Christopher Gillberg

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

Computerized Training of Working Memory in Children With ADHD-A Randomized, Controlled Trial

OBJECTIVE Deficits in executive functioning, including working memory (WM) deficits, have been suggested to be important in attention-deficit/hyperactivity disorder (ADHD). During 2002 to 2003, the authors conducted a multicenter, randomized, controlled, double-blind trial to investigate the effect of improving WM by computerized, systematic practice of WM tasks. METHOD Included in the trial were 53 children with ADHD (9 girls; 15 of 53 inattentive subtype), aged 7 to 12 years, without stimulant medication. The compliance criterion (>20 days of training) was met by 44 subjects, 42 of whom were also evaluated at follow-up 3 months later. Participants were randomly assigned to use either the treatment computer program for training WM or a comparison program. The main outcome measure was the span-board task, a visuospatial WM task that was not part of the training program. RESULTS For the span-board task, there was a significant treatment effect both post-intervention and at follow-up. In addition, there were significant effects for secondary outcome tasks measuring verbal WM, response inhibition, and complex reasoning. Parent ratings showed significant reduction in symptoms of inattention and hyperactivity/impulsivity, both post-intervention and at follow-up. CONCLUSIONS This study shows that WM can be improved by training in children with ADHD. This training also improved response inhibition and reasoning and resulted in a reduction of the parent-rated inattentive symptoms of ADHD.

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.

Natural Outcome of ADHD With Developmental Coordination Disorder at Age 22 Years: A Controlled, Longitudinal, Community-Based Study

OBJECTIVE There is a need for controlled longitudinal studies in the field of attention disorders in the general population. METHOD In a community-based follow-up study, 55 of 61 subjects aged 22 years, who had attention-deficit/hyperactivity disorder (ADHD) with and without comorbid developmental coordination disorder (DCD) at initial workup at age 7 years, were compared, on a multitude of outcome variables, with 46 of 51 age-matched subjects without such diagnoses. None of the subjects had received stimulant treatment. Psychiatrists performing the follow-up study were blind to original diagnostic group status. RESULTS In the ADHD/DCD group 58% had a poor outcome compared with 13% in the comparison group (p < .001). Remaining symptoms of ADHD, antisocial personality disorder, alcohol abuse, criminal offending, reading disorders, and low educational level were overrepresented in the ADHD/DCD groups. The combination of ADHD and DCD appeared to carry a particularly gloomy outlook. CONCLUSIONS Childhood ADHD and DCD appears to be a most important predictor of poor psychosocial functioning in early adulthood. It would seem appropriate to screen for such disorders in schools and clinics so that therapies may be started early.

A Screening Questionnaire for Asperger Syndrome and Other High-Functioning Autism Spectrum Disorders in School Age Children

The high-functioning Autism Spectrum Screening Questionnaire (ASSQ) is a 27-item checklist for completion by lay informants when assessing symptoms characteristic of Asperger syndrome and other high-functioning autism spectrum disorders in children and adolescents with normal intelligence or mild mental retardation. Data for parent and teacher ratings in a clinical sample are presented along with various measures of reliability and validity. Optimal cutoff scores were estimated, using Receiver Operating Characteristic analysis. Findings indicate that the ASSQ is a useful brief screening device for the identification of autism spectrum disorders in clinical settings.

'Theory of mind' in the brain. Evidence from a PET scan study of Asperger syndrome.

THE ability to attribute mental states to others (‘theory of mind’) pervades normal social interaction and is impaired in autistic individuals. In a previous positron emission tomography scan study of normal volunteers, performing a ‘theory of mind’ task was associated with activity in left medial prefrontal cortex. We used the same paradigm in five patients with Asperger syndrome, a mild variant of autism with normal intellectual functioning. No task-related activity was found in this region, but normal activity was observed in immediately adjacent areas. This result suggests that a highly circumscribed region of left medial prefrontal cortex is a crucial component of the brain system that underlies the normal understanding of other minds.

The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood

OBJECTIVE Autism spectrum disorders are considered to be among the most heritable mental disorders, a notion based on surprisingly sparse data from small clinical studies. Population-based studies of the heritability of other neuropsychiatric disorders and comorbidities among them have also been sparse. The authors sought to address both of these issues. METHOD Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2000 (N=10,895) were interviewed regarding autism spectrum disorders and associated conditions (response rate, 80%). Concordance rates and structural equation modeling were used for evaluating causes for familial aggregation and overlap between conditions. RESULTS Monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder. Genetic effects accounted for 80% (95% CI=29-91) of the variation in liability for autism spectrum disorders, 79% (95% CI=61-88) for ADHD, 70% (95% CI=35-83) for developmental coordination disorder, and 56% (95% CI=37-68) for tic disorder. Among monozygotic co-twins of children with autism spectrum disorders, the probability of having a diagnosis of ADHD was 44%, compared with 15% for dizygotic co-twins. Differences in cross-disorder effects between monozygotic and dizygotic twins were observed for most other comorbidities, and substantial proportions of the genetic variance for autism spectrum disorders was shared with each of the other disorders. CONCLUSIONS Different neuropsychiatric disorders seem to have a common genetic etiology, suggesting caution in the use of diagnostic entities and proband status in efforts to uncover genes predisposing to autism spectrum disorders.

The Comorbidity of ADHD in the General Population of Swedish School-age Children

This study examined patterns of comorbid/associated diagnoses and associated problems in a population sample of children with and without DSM-III-R attention-deficit hyperactivity disorder (ADHD). Half (N = 409) of a mainstream school population of Swedish 7-year-olds were clinically examined, and parents and teachers were interviewed and completed questionnaires. The children were followed up 2-4 years later. Eighty-seven per cent of children meeting full criteria for ADHD (N = 15) had one or more and 67% at least two--comorbid diagnoses. The most common comorbidities were oppositional defiant disorder and developmental coordination disorder. Children with subthreshold ADHD (N = 42) also had very high rates of comorbid diagnoses (71% and 36%), whereas those without ADHD (N = 352) had much lower rates (17% and 3%). The rate of associated school adjustment, learning, and behaviour problems at follow-up was very high in the ADHD groups. We concluded that pure ADHD is rare even in a general population sample. Thus, studies reporting on ADHD cases without comorbidity probably refer to highly atypical samples. By and large, such studies cannot inform rational clinical decisions.

Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders.

BackgroundIndividuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs.MethodsAutistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Aspergers disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians.ResultsCore autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects.ConclusionASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.

Outcome and prognostic factors in infantile autism and similar conditions: A population-based study of 46 cases followed through puberty

This follow-up study reports data from a population-based series of children in the Göteborg region of Sweden diagnosed in childhood as suffering from infantile autism and other childhood psychoses and followed through to the ages of 16–23 years. The results of the study are in good accord with the only previous population-based study of the same kind. IQ at diagnosis and communicative speech development before 6 years were the most important prognostic factors, but other trends were seen that also compare favorably with previous studies. Some previously unreported trends also emerged.