No association of a dodecamer duplication in the human opposite paired (HOPA) gene with mental retardation and schizophrenia in Chinese patients from Taiwan

The human opposite paired-containing (HOPA) gene is believed to be a co-activator of the thyroid hormone receptor and involved in thyroid hormone signal transduction. The gene consists of 45 exons and includes a dodecamer duplication in exon 43, which has been reported to be associated with mental retardation, autism, psychiatric disorders and hypothyroidism. We were interested to know if the 12-bp duplication variant of the HOPA gene is a risk factor for mental retardation and schizophrenia in the Chinese population. We investigated the prevalence of the 12-bp variant in a sample of Chinese mental retardation and schizophrenic patients from Taiwan by PCR-based genotyping. None of the mentally retarded and schizophrenic patients were found to have this dodecamer duplication variant. Our results indicate that the HOPA polymorphism might be very rare in our population and is unlikely to be a major risk factor for mental retardation and schizophrenia in the Chinese population.     

Analysis of MECP2 gene copy number in boys with autism

Autism is a severe neurodevelopmental disorder with a strong genetic basis.The methyl-CpG binding protein 2 gene (MECP2) is a dosage-sensitive gene in brain development and has been implicated as a candidate gene for autism. Duplication of the MECP2 gene has been reported in a few boys with autistic features. To further investigate the association of MECP2 duplication with autism, the authors performed real-time quantitative polymerase chain reaction (PCR) to detect copy number variations of the MECP2 gene in 82 autistic boys. No copy number variation was found in these patients, indicating that duplication of the MECP2 gene is not frequent in autistic patients. The authors consider that duplication of the MECP2 gene has no major effect on the susceptibility to autism. Replication of studies in a large-sized sample and a well-characterized subgroup of autism are warranted to further identify the association of MECP2 gene duplication with autism.     

Advanced Theory of Mind in High-Functioning Adults with Autism

Twenty-four high-functioning adults with autism (16 men) who passed a first-order theory-of-mind task and 24 nonautistic adults (10 men) attributed mental states to recordings of various verbal intonations and to photos of people's eyes to assess advanced theory of mind. Participants with autism performed significantly worse than nonautistic participants on both tasks. Thus, the previously described inattention to others' eyes exhibited by adults with autism is not solely responsible for their inability to attribute mental states from eyes, as they also did not correctly attribute mental states from voices. These findings support the view that a core deficit for people with autism lies in their theory of mind, that is, their inability to attribute mental states to others.     

Patterns of emotional and behavioural disturbance associated with autistic traits in young people with severe intellectual disabilities and challenging behaviours

Emotional and behavioural disturbance was assessed in 82 individuals with severe intellectual disabilities and challenging behaviour using the Diagnostic Assessment for the Severely Handicapped-II (DASH-II). Levels of disturbance were compared firstly in individuals with and without features of autism as assessed by the DASH-II, and secondly in individuals with varying severities of autism. In both cases levels of ability and overall severity of behaviour disorder were comparable across groups. Individuals with autistic features were found to have significantly higher scores than nonautistic individuals on the DASH-II organic disorder, anxiety, mania, PDD/autism and stereotypies subscales. When participants with autistic features were separated into groups of severe and moderate autism and compared with nonautistic participants, significant effects of group were found for scores on the anxiety, mood, mania, PDD/autism, schizophrenia and stereotypies subscales. Scheffé tests were conducted to further evaluate between-group differences. Item analysis showed seven DASH-II items to have a 30% or more difference between levels of endorsement in autistic and nonautistic individuals, with six further items showing a 20% or greater difference in levels of endorsement. Findings are compared to those from previous research and implications for the conceptualisation of emotional and behavioural disorders in individuals with autism are discussed.     

