Carina Gillberg

The Autism - Tics, AD/HD and other Comorbidities inventory (A-TAC): further validation of a telephone interview for epidemiological research

BackgroundReliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health.The aim of this study is to provide further validity data for a parent telephone interview focused on Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported.MethodsParents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome.ResultsAreas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD).ConclusionsThe previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.

The Asperger Syndrome (and High-Functioning Autism) Diagnostic Interview (ASDI): A Preliminary Study of a New Structured Clinical Interview

The development of the Asperger Syndrome (and high- functioning autism) Diagnostic Interview (ASDI) is described. Preliminary data from a clinical study suggest that inter-rater reliability and test-retest stability may be excellent, with kappas exceeding 0.90 in both instances. The validity appears to be relatively good. No attempt was made in the present study to validate the instrument as regards the distinction between Asperger syndrome and high-functioning autism.

Identification of pathway-biased and deleterious melatonin receptor mutants in autism spectrum disorders and in the general population

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration of the melatonin pathway has been reported in circadian disorders, diabetes and autism spectrum disorders (ASD). However, very little is known about the genetic variability of melatonin receptors in humans. Here, we sequenced the melatonin receptor MTNR1A and MTNR1B, genes coding for MT1 and MT2 receptors, respectively, in a large panel of 941 individuals including 295 patients with ASD, 362 controls and 284 individuals from different ethnic backgrounds. We also sequenced GPR50, coding for the orphan melatonin-related receptor GPR50 in patients and controls. We identified six non-synonymous mutations for MTNR1A and ten for MTNR1B. The majority of these variations altered receptor function. Particularly interesting mutants are MT1-I49N, which is devoid of any melatonin binding and cell surface expression, and MT1-G166E and MT1-I212T, which showed severely impaired cell surface expression. Of note, several mutants possessed pathway-selective signaling properties, some preferentially inhibiting the adenylyl cyclase pathway, others preferentially activating the MAPK pathway. The prevalence of these deleterious mutations in cases and controls indicates that they do not represent major risk factor for ASD (MTNR1A case 3.6% vs controls 4.4%; MTNR1B case 4.7% vs 3% controls). Concerning GPR50, we detected a significant association between ASD and two variations, Δ502–505 and T532A, in affected males, but it did not hold up after Bonferonni correction for multiple testing. Our results represent the first functional ascertainment of melatonin receptors in humans and constitute a basis for future structure-function studies and for interpreting genetic data on the melatonin pathway in patients.

Possible association between the androgen receptor gene and autism spectrum disorder

Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.

The Autism—Tics, AD/HD and other Comorbidities (A-TAC) telephone interview: Convergence with the Child Behavior Checklist (CBCL)

Objective: To compare telephone interview screening for child psychiatric/neuropsychiatric disorders using the inventory of Autism—Tics, Attention deficit/hyperactivity disorder (AD/HD) and other Comorbidities (A-TAC) with results from the Child Behavior Checklist (CBCL). Background: The A-TAC is a parent telephone interview focusing on autism spectrum disorders (ASDs) and co-existing problems, developed for lay interviewers. Subjects and methods: A-TAC telephone interviews and CBCL questionnaires were obtained from parents of 106 Swedish twin pairs aged 9 and 12 years. Results: Correlations between A-TAC modules and CBCL scales aimed at measuring similar concepts were generally significant albeit modest, with correlation coefficients ranging from 0.30 through 0.55. Conclusion: The A-TAC has convergent validity with the CBCL in several problem areas, but the A-TAC also provides more detailed and specific assessments of ASD symptoms and related neuropsychiatric problems.

Effects of autism spectrum disorders on outcome in teenage-onset anorexia nervosa evaluated by the Morgan-Russell outcome assessment schedule: a controlled community-based study

BackgroundThe purpose of the study was to evaluate time trends and effects of co-existing autism spectrum disorders (ASD) on outcome in an ongoing long-term follow-up study of anorexia nervosa (AN).MethodsThe Morgan-Russell Outcome Assessment Schedule (MROAS) was used at 6-, 10- and 18-year follow-up of a representative sample of 51 individuals with teenage-onset AN and a matched group of 51 healthy comparison cases. The full multinomial distribution of responses for the full scale and each of the subscales was evaluated using exact nonparametric statistical methods. The impact of diagnostic stability of ASD on outcome in AN was evaluated in a dose–response model.ResultsThere were no deaths in either group. Food intake and menstrual pattern were initially poor in the AN group but normalised over time. MROAS ‘mental state’ was much poorer in the AN group and did not improve over time. The psychosexual MROAS domains ‘attitudes’ and ‘aims’ showed persistent problems in the AN group. In the MROAS socioeconomic domain, the subscales ‘personal contacts’, ‘social activities’ and ‘employment record’ all showed highly significant between-group differences at all three follow-ups. A statistically significant negative dose–response relationship was found between a stable diagnosis of ASD over time and the results on the subscales ‘mental state’, ‘psychosexual state’ and ‘socio-economic state’.ConclusionsOutcome of teenage-onset AN is favourable with respect to mortality and persisting eating disorder, but serious problems remain in the domains ‘mental state’, ‘psychosexual function’ and ‘socioeconomic state’. Outcome is considerably worse if ASD is present. Treatment programmes for AN need to be modified so as to accommodate co-existing ASD.

