ABSTRACT
Involuntary moaning has been reported in sporadic cases of neurodegenerative diseases. A five-generation Hispanic family with eight members exhibiting involuntary moaning, most of whom with isolated moaning in the absence of any additional neurological disorder carried a missense variant in the NEFH gene segregating in the family.
Subject(s)
Heredodegenerative Disorders, Nervous System/genetics , Neurofilament Proteins/genetics , Adult , Child , Female , Heredodegenerative Disorders, Nervous System/physiopathology , Heterozygote , Hispanic or Latino , Humans , Male , Mutation, Missense , Pedigree , Phonetics , Tics/geneticsSubject(s)
Pantothenate Kinase-Associated Neurodegeneration/diagnosis , Tics/diagnosis , Adolescent , Brain/diagnostic imaging , Diagnosis, Differential , Humans , Male , Pantothenate Kinase-Associated Neurodegeneration/drug therapy , Pantothenate Kinase-Associated Neurodegeneration/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Tics/drug therapy , Tics/genetics , Tourette Syndrome/diagnosisABSTRACT
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
Subject(s)
Laminin/genetics , Myasthenic Syndromes, Congenital/genetics , Neuromuscular Junction Diseases/genetics , Adult , Face/diagnostic imaging , Face/physiopathology , Female , Homozygote , Humans , Myasthenic Syndromes, Congenital/complications , Myasthenic Syndromes, Congenital/diagnostic imaging , Myasthenic Syndromes, Congenital/physiopathology , Myopia/complications , Myopia/diagnostic imaging , Myopia/genetics , Myopia/physiopathology , Neuromuscular Junction Diseases/complications , Neuromuscular Junction Diseases/diagnostic imaging , Neuromuscular Junction Diseases/physiopathology , Tics/complications , Tics/diagnostic imaging , Tics/genetics , Tics/physiopathology , Young AdultABSTRACT
Several lines of evidence support a "dopaminergic hypothesis" in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18-71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways.
Subject(s)
DNA Methylation , Receptors, Dopamine D2/genetics , Tourette Syndrome/genetics , Adolescent , Adult , Aged , Catechol O-Methyltransferase/genetics , Catechol O-Methyltransferase/metabolism , Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Epigenesis, Genetic , Female , Humans , Male , Middle Aged , Receptors, Dopamine D2/metabolism , Severity of Illness Index , Tics/genetics , Tics/metabolism , Tourette Syndrome/metabolism , Young AdultABSTRACT
BACKGROUND: Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison. CASE PRESENTATION: In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. CONCLUSIONS: ANO3 encodes anoctamin-3, a Ca+2-dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.
Subject(s)
Blepharospasm/genetics , Chloride Channels/genetics , Dysarthria/genetics , Dystonia/genetics , Hyperkinesis/genetics , Tics/genetics , Abdomen/diagnostic imaging , Amino Acid Sequence , Anoctamins , Blepharospasm/complications , Blepharospasm/pathology , Dysarthria/complications , Dysarthria/pathology , Dystonia/complications , Dystonia/pathology , Electrophysiology , Exons , Female , Heterozygote , Humans , Hyperkinesis/complications , Hyperkinesis/pathology , Middle Aged , Molecular Sequence Data , Mutation, Missense , Pedigree , Polymorphism, Genetic , Sequence Alignment , Tics/complications , Tics/pathologyABSTRACT
OBJECTIVE: To identify heritable symptom-based subtypes of Tourette syndrome (TS). METHODS: Forty-nine motor and phonic tics were examined in 3,494 individuals (1,191 TS probands and 2,303 first-degree relatives). Item-level exploratory factor and latent class analyses (LCA) were used to identify tic-based subtypes. Heritabilities of the subtypes were estimated, and associations with clinical characteristics were examined. RESULTS: A 6-factor exploratory factor analysis model provided the best fit, which paralleled the somatotopic representation of the basal ganglia, distinguished simple from complex tics, and separated out socially disinhibited and compulsive tics. The 5-class LCA model best distinguished among the following groups: unaffected, simple tics, intermediate tics without social disinhibition, intermediate with social disinhibition, and high rates of all tic types. Across models, a phenotype characterized by high rates of social disinhibition emerged. This phenotype was associated with increased odds of comorbid psychiatric disorders, in particular, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder, earlier age at TS onset, and increased tic severity. The heritability estimate for this phenotype based on the LCA was 0.53 (SE 0.08, p 1.7 × 10(-18)). CONCLUSIONS: Expanding on previous modeling approaches, a series of TS-related phenotypes, including one characterized by high rates of social disinhibition, were identified. These phenotypes were highly heritable and may reflect underlying biological networks more accurately than traditional diagnoses, thus potentially aiding future genetic, imaging, and treatment studies.