Social class distribution of fathers of children enrolled in the Iowa Autism program

The social class distribution of fathers with autistic children attending a locally well-known and state-supported modern autism program was examined and was compared to the social class distributions observed in a nonautistic, mentally retarded population, in children with other psychiatric disorders, and in the general population from which the present autistic sample was drawn. No significant differences were found among the groups. The findings supported the view that if studies are not biased by certain selection factors outside the autistic child's clinical picture and diagnosis, and if services become better known and readily available, then no differences in social class distribution between autistic and nonautistic groups occur. The results suggest that social class is not an important factor in the origin of autistic syndrome.     

Monoamine oxidase activity in blood platelets from autistic children

In order to evaluate the possible abnormality in monoamine oxidase (MAO) activity in early infantile autism, blood platelet samples were obtained from 20 autistic children, aged 2--12 years. MAO activity, measured fluorometrically using serotonin as substrate, was 5.24 +/- 1.65 (Mean +/- Standard Deviation) nM/MG protein/hour in these autistic children. This value was not significantly different from either that in 30 age-matched normal children or that in 39 nonautistic children with various psychiatric and neurological disorders, although autistic children had higher platelet serotonin concentration than these nonautistic individuals.     

Single-photon emission computed tomography of the brain in autism: effect of the developmental level

Brain single-photon emission computed tomography was performed in 22 autistic and 10 nonautistic disabled patients. The regional cerebral blood flow in both laterotemporal and dorso-medio-lateral frontal areas decreased significantly in the autistic group compared with in nonautistic group. In the autistic group, the regional cerebral blood flow was significantly higher in the right temporal and right parietal lobes than that in the left ones. Inversely, the regional cerebral blood flow in the frontal and occipital lobes was significantly higher on the left side than on the right side. In the nonautistic group, except for in the dorso-medio-lateral frontal lobes (left > right), there was no difference in the regional cerebral blood flow in either cerebrum or cerebellum. A positive correlationship between regional cerebral flow and development quotient (intelligence quotient) was observed in the left laterotemporal and both dorso-medio-lateral frontal areas, and a negative one was observed in the cerebellar vermis area. These results suggest that the regional cerebral blood flow decrease in the temporal and frontal areas relates to not only the brain mechanism of autism reported previously but also intelligence levels.     

Monoamine Oxidase Activity in Blood-Platelets From Autistic Children

In order to evaluate the possible abnormality in monoamine oxidase (MAO) activity in early infantile autism, blood platelet samples were obtained from 20 autistic children, aged 2–12 years. MAO activity, measured fluorometrically using serotonin as substrate, was 5.24 ± 1.65 (Mean ± Standard Deviation) nM/mg protein/hour in these autistic children. This value was not significantly different from either that in 30 age-matched normal children or that in 39 nonautistic children with various psychiatric and neurological disorders, although autistic children had higher platelet serotonin concentrations than these nonautistic individuals.     

Autism in children with congenital rubella

In the course of studying the behavioral characteristics of 243 preschool children with congenital rubella, we identified the syndrome of autism in 10 children and a partial syndrome of autism in an additional 8. These findings are discussed against the background of the behavioral investigations of rubella children. The methodology of our psychiatric study and the criteria for a diagnosis of autism are presented. The incidence of autism is considered with regard to the prevalence of other psychiatric disorders in this group and the physical status of the children. Two case histories of autistic rubella children are given and their behavioral characteristics are contrasted with nonautistic rubella children with matching sensory and other defects. The prevalence rate is compared with that found in two epidemiological studies and also with the rate indicated by other centers studying rubella children. Etiological implications of these findings are discussed. It is argued that these data support the concept of organic causation of the syndrome of autism.This study was done under a grant from the Children's Bureau, HEW No. H-220 (C2).     

