.

Large CAG/CTG repeats are associated with childhood-onset schizophrenia.

Recent studies have shown an association between trinucleotide repeat expansions (TREs) and adult-onset schizophrenia (AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. We have used the repeat expansion detection (RED) method to investigate the occurrence of repeat expansions in a group of well-characterized COS patients as well as a set of clinically related childhood-onset psychosis cases labeled 'multidimensionally impaired' (MDI). The difference observed in the CAG/CTG RED product distribution between normal (n = 44) and COS (n = 36) samples was only marginally significant (P = 0.036). However, male COS samples (n = 20) had a significantly different RED product distribution compared to male controls (n = 25, P = 0.002) with longer RED products in COS. No such difference was seen in females (ncont = 19; ncos = 16; P = 0.236). The difference remained significant between male COS (n = 12) and male controls (n = 24) when only Caucasian samples were used (P = 0.003). Similarly, the RED product distribution in male MDI samples (n = 18) was significantly different compared to male controls (P = 0.018). Some of the detected TREs in all three populations (COS, MDI and control) correlated with expanded alleles found at the CTG18.1 locus on chromosome 18. In conclusion, we have found an association between TREs and COS. This association is specifically significant in the male population. Thus, the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, possibly in combination with other factors.

425. Clinical and biological correlates of cytogenetic abnormalities in childhood-onset psychosis

425. Clinical and biological correlates of cytogenetic abnormalities in childhood-onset psychosis