Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights.

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

An International Clinical Study of Ability and Disability in Autism Spectrum Disorder Using the WHO-ICF Framework.

This is the fourth international preparatory study designed to develop International Classification of Functioning, Disability and Health (ICF, and Children and Youth version, ICF-CY) Core Sets for Autism Spectrum Disorder (ASD). Examine functioning of individuals diagnosed with ASD as documented by the ICF-CY in a variety of clinical settings. A cross-sectional study was conducted, involving 11 units from 10 countries. Clinical investigators assessed functioning of 122 individuals with ASD using the ICF-CY checklist. In total, 139 ICF-CY categories were identified: 64 activities and participation, 40 body functions and 35 environmental factors. The study results reinforce the heterogeneity of ASD, as evidenced by the many functional and contextual domains impacting on ASD from a clinical perspective.

[An Adolescent Case of ASD Presenting with Persistent Catatonia and Epileptic EEG Discharge].

A 26-year-old man developed a catatonic state after his grandmother's death and the Great East Japan Earthquake. He was admitted to hospital because of the prolonged severe stupor. Electroencephalography (EEG) revealed focal (F3 electrode) and generalized epileptic abnormalities. He was administered antiepileptic agents and benzodiazepines, but his stupor did not improve in spite of a reduced frequency of epileptic EEG abnormalities. His clinical his- tory did not suggest any psychotic disorders. Thereafter, extensive physical examinations were performed, but an organic cause of the stupor was not determined. For about two years, he was unable to intake food without tubal feeding, have a conversation, or move spontaneously. One day, a generalized tonic-clonic seizure (GTC) occurred spontaneously for the first time in his life, and then his stupor markedly improved. Thereafter, he could eat food spontaneously, have a fluent conversation, and move actively. After his condition had improved, we asked his parents about his developmental history, clinical history, and present state. According to clini- cal interviews including the use of PARS (Pervasive Developmental Disorders Autism Society Japan Rating Scale), DISCO (Diagnostic Interview for Social and Communication Disorders), and WAIS-III (Wechsler Adult Intelligence Scale-third edition), he was diagnosed with autistic spectrum disorder (ASD) and mild intellectual disability. It was considered that his stupor had occurred secondary to ASD. Wing et al. reported that catatonia occurred in about 17% of ASD adolescents and young adults as a later complication. It is possible that this case, without any psychotic disorders and with ASD that has been undiagnosed until young adult, progress to such a severe and prolonged catatonic state. We report this case to show that severe catatonia is possible in adolescents and young adults during the carry-over period in ASD patients.

Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder.

OBJECTIVE: This case-control study investigated the relationship between the risk of Autism Spectrum Disorder (ASD) onset, and early exposure to the combined Measles-Mumps-Rubella (MMR) vaccine and thimerosal consumption measured from vaccinations in the highly genetically homogenous Japanese population. METHODS: Vaccination histories at 1, 3, 6, 12, 18, 24, and 36 months from birth were investigated in ASD cases (189 samples), and controls (224 samples) matching age and sex in each case. Crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to determine relationship between MMR vaccination and ASD. The differences in mean values of the thimerosal dosage between cases and controls were analyzed using an unpaired t-test. MMR vaccination and thimerosal dosage were also investigated using a conditional multiple-regression model. RESULTS: There were no significant differences in MMR vaccination and thimerosal dosage between cases and controls at any age. Furthermore, the ORs (95% CIs) of MMR vaccination and thimerosal dosage associated with ASD in the conditional multiple regression model were, respectively, 0.875 (0.345-2.222) and 1.205 (0.862-1.683) at age 18 months, 0.724 (0.421-1.243) and 1.343 (0.997-1.808) at 24 months, and 1.040 (0.648-1.668) and 0.844 (0.632-1.128) at 36 months. Thus, there were no significant differences. CONCLUSIONS: No convincing evidence was found in this study that MMR vaccination and increasing thimerosal dose were associated with an increased risk of ASD onset.

Verification of the utility of the social responsiveness scale for adults in non-clinical and clinical adult populations in Japan.