Subject(s)
Inhibition, Psychological , Social Behavior , Tics/genetics , Tourette Syndrome/genetics , Adolescent , Adult , Age of Onset , Attention Deficit Disorder with Hyperactivity/epidemiology , Canada/epidemiology , Comorbidity , Factor Analysis, Statistical , Female , Humans , Male , Netherlands/epidemiology , Obsessive-Compulsive Disorder/epidemiology , Phenotype , Tics/diagnosis , Tics/epidemiology , Tourette Syndrome/diagnosis , Tourette Syndrome/epidemiology , United Kingdom/epidemiology , United States/epidemiology , Young AdultABSTRACT
Chronic tic disorders (TD), attention-deficit/hyperactivity-disorder (ADHD), and obsessive-compulsive disorder (OCD) frequently co-occur in clinical and epidemiological samples. Family studies have found evidence of shared familial transmission between TD and OCD, whereas the familial association between these disorders and ADHD is less clear. This study aimed to investigate to what extent liability of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms is caused by shared or distinct genetic or environmental influences, in a large population-representative sample of Swedish adult twins (n = 21,911). Tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms showed modest, but significant covariation. Model fitting suggested a latent liability factor underlying the three phenotypes. This common factor was relatively heritable, and explained significantly less of the variance of attention-deficit/hyperactivity symptom liability. The majority of genetic variance was specific rather than shared. The greatest proportion of total variance in liability of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms was attributed to specific non-shared environmental influences. Our findings suggest that the co-occurrence of tics and obsessive-compulsive symptoms, and to a lesser extent attention-deficit/hyperactivity symptoms, can be partly explained by shared etiological influences. However, these phenotypes do not appear to be alternative expressions of the same underlying genetic liability. Further research examining sub-dimensions of these phenotypes may serve to further clarify the association between these disorders and identify more genetically homogenous symptom subtypes. © 2016 Wiley Periodicals, Inc.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Obsessive-Compulsive Disorder/genetics , Tic Disorders/genetics , Adult , Attention Deficit Disorder with Hyperactivity/etiology , Comorbidity , Female , Genetic Variation/genetics , Humans , Male , Middle Aged , Obsessive-Compulsive Disorder/etiology , Obsessive-Compulsive Disorder/psychology , Sweden , Tic Disorders/etiology , Tic Disorders/psychology , Tics/etiology , Tics/genetics , TwinsABSTRACT
OBJECTIVES: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. RESULTS: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). CONCLUSIONS: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Methylphenidate/adverse effects , Methylphenidate/therapeutic use , Nail Biting , Serotonin Plasma Membrane Transport Proteins/genetics , Tics/chemically induced , Tics/genetics , Adolescent , Alleles , Attention Deficit Disorder with Hyperactivity/complications , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/therapeutic use , Child , Female , Genotype , Humans , Male , Polymorphism, Genetic/genetics , Republic of Korea , Tics/complications , Treatment OutcomeABSTRACT
