Gastrodin alleviates Tourette syndrome via Nrf-2/HO-1/HMGB1/NF-кB pathway.

The aim is to study the effects of gastrodin (GA) on striatal inflammation and oxidative stress in rats with Tourette syndrome (TS). The rat model of TS was induced by 3,3'-iminodipropionitrile. Behavioral tests were carried out by stereotype experiment. The concentrations of amino acid transmitters glutamic acid (Glu) and γ-aminobutyric acid (GABA) in striatum were determined by high-performance liquid chromatography. Superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and striatum were detected by commercial kits. Cytokines in serum and striatum were detected by enzyme-linked immunosorbent assay kits. Western blot analysis was used to detect striatum nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1)/high mobility group box 1 protein (HMGB1)/nuclear factor-кB (NF-кB) pathway-related proteins. The expressions of Nrf-2 and P-NF-кBp65 in striatum were detected by immunohistochemistry. Compared with the control group, the stereotype scores of rats in the model group significantly increased, and the contents of Glu and GABA in striatum obviously increased. GA significantly reduced the stereotype scores and decreased the contents of Glu and GABA. The levels of SOD in serum and striatum were decreased and the content of MDA in serum and striatum were increased compared with the control group, while GA significantly restored the changes. GA significantly adjusted Nrf-2/HO-1/HMGB1/NF-кB pathway-related proteins changes consistent with immunohistochemical changes. GA may protect striatum of rats with TS by regulating Nrf-2/HO-1/HMGB1/NF-кB pathway protein changes in striatum.

Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study.

Tourette syndrome (TS) is a polygenic neuropsychiatric disease. Previous studies have indicated that dysregulation in the histaminergic system may play a crucial role in disease onset. In this study, we investigated the role of the histidine decarboxylase gene (HDC) in TS susceptibility in the Chinese Han population. After genotyping 241 TS nuclear families trios, we analyzed three tag HDC single nucleotide polymorphisms (rs854150, rs854151, and rs854157) in a family-based study using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT showed no over-transmission in these SNPs across the HDC region (for rs854150: χ2 = 0.472, P = 0.537, OR = 1.097, 95%CI = 0.738-1.630; for rs854151: χ2 = 0.043, P = 0.889, OR = 1.145, 95%CI = 0.767-1.709; for rs854157:χ2 = 0.984, P = 0.367, OR = 1.020, 95%CI = 0.508-2.049). HRR also showed the same tendency (for rs854150: χ2 = 0.211, P = 0.646, OR = 1.088, 95%CI = 0.759-1.559; for rs854151: χ2 = 0.134, P = 0.714, OR = 0.935, 95%CI = 0.653-1.339; for rs854157:χ2 = 0.841, P = 0.359, OR = 1.206, 95%CI = 0.808-1.799). Additionally, the haplotype-based haplotype relative risk showed a negative association. Although these findings indicate an unlikely association between HDC and TS in the Chinese Han population, a potential role for HDC cannot be ruled out in TS etiology. Future research should investigate this more thoroughly using different populations and larger samples.

Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Support of the histaminergic hypothesis in Tourette syndrome: association of the histamine decarboxylase gene in a large sample of families.

BACKGROUND: Gilles de la Tourette Syndrome is a neurodevelopmental disorder that is caused by the interaction of environment with a complex genetic background. The genetic etiology of the disorder remains, so far, elusive, although multiple promising leads have been recently reported. The recent implication of the histamine decarboxylase (HDC) gene, the key enzyme in histamine production, raises the intriguing hypothesis of a possible role of histaminergic dysfunction leading to TS onset. METHODS: Following up on the finding of a nonsense mutation in a single family with TS, we investigated variation across the HDC gene for association with TS. As a result of a collaborative international effort, we studied a large sample of 520 nuclear families originating from seven European populations (Greek, Hungarian, Italian, Polish, German, Albanian, Spanish) as well as a sample collected in Canada. RESULTS AND CONCLUSIONS: Interrogating 12 tagging SNPs (tSNP) across the HDC region, we find strong over-transmission of alleles at two SNPs (rs854150 and rs1894236) in the complete sample, as well as a statistically significant associated haplotypes. Analysis of individual populations also reveals signals of association in the Canadian, German and Italian samples. Our results provide strong support for the histaminergic hypothesis in TS etiology and point to a possible role of histamine pathways in neuronal development.

