The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.

This paper examines how COMT158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMTMET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMTMET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.

Intellectual functioning in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial syndrome) is associated with an increased risk of various disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). With this study, we aimed to investigate the relation between intellectual functioning and severity of ASD and ADHD symptomatology in 22q11DS. METHOD: A sample of 102 individuals (62 females) with 22q11DS aged 9 to 18.5 years were assessed using age appropriate Wechsler scales of intelligence as well as psychological and psychiatric assessment to evaluate the presence of ASD and ADHD symptomatology. RESULTS: Intelligence profiles were characterised by lower scores on the factor perceptual organisation and higher scores on the factor processing speed, with on subtest level higher scores on digit span and lower scores on arithmetic and vocabulary as compared with the mean factor or subtest score respectively. No differences in intelligence profiles were found between subgroups with and without ASD and/or ADHD. Low scores on coding were associated with higher severity of ASD symptomatology, while lower scores on block design were associated with more severe ADHD symptomatology. CONCLUSIONS: On several sub-domains of intelligence, poorer performance was associated with higher severity of ASD and ADHD symptomatology. The impact of developmental disorders in 22q11DS can be traced in specific domains of intellectual functioning as well as in severity of symptomatology.

A double hit implicates DIAPH3 as an autism risk gene.

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

Neuroendocrine markers of high risk for psychosis: salivary testosterone in adolescent boys with prodromal symptoms.

BACKGROUND: The peak in age of onset of psychotic disorders such as schizophrenia during puberty and early adulthood suggests a relationship between the expression of psychopathology and the changes in the brain and body that take place during this dynamic maturational period, including a dramatic increase in circulating oestrogens and androgens. This study examined levels of salivary testosterone and oestradiol in adolescents with prepsychotic, prodromal symptoms, as this may mediate risk for psychosis by having an impact on brain development. METHOD: In 21 male adolescents with prodromal symptoms and 21 male non-clinical controls levels of testosterone and oestradiol were measured in saliva. Tanner pubertal stage and prodromal symptoms were also assessed. RESULTS: Levels of testosterone were significantly lower in adolescents with prodromal symptoms as compared with non-clinical controls. No group differences in oestradiol were found. In the total sample, level of testosterone was significantly correlated with age and Tanner pubertal stage. CONCLUSIONS: Our observations are in line with current hypotheses stressing the role of neuroendocrine factors during adolescence in the expression of psychotic symptoms. From a developmental perspective, susceptibility to psychotic disorders increases during adolescence. Our data suggest that testosterone might, in part, mediate this increased vulnerability. Further research is needed to assess the mediating, neural, mechanisms through which testosterone may have an impact on the development of psychotic symptoms. In the search for early risk markers for psychosis, studying neuroendocrine factors might increase our understanding of 'at-risk' developmental pathways.

Misattribution of facial expressions of emotion in adolescents at increased risk of psychosis: the role of inhibitory control.

BACKGROUND: By studying behavior, cognitive abilities and brain functioning in adolescents at high risk for psychosis, we can gain an insight into the vulnerability markers or protective factors in the development of psychotic symptoms. Although many high-risk studies have focused on impairments in neurocognitive functions, such as memory and attention, very few studies have investigated problems in processing social cues such as facial expressions as a possible vulnerability marker for psychosis. METHOD: Thirty-six adolescents at ultra-high risk (UHR) for psychosis and 21 non-clinical controls completed a face recognition test, a facial affect labeling test and an inhibitory control test. Schizotypal traits and schizophrenia symptoms were assessed using a schizotypy questionnaire and the Positive and Negative Syndrome Scale (PANSS). RESULTS: The UHR group showed impairments in labeling facial expressions of others, in addition to a spared ability to recognize facial identity. More specifically, the UHR group made more errors in labeling neutral expressions compared to the controls, and an analysis of error types indicated that neutral faces were misattributed as being angry. The degree of misattribution of neutral-as-angry faces correlated significantly with reduced inhibitory control. CONCLUSIONS: Our findings suggest that misattributing social cues might contribute to vulnerability for psychosis. This social cognitive deficit may be related to problems in inhibitory control, which potentially plays an important role in the selection of appropriate social meaning. These findings may have relevance for understanding the mechanisms underlying prodromal social dysfunction, which should be targeted in future remediation interventions.

Minor physical anomalies in autism: a meta-analysis.

Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences play a causal role. Despite the compelling evidence for a strong heritability, the etiology and molecular mechanisms underlying autism remain unclear. High phenotypic variability and genetic heterogeneity confounds the identification of susceptibility genes. The lack of robust indicators to tackle this complexity in autism has led researchers to seek for novel diagnostic tools to create homogenous subgroups. Several studies have indicated that patients with autism have higher rates of minor physical anomalies (MPAs) and that MPAs may serve as a diagnostic tool; however, the results have been inconsistent. Using the cumulative data from seven studies on MPAs in autism, this meta-analysis seeks to examine whether the aggregate data provide evidence of a large mean effect size and statistical significance for MPAs in autism. It covers the studies using multiple research methods till June 2007. The current results from seven studies suggested a significant association of MPAs in autism with a robust pooled effect size (d=0.84), and thereby provide the strongest evidence to date about the close association between MPAs and autism. Our results emphasize the importance of MPAs in the identification of heterogeneity in autism and suggest that the success of future autism genetics research will be exploited by the use of MPAs. Implications for the design of future studies on MPAs in autism are discussed and suggestions for further investigation of these important markers are proposed. Clarifying this relation might improve understanding of risk factors and molecular mechanisms in autism.

Pathways to psychosis: a comparison of the pervasive developmental disorder subtype Multiple Complex Developmental Disorder and the "At Risk Mental State".

BACKGROUND: The comparison of high-risk populations with different developmental pathways to psychosis may lend more insight into the heterogeneity of the manifestation of the psychotic syndrome, and possible differing etiological pathways. AIM: To compare high-risk traits and symptoms in two populations at risk for psychosis, i.e. (1) help-seeking adolescents presenting with prodromal symptoms meeting the criteria for At Risk Mental State (ARMS), and (2) adolescents with Multiple Complex Developmental Disorder (MCDD), a PDD-NOS subtype characterized by severe, early childhood-onset deficits in affect regulation, anxieties, disturbed social relationships, and thought disorder. METHOD: 80 ARMS- and 32 MCDD-adolescents (12-18 years) were compared on prodromal symptoms (Structured Interview of Prodromal Symptoms, and Bonn Scale for the Assessment of Basic Symptoms-Prediction list), and autism traits (Social Communication Questionnaire). In addition, both high-risk groups were compared with 82 healthy controls on schizotypal traits (Schizotypal Personality Questionnaire-Revised). RESULTS: Although the high-risk groups clearly differed in early developmental and treatment histories as well as autism traits, they did not differ with regard to schizotypal traits and basic symptoms, as well as disorganized and general prodromal symptoms. There were, however, group differences in positive and negative prodromal symptoms. Interestingly, 78% of the adolescents with MCDD met criteria for ARMS. CONCLUSION: These findings suggest that children diagnosed with MCDD are at high risk for developing psychosis later in life, and support the notion that there are different developmental pathways to psychosis. Follow-up research is needed to compare the rates of transition to psychosis in both high-risk groups.

A new symptom model for autism cross-validated in an independent sample.

BACKGROUND: Results from several studies indicated that a symptom model other than the DSM triad might better describe symptom domains of autism. The present study focused on a) investigating the stability of a new symptom model for autism by cross-validating it in an independent sample and b) examining the invariance of the model regarding three covariates: symptom severity, intelligence, and age. METHOD: The validity of the symptom model was examined in an independent sample of N = 263 children and adolescents with autism spectrum disorders, and model invariance was studied in a larger sample of N = 356 children and adolescents with autism spectrum disorders. The fit of the symptom model to the sample data was compared to that of alternative models (including the DSM triad), and the invariance of the new model was investigated for each covariate by multiple-group comparisons. RESULTS: The fit of the new symptom model was better than that of two alternative models. It could not be compared to that of the DSM triad, because the latter encountered empirical identification problems. There were no significant or substantive differences between the estimated model in each of the dichotomised groups for any of the three covariates, which indicated factorial invariance of both structural form and factor loadings. CONCLUSIONS: The symptom model appeared to be relatively stable: It could be cross-validated in the independent sample and factorial invariance was shown between the dichotomised groups for each covariate. Further model validation with instruments other than the Autism Diagnostic Interview-Revised (ADI-R) is recommended.

Integrity of lateral and feedbackward connections in visual processing in children with pervasive developmental disorder.

