Judith Sinzig

Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms

BackgroundRecent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD.MethodsChildren aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used.ResultsThere was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task.ConclusionOur findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.

Attention Deficit/Hyperactivity Disorder in Children and Adolescents with Autism Spectrum Disorder: Symptom or Syndrome?

Objective: This study aims to evaluate ADHD-like symptoms in children with autism spectrum disorder (ASD) based on single-item analysis, as well as the comparison of two ASD subsamples of children with ADHD (ASD+) and without ADHD (ASD-). Methods: Participants are 83 children with ASD. Dimensional and categorical aspects of ADHD are evaluated using a diagnostic symptom checklist according to DSM-IV. Results: Of the sample, 53% fulfill DSM-IV criteria for ADHD. The comparison of the ASD+ and the ASD- samples reveals differences in age and IQ. Correlations of ADHD and PDD show significant results for symptoms of hyperactivity with impairment in communication and for inattention with stereotyped behavior. Item profiles of ADHD symptoms in the ASD+ sample are similar to those in a pure ADHD sample. Conclusion: The results of our study reveal a high phenotypical overlap between ASD and ADHD. The two identified subtypes, inattentive-stereotyped and hyperactive-communication impaired, reflect the DSM classification and may theoretically be a sign of two different neurochemical pathways, a dopaminergic and a serotonergic. (J. of Att. Dis. 2009; 13(2) 117-126)

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome‐wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM‐IV criteria; Human660W‐Quadv1; Illumina, San Diego, CA) and on 1,300 population‐based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P‐values (best P‐value: 8.38 × 10−7) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P‐values (P‐values ≤ 7.57 × 10−5) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect‐size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta‐analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect‐size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome‐wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P‐values compared to SNPs within random sets of genes of the same size. We did not find genome‐wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

Comparative efficacy of once-a-day extended-release methylphenidate, two-times-daily immediate-release methylphenidate, and placebo in a laboratory school setting.

AbstractBackgroundGiven the dosing limitations of methylphenidate short–acting preparations in treating ADHD, galenics with longer release of the substance were developed mainly to avoid drug intake during school hours.ObjectivesThis investigation was conducted to assess the efficacy and the duration of action of a new extended-release formulation of methylphenidate (Medikinet® retard) as a once–daily treatment for children with attention–deficit hyperactivity disorder (ADHD).MethodThis was a randomized, double–blind, crossover multicentre study with three treatment conditions: once–daily extended–release methylphenidate, twice–daily immediate–release methylphenidate and placebo given to 79 children (8–14 years old) with ADHD. Daily assessments in an analogue classroom setting included blind ratings of attention and deportment and a performance measure (math test) obtained 5 times over an 8–hour period. Secondary measures included an ADHD rating scale, based on DSMIV/ ICD–10 separately rated for the morning and the afternoon.ResultsBoth active treatment conditions displayed significant time course effects and were superior to placebo in improving all efficacy measures. Once a day extended–release methylphenidate was not different from the same dose of twice daily immediate–release methylphenidate.ConclusionsThese data provide support for the benefit of this novel, once-daily methylphenidate preparation in the treatment of ADHD. The longer duration of action of Medikinet Retard has the potential to simplify psychostimulant treatment, thus reducing dose diversion and eliminating the need for in–school administration.

Attention profiles in autistic children with and without comorbid hyperactivity and attention problems.

Objective: Psychopathological, neuropsychological and genetic findings indicate an association between ASD Spectrum Disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The goal of this study was to compare the neuropsychological profiles of attention functions in children with ADHD and with ASD and without comorbid ADHD. The hypothesis was that either ADHD and autistic children with comorbid ADHD symptoms were more impaired in inhibition and sustained attention performance and that all individuals with ASD show more deficits in divided attention. Method: Children aged 6 to 18 years old with ADHD (n = 30) or ASD with (n = 21) and without comorbid ADHD (n = 20) and 30 healthy children were included consecutively. Psychopathology was evaluated using the KIDDIE-SADS and symptom checklists for ADHD and ASD according to DSM-IV. Assessed neuropsychological functioning included inhibition, sustained as well as divided attention and alertness tasks. Results: Age and IQ-corrected z-scores were used. Statistically significant group effects were found for the variables sustained attention median (F = 3.2, = .02), hits (F = 3.3, p = .02) and false alarms (F = 3.9, p = .01), divided attention hits (F = 3.3, p = .02), errors (F = 3.1, p = .03) and false alarms (F = 3.3, p = .03) and alertness false alarms (F = 2.9, p = .04). Pearson Correlations revealed associations between ADHD symptoms and sustained attention in the ADHD group and between ADHD symptoms and inhibition in the ASD+ group. Conclusion: Our hypothesis was partly confirmed as ADHD children showed more deficits in sustained attention and ASD children in divided attention tasks. However there was no evidence that children with ASD and comorbid ADHD symptoms have a specific profile in comparison to pure ASD children.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ⩽1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10−4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756–162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10−3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10−2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder†

Children with attention‐deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome‐wide association study (GWAS) for ADHD based on 495 patients and 1,300 population‐based controls and performed in silico analyses of the SNPs in an ADHD meta‐analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X‐type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10−4; Pcorr = 0.01). In the meta‐analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein‐coupled receptor, family C, group 5, member B; P = 7.2 × 10−4; Pcorr = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine‐6‐phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen‐activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta‐analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.

Use of early intervention for young children with autism spectrum disorder across Europe

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities.

Exploring the genetic link between RLS and ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.

Rare Mutations of CACNB2 Found in Autism Spectrum Disease-Affected Families Alter Calcium Channel Function

Autism Spectrum Disorders (ASD) are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C) and CaVβ2 (CACNB2) were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L) found in ASD-affected families, two of them described here for the first time (G167S and F240L). All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells). Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L) showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.