INTRODUCTION: Gilles de la Tourette's syndrome (TS) is both genotypically and phenotypically heterogeneous. Gene-finding strategies have had limited success, possibly because of symptom heterogeneity. OBJECTIVE: This study aimed at specifically investigating heritabilities of tic symptom factors in a relatively large sample of TS patients and family members. PARTICIPANTS AND METHODS: Lifetime tic symptom data were collected in 494 diagnosed individuals in two cohorts of TS patients from the USA (n=273) and the Netherlands (n=221), and in 351 Dutch family members. Item-level factor analysis, using a tetrachoric correlation matrix in SAS (v9.2), was carried out on 23 tic symptoms from the Yale Global Tic Severity Scale. RESULTS: Three factors were identified explaining 49% of the total variance: factor 1, complex vocal tics and obscene behaviour; factor 2, body tics; and factor 3, head/neck tics. Using Sequential Oligogenic Linkage Analysis Routine, moderate heritabilities were found for factor 1 (h2r=0.21) and factor 3 (h2r=0.25). Lower heritability was found for overall tic severity (h2r=0.19). Bivariate analyses indicated no genetic associations between tic factors. CONCLUSION: These findings suggest that (i) three tic factors can be discerned with a distinct underlying genetic architecture and that (ii) considering the low tic heritabilities found, only focusing on the narrow-sense TS phenotype and leaving out comorbidities that are part of the broader sense tic phenotype may lead to missing heritability. Although these findings need replication in larger independent samples, they might have consequences for future genetic studies in TS.
Subject(s)
Tics/genetics , Tourette Syndrome/genetics , Adolescent , Adult , Costa Rica , Female , Humans , Male , Middle Aged , Netherlands , Obsessive-Compulsive Disorder/diagnosis , Obsessive-Compulsive Disorder/genetics , Obsessive-Compulsive Disorder/physiopathology , Psychiatric Status Rating Scales , Tics/diagnosis , Tics/physiopathology , Tourette Syndrome/diagnosis , Tourette Syndrome/physiopathology , United States , Young AdultABSTRACT
Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5'-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.
Subject(s)
Endopeptidases/genetics , Gene Deletion , Tourette Syndrome/genetics , Animals , Attention Deficit Disorder with Hyperactivity/genetics , Case-Control Studies , Chromosomes, Human, Pair 7/genetics , DNA Copy Number Variations , Denmark , Exons , Female , Gene Rearrangement , Genetic Predisposition to Disease , Humans , In Situ Hybridization, Fluorescence , Male , Mice , Microarray Analysis , Obsessive-Compulsive Disorder/genetics , Sequence Analysis, DNA , Tics/genetics , White People/geneticsABSTRACT
Tourette syndrome (TS) is a heritable disorder characterized by tics that are decreased in some patients by treatment with alpha adrenergic agonists and dopamine receptor blockers. Thus, this study examines the relationship between catecholamine gene expression in blood and tic severity. TS diagnosis was confirmed using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria and tic severity measured using the Yale Global Tic Severity Scale (YGTSS) for 26 un-medicated subjects with TS. Whole blood was collected and Ribonucleic acid (RNA) processed on Affymetrix Human Exon 1.0 ST arrays. An Analysis of Covariance (ANCOVA) identified 3627 genes correlated with tic severity (p<0.05). Searches of Medical Subject Headings, Gene Ontology, Allen Mouse Brain Atlas, and PubMed determined genes associated with catecholamines and located in the basal ganglia. Using GeneCards, PubMed, and manual curation, seven genes associated with TS were further examined: DRD2, HRH3, MAOB, BDNF, SNAP25, SLC6A4, and SLC22A3. These genes are highly associated with TS and have also been implicated in other movement disorders, Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD). Correlation of gene expression in peripheral blood with tic severity may allow inferences about catecholamine pathway dysfunction in TS subjects. Findings built on previous work suggest that at least some genes expressed peripherally are relevant for central nervous system (CNS) pathology in the brain of individuals with TS.
