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Summary: Recent studies have provided much needed data on the probability of seizure remission among adults with chronic intractable epilepsy treated medically. Here we provide an extended follow-up to our earlier study in order to provide a more comprehensive picture of long-term prognosis in this patient population during medical treatment. The prevalence cohort was followed for two outcomes—complete seizure remission for ≥12 months and subsequent seizure relapse among those attaining a seizure remission. The study outcomes were estimated using Kaplan–Meier analysis. We found that the probability of attaining a ≥12 months of complete seizure freedom to be approximately 3–4% per year through 8 years of follow-up. By year 5 since the start of seizure remission, the cumulative probability of seizure relapse was 81%, although only half of the patients with seizure relapse went on to experience their previous seizure frequency. [ABSTRACT FROM AUTHOR]

Depression is the most common comorbid condition in epilepsy. The cause of this comorbidity is unknown, and could involve psychosocial consequences of epilepsy, treatment side effects, seizure manifestations, or common neurobiologic mechanisms. One hypothesis of particular interest is a shared genetic susceptibility to epilepsy and depression. We tested this hypothesis by studying depressive symptoms in families with an identified genetic form of epilepsy: autosomal dominant partial epilepsy with auditory features caused by mutations in the leucine-rich, glioma inactivated 1 gene ( LGI1). A standardized depression screen was administered to 94 individuals from 11 families with mutations in LGI1, including 38 mutation carriers with epilepsy (AC), 11 clinically unaffected mutation carriers (UC), and 45 noncarriers (NC). Current depressive symptom scores were significantly higher in AC than in NC, an association that remained after excluding depressive symptoms that appeared likely to be caused by antiepileptic medication use. However, scores did not differ between UC and NC. Although LGI1 mutation carriers who were clinically affected with epilepsy had increased depressive symptoms, mutation carriers without epilepsy did not. These findings suggest that the increase in depressive symptoms in affected individuals from these families is related to epilepsy or its treatment rather than to LGI1 mutations per se. [ABSTRACT FROM AUTHOR]

To investigate the cumulative probabilities of ≥12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management. A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan–Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and ≥12 month seizure remission and (2) between clinical factors and seizure relapse following remission. One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving ≥12 month seizure remission or subsequent seizure relapse. Some people with intractable epilepsy achieve ≥12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission. [ABSTRACT FROM AUTHOR]

Abstract: Some twin studies suggest that substance initiation and dependence are part of a complex, two-stage process and that some genetic influences are stage-specific, acting on either the transition from abstinence to initiation, or on the transition from use to dependence. However, questions remain about the two-stage model, especially for illicit drugs. Using a familial aggregation design, we tested the hypothesized two-stage model of dependence on illicit substances and alcohol in a large, nationally representative sample. Family history of drug or alcohol problems is significantly associated with initiation that does not progress to dependence (i.e., conditional initiation). Furthermore, family history of drug or alcohol problems is significantly associated with dependence even after conditioning on factors influencing initiation (i.e., conditional dependence). These results suggest that substance initiation and dependence involve at least partially distinct familial factors. The possibility that different genetic factors affect initiation and dependence has important implications for control group selection in case–control genetic association studies, and may explain some inconsistent results for drug dependence. If some genetic factors are stage-specific (i.e., not common across initiation and dependence), inclusion of abstainers in the control group may mix the genetic effects for initiation with those for transition to dependence, providing unclear results. Depending on the specific question about the nature of the genetic effect (whether on initiation, on dependence, or both), investigators designing case–control genetic association studies should carefully consider inclusion and exclusion criteria of the control group. [Copyright &y& Elsevier]

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. [ABSTRACT FROM AUTHOR]

