Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

A randomized controlled trial of preschool-based joint attention intervention for children with autism.

BACKGROUND: Deficits in joint attention (JA) and joint engagement (JE) represent a core problem in young children with autism as these affect language and social development. Studies of parent-mediated and specialist-mediated JA-intervention suggest that such intervention may be effective. However, there is little knowledge about the success of the intervention when done in preschools. AIM: Assess the effects of a preschool-based JA-intervention. METHODS: 61 children (48 males) with autistic disorder (29-60 months) were randomized to either 8 weeks of JA-intervention, in addition to their preschool programs (n = 34), or to preschool programs only (n = 27). The intervention was done by preschool teachers with weekly supervision by trained counselors from Child and Adolescent Mental Health Clinics (CAMHC). Changes in JA and JE were measured by blinded independent testers using Early Social Communication Scale (ESCS) and video taped preschool teacher-child and mother-child play at baseline and post-intervention. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov: NCT00378157. RESULTS: Intention-to-treat analysis showed significant difference between the intervention and the control group, with the intervention group yielding more JA initiation during interaction with the preschool teachers. The effect generalized to significantly longer duration of JE with the mothers. CONCLUSIONS: This is the first randomized study to show positive and generalized effects of preschool-based JA-intervention.

[Urine peptide patterns in children with milder types of autism]. / Peptidmønstre i urin hos barn med mildere former for autisme.

BACKGROUND: Autism is a severe developmental disorder. The condition is probably not homogenous. Elevated urine peptides have been found in individuals affected by autism spectrum disorders. This finding may be explained by characteristics of the samples studied. Autistic children without mental retardation (high-functioning autism) or mild mental retardation may represent a more homogenous group among those suffering from autism spectrum disorders. The purpose of this study is to compare urine peptide patterns in this group of patients with healthy controls. This has never been done before. METHOD: Urine from the first miction was frozen immediately in order to inhibit bacterial growth and enzymatic degeneration. Peptides from the urine samples were later analysed by high pressure liquid chromatography (HPLC). RESULTS: No significant differences in urine peptide values were found between the autism spectrum disorders group and the controls. There was an age dependent decrease in peptides, with values decreasing with the age of the child. Three individuals in the autism group (17%) and one in the familiar control group (0.05%) had high levels of urine peptides. No one in the same age non-familiar control group had elevated levels of urine peptides. INTERPRETATION: This study shows that high-functioning autism cannot be identified by the urine peptide pattern.

Exploring the agreement between questionnaire information and DSM-IV diagnoses of comorbid psychopathology in children with autism spectrum disorders.

Autism spectrum disorders are often comorbid with other psychiatric symptoms and disorders. However, identifying psychiatric comorbidity in children with autism spectrum disorders is challenging. We explored how a questionnaire, the Child Behavior Check List, agreed with a Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV)-based semi-structured interview, the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS). The sample comprised 55 children and adolescents (age 6 to 18 years) with autism spectrum disorders, including the main autism spectrum disorder subgroups and the broad range of cognitive and language functioning. High rate of psychopathology was found both through questionnaire and interview assessment. Using predefined Child Behavior Check List cutoffs, we found good agreement between the Child Behavior Check List and the Kiddie-SADS for identifying attention deficit/hyperactivity disorder, depressive disorders, and oppositional defiant disorder. However, overall the specificity of the Child Behavior Check List was low. The Child Behavior Check List was not useful for identifying anxiety disorders. The Child Behavior Check List may capture core symptoms of autism spectrum disorders as well as comorbid psychopathology, and clinicians should be aware that the Child Behavior Check List may be unspecific when used in children and adolescents with autism spectrum disorders.

Analysis of ten candidate genes in autism by association and linkage.

We studied the possible involvement of ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight families with two affected siblings and one family with two affected half-siblings, recruited by the Paris Autism Research International Sibpair Study (PARIS), were tested using the transmission disequilibrium test and two-point affected sib-pair linkage analysis. We found no evidence for association or linkage with intragenic or linked markers. Our family sample has good power for detecting a linkage disequilibrium of 0.80. Thus, these genes are unlikely to play a major role in the families studied, but further studies in a much larger sample would be needed to highlight weaker genetic effects.

Copy number variation findings among 50 children and adolescents with autism spectrum disorder.

OBJECTIVES: Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopment disorders with a complex genetic aetiology. The aim of this study was to identify copy number variations (CNVs) with a clinical significance for ASD. MATERIALS AND METHODS: Array-based comparative genomic hybridization was applied to detect CNVs in a clinically well-characterized population of 50 children and adolescents with ASD. RESULTS: Nine CNVs with predicted clinical significance were identified among eight individuals (detection rate 16%). Three of the CNVs are recurrently associated with ASDs (15q11.2q13.1) or have been identified in ASD populations [3p14.2 and t(8;12)(p23.1;p13.31)]. The remaining regions (15q11.2, 10q21.1, Xp22.2, 16p13.3 and 22q13.1) have not been reported previously as candidate genes for ASD. CONCLUSION: This study identified five novel CNVs among the individuals. The causal relationship between identified CNVs and the ASD phenotype is not fully established. However, the genes involved are associated with ASD and/or other neuropsychiatric disorders, or implicated in synaptic and neuronal activity, thus suggesting clinical significance. Further identification of ASD-associated CNVs is required, together with a broad clinical characterization of affected individuals to identify genotype-phenotype correlations.

Is long-term prognosis for pervasive developmental disorder not otherwise specified different from prognosis for autistic disorder? Findings from a 30-year follow-up study.

We followed 74 children with autistic disorder (AD) and 39 children with pervasive developmental disorder not otherwise specified (PDD NOS) for 17-38 years in a record linkage study. Rates of disability pension award, marital status, criminality and mortality were compared between groups. Disability pension award was the only outcome measure that differed significantly between the AD and PDD NOS groups (89% vs. 72%, p < 0.05). The lower rate of disability pension award in the PDD NOS group was predicted by better psychosocial functioning. The lack of substantial differences in prognosis between the groups supports a dimensional description of autism spectrum disorder, in line with proposed DSM-V revision.

Kiddie-SADS reveals high rates of DSM-IV disorders in children and adolescents with autism spectrum disorders.

Prevalence of current comorbid DSM-IV disorders was assessed in a special school population of children and adolescents with ASD (N = 71, age 6.0-17.9 years), representing all cognitive levels and main ASD subgroups. Symptoms were assessed through parent interview and association to child characteristics was explored. Seventy-two percent was diagnosed with at least one comorbid disorder. Anxiety disorders (41%) and attention deficit/hyperactivity disorder (31%) were most prevalent. Obsessive-compulsive disorder was more common in older children, and oppositional defiant disorder/conduct disorder more prevalent in pervasive developmental disorder, not otherwise specified. Our results show high rates of comorbid DSM-IV disorders and underscore the importance of such evaluation in children ASD. However, diagnostic challenges are present and future research on the diagnostic validity of comorbid psychiatric disorders is needed.