Subject(s)
Genetic Predisposition to Disease , Tics/genetics , Tourette Syndrome/genetics , Adolescent , Brain-Derived Neurotrophic Factor/genetics , Child , Female , Gene Expression , Genetic Association Studies , Humans , Male , Monoamine Oxidase/genetics , Organic Cation Transport Proteins/genetics , Receptors, Dopamine D2/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Severity of Illness Index , Synaptosomal-Associated Protein 25/geneticsABSTRACT
Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721), recently related to the invariant c.4A>G missense change in SHOC2, is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated with growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We report on a patient with molecularly confirmed NS/LAH exhibiting severe short stature associated with GH insensitivity (GHI), and chronic complex tics, a neurological feature never described before in this syndrome. IGF1 generation test revealed only a blunted increase in IGF1 after exogenous GH treatment, revealing mild GH insensitivity associated with proper STAT5 activation. Most common causes of secondary tics in childhood were excluded.
Subject(s)
Laron Syndrome/genetics , Loose Anagen Hair Syndrome/genetics , Noonan Syndrome/genetics , Tics/genetics , Child , Female , Humans , Insulin-Like Growth Factor I/metabolism , STAT5 Transcription Factor/metabolism , Tics/complicationsABSTRACT
Fragile X syndrome is caused by CGG trinucleotide repeat expansion within the fragile X mental retardation 1 gene, when repeat number exceeds 200. The typical psychiatric profile of fragile X syndrome patients includes cognitive and behavioral deficits, psychiatric comorbidity, and autistic characteristics. Specific psychiatric features have not yet been clarified, specifically in relationship to age and genetic characteristics. The objective of this study was to characterize psychiatric comorbidities in subjects with fragile X syndrome at different ages. Subjects with fragile X syndrome and their unaffected siblings were recruited and their parents filled out functional-behavioral and psychiatric comorbidities questionnaires. Adolescents with fragile X syndrome showed decreased prevalence of functional-behavioral deficits. Incidence and severity of most psychiatric comorbidities were lower in older subjects. Incidence of generalized anxiety disorder increased with age in the fragile X syndrome group. The typical profile of patients with fragile X syndrome changes with age. Unaffected siblings exhibit anxiety and motor tics.
Subject(s)
Aging/psychology , Autistic Disorder/epidemiology , Fragile X Syndrome/epidemiology , Fragile X Syndrome/psychology , Siblings/psychology , Adolescent , Anxiety/epidemiology , Anxiety/genetics , Autistic Disorder/genetics , Child , Child, Preschool , Comorbidity , Female , Humans , Infant , Male , Severity of Illness Index , Surveys and Questionnaires , Tics/epidemiology , Tics/geneticsABSTRACT
Gilles de la Tourette syndrome is a complex neuropsychiatric disorder with a strong genetic basis. We identified a male patient with Tourette syndrome-like tics and an apparently balanced de novo translocation [46,XY,t(2;7)(p24.2;q31)]. Further analysis using array comparative genomic hybridisation (CGH) revealed a cryptic deletion at 7q31.1-7q31.2. Breakpoints disrupting this region have been reported in one isolated and one familial case of Tourette syndrome. In our case, IMMP2L, a gene coding for a human homologue of the yeast inner mitochondrial membrane peptidase subunit 2, was disrupted by the breakpoint on 7q31.1, with deletion of exons 1-3 of the gene. The IMMP2L gene has previously been proposed as a candidate gene for Tourette syndrome, and our case provides further evidence of its possible role in the pathogenesis. The deleted region (7q31.1-7q31.2) of 7.2 Mb of genomic DNA also encompasses numerous genes, including FOXP2, associated with verbal dyspraxia, and the CFTR gene.