The following paper examines the application of the principles of operant conditioning to the prediction of individual behavior in an organizational setting. The review centers about the extended operant conditioning model of Jablonsky and DeVries (Organizational Behavior and Human Performance, 1972, 7, 340-358). Conceptual errors, such as in an incorrect application of negative reinforcement and an incomplete operant conditioning framework are discussed. Several suggestions for future models are given. Examines the application of the principles of operant conditioning to the prediction of individual behavior in an organizational setting. Review centering on the extended operant conditioning model of Jablonsky and DeVries; Discussion of conceptual errors. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette Syndrome (TS) is a common, albeit still under-diagnosed, neuropsychiatric disorder that is caused by a complex genetic basis, interacting with environmental factors. This symposium will showcase exciting findings from all current large-scale collaborative efforts aiming to elucidate the genetic background of TS, through diverse approaches and studies of several thousands of individuals with TS; genome-wide association studies (GWAS) aiming to identify common variants associated to the disorder, whole-exome sequencing approaches seeking rare variants, gene-expression studies aiming to identify the relative contribution of genetics versus environmental factors, and sophisticated approaches aiming to dissect complex and comorbid phenotypes. We will present novel TS susceptibility genes implicated on a genome-wide significance level either by GWAS, large-scale CNV scans or whole-exome sequencing and introduce heritable TS sub-phenotypes. We will also present large-scale GWAS meta-analysis of TS together with other, often comorbid neurodevelopmental disorders, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and autism. Finally, after more than two decades of active research aiming to identify the genetic background of TS etiology, we are on the verge of a new era, yielding exciting and rapid discoveries in the field of TS genetics. Investigators from around the world, representing multiple disciplines and scientific approaches, are joining their efforts in large-scale initiatives supported both by the European Union and US National funding agencies. Propelled by the gradual availability of large scale TS cohorts, novel methodologies for the study of both common and rare genetic variants, and importantly, sheer enthusiasm by multiple researchers working together across different countries, the new era of TS genetics holds the promise to identify novel targets for improved therapies. [ABSTRACT FROM AUTHOR]

Summary: Objective: Mood disorders are the most common comorbid conditions in epilepsy, but the cause remains unclear. One possible explanation is a shared genetic susceptibility to epilepsy and mood disorders. We tested this hypothesis by evaluating lifetime prevalence of mood disorders in relatives with and without epilepsy in families containing multiple individuals with epilepsy, and comparing the findings with rates from a general population sample. Methods: The Composite International Diagnostic Interview was administered to 192 individuals from 60 families, including 110 participants with epilepsy of unknown cause (50 focal epilepsy [FE], 42 generalized epilepsy [GE], 6 FE and GE, 12 unclassifiable) and 82 relatives without epilepsy (RWOE). Odds ratios (ORs) for lifetime prevalence of mood disorders in participants with versus without epilepsy were computed through logistic regression, using generalized estimation equations to account for familial clustering. Standardized prevalence ratios (SPRs) were used to compare prevalence in family members with general population rates. Results: Compared with RWOE, ORs for mood disorders were significantly increased in participants with FE (OR = 2.4, 95% confidence interval [CI] = 1.1‐5.2) but not in those with GE (OR = 1.0, 95% CI = 0.4‐2.2). In addition, prevalence of mood disorders was increased in individuals with epilepsy who had ≥1 relative with FE. Compared with general population rates, mood disorders were significantly increased in individuals with FE but not in those with GE. Rates were also increased in RWOE, but not significantly so (SPR = 1.4, P = .14). Significance: These findings are consistent with the hypothesis of shared genetic susceptibility to epilepsy and mood disorders, but suggest (1) the effect may be restricted to FE, and (2) the shared genetic effect on risk of mood disorders and epilepsy may be restricted to individuals with epilepsy, that is, to those in whom the genetic risk for epilepsy is “penetrant.” [ABSTRACT FROM AUTHOR]