Gender differences in autism spectrum disorders: Divergence among specific core symptoms

Community‐based studies have consistently shown a sex ratio heavily skewed towards males in autism spectrum disorders (ASD). The factors underlying this predominance of males are largely unknown, but the way girls score on standardized categorical diagnostic tools might account for the underrecognition of ASD in girls. Despite the existence of different norms for boys and girls with ASD on several major screening tests, the algorithm of the Autism Diagnosis Interview‐Revised (ADI‐R) has not been reformulated. The aim of our study was to investigate which ADI‐R items discriminate between males and females, and to evaluate their weighting in the final diagnosis of autism. We then conducted discriminant analysis (DA) on a sample of 594 probands including 129 females with ASD, recruited by the Paris Autism Research International Sibpair (PARIS) Study. A replication analysis was run on an independent sample of 1716 probands including 338 females with ASD, recruited through the Autism Genetics Resource Exchange (AGRE) program. Entering the raw scores for all ADI‐R items as independent variables, the DA correctly classified 78.9% of males and 72.9% of females (P < 0.001) in the PARIS cohort, and 72.2% of males and 68.3% of females (P < 0.0001) in the AGRE cohort. Among the items extracted by the stepwise DA, four belonged to the ADI‐R algorithm used for the final diagnosis of ASD. In conclusion, several items of the ADI‐R that are taken into account in the diagnosis of autism significantly differentiates between males and females. The potential gender bias thus induced may participate in the underestimation of the prevalence of ASD in females. Autism Res 2016,.

The role of general anesthesia on traits of neurodevelopmental disorders in a Swedish cohort of twins

BACKGROUND The role of general anesthetics as a risk factor for possible neurodevelopmental disorders (NDDs) in humans is unresolved. The investigation of the role of anesthetics in the development of postgeneral anesthesia (anesthesia onward) NDDs has proven to be complicated, partly because of the inherent confounding in clinical cohort studies, and partly by the fact that anesthetics are only one part in the complex process of anesthesia-surgery. METHODS Utilizing the Swedish databases Child and Adolescent Twins Study in Sweden (CATSS) and National Patient Register (NPR), we investigated twins discordant for anesthesia, born between 1997 and 2004 for traits of NDDs. We identified 68 twin pairs discordant for anesthesia and explored traits of Attention-Deficit/Hyperactivity Disorder (ADHD), Learning Disability (LD), and Autism Spectrum Disorder (ASD) in them while simultaneously taking congenital abnormalities and systemic disorders (CSDs) into account. We analyzed the possible effect of anesthesia on neurodevelopmental problems, and we analyzed the within-pair differences using conditional linear regression. RESULTS Twins with a recorded episode of anesthesia had higher traits of NDDs than twins without; similarly twins with CSDs had higher mean scores on all traits than twins without CSDs. The within-pair analyses suggested that exposure to anesthesia was associated with higher scores of ADHD (regression coefficient 1.02 and 95% confidence intervals: 0.27-1.78) in monozygotic (MZ) twins discordant for anesthesia. This effect remained when adjusting for congenital abnormalities. DISCUSSION Our finding that traits of ADHD were slightly associated with anesthesia in a genetically sensitive design is in need of replication and warrants further investigation. Future studies should aim to elucidate mechanisms behind this possible association (e.g. anesthetics doses, age at exposure, exposure duration).

Anxiety and depression in adolescents with ADHD and autism spectrum disorders; correlation between parent- and self-reports and with attention and adaptive functioning

Abstract Background: Adolescents with attention-deficit/hyperactive disorder (ADHD) or autism spectrum disorder (ASD) are at high risk of anxiety and depression. This is important to identify in the clinical assessment to understand its impact. Aims: The aim of this study is to investigate the correlation between parent- and self-reports of anxiety and depression in adolescents with ADHD or ASD, as well as the correlation with adaptive functioning and performance on an attention test. Method: A total of 65 adolescents with an ADHD diagnosis (n = 24) or an ASD diagnosis (n = 41) filled out Beck Youth Inventories of Emotional and Social Impairment (BYI) to assess depression and anxiety and completed a Continuous Performance Test (QbTest) measuring ADHD symptoms. Parents of the participants completed the internalizing domain in the Five to Fifteen questionnaire (FTF), measuring symptoms of anxiety and depression, and the Vineland Adaptive Behavior Scales (VABS) about the adolescent’s adaptive functioning. Results: Approximately a third of the study group self-reported substantial internalizing mental symptoms not always recognized by parents, and not always obvious in adaptive function or performance at ADHD test. Correlations between BYI and FTF were low. The BYI depression inventory correlated negatively with VABS and positively with activity level in a subgroup medicated for ADHD. There was a stronger correlation between girls BYI and FTF results as compared with boys. Conclusions: The results highlight the need for identification of anxiety and depression, using both self- and parent report. Present anxiety and depression symptoms do not seem to affect the clinical assessment of ASD and ADHD.

Kinderen met op kleuterleeftijd lichte ontwikkelingsafwijkingen op neurologisch gebied

Een groep kinderen met in het zevende levensjaar aandachtsstoornissen, beweging en perceptie ’ willekeurig gekozen uit de totale populatie van dergelijke kinderen in Goteborg, Zweden ’ werd wat betreft gedrag en schoolprestaties op de leeftijd van 13 jaar vergeleken met een groep normale kinderen. De gevolgde groep scoorde steeds hoog bij ernstige gedragsstoornissen, naar het oordeel van leraren, ouders en ook van henzelf.