Subject(s)
Chromosome Breakpoints , Chromosomes, Human, Pair 7/genetics , DNA/analysis , Endopeptidases/genetics , Tics/genetics , Tourette Syndrome , Apraxias/genetics , Apraxias/physiopathology , Chromosomes, Human, Pair 7/ultrastructure , Comparative Genomic Hybridization , Cystic Fibrosis Transmembrane Conductance Regulator/deficiency , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Endopeptidases/metabolism , Exons , Forkhead Transcription Factors/deficiency , Forkhead Transcription Factors/genetics , Humans , In Situ Hybridization, Fluorescence , Male , Oligonucleotide Array Sequence Analysis , Pedigree , Sequence Deletion , Tics/physiopathology , Tourette Syndrome/genetics , Tourette Syndrome/physiopathology , Translocation, GeneticABSTRACT
Tourette disorder (TD) is a childhood onset neuropsychiatric syndrome defined by persistent motor and vocal tics. Despite a long-standing consensus for a strong genetic contribution, the pace of discovery compared to other disorders of similar prevalence has been slow, due in part to a paucity of studies and both clinical heterogeneity and a complex genetic architecture. However, the potential for rapid progress is high. Recent rare variant findings have pointed to the importance of copy number variation, the overlap of risks among distinct diagnostic entities, the contribution of novel molecular mechanisms, and the value of family based studies. Finally, analysis of a cohort of sufficient size to identify common polymorphisms of plausible effect is underway, promising key information regarding the contribution of common alleles to TD.
Subject(s)
Tics/genetics , Tourette Syndrome/genetics , Chromosome Aberrations , DNA Copy Number Variations/genetics , Genetic Association Studies , Genetic Linkage , Humans , Tics/physiopathology , Tourette Syndrome/pathologyABSTRACT
BACKGROUND: Tourette Syndrome (TS) has been linked to both genetic and environmental factors. Gene-expression studies provide valuable insight into the causes of TS; however, many studies of gene expression in TS do not account for the effects of medication. MATERIALS & METHODS: To investigate the effects of medication on gene expression in TS patients, RNA was isolated from the peripheral blood of 20 medicated TS subjects (MED) and 23 unmedicated TS subjects (UNMED), and quantified using whole-genome Affymetrix microarrays. RESULTS: D2 dopamine receptor expression correlated positively with tic severity in MED but not UNMED. GABA(A) receptor ε subunit expression negatively correlated with tic severity in UNMED but not MED. Phenylethanolamine N-methyltransferase expression positively correlated with tic severity in UNMED but not MED. CONCLUSION: Modulation of tics by TS medication is associated with changes in dopamine, norepinephrine and GABA pathways.
Subject(s)
Gene Expression , RNA/blood , Tics/drug therapy , Tourette Syndrome/drug therapy , Basic Helix-Loop-Helix Transcription Factors/genetics , Child , Female , Gene Expression Profiling , Humans , Male , Oligonucleotide Array Sequence Analysis , Phenylethanolamine N-Methyltransferase/genetics , RNA/genetics , Receptors, Dopamine D2/genetics , Receptors, GABA-A/genetics , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness Index , Tics/blood , Tics/complications , Tics/genetics , Tourette Syndrome/blood , Tourette Syndrome/complications , Tourette Syndrome/geneticsABSTRACT
BACKGROUND: Previous studies have aimed to identify subtypes of obsessive-compulsive disorder (OCD) based on their age of onset (AOO). Obsessive-compulsive spectrum disorders (OCS disorders) such as tic disorders have been particularly associated with an early onset in some studies. However, subtypes of early- and late-onset OCD are unevenly determined, and the biological and the clinical validity of these subtypes are unknown. This study was undertaken to discriminate the subtypes of OCD in different AOO levels and to test the hypothesis that different AOO bands are associated with a differential pattern of comorbidity. METHODS: Two hundred fifty-two patients with OCD were interviewed directly with the German version of the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety Version, which provides DSM-IV diagnosis. Subgroups with different ages of onset were investigated (cut-off levels of 10, 15, and 18 years). RESULTS: Subjects with an early AOO (onset < or =10 years) were significantly more likely to have OCS disorders (odds ratio [OR]=3.46; P=.001; 95% confidence interval [CI]: 1.72-6.96), in particular tic/Tourette's disorders (OR=4.63; P=.002; 95% CI: 1.78-12.05), than were late-onset subjects. CONCLUSIONS: For most mental disorders (e.g., anxiety and mood disorders), no associations with AOO of OCD were identified. However, subjects in the early-onset group (< or =10 years) had a significant increase in comorbid tic and Tourette's disorders. Future research should examine potential neurobiological features associated with early-onset presentations of OCD. Early detection and management of comorbidities may offset impairments later in life.