A comparative study of attachment behavior in young children with autism or other psychiatric disorders

The present study examined attachment behavior in children with autism and children with other developmental or psychiatric disorders. The groups were matched on chronological and mental age, IQ, and socioeconomic status. When a modified Strange Situation paradigm was used, no group differences were found in proximity seeking, contact maintenance, proximity avoidance, or contact resistance; the groups also did not differ in their overall security ratings. Attachment security was related to several developmental variables in the autistic group but not in the nonautistic comparison group. This suggests that attachment formation may involve different processes in autistic children than in nonautistic children of equivalent intellectual level.     

Autism in two females with duplications involving Xp11.22-p11.23

We present two phenotypically similar females with Xp duplication who have autism and epilepsy. Case 1 is a 14-year-old Honduran female with autism and medically refractory complex partial, secondarily generalized epilepsy. Case 2 is a 3-year-old Austrian female with autism and medically refractory complex partial epilepsy. Both patients also share features of severe intellectual disability (case 1 has a developmental quotient of 23, case 2 has a developmental quotient of 42) and dysmorphic facial features. Autism was confirmed by thorough clinical evaluations and testing. Case 1 has a karyotype of 46,X,dup(X)(p11.2-p22.33) and a highly skewed X-inactivation pattern (94:6). Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal. Case 2 has a 5-megabase duplication of Xp11.22-p11.23 on chromosome microarray analysis. The patient has a random X-inactivation pattern (77:23). Brain MRI was normal, but EEG was abnormal. Both patients have duplications involving the Xp11.22-p11.23 region, indicating that this is an area of interest for future translational autism research.     

Brief report: Differences in sex ratios in autism as a function of measured intelligence

Results from analyses of sex ratios as a function of IQ are presented for 623 autistic children (487 males, 136 females) and 506 nonautistic, communication-handicapped and behavior-disordered children (374 males, 132 females). Proportionately more autistic females were found to have IQs of 34 or below than above 34. However, a linear trend of an increasing number of males with increasing intelligence was found only for nonautistic subjects. The relevance of these findings to genetic factors and the heterogeneity of autism is discussed.     

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.     

The human secretin gene in children with autistic spectrum disorder: screening for polymorphisms and mutations

We screened 29 children with autism for mutation in the human secretin gene using single-strand conformation polymorphism. No mutation was detected in exon 2, 3, or 4. Polymerase chain reaction and DNA sequence of 5' variable number of tandem repeats showed two polymorphisms with deletion or duplication of a repeat unit that failed to show any gene expression with transient transfection assay. We did not find evidence of a relationship between human secretin gene mutation and autism.     

Autism and head circumference in the first year of life.

BACKGROUND: It has been reported that children with autism and pervasive developmental disorder have a significantly smaller head circumference at birth and that their head circumference then increases disproportionately rapidly in the first year of life. METHODS: We attempted to replicate these findings using 15 narrowly defined autistic children from the National Collaborative Perinatal Project and approximately 40,000 nonautistic control subjects. RESULTS: The autistic group had a slightly but not significantly larger head circumference at birth. At 4 months, the head circumference in the autistic group was not significantly larger than that of control subjects, but body weight and length were significantly larger in the autistic group. CONCLUSIONS: We believe this is the first report of significant general body growth in autistic children in infancy; the larger head circumference may be part of this excessive general growth.     

Clinical and biochemical effects of calcium-hopantenate on neuroleptics-induced tardive dyskinesia

Calcium-hopantenate (HOPA), a derivative of GABA, was administered to 9 psychiatric patients with neuroleptics-induced tardive dyskinesia. In a clinical study, involuntary movements have improved significantly after a 4-8-week medication. Although there was no correlation between the cerebrospinal fluid (CSF) levels of HOPA, GABA, HVA or clinical response, the CSF HOPA levels significantly correlated with changes in the CSF GABA levels. These results suggest that HOPA alleviates the symptoms of tardive dyskinesia being mediated by the central GABAergic mechanisms.     

