Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

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

Auricular reconstruction enhances the development of a stable personality.

ZusammenfassungLangzeitwirksame Methylphenidatpräparate mit einer zweistufigen Freisetzungsdynamik (Stufe 1: rasch; Stufe 2: verzögert) erlauben eine morgendliche Einmalgabe und werden so der Unterstützung von Schulkindern mit ADHS besser gerecht. Das diesbezüglich erste deutsche Arzneimittel (Medikinet® Retard 20 mg) sollte daher auf seine Wirksamkeit und Verträglichkeit geprüft werden.In einer plazebokontrollierten, randomisiert-parallelen, doppelblinden, multizentrischen Studie wurden 85 normal intelligente Kinder (Alter 6–16 Jahre, Diagnose ADHS) untersucht. Die Dauer der Behandlung mit Medikinet Retard (n = 43) bzw. Plazebo (n = 42) betrug 4 Wochen mit wöchentlichen Visiten und einer wöchentlichen Titrierung. Hauptzielkriterium war die Symptomatik im Fremdbeurteilungsbogen für hyperkinetische Störungen (FBB-HKS durch die Lehrer) im Vergleich der Woche 0 (Anfangswert) gegenüber der Woche 4 (Endwert). Unerwünschte Ereignisse und unerwünschte Arzneimittelwirkungen (UAW) sowie laborchemische und kardiovaskuläre Parameter wurden erfasst und EEG, internistische und neurologische Untersuchung durchgeführt.Es zeigte sich eine deutlich positive Medikamentenwirkung (U-Test: p <0,001). Die Effektstärke der Veränderungen lag bei d = 1,03. Die Dauer der Wirksamkeit hielt für das langzeitwirksame Methylphenidat meistens den gesamten Schulvormittag an. Die Verträglichkeit von Medikinet Retard wurde von Eltern, Patienten und Ärzten als gut bis sehr gut eingeschätzt.Damit liegen im deutschsprachigen Raum erstmals Daten für eine erfolgreiche Symptomreduktion und gute Verträglichkeit eines langzeitwirksamen Methylphenidatpräparates (Medikinet Retard) vor. Die zweistufige Freisetzungsdynamik erlaubt eine praxistaugliche morgendliche Einmalgabe.

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