Objective: We sought to determine which combination of clinical and electroencephalography (EEG) characteristics differentiate between an antiseizure medication (ASM)–resistant vs ASM‐responsive outcome for patients with idiopathic generalized epilepsy (IGE). Methods: This was a case‐control study of ASM‐resistant cases and ASM‐responsive controls with IGE treated at five epilepsy centers in the United States and Australia between 2002 and 2018. We recorded clinical characteristics and findings from the first available EEG study for each patient. We then compared characteristics of cases vs controls using multivariable logistic regression to develop a predictive model of ASM‐resistant IGE. Results: We identified 118 ASM‐resistant cases and 114 ASM‐responsive controls with IGE. First, we confirmed our recent finding that catamenial epilepsy is associated with ASM‐resistant IGE (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.32–10.41, for all study subjects) after covariate adjustment. Other independent factors seen with ASM resistance include certain seizure‐type combinations (absence, myoclonic, and generalized tonic‐clonic seizures [OR 7.06, 95% CI 2.55–20.96]; absence and generalized tonic‐clonic seizures [OR 4.45, 95% CI 1.84–11.34]), as well as EEG markers of increased generalized spike‐wave discharges (GSWs) in sleep (OR 3.43, 95% CI 1.12–11.36 for frequent and OR 7.21, 95% CI 1.50–54.07 for abundant discharges in sleep) and the presence of generalized polyspike trains (GPTs; OR 5.49, 95% CI 1.27–38.69). The discriminative ability of our final multivariable model, as measured by area under the receiver‐operating characteristic curve, was 0.80. Significance: Multiple clinical and EEG characteristics independently predict ASM resistance in IGE. To improve understanding of a patient's prognosis, clinicians could consider asking about specific seizure‐type combinations and track whether they experience catamenial epilepsy. Obtaining prolonged EEG studies to record the burden of GSWs in sleep and assessing for the presence of GPTs may provide additional predictive value. [ABSTRACT FROM AUTHOR]

The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson's disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age- and sex-matched Ashkenazi Jewish patients with Parkinson's disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6-fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV. Of interest, we identified 2 leucine-rich repeat kinase carriers with bipolar disorder; no mutation-negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test-Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine-rich repeat kinase Parkinson's disease, warranting further evaluation. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Summary: We examined whether duration of epilepsy prior to temporal lobe resection has decreased over the years as a result of increasing body of evidence in the literature showing the benefits of anterior temporal resection. We stratified the 213 patients, who had their first temporal lobe resection at our center between 1996 and 2007 into three groups in order to detect any trends in duration of epilepsy: group A (surgery between 1996 and 1999); group B (surgery between 2000 and 2003); group C (surgery between 2004 and 2007). No difference in mean duration of epilepsy was detected between the three groups (p =0.54). The mean duration in epilepsy prior to temporal lobe resection has persisted at greater than 20 years during the past two decades. [Copyright &y& Elsevier]

Background: A well-characterized single nucleotide polymorphism (472G/A-Val/Met-SNP8) in the coding sequence of the catechol-O-methyltransferase (COMT) gene leads to a three- to fourfold difference in enzymatic activity and clinical and animal studies suggest a role in anxiety states like panic disorder.Methods: Subjects from 70 panic disorder pedigrees, and 83 “triads”, were genotyped at seven single nucleotide polymorphisms (SNPs), polymorphic microsatellites in the first intron of COMT and ∼339kb upstream of COMT (D22S944) and analyzed for genetic association and linkage.Results: Linkage analysis showed elevated LOD scores for 472G/A (SNP 8), silent exon 3 substitution (186C/T-SNP 5), and the marker D22S944 (2.88, 2.62, and 2.93, respectively), using a variety of diagnostic and genetic models. Association tests were not significant for the SNPs, but were highly significant for D22S944 (p = .0001–.0003). One three-marker haplotype formed from the above three polymorphisms was significantly associated with panic disorder (p = .0001), as was the “global” p value for this combination (p = .005). In addition, numerous haplotypes with combinations of D22S944 and COMT SNPs were found to be significantly associated with panic disorder.Conclusions: Our findings provide strong evidence for a susceptibility locus for panic disorder either within the COMT gene or in a nearby region of chromosome 22. [ABSTRACT FROM AUTHOR]