Association of poly(ADP-ribose) polymerase-1 polymorphism with Tourette syndrome.

Tourette syndrome (TS) is an etiologically heterogeneous disorder, the pathogenesis of which is incompletely understood. Poly(ADP-ribose) polymerase 1 (PARP1) is involved in regulation of developmental processes and cellular differentiation, in transcription regulation, in DNA repair, and in cell death. However, the relationship between TS and single nucleotide polymorphisms (SNPs) of PARP1 is unknown. Therefore, the aim of this experiment was to test the hypothesis that whether the PARP1 SNP, rs1805404 (c.243C>T, Asp81Asp), had an association with TS. A case-control experiment was designed to test this hypothesis. 123 TS children and 122 normal children were enrolled in this study. Polymerase chain reaction restriction fragment length polymorphism was used for the detection of the PARP1 SNP, rs1805404, in TS patients and normal children. The data showed that there is a significant difference in genotype distributions between these two groups. The CT genotype was a risk factor for TS with an odds ratio of 2.34 for the CT versus TT genotype (95% CI 1.16-4.74). The data also showed this SNP had an association with TS under recessive model (P = 0.0426), and TT genotype had a protective effect against TS with an odds ratio of 0.50 (95% CI 0.26-0.98). The findings of this study suggested that variants in the PARP1 gene might play a role in susceptibility to TS.

Mutation screening of the HDC gene in Chinese Han patients with Tourette syndrome.

Tourette Syndrome (TS) is a complex neuropsychiatric disorder characterized by vocal and motor tics. While environmental causes have been proposed to play a role, genetic factors are believed to be the main determinants of the disorder and its clinical manifestations. Recently, a heterozygous W317X mutation in the histidine decarboxylase gene (HDC) was reported to be responsible for TS in a two-generation pedigree. To investigate whether the HDC gene play a role in TS in Chinese Han population, we performed genetic analysis of the coding region of the HDC gene in 100 Chinese Han patients with TS. Three variants were found including a C > T transition (IVS1 + 52C > T), a novel C > A transition (c.426C > A) in exon 4, and a novel G > A transition (c.1743G > A) in exon 12, both predicted with no amino acid change. Extended analysis was conducted in a total of 120 TS patients and 240 sex, age, and ethnicity matched healthy controls. No significant differences in genotypic and allele distribution between patients and controls for these three variants (P = 0.274, P = 1.000 and P = 0.632 for genotypic distribution, respectively; P = 0.143, P = 1.000 and P = 0.582 for allele distribution, respectively) were observed, suggesting variants in the HDC gene may play little or no role in TS susceptibility in Chinese Han population.

Analysis of the dopamine beta hydroxylase gene in Gilles de la Tourette syndrome.

Numerous lines of evidence support the role of the catecholamines in the development of tics and Gilles de la Tourette syndrome (GTS). Dopamine-beta-hydroxylase (DBH) is the key enzyme in the conversion of dopamine to norepinephrine and the alleles of several polymorphisms of the DBH gene are correlated with individual variation in serum levels of the enzyme. We investigated the genetic relationship of the gene for DBH to GTS in two samples, one collected in Canada and one collected in Turkey. In total 106 affected probands and siblings in 71 nuclear pedigrees and 40 affected individuals and 71 family members in five multi-generational pedigrees were genotyped for three polymorphisms in the DBH locus. In the Canadian pedigrees we found no convincing evidence for linkage either in the multi-generational pedigrees or association in the nuclear families. We found significant evidence for association in the Turkish pedigrees (n = 29) for the 19 bp insertion/deletion markers; however, there was no supporting evidence for association with the other two markers. Based on the small sample size and low number of informative transmissions, we conclude that the results from the 19 bp insertion/deletion markers may be a chance false positive finding. These findings, in total, suggest that the DBH locus is unlikely to be a major gene influencing the susceptibility to DBH.

