Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P ¼ 0.049; rs11178997, P ¼ 0.034), but not for the third SNP in intron 2 (rs4565946, P ¼ 0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P ¼ 0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes. Keywords: ADHD; serotonin; TPH2; sib pairs Attention-deficit/hyperactivity disorder (ADHD) is a common syndrome first diagnosed in childhood and frequently persistent throughout adult life. Prevalence ranges between 3 and 9% dependent on the nature of the population sampled and the method of ascertainment.1,2 Although heritability estimates are consistently high, averaging around 0.8, ADHD is a genetically complex disorder characterized by multifactorial inheritance involving numerous genes of moderate effect. 2-5While an imbalance in dopaminergic neurotransmission appears to be an important factor predisposing to ADHD, interaction between the dopamine (DA) and serotonin (5-HT) systems has been implicated in both the pathophysiology of ADHD and the mechanism of action of widely used stimulant compounds. By inhibition of the dopamine transporter (DAT), which was reported to be increased in the striatum in ADHD patients, 6 methylphenidate (MPH) is highly effective in reducing the symptoms of ADHD. DAT knockout (KO) mice display a phenotype with increased locomotor activity, 7 which is reversed by MPH-induced increases in 5-HT neurotransmission. 8On the other hand, the hyperlocomotion in DAT KO mice is attenuated by the selective 5-HT reuptake inhibitor (SSRI) fluoxetine or the 5-HT precursor 5-hydroxytryptophan. 9 Early studies reported low platelet 5-HT levels in ADHD patients 10,11 and there is an extensive data base that ADHD-specific syndromal dimensions including impulsive behavior, aggressiveness and substance abuse are linked to alterations

The Autism Diagnostic Observation Schedule is a semi-structured, standardized assessment tool for individuals with suspected autism spectrum disorders (ASD) and is deemed to be part of the gold standard for diagnostic evaluation. Good diagnostic accuracy and interpersonal objectivity have been demonstrated for the ADOS in research setting. The question arises whether this is also true for daily clinical practice and whether diagnostic accuracy depends on specialized experience in the diagnostic evaluation. The present study explores the diagnostic accuracy of the original and the revised version of the ADOS for Modules 1 through 4. Thus, seven cases of ADOS executions were recorded and coded by a group of experts of specialized outpatient clinics for ASD. In an extensive consensus process, including video analysis of every minute of the ADOS executions, a "gold standard" coding for every case was defined. The videos of the ADOS administration were presented to a large group of clinicians (from daily clinical routine care) and their codings (n = 189) were obtained and analysed. Variance of coding and congruence with the expert coding were determined. High variance was found in the codings. The accuracy of the coding depends on the experience of the coder with the ADOS as well as on characteristics of the cases and the quality of the administration of the ADOS. Specialization in the diagnostic of ASD has to be claimed. Specialized outpatient clinics for ASD are required which guarantee a qualified diagnostic/differential diagnostic and case management with the aim of demand-oriented supply of individual cases.

The dimensional structure of higher functioning autism phenotype was investigated by factor analysis. The goal of this study was to identify the degree to which early symptoms of autism (measured using the ADI-R) could be predictive of the current symptoms of autism as identified using the ADOS, the adaptive behavior scales, IQ scores and theory of mind scores. Participants included 140 subjects with Full Scale IQ > 70 (104 with autism spectrum diagnosis, 36 with non autism diagnosis, age range 6-24). For the early development as well as for the current presentation a multi-factor solution was found. In line with other studies we found that the social interaction and communication domains are closely related to one factor namely: Social communication. An additional factor implies anxious and compulsive behavior which is associated with current social communication functioning.

There is an ongoing debate whether a differentiation of autistic subtypes, especially between Asperger Syndrome (AS) and high-functioning-autism (HFA) is possible and if so, whether it is a categorical or dimensional one. The aim of this study was to examine the possible clustering of responses in different symptom domains without making any assumption concerning diagnostic appreciation. About 140 children and adolescents, incorporating 52 with a diagnosis of AS, 44 with HFA, 8 with atypical autism and 36 with other diagnoses, were examined. Our study does not support the thesis that autistic disorders are discrete phenotypes. On the contrary, it provides evidence that e.g. AS and autism are not qualitatively distinct disorders, but rather different quantitative manifestations of the same disorder.

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We found no significant influence of genetic factors for activity, attention, and impulsivity. The authors conclude that further investigation of heritability of ADHD is necessary using larger sample sizes and objective measures.

The mean pre-post changes found in all parameters investigated consistently correspond with benefits desired from medication with MPH in children with HD. Absolute differences in microevents and variability seem to depend on the daily dose of MPH after adjustment for BMI.