Abstract Background Tourette syndrome (TS) has a well-established genetic background, but its genetic architecture remains largely unknown. The authors investigated the role of polygenic risk scores (PRSs) derived from a TS genome-wide association study in relation to the occurrence of tics and associated traits in a general population cohort. Methods Using the most recent TS genome-wide association study (n = 4819 cases; n = 9488 controls) as the discovery sample, PRSs were calculated in Avon Longitudinal Study of Parents and Children participants (n = 8941). Regression analyses were used to assess whether PRS predicted the presence and chronicity of tics, and symptom severity of obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and autism spectrum disorder in Avon Longitudinal Study of Parents and Children participants. Results Following correction for multiple testing, the PRS significantly predicted the presence (R 2 =.48%, p empirical =.01, Q =.04) but not the chronicity (R 2 =.16%, p empirical =.07 , Q =.14) of tics in the Avon Longitudinal Study of Parents and Children cohort; it did not predict the severity of obsessive-compulsive disorder (R 2 =.11%, p empirical =.11, Q =.15), attention-deficit/hyperactivity disorder (R 2 =.09%, p empirical =.19, Q =.21), or autism spectrum disorder (R 2 =.12%, p empirical =.09, Q =.14). Conclusions The authors found a significant polygenic component of tics occurring in a general population cohort based on PRS derived from a genome-wide association study of individuals with a TS diagnosis. This finding supports the notion that tics along a spectrum from nonclinical to clinical symptom levels share a similar genetic background. [ABSTRACT FROM AUTHOR]

Objective: To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. Methods: Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. Results: Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00-14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88-5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53-9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69-81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. Significance: Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period. [ABSTRACT FROM AUTHOR]

Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene ( GDNF) was significant in the discovery cohort after correction ( P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort ( P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS. [ABSTRACT FROM AUTHOR]

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT-linked polymorphic region 5-HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine-to-valine at position 425 (I425V). The higher expressing 5-HTTLPR/rs25531 LA allele was more prevalent in TD probands than in controls (χ2 = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls ( P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group ( P = 0.0013; OR, 2.14). Furthermore, the rare gain-of-function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family-adjusted significance of χ2 = 15.03 ( P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. Methods: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. Results: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10−4 − 1.6 × 10−2), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. Conclusions: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Abstract: Patients with epilepsy are frequently confronted with complex treatment decisions. Communicating treatment risks is often difficult because patients may have difficulty with basic statistical concepts (i.e., low numeracy) or might misconceive the statistical information based on the way information is presented, a phenomenon known as “framing bias.” We assessed numeracy and framing bias in 95 adults with chronic epilepsy and explored cognitive correlates of framing bias. Compared with normal controls, patients with epilepsy had significantly poorer performance on the Numeracy scale (P =0.02), despite a higher level of education than normal controls (P <0.001). Compared with patients with higher numeracy, patients with lower numeracy were significantly more likely to exhibit framing bias. Abstract problem solving performance correlated with the degree of framing bias (r =0.631, P <0.0001), suggesting a relationship between aspects of executive functioning and framing bias. Poor numeracy and susceptibility framing bias place patients with epilepsy at risk for uninformed decisions. [ABSTRACT FROM AUTHOR]

Tourette'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 L-histidine 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. [ABSTRACT FROM AUTHOR]

FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in β toxicity. Towards this goal, we generated β transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of β and increased lifespan in β flies, whereas loss of function of FKBP52 exacerbated these β phenotypes. Interestingly, the β pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/-) cells have increased intracellular copper and higher levels of β. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of β peptides. [ABSTRACT FROM AUTHOR]

Summary: Background: Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish–Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. Methods: We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype–phenotype differences were also assessed. Findings: Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish–Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype–phenotype differences were not found. Interpretation: Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. Funding: Dystonia Medical Research Foundation; Bachmann–Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation. [Copyright &y& Elsevier]