Subject(s)
Obsessive-Compulsive Disorder/epidemiology , Tourette Syndrome/epidemiology , Adolescent , Adult , Age of Onset , Anorexia Nervosa/diagnosis , Anorexia Nervosa/epidemiology , Anorexia Nervosa/genetics , Anorexia Nervosa/psychology , Body Dysmorphic Disorders/diagnosis , Body Dysmorphic Disorders/epidemiology , Body Dysmorphic Disorders/genetics , Body Dysmorphic Disorders/psychology , Child , Comorbidity , Cross-Sectional Studies , Disruptive, Impulse Control, and Conduct Disorders/diagnosis , Disruptive, Impulse Control, and Conduct Disorders/epidemiology , Disruptive, Impulse Control, and Conduct Disorders/genetics , Disruptive, Impulse Control, and Conduct Disorders/psychology , Female , Germany , Humans , Hypochondriasis/diagnosis , Hypochondriasis/epidemiology , Hypochondriasis/genetics , Hypochondriasis/psychology , Incidence , Interview, Psychological , Male , Mass Screening/statistics & numerical data , Middle Aged , Mood Disorders/diagnosis , Mood Disorders/epidemiology , Mood Disorders/genetics , Mood Disorders/psychology , Obsessive-Compulsive Disorder/diagnosis , Obsessive-Compulsive Disorder/genetics , Obsessive-Compulsive Disorder/psychology , Personality Assessment , Somatoform Disorders/diagnosis , Somatoform Disorders/epidemiology , Somatoform Disorders/genetics , Somatoform Disorders/psychology , Substance-Related Disorders/diagnosis , Substance-Related Disorders/epidemiology , Substance-Related Disorders/genetics , Substance-Related Disorders/psychology , Tics/diagnosis , Tics/epidemiology , Tics/genetics , Tics/psychologyABSTRACT
The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (etap (2) = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, etap (2) = 0.10) and teacher-rated tics (p = 0.04; etap (2) = 0.07). There was also evidence of a possible interaction (p = 0.02, etap (2) = 0.09) of BDNF genotype with DAT1 3' VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples.
Subject(s)
Anxiety/genetics , Attention Deficit Disorder with Hyperactivity/genetics , Brain-Derived Neurotrophic Factor/genetics , Catechol O-Methyltransferase/genetics , Child Development Disorders, Pervasive/genetics , Polymorphism, Single Nucleotide/genetics , Tics/genetics , Child , Female , Genetic Association Studies , Genetic Markers , Genotype , Humans , Male , Polymerase Chain ReactionSubject(s)
Biological Evolution , Obsessive-Compulsive Disorder/psychology , Adult , Ceremonial Behavior , Child , Child, Preschool , Diagnostic and Statistical Manual of Mental Disorders , Diffusion Magnetic Resonance Imaging , Frontal Lobe/physiopathology , Genotype , Humans , Obsessive-Compulsive Disorder/classification , Obsessive-Compulsive Disorder/genetics , Obsessive-Compulsive Disorder/therapy , Parietal Lobe/physiopathology , Phenotype , Risk Factors , Stereotyped Behavior , Tics/classification , Tics/genetics , Tics/psychology , Tics/therapyABSTRACT
Juvenile Huntington's disease (JHD) is mostly characterized by rigidity, myoclonus, bradykinesia, dystonia and seizure. We report a 9-year-old male JHD patient presenting excessive blinking as the initial symptom two years prior to typical JHD symptoms. Genetic analysis revealed expansion of 108 CAG repeats and magnetic resonance imaging showed caudate atrophy with lateral ventricular enlargement.