Atypical Gilles de la Tourette Syndrome with beta-mannosidase deficiency.

BACKGROUND: beta-Mannosidosis is a rare inborn error of metabolism with various phenotypes, including mental retardation, behavioral problems, hearing loss, and recurrent airway infections in childhood. To our knowledge, there is no published description of Gilles de la Tourette syndrome in association with this enzymatic deficiency. OBJECTIVE: To describe a unique case of Gilles de la Tourette syndrome associated with beta-mannosidosis. SETTING: University hospital. Patient An 18-year-old man exhibited motor and vocal tics since childhood, attention-deficit/hyperactivity disorder, impulsivity, and aggressiveness compatible with Gilles de la Tourette syndrome. A screen for inborn errors of metabolism was made because of the atypical association with slight mental retardation and bilateral perceptive hypoacousia. RESULTS: Urinary analysis showed disacchariduria, and leukocyte analysis revealed a profound deficit in beta-mannosidase activity. Two novel mutations in the beta-mannosidase gene were found: a new splice mutation in one allele, and a unique 10-base-pair insertion in the other. CONCLUSIONS: This case illustrates the phenotypic variability of inborn errors of metabolism in adults and demonstrates the need to screen inborn errors of metabolism in atypical Gilles de la Tourette syndrome.

Hypothalamic digoxin deficiency in obsessive compulsive disorder and la Tourette's syndrome.

The isoprenoid pathway related cascade was assessed in 15 patients with obsessive compulsive disorder (OCD) and la Tourette's syndrome (TS). The pathway was also assessed in right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals to assess whether hemispheric dominance has any correlation with these disease states. The levels of serum digoxin, HMG CoA reductase activity, and dolichol were found to be decreased in OCD and la Tourette's syndrome as well as in left hemispheric dominant individuals with a corresponding increase in RBC Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. There was an increase in tyrosine and its catabolites, and a reduction in tryptophan and its catabolites in the serum. The total and individual glycosaminoglycan (GAG) fractions, carbohydrate residues of glycoproteins, and the concentration of glycolipids decreased in the serum. The activity of GAG degrading enzymes and glycohydrolases were decreased. The RBC membrane glycoconjugates were increased while the membrane cholesterol:phospholipid ratio was decreased. The activity of free radical scavenging enzymes increased while the concentration of free radicals decreased significantly. On the other hand, there was hyperdigoxinemia and the reverse biochemical patterns in those with right hemispheric dominance. Membrane Na(+)-K+ ATPase stimulation can result in decreased intracellular Ca2+ and increased magnesium levels. Increased levels of dopamine can lead to a tic syndrome, while reduced levels of serotonin and increased dopamine can both lead to obsessive compulsive disorder. Decrease in fucose and sialo-ligands, increased immunosuppressive morphine levels, decreased T-cell calcineurin signal transduction related to decreased intracellular calcium, reduced free radical production, and altered presentation of bacterial glycoconjugate antigens can lead to a hypoimmune response and recurrent respiratory infection in OCD patients. OCD and la Tourette's syndrome are associated with left hemispheric chemical dominance.

Association between the low molecular weight cytosolic acid phosphatase gene ACP1*A and comorbid features of Tourette syndrome.

Protein tyrosine phosphatases have been implicated in the regulation of serotonergic and dopaminergic activity in the central nervous system. In a recent study we found that nonA/nonA homozygosity at the locus codifying for the low molecular weight protein tyrosine phosphatase (ACP1) was associated with increased rates of major depression in males (P<0.00003), suggesting that the ACP1*A single nucleotide polymorphism (SNP) may be an important marker for psychopathology. In the present study we examined the ACP1*A SNP in 539 screened controls and 184 male Tourette syndrome (TS) cases, all Caucasians of European descent. The frequency of the nonA allele was markedly increased in TS cases relative to controls (P<0.0005), but this difference was restricted to cases with comorbid attention-deficit hyperactivity disorder (P<0.0001) and conduct disorder (P<0.0002), while having little relevance to TS itself.