Myoclonus-dystonia (M-D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys ( P < 0.0097). We found no association between mutation type and phenotype. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Panic disorder (PD) is a common illness with a definite but “complex” genetic contribution and estimated heritability of 30–46%. Methods: We report a genome scan in 120 multiplex PD pedigrees consisting of 1591 individuals of whom 992 were genotyped with 371 markers at an average spacing of 9cM. Parametric two-point, multipoint, and nonparametric analyses were performed using three PD models (Broad, Intermediate, Narrow) and allowing for homogeneity or heterogeneity. The two-point analyses were also performed allowing for independent male and female recombination fractions (θ). Genome-wide significance was empirically evaluated using simulations of this dataset. Results: Evidence for linkage reached genome-wide significance in one region on chromosome 15q (near GABA-A receptor subunit genes) and was suggestive at loci on 2p, 2q and 9p using an averaged θ. Analyses allowing for sex-specific θ’s were consistent except that support at one locus on 2q increased to genome-wide significance and an additional region of suggestive linkage on 12q was identified. However, differences in male and female recombination fractions predicted by the sex-specific approach were not consistent with current physical maps. Conclusions: These data provide evidence for chromosomal regions on 15q and 2q that may be important in genetic susceptibility to panic disorder. Although we are encouraged by the findings of analyses using sex-specific recombination fractions, we also note that further understanding of this analytic strategy will be important. [Copyright &y& Elsevier]

Highlights from the article: Su67polygenic risk scores derived from a tourette syndrome gwas predict presence of tics in the avon longitudinal study of parents and children (alspac) cohort The authors investigated the role of polygenic risk scores (PRS) derived from a TS genome-wide association study (GWAS) in relation to the occurrence of tics and associated traits in a general population cohort. B Discussion: b The authors found a significant polygenic component of tics occurring in a general population cohort based on PRS derived from a GWAS of individuals with a TS diagnosis.

Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (θ=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p = 0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder. [ABSTRACT FROM AUTHOR]

Substantial evidence supports that there is a genetic component to panic disorder (PD). Until recently, attempts at localizing genes for PD by using standard phenotypic data have not proven successful. Previous work suggests that a potential subtype of PD called the panic syndrome exists, and it is characterized by a number of medical conditions, most notably bladder/renal disorders. In the current study, a genome scan with 384 microsatellite markers was performed on 587 individuals in 60 multiplex pedigrees segregating PD and bladder/kidney conditions. Using both single-locus and multipoint analytic methods, we found significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds score = 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds score = 3.57 at D13S793) under a dominantgenetic model and a broad phenotypic definition. Multipoint analyses did not support the observation on chromosome 22. The chromosome 13 findings were corroborated by multipoint findings, and extend our previous findings from 19 of the 60 families. Several other regions showed elevated scores by using when one analytic method was used, but not the other. These results suggest that there are genes on chromosome 13q, and possibly on chromosome 22 as well, that influence the susceptibility toward a pleiotropic syndrome that includes PD, bladder problems, severe headaches, mitral valve prolapse, and thyroid conditions. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications" is presented.

Based on the contribution of de novo coding variants to other neurodevelopmental disorders, and their utility for hypothesis-naive gene discovery, we whole-exome sequenced 325 Tourette syndrome trios (311 passed quality control) from the TIC Genetics consortium, and identified de novo sequence variants. We observed a strong association for de novo likely gene disrupting (LGD; insertion of premature stop codon, disruption of canonical splice site, or frameshift insertion/deletion) variants as well as de novo damaging variants (LGD + probably damaging missense [Mis3]) variants. We replicated these findings in 186 TS trios (173 after quality control) from the TSAICG Consortium, and performed a combined analysis strongly associating de novo LGD (RR 2.32, 95% CI 1.37-3.93, p = 0.002) and damaging (RR 1.37, 95% CI 1.11-1.69, p = 0.003) variants with TS risk. We estimate that de novo damaging variants in approximately 12% of patients contribute risk through the perturbation of approximately 400 risk genes. Finally, we leveraged recurrent de novo damaging variants and the TADA algorithm to identify one high confidence (false discovery rate (FDR) < 0.10) TS risk gene: WWC1 (WW and C2 Domain Containing 1); and three probable (FDR < 0.30) TS risk genes: CELSR3 (Cadherin EGF LAG Seven-Pass G-Type Receptor 3); NIPBL (Nipped-B-Like); and FN1 (Fibronectin 1). These findings establish the contribution of de novo variants to TS risk and highlight that de novo based gene discovery is a viable path forward for this disorder. [ABSTRACT FROM AUTHOR]

Summary Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. Video Abstract [ABSTRACT FROM AUTHOR]