BACKGROUND: Recently great attention has been paid to the still unmet clinical needs of most adults with autism spectrum disorder (ASD) who live in the community, an increasing number of whom visit psychiatric clinics to seek accurate diagnosis and treatment of concurrent psychiatric symptoms. However, different from the case of children diagnosed with ASD in childhood, it is difficult in adults to identify the ASD symptoms underlying psychopathology and to differentiate ASD from other psychiatric disorders in general psychiatric practice. This study aimed to verify the utility of the Social Responsiveness Scale-Adult version (SRS-A), a quantitative measure for identifying ASD symptoms, in non-clinical and clinical adult populations in Japan. METHODS: The total sample aged 19 to 59 years consisted of a non-clinical population (n =592) and clinical population with and without ASD (n =142). We examined score distributions of the Japanese version of the scale, and the effects of gender, age, and rater on the distribution. We analyzed factor structure and internal consistency in the non-clinical normative sample, and analyzed convergent, divergent, and discriminative validities in the clinical sample. We applied receiver operator characteristic (ROC) analysis to determine optimal cutoff scores discriminating the ASD clinical population from the non-ASD clinical population. RESULTS: The score distributed continuously, which replicated findings in children. For non-clinical adults, except in men aged 19 to 24 years, we found no or few gender, age, or rater effects. Both single- and two-factor models were supported for adults. Total SRS-A scores demonstrated high internal consistency and capably discriminated adults with ASD from those with non-ASD psychiatric disorders such as major depressive disorder, schizophrenia, and bipolar disorder with an overlap across diagnoses. Moderate to high correlations of the SRS-A with other-rated ASD measures indicated sufficient convergent validity. Based on the ROC analysis, we recommend cutoff points by gender for use in clinical settings. CONCLUSION: This study provides additional supportive evidence that the Japanese version SRS-A can reliably and validly measure ASD symptoms in non-clinical and clinical adult populations, and thus can serve as a useful tool for ASD research as well as for secondary screening in Japanese adults.

[Case study of 10 subjects diagnosed with autism spectrum disorders in adulthood and currently under long-term follow-up].

This study involved 10 adults with autism spectrum disorders (ASD) who were referred to a specialized developmental disability clinic and were being treated for periods extending to years. Checks included past diagnoses, the chief complaint at the first examination, psychiatric symptoms, medication, employment, and whether a diagnosis of ASD would have been possible during their formative years. Their age at referral was 21-30 and, at the time of this study, they were aged 25-40. There were eight males and two females, and their treatment periods were between four and 16 years. Using DSM-IV-TR criteria, six were diagnosed with autistic disorders and four with PDDNOS. Wing and Gould criteria showed nine with Asperger syndrome and one with autism. Their IQ ranged from 88 to 121, with the mean score being 103 (SD = 10.0). Eight of the 10 had previously been examined in psychiatric clinics, which identified two as having depression, two with schizophrenia, one with Obsessive-Compulsive Disorder, and one with autism/Asperger syndrome, and there was no diagnosis for the other two. For these eight cases, the PDD-Autism Society Japan Rating Scale (PARS) was used. The PARS early childhood peak score ranged from 9 to 41, so all reached the cutoff point of 9. At the time of this study, the following psychiatric symptoms were noted: three cases of depression, two of anxiety, one with auditory hallucinations, and one who displayed odd behavior and facial expressions that became apparent during the follow-up. In two cases there seemed to be no apparent psychiatric co-morbidity. The current PARS scores of 8 cases were between 12 and 38, and four cases exceeded the cutoff point of 20. One was taking anti-psychotic drugs for auditory hallucinations, four were using SSRI for anxiety and depression, and one was occasionally prescribed medication for anxiety. Four were not on medication. When diagnosing ASD in adulthood, interviewing using such instruments as PARS seemed useful. We should keep in mind that families tend not to recognize co-morbid psychotic symptoms.

Reliability and validity of autism diagnostic interview-revised, Japanese version.

To examine the inter-rater reliability of Autism Diagnostic Interview-Revised, Japanese Version (ADI-R-JV), the authors recruited 51 individuals aged 3-19 years, interviewed by two independent raters. Subsequently, to assess the discriminant and diagnostic validity of ADI-R-JV, the authors investigated 317 individuals aged 2-19 years, who were divided into three diagnostic groups as follows: autistic disorder (AD), pervasive developmental disorder not otherwise specified, and other psychiatric diagnosis or no diagnosis, according to the consensus clinical diagnosis. As regards inter-rater reliability, intraclass correlation coefficients of greater than 0.80 were obtained for all three domains of ADI-R-JV. As regards discriminant validity, the mean scores of the three domains was significantly higher in individuals with AD than in those of other diagnostic groups. As regards diagnostic validity, sensitivity and specificity for correctly diagnosing AD were 0.92 and 0.89, respectively, but sensitivity was 0.55 for individuals younger than 5 years. Specificity was consistently high regardless of age and intelligence. ADI-R-JV was shown to be a reliable tool, and has sufficient discriminant validity and satisfactory diagnostic validity for correctly diagnosing AD, although the diagnostic validity appeared to be compromised with respect to the diagnosis of younger individuals.