Postprandial changes in superoxide dismutase activity in subjects with Gilles de la Tourette syndrome and controls.

Erythrocyte measures of copper-zinc superoxide dismutase (CuZnSOD) were performed on 11 subjects with a clinical diagnosis of Gilles de la Tourette syndrome (GTS) and 6 healthy controls at specified intervals throughout the day. There were no significant differences between GTS subjects and controls but in both subjects and controls there was a significant increase in SOD, 75 min postprandially, which decreased to baseline 135 min postprandially. This has implications for the timing of biological samples in future studies of SOD. Possible reasons for the increase are discussed.

Exon and intron variants in the human tryptophan 2,3-dioxygenase gene: potential association with Tourette syndrome, substance abuse and other disorders.

Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Functional variants of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies show a significant association of one or more of these polymorphisms and Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G-->T variant was significantly associated with platelet serotonin levels. Only the association with TS was significant with a Bonferroni correction (p = 0.005). Our purpose here is not to claim these associations are proven, but rather to report preliminary results and show that easily testable polymorphisms are available. We hope to encourage additional research into the potential role the TDO2 gene in these and other psychiatric disorders.

Erythromycin interaction with risperidone or clomipramine in an adolescent.

An adverse event is described which appeared when the macrolide antibiotic erythromycin was added to a regimen of risperidone 0.5 mg bid and clomipramine 50 mg tid in a 15-year-old male being treated for Tourette's, obsessive-compulsive, and attention-deficit hyperactivity disorders. An acute onset of behavioral symptoms, including agitation, labile mood, incessant talking, and argumentativeness, began within 24 h of starting the erythromycin and persisted for 9 days after its discontinuation. It was followed by a return to stable functioning on the prior risperidone-clomipramine regimen. Erythromycin, risperidone, and clomipramine are all metabolized by the hepatic cytochrome P450 system. It is postulated that the addition of erythromycin, a known inhibitor of CYP3A and CYP1A2, resulted in alterations in the metabolism of clomipramine and risperidone. Clomipramine metabolism is dependent upon the isoenzymes CYP2D6 and CYP1A2, and risperidone is a substrate for CYP2D6. Erythromycin would inhibit demethylation of clomipramine at the 1A2 isoenzyme and lead to a dual interaction between risperidone and clomipramine at the CYP2D6 isoenzyme. The subsequent increases in plasma levels of clomipramine, risperidone, their metabolites, or a combination of these agents could explain the adverse effects noted in this patient. In the absence of risperidone, clomipramine could have been metabolically cleared by CYP2D6. In the absence of clomipramine, risperidone clearance would not be affected by erythromycin. So the proposed mechanism requires an interaction involving all three agents: erythromycin, clomipramine, and risperidone. Alterations in plasma protein binding may also have played a role, because all three agents are extensively protein bound. Caution is urged when prescribing erythromycin with psychotropic drugs that are highly protein bound and/or are metabolized by the same P450 isoenzymes.

Linkage to Tourette syndrome is excluded for red-cell acid phosphatase (ACP1) and flanking markers on chromosome 2pter-2p23.

A recent linkage study of Tourette syndrome with markers in the distal region of chromosome 2p gave a contradictory result with red-cell acid phosphatase (ACP1) compared to the nearby anonymous DNA markers. A modifier gene that is suspected of leading to reduced penetrance of the gene that causes the degenerative neurologic disorder Joseph disease has been hypothesized to lie on chromosome 2p25 near the ACP1 locus. Because Tourette syndrome (TS) has also been shown to have reduced sex-specific penetrance, ACP1 typings were performed on 12 families segregating TS, and pair-wise linkage analysis was carried out. Linkage was excluded for nearly 15 cM on either side of the ACP1 locus. Unpublished exclusion data from several laboratories permit exclusion of a linkage group extending from 2pter to 2p23. Furthermore, no support for the presence of any type of modifier of TS gene expression could be seen in these data.

