L-Histidine Decarboxylase and Tourette's Syndrome

Abstract

SummaryTourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding Lhistidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.Tourette's Syndrome is Characterized by Childhood Onset, Waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical-striatal-thalamiccortical circuitry. 1 Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive-compulsive disorder and attention deficithyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority. 2 The large genetic contribution to Tourette's syndrome is well established. 3 4,5 However, mutations are found in only a small proportion of affected persons, and the protein's normal function and the manner in which it may contribute to Tourette's syndrome are not yet well understood.In light of the probable genetic heterogeneity underlying Tourette's syndrome, we sought families in which the syndrome is transmitted in a mendelian fashion, which is rare. As has been shown for other complex disorders, gene discovery in such families may help to uncover molecular mechanisms of disease. 6 MethodsMethods are described briefly here; for complete details, see the Supplementary Appendix, available with the full text of this article at NEJM.org. All studies were approved by the Yale Institutional Review Board, and all participants provided written informed consent.A nonconsanguineous two-generation pedigree was referred to our laboratory (Fig. 1). The father and all eight offspring met the criteria for Tourette's syndrome in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (Table S1 in the Supplementary Appendix). Two children and the father also have obsessive-compulsive disorder. The mother, her parents, and her extended family are reportedly free from Tourette's syndrome, chronic tics, and obsessive-compulsive disorder.DNA samples from all family members in the two-generation pedigree were genotyped by means of Affymetrix GeneChip Human Mapping 100K Arrays and short-tandem-repeat markers that had been identified within the lod -2 linkage interval (the equivalent of a conf...

Differential Modulation of Excitatory and Inhibitory Striatal Synaptic Transmission by Histamine

“…Interestingly, recent studies have indicated a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome (Ercan-Sencicek et al, 2010) and the effect of L-dopa treatment in Parkinson's disease (Yanovsky et al, 2011), suggesting histaminergic drugs might well be efficacious for these and other disorders involving the basal ganglia (Schwartz, 2011). Last, the widespread projections of the histaminergic system suggest that histamine might modulate information processing similarly in widespread regions of the brain.…”

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

“…Much attention has been paid to dopaminergic candidates, and there is evidence of a significant association between TS and a dopamine transporter polymorphism (DAT1 Ddel) (Yoon et al, 2007b). Several recent candidate genes have included: a heterozygous loss of function mutation in L-histidine decarboxylase, which encodes the rate limiting enzyme in histamine biosynthesis (Ercan-Sencicek et al, 2010); functional variations of the SLITRK1 gene, with homology to a known axon guidance molecule (Scharf et al, 2008); and DLGAP3, a postsynaptic scaffolding protein highly expressed in striatal glutamatergic synapses (Crane et al, 2011).…”

Tourette Syndrome research highlights 2014

“…Castellan Baldan et al 1, 2 report on characterization of a possible animal model for Tourette syndrome, chosen because of a family with Tourette syndrome linked to a loss-of-function mutation in the histidine decarboxylase gene 3, 4 . Histidine decarboxylase knock-out mice 5 exhibited tic-like stereotypies after a D-amphetamine challenge (see Figure 1, panel E in ref.…”