The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: the first case-control study in Asia.

OBJECTIVE: The aim of this study was to investigate the relationship between autism spectrum disorder (ASD) and general vaccinations, including measles-mumps-rubella (MMR) vaccine, in Japanese subjects, a population with high genetic homogeneity. PATIENTS AND METHODS: A case-control study was performed. Cases (n=189) were diagnosed with ASD, while controls (n=224) were volunteers from general schools, matched by sex and birth year to cases. Vaccination history and prenatal, perinatal, and neonatal factors from the Maternal and Child Health handbook, which was part of each subject's file, were examined. To determine the relationship between potential risk factors and ASD, crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and the differences in mean values of the quantitative variables between cases and controls were analyzed using an unpaired t-test. Moreover, MMR vaccination and the effect of the number of vaccine injections were investigated using a conditional multiple regression model. RESULTS: For MMR vaccination, the OR was 1.04 (95% CI, 0.65-1.68), and no significant differences were found for the other vaccines. For all of the prenatal, perinatal and neonatal factors, there were no significant differences between cases and controls. Furthermore, regarding the presence of ASD, MMR vaccination and the number of vaccine injections had ORs of 1.10 (95% CI, 0.64-1.90) and 1.10 (95% CI, 0.95-1.26), respectively, in the conditional multiple regression model; no significant differences were found. CONCLUSIONS: In this study, there were not any convincing evidences that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population. Therefore, these findings indicate that there is no basis for avoiding vaccination out of concern for ASD.

Establishing the cut-off point for the Oppositional Defiant Behavior Inventory.

The purpose of the present paper was to make a detailed examination of the cut-off point for the Oppositional Defiant Behavior Inventory (ODBI). The subjects were 56 untreated boys (age 6-15 years), who were diagnosed to have oppositional defiant disorder and who presented between December 2001 and March 2008. Controls were 690 boys with no history of contacting hospitals and no developmental or behavioral disorders at two elementary schools and two junior high schools in a city and its suburbs. It was shown that the level of opposition in boys could be evaluated regardless of the age groups by the ODBI, because there was no significant difference in the ODBI score for the one-way analysis of variance. Based on the sensitivity (88.2%), specificity (90.0%), positive predictive value (75.0%) and negative predictive value (95.7%), a score of 20 points was thus established as a suitable cut-off point to distinguish the children who are eligible for ODD diagnosis from those who are not.

[Autism-spectrum quotient (AQ) Japanese children's version " comparison between high-functioning children with autism spectrum disorders and normal controls].

The Autism-Spectrum Quotient (AQ) children's version has confirmed reliability and validity in the UK. In the current study, the children's AQ was administered in Japan to investigate whether the UK results are found in a very different culture. Two groups of children from primary and secondary schools were assessed: Group 1 (n = 81) children with Autism Spectrum Disorders (ASD, including Asperger Syndrome and high-functioning autism); Group 2 (n = 372) randomly selected controls, age-matched with Group 1. The children with ASD had a mean AQ score of 31.9 (SD = 6.69), which was significantly higher than controls (mean AQ = 11.7, SD = 5.94). Males scored significantly higher than females in the control group, but not in the ASD group. The pattern of difference between the Japanese clinical group and the control group was remarkably similar to the findings in the UK.

[Diagnostic criteria for Asperger syndrome].

The diagnostic criteria for Asperger syndrome (AS) are still controversial. ICD-10 and DSM-IV are usually used as a formal diagnostic criteria for AS. However, many papers point out there are many problems in ICD-10/DSM-IV. It is indicated that the diagnosis of AS using ICD-10/DSM-IV criteria is virtually impossible due to the rule of onset and precedence. ICD-10/DSM-IV criteria don't include core symptoms of AS, such as odd speech and limited intelligent interests reported by Hans Asperger. Most of the cases which are diagnosed as AS clinically meet the diagnostic criteria for autism or atypical autism(PDD-NOS) in ICD-10/DSM-IV. ICD-10/DSM-IV criteria is too narrow to diagnose AS. This causes much confusion and disadvantage for families, clinicians and researchers. We need to establish the clinically useful and reliable diagnostic criteria for AS.

The autism-spectrum quotient (AQ) children's version in Japan: a cross-cultural comparison.