CSF cholinesterase activity in Gilles de la Tourette's syndrome.

Cerebrospinal fluid acetylcholinesterase (AChE) activity was studied as a possible marker for central cholinergic neuronal function in seven patients with Gilles de la Tourette's syndrome. No significant differences were found between CSF AChE activity in untreated or haloperidol-treated patients and control populations. These data do not appear to support a pathophysiologic association between the cholinergic system and Gilles de la Tourette's syndrome.

Enzyme activity in Tourette's syndrome.

Activity levels of platelet monoamine oxidase (MAO), plasma amine oxidase (PAO), erythrocyte catechol-o-methyltransferase, and dopamine-beta-hydroxylase were measured in 24 drug-free patients with Tourette's syndrome (TS) and in 24 normal control subjects matched for age and sex. Only MAO and PAO activity levels were significantly higher in patients than in controls. Activity of the four enzymes was uncorrelated with age, sex, age of onset of illness, severity of illness, family history of tics and Ts, and ethnic-religious background. The hypothesis that probands with heavily loaded pedigrees or with Ashkenazi ethnic-religious background would be more biochemically deviant was not supported.

Monoamine oxidase and catechol-O-methyltransferase activities in cultured fibroblasts and blood cells from children with autism and the Gilles de la Tourette syndrome.

Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) activities were measured in cells from children with autism (n = 5) and the Gilles de la Tourette syndrome (n = 5). Monoamine oxidase activities in cultured skin fibroblasts (type A) and platelets (type B) from the same individual were not correlated. COMT activities in fibroblasts and red blood cells showed a negative but not significant correlation (r = -0.42). Fibroblast MAO and COMT activities from patients were similar to values from controls matched for age, race, and sex. Increasing clinical severity of illness in both disorders, however, correlated significantly with higher fibroblast MAE activity. Cultured fibroblasts provide a means of measuring enzyme activities independently of the individual's current physiological and psychological state.

Serum dopamine-beta-hydroxylase activity: clinical applications in child psychiatry.

Serum dopamine-beta-hydroxylase (DBH) activity was measured in 44 children with psychiatric disorders and 44 controls in order to determine significant variables affecting its potential use as a marker for specific molecular pathology in the neuropsychiatric disorders of childhood. The assay procedure was reliable and the serum enzyme activity for individuals appears to be stable. There is a very broad distribution of serum DBH activity in the population, and it is similar in males and females. The genetic determination of serum DBH activity was clear in this study, and the enzyme activity increased with age through childhood and adolescence. Thyroid hormone had no effect on serum DBH activity in euthyroid subjects. No difference in mean serum DBH activity emerged across diagnostic groups. When the findings were considered in relation to the results of other studies, it was concluded that the wide range of serum DBH activities in normal and patient populations, as well as developmental effects on the activity of the enzyme, make comparison of DBH activity among diagnostic groups in childhood difficult. Large subject groups, and a consideration of genetic and developmental effects, will clarify possible syndrome-related differences in enzyme activity.

Hypoxanthine guanine phosphoribosyltransferase (HGPRT) in Gilles de la Tourette syndrome.

Hypoxanthine guanine phosphoribosyltransferase (HGPRT) and adenosine phosphoribosyltransferase (APRT) were examined from 11 individuals with Gilles de la Tourette syndrome, 10 of their first- or second-degree relatives, and 3 normal controls. It has been suggested that in some self-mutilating Tourette patients, HGPRT shows a time-related loss of activity at 4 degrees C, and an unusual isoelectrofocusing pattern. Although 3 patients experienced self-mutilation, no consistent abnormalities were found in the temperature-stability of their HGPRT at 4 degrees C and 70 degrees C, or in isoelectrofocusing of HGPRT purified by immunoprecipitation. An alteration of the purine metabolic pathway in Tourette syndrome has not been established.