Investigation of gene-environment interactions in relation to tic severity.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Development of the Korean Developmental Screening Test for Infants and Children (K-DST).

BACKGROUND: Most developmental screening tools in Korea are adopted from foreign tests. To ensure efficient screening of infants and children in Korea, a nationwide screening tool with high reliability and validity is needed. PURPOSE: This study aimed to independently develop, standardize, and validate the Korean Developmental Screening Test for Infants and Children (K-DST) for screening infants and children for neurodevelopmental disorders in Korea. METHODS: The standardization and validation conducted in 2012-2014 of 3,284 subjects (4-71 months of age) resulted in the first edition of the K-DST. The restandardization and revalidation performed in 2015-2016 of 3.06 million attendees of the National Health Screening Program for Infants and Children resulted in the revised K-DST. We analyzed inter-item consistency and test-retest reliability for the reliability analysis. Regarding the validation of K-DST, we examined the construct validity, sensitivity and specificity, receiver operating characteristic curve analysis, and a criterion-related validity analysis. RESULTS: We ultimately selected 8 questions in 6 developmental domains. For most age groups and each domain, internal consistency was 0.73-0.93 and test-retest reliability was 0.77-0.88. The revised K-DST had high discriminatory ability with a sensitivity of 0.833 and specificity of 0.979. The test supported construct validity by distinguishing between normal and neurodevelopmentally delayed groups. The language and cognition domain of the revised K-DST was highly correlated with the K-Bayley Scales of Infant Development-II's Mental Age Quotient (r=0.766, 0.739), while the gross and fine motor domains were highly correlated with Motor Age Quotient (r=0.695, 0.668), respectively. The Verbal Intelligence Quotient of Korean Wechsler Preschool and Primary Scales of Intelligence was highly correlated with the K-DST cognition and language domains (r=0.701, 0.770), as was the performance intelligence quotient with the fine motor domain (r=0.700). CONCLUSION: The K-DST is reliable and valid, suggesting its good potential as an effective screening tool for infants and children with neurodevelopmental disorders in Korea.

Cross-Cultural Aspect of Behavior Assessment System for Children-2, Parent Rating Scale-Child: Standardization in Korean Children.

PURPOSE: Our study aimed to examine psychometric properties and cross-cultural utility of the Behavior Assessment System for Children-2, Parent Rating Scale-Child (BASC-2 PRS-C) in Korean children. MATERIALS AND METHODS: Two study populations were recruited: a general population sample (n=2115) of 1st to 6th graders from 16 elementary schools and a clinical population (n=219) of 6-12 years old from 5 child psychiatric clinics and an epidemiological sample of autism spectrum disorder. We assessed the validity and reliability of the Korean version of BASC-2 PRS-C (K-BASC-2 PRS-C) and compared subscales with those used for US populations. RESULTS: Our results indicate that the K-BASC-2 PRS-C is a valuable instrument with reliability and validity for measuring developmental psychopathology that is comparable to those in Western population. However, there were some differences noted in the mean scores of BASC-2 PRS-C between Korean and US populations. CONCLUSION: K-BASC-2 PRS-C is an effective and useful instrument with psychometric properties that permits measurement of general developmental psychopathology. Observed Korean-US differences in patterns of parental reports of children's behaviors indicate the importance of the validation, standardization and cultural adaptation for tools assessing psychopathology especially when used in populations different from those for which the instrument was originally created.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

Neurodevelopmental disorders of children screened by the infantile health promotion system.

OBJECTIVE: To perform an in depth evaluation of children, and thus provide a systematic method of managing children, who after infantile health screening, were categorized as suspected developmental delay. METHOD: 78 children referred to the Developmental Delay Clinic of Ilsan Hospital after suspected development delay on infantile health examinations were enrolled. A team comprised of a physiatrist, pediatrician and pediatric psychiatrist examined the patients. Neurological examination, speech and cognitive evaluation were done. Hearing tests and chromosome studies were performed when needed clinically. All referred children completed K-ASQ questionnaires. Final diagnoses were categorized into specific language impairment (SLI), global developmental delay (GDD), intellectual disability (ID), cerebral palsy (CP), motor developmental delay (MD) or autism spectrum disorder (ASD). RESULTS: 72 of the 78 patients were abnormal in the final diagnosis, with a positive predictive value of 92.3%. Thirty (38.4%) of the 78 subjects were diagnosed as GDD, 28 (35.8%) as SLI, 5 (6.4%) as ASD, 9 (12.5%) as MD, and 6 (7.6%) as normal. Forty five of the 78 patients had risk factors related to development, and 18 had a positive family history for developmental delay and/or autistic disorders. The mean number of abnormal domains on the K-ASQ questionnaires were 3.6 for ASD, 2.7 for GDD, 1.8 for SLI and 0.6 for MD. Differences between these numbers were statistically significant (p<0.05). CONCLUSION: Because of the high predictive value of the K-ASQ, a detailed evaluation is necessary for children suspected of developmental delay in an infantile health promotion system.

Characteristics of late-onset epilepsy and EEG findings in children with autism spectrum disorders.

PURPOSE: To investigate the clinical characteristics of late-onset epilepsy combined with autism spectrum disorder (ASD), and the relationship between certain types of electroencephalography (EEG) abnormalities in ASD and associated neuropsychological problems. METHODS: Thirty patients diagnosed with ASD in early childhood and later developed clinical seizures were reviewed retrospectively. First, the clinical characteristics, language and behavioral regression, and EEG findings of these late-onset epilepsy patients with ASD were investigated. The patients were then classified into 2 groups according to the severity of the EEG abnormalities in the background rhythm and paroxysmal discharges. In the severe group, EEG showed persistent asymmetry, slow and disorganized background rhythms, and continuous sharp and slow waves during slow sleep (CSWS). RESULTS: Between the two groups, there was no statistically significant difference in mean age (P=0.259), age of epilepsy diagnosis (P=0.237), associated family history (P=0.074), and positive abnormal magnetic resonance image (MRI) findings (P=0.084). The severe EEG group tended to have more neuropsychological problems (P=0.074). The severe group statistically showed more electrographic seizures in EEG (P=0.000). Rett syndrome was correlated with more severe EEG abnormalities (P=0.002). Although formal cognitive function tests were not performed, the parents reported an improvement in neuropsychological function on the follow up checkup according to a parent's questionnaire. CONCLUSION: Although some ASD patients with late-onset epilepsy showed severe EEG abnormalities, including CSWS, they generally showed an improvement in EEG and clinical symptoms in the long-term follow up. In addition, severe EEG abnormalities tended to be related to the neuropsychological function.

Prevalence of autism spectrum disorders in a total population sample.

OBJECTIVE: Experts disagree about the causes and significance of the recent increases in the prevalence of autism spectrum disorders (ASDs). Limited data on population base rates contribute to this uncertainty. Using a population-based sample, the authors sought to estimate the prevalence and describe the clinical characteristics of ASDs in school-age children. METHOD: The target population was all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. To identify cases, the authors used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures. RESULTS: The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91-3.37), with 1.89% (95% CI=1.43-2.36) in the general-population sample and 0.75% (95% CI=0.58-0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group. CONCLUSIONS: Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. These findings suggest that rigorous screening and comprehensive population coverage are necessary to produce more accurate ASD prevalence estimates and underscore the need for better detection, assessment, and services.