Laboratory predictions of infantile autism based on 5-hydroxytryptamine efflux from blood platelets and their correlation with the rimland E-2 score

Experiments were conducted to determine the possibility of predicting a diagnosis of autism on the basis of an abnormally high release of¹⁴C-5-hydroxy-tryptamine from 5-HT loaded blood platelets of children. Such increased 5-HT release was previously reported by the authors for blood platelets of children diagnosed as autistic according to the Rimland E-2 score. The platelets of 10 psychotic children (including a number of subjects diagnosed as autistic by the E-2 score) were examined without knowledge of the diagnosis, in order to determine whether the biochemical results correlated with the E-2 score. On the basis of experimental data it was possible to predict that six children were autistic and four were nonautistic psychotics. According to the E-2 score, seven children were autistic and three nonautistic psychotics. The authors conclude that there is a correlation between a diagnosis of infantile autism by the E-2 score and enhanced release of radioactive 5-HT from 5-HT-loaded blood plateletsin vitro.This research was supported in part by National Institutes of Health Grant RR 00 284 and National Institute of Mental Health Grant HD 08429.     

Role taking and social competence in autism and mental retardation

Recent data suggest that individuals with autism show deficits in social cognitive abilities when compared with nonautistic persons matched for mental age. These deficits have been proposed as a basis for the social interaction difficulties seen in autistic persons. In the present study, autistic youth were compared with a matched group of nonautistic mentally retarded youth on three role-taking tasks and three measures of social competence. Results indicated that the autistic group was relatively deficient on each of the social competence measures and on one of the role-taking measures. The role-taking measure on which the groups differed also correlated significantly with each of the social competence measures. Results were discussed in terms of the interplay between social cognitive abilities and social interaction.     

The association of a HOPA polymorphism with major depression and phobia

Thyroid hormone has a prominent role in the development and homeostasis of the central nervous system (CNS). Consequently, genes participating in thyroid hormone receptor (THR)-mediated signal transduction are prime candidates for neuropsychiatric illness susceptibility factors. Previously, we have associated exonic polymorphisms in a Xq13 thyroid receptor coactivator named HOPA with a modest increase in vulnerability to a broad spectrum of neuropsychiatric illness, including depression, psychosis, and hypothyroidism. In order to test and extend these findings, we have now examined the relationship between HOPA polymorphisms and neuropsychiatric illness in a cohort of Iowa adoptees. Consistent with our prior findings, HOPA polymorphisms were associated with an increased risk for major depression. There was suggestive evidence that the increased psychiatric morbidity in these subjects could represent epistasis, e.g., an interaction between the HOPA variant and a genetic diathesis for another psychiatric condition such as biologic parent antisocial behavior. Information about biologic parent behavior and the adoptive home environment was used to determine depressive symptoms attributable to gene-environment interaction. HOPA variant subjects continued to show significant differences in depressive symptoms when controlling for gene-environment interaction. Finally, because obesity is associated with hypothyroidism and HOPA polymorphisms are associated with hypothyroidism, we analyzed weight with respect to HOPA allele status. We found that that HOPA polymorphisms were associated with increased risk for obesity (P <.001). In summary, we conclude that HOPA polymorphisms may be a moderate risk factor for increased susceptibility to a broad spectrum of neuropsychiatric illness and hypothesize that the type of illness manifested might be related to a separate genetic diathesis.     

Laughter Differs in Children with Autism: An Acoustic Analysis of Laughs Produced by Children With and Without the Disorder

Few studies have examined vocal expressions of emotion in children with autism. We tested the hypothesis that during social interactions, children diagnosed with autism would exhibit less extreme laugh acoustics than their nonautistic peers. Laughter was recorded during a series of playful interactions with an examiner. Results showed that children with autism exhibited only one type of laughter, whereas comparison participants exhibited two types. No group differences were found for laugh duration, mean fundamental frequency (F₀) values, change in F₀, or number of laughs per bout. Findings are interpreted to suggest that children with autism express laughter primarily in response to positive internal states, rather than using laughter to negotiate social interactions.