Enhanced visual detail processing in subjects with pervasive developmental disorder (PDD) has been related to impairments in feature integration. The functional integrity of two types of neuronal connections involved in visual feature integration, namely horizontal and feedbackward connections, were tested. Sixteen children with PDD and 17 age- and IQ-matched control children (mean age 13.3 years) were included. In a texture segregation task the difference in ERP response to homogeneous and checkered visual stimuli was determined. Additionally, in a contour integration task subjects had to point out a contour consisting of colinearly aligned Gabor signals in backgrounds increasing in noise. Children with PDD showed a normal performance on the contour integration task, suggesting that neurons in the primary visual cortex of children with PDD can effectively integrate the activity of local detectors that process different aspects of the same object information by making use of long-range lateral connections. The amplitude of ERP activity related to texture segregation was also not different between the PDD and control groups, indicating functional visual feedback mechanisms between V1 and higher order areas in subjects with PDD. However, a difference in latency of texture-segmentation related activity between the groups was noted. This effect did not reach significance, which could be due to the small N of the study. Therefore, the data need replication in a study with larger samples before more definitive conclusions can be drawn.

The impact of hyperactivity and leptin on recovery from anorexia nervosa.

In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery. Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.

Abnormal spatial frequency processing in high-functioning children with pervasive developmental disorder (PDD).

OBJECTIVE: Basic abnormalities in visual information processing could be associated with the local visual bias often found in subjects with PDD. Therefore, the present study investigated the existence of deficits in spatial frequency processing at an early sensory level in children with PDD. METHODS: Visual evoked potentials (VEPs) and VEP dipole sources elicited by high and low spatial frequency gratings were analyzed in high-functioning children with PDD and matched controls. RESULTS: Around 80 ms (N80-latency) children with PDD did not show the same robust differences between high and low spatial frequencies in VEP amplitude and VEP brain sources as controls, because of atypical processing of high frequencies. Analyses at the P1-latency (130 ms) revealed that, although similar inferior-medial brain sources were activated for the processing of both spatial frequencies in the PDD and control group, source strength in response to both frequencies was weaker in the PDD compared to control group. Moreover, additional superior-lateral brain sources were activated during the processing of both frequencies in the PDD group. CONCLUSIONS: Decreased specialized processing of high and low spatial frequencies might be a robust characteristic of PDD. Early in processing abnormalities in high spatial frequency processing seem to occur in PDD. At a later phase in processing there seems to be both atypical high and low spatial frequency processing. Considering that the processing of specific spatial frequencies plays an important role in the processing of global and local aspects of hierarchical stimuli and faces and of emotions, present data suggest that peculiarities in PDD subjects with respect to these stimuli might be related to an abnormality in more fundamental visual processes. SIGNIFICANCE: A basic abnormality in visual frequency processing is established in children with PDD.

Visual information processing in high-functioning individuals with autism spectrum disorders and their parents.

The authors assessed visual information processing in high-functioning individuals with pervasive developmental disorders (PDD) and their parents. The authors used tasks for contrast sensitivity, motion, and form perception to test visual processing occurring relatively early and late in the magnocellular-dorsal and parvocellular-ventral pathways. No deficits were found in contrast sensitivity for low or high spatial frequencies or for motion or form perception between individuals with PDD in comparison with a matched control group. Individuals with PDD performed equally with or better than controls on motion detection tasks. In addition, the authors did not find differences on any of the tasks between parents of the PDD group and matched control parents. These results indicate that high-functioning individuals with PDD and their parents are able to process visual stimuli that rely on early or late processing in the magnocellular-dorsal and parvocellular-ventral pathways as well as controls.

Time-varying differences in evoked potentials elicited by high versus low spatial frequencies: a topographical and source analysis.

OBJECTIVE: To investigate time-varying differences in visual-evoked potentials (VEPs) and dipoles elicited by high versus low spatial frequencies. The main question was whether different spatial frequencies are processed in distinct cortical areas, especially after 100 ms. An additional question was whether and how a hemispheric balance in spatial frequency processing develops over time. METHODS: Stimuli were square-wave gratings, with spatial frequencies of 0.75, 1.5, and 6 c/d. VEPs and dipole models were analyzed at various latencies. RESULTS: For the time-window of 80-100 ms, spatial frequency-related differences in VEPs and dipoles in posterior regions as reported previously were replicated: lower spatial frequencies were associated with more positivity in the VEP and with more anterior and radial sources than high frequencies. However, after 100 ms differences in amplitude, but not in topography and dipoles, were found between the different spatial frequencies. Between 180-200 ms a right hemisphere dominance was found for all frequencies. CONCLUSIONS: After 100 ms, VEPs in response to different spatial frequencies seem to be generated in the same cortical areas. Also, no evidence for frequency-related hemispheric lateralization was found. SIGNIFICANCE: Insight is provided into the functional-anatomical basis of longer-latency frequency-related differences in processing.