In the current study, the child AQ was administered in Japan, to examine whether the UK results for reliability and validity generalize to a different culture. Assessment groups were: Group 1: n = 81 children with Asperger Syndrome (AS) or high-functioning autism (HFA); Group 2: n = 22 children diagnosed PDD-NOS with average IQ; and Group 3: n = 372 randomly selected controls from primary and secondary schools. Both clinical groups scored significantly higher than controls (AS/HFA mean AQ = 31.9, SD = 6.93; PDD-NOS mean AQ = 28.0, SD = 6.88; controls mean AQ = 11.7, SD = 5.94). Among the controls, males scored significantly higher than females. The pattern of difference between clinical groups and controls was found to be similar in both countries.

MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan.

It has been suggested that the measles, mumps, and rubella vaccine (MMR) is a cause of regressive autism. As MMR was used in Japan only between 1989 and 1993, this time period affords a natural experiment to examine this hypothesis. Data on 904 patients with autism spectrum disorders (ASD) were analyzed. During the period of MMR usage no significant difference was found in the incidence of regression between MMR-vaccinated children and non-vaccinated children. Among the proportion and incidence of regression across the three MMR-program-related periods (before, during and after MMR usage), no significant difference was found between those who had received MMR and those who had not. Moreover, the incidence of regression did not change significantly across the three periods.

Empathizing and systemizing in adults with and without autism spectrum conditions: cross-cultural stability.

UNLABELLED: This study tests the empathizing-systemizing (E-S) theory of sex differences and the extreme male brain (EMB) theory of autism. Three groups of participants took part: n = 48 people with autism spectrum, n = 137 general population controls, and n = 1,250 university student controls. Each participant completed the Empathy Quotient (EQ) and the Systemizing Quotient (SQ). RESULTS: The autism spectrum condition (ASC) group scored significantly lower than controls on the EQ, and significantly higher on the SQ. Among both control groups, females scored significantly higher than males on the EQ, whilst males scored significantly higher than females on the SQ. The distribution of 'brain types', based on the difference between EQ and SQ scores, showed distinct profiles for people with ASC, control males and control females.

The clinical necessity for assessing Attention Deficit/Hyperactivity Disorder (AD/HD) symptoms in children with high-functioning Pervasive Developmental Disorder (PDD).

Although the DSM-IV diagnostic criteria for Attention Deficit/Hyperactivity Disorder (AD/HD) exclude Pervasive Developmental Disorder (PDD), some clinicians find that the two disorders can be comorbid and, in fact, make a dual diagnosis. Nevertheless, few empirical studies have investigated the clinical necessity for this practice. In the first of our two studies, children with high-functioning PDD were selected from among 520 outpatients. Of these, children also meeting the DSM-IV criteria for AD/HD were identified through a psychologist's observation, the completion of the ADHD-Rating Scale by parents and/or teachers, and a child psychiatrist's examination. We then examined the impact of PDD subtype and age on the co-occurrence rate. Study 2 analyzed comorbidity in two cases taken from Study 1. Of the 53 subjects in Study 1, 36 children also met the DSM-IV criteria for AD/HD. The co-occurrence rate for Asperger's Disorder (AS)/Pervasive Developmental Disorder, Not Otherwise Specified (PDDNOS) (85%) was significantly higher than for Autistic Disorder (57.6 %), and AD/HD symptoms were more common in younger children. Study 2 demonstrated the existence of comorbidity of PDD and AD/HD as separate disorders. We conclude not only that AD/HD symptoms occur frequently in children with PDD, but also that in some cases a dual diagnosis is essential to the implementation of effective treatment.

The reliability and validity of the Oppositional Defiant Behavior Inventory.

OBJECTIVE: The aim of this study was to develop an evaluation scale for use as a supplementary tool for the diagnosis of oppositional defiant disorder (ODD). METHOD: The subjects were 98 Japanese children (91 males and 7 females), aged 6-15 years, diagnosed with attention deficit/hyperactivity disorder (ADHD) or ODD. Internal consistency, test-retest reliability, concurrent validity and divergent validity of the oppositional defiant behavior inventory (ODBI), an evaluation scale of oppositional defiant tendency, were examined. RESULTS: Cronbach's alpha coefficient of the ODBI was 0.925. The correlation coefficient between the test and the retest was 0.820 (p < 0.0001). Both the ODBI scores (test and retest) were correlated with the number of items that matched the ODD diagnostic criteria of DSM-IV (r = 0.660, 0.659, p < 0.001), and with the ODD-scale of Disruptive Behavior Disorders Rating Scale (r = 0.725, 0.654, p < 0.001). Compared with the ADHD group or controls, the ADHD and ODD group showed a significantly higher ODBI score at p < 0.0001. CONCLUSION: The concurrent use of this scale with clinical examination is expected to increase the accuracy of the diagnosis of ODD.