The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study.

In a double-blind placebo-controlled crossover trial 23 autistic children, aged 3-7 years, were treated with a mean daily dosage of 1 mg/kg naltrexone for 4 weeks. Drug effects were monitored with behavior checklists rated by parents and teachers, and ethological playroom observations. On average, parents' checklists and playroom data could not differentiate between naltrexone treatment and placebo treatment; however, teachers significantly favored naltrexone treatment. They reported a decrease in hyperactivity and irritability. No effects of naltrexone on social and stereotypic behavior could be demonstrated.

Auditory event-related brain potentials in autistic children and three different control groups.

ERPs to auditory stimuli, generated during an oddball task, were obtained in a group of autistic children and three control groups (normal, ADDH, and dyslectic children, respectively). The task included the presentation of standards, deviants, and novels and had a (between-group) passive vs. active (counting) condition. It was examined whether 1) it was possible to replicate several earlier findings, 2) autistics manifest an abnormal lateralization pattern of ERPs, 3) autistics have an abnormal mismatch negativity (MMN), and 4) differences between autistics and normals are really specific to the autistic group. The only finding that could be replicated was that autistics have a smaller A/Pcz/300. There was no evidence for abnormal lateralization or abnormal MMN; however, there was an unexpected effect of the task manipulation on the amplitude of the P3: in autistics, the occipital P3 to deviant stimuli was significantly larger in the active than in the passive condition, a finding, like the replication of the smaller A/Pcz/300, specific to the autistic group. It was suggested that the auditory occipital task effect is related to understimulation of the occipital lobe by visual stimuli in autistic children.

Adrenal androgens and aggression in conduct disorder prepubertal boys and normal controls.

BACKGROUND: The evidence for a role of androgens in human aggression is less convincing than in animals. We examined the relationship between androgens and aggression in prepubertal boys who were diagnosed as suffering from severe aggression and antisocial behavior. METHODS: Plasma levels of testosterone (T), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS) were measured in 15 boys with a conduct disorder (CD) and 25 normal control (NC) boys. Parents and teachers of the children rated the intensity of aggression and delinquency over the last 6 months. RESULTS: CD boys had significantly higher levels of DHEAS and marginally significantly higher levels of A; there were no differences in T. Moreover, DHEAS levels were significantly positively correlated with the intensity of aggression and delinquency as rated by both parents and teachers. CONCLUSIONS: The results suggest that adrenal androgen functioning plays an important role in the onset and maintenance, of aggression in young boys.

ERP differences among subtypes of pervasive developmental disorders.

BACKGROUND: Children with multiple complex developmental disorder (MCDD) have been distinguished from autistic children on the basis of chart reviews. It was questioned whether it is possible to find other, e.g., event-related potential (ERP), evidence for this assertion. METHODS: ERPs were measured in response to stimuli in a visual oddball task in autistic, MCDD, attention deficit disorder, dyslexic, and normal control children, to study whether ERP peaks can be used to distinguish autistic and MCDD children, and to classify the aforementioned groups. RESULTS: It was found that the P3 at four different leads and the frontal Nc showed differences among the groups, and that the autistic and MCDD groups differed from each other as well as from the other groups. Also, it was found that, using discriminant analyses in which these parameters were included, children were classified above chance level. Especially in the MCDD group, a high percentage of correct classification was seen. CONCLUSIONS: ERP parameters indicate that autistic and MCDD children might differ in underlying pathology and might therefore, better be regarded as two separate diagnostic entities.

Eye movements, visual attention, and autism: a saccadic reaction time study using the gap and overlap paradigm.

BACKGROUND: On the basis of the literature on autism, it was hypothesized that children with autism have deficits in attentional (dis-)engagement mechanisms. METHODS: A saccadic gap-overlap task was used to study visual engagement and disengagement in 16 high-functioning autistic children of about 10 years of age and 15 age- and IQ-matched normal control children. Subjects were asked to make saccadic eye movements from a fixation point to a suddenly appearing target as fast as possible. The saccadic reaction time was compared in two conditions: 1) the overlap condition, in which the fixation point was continuously visible, and 2) the gap condition, in which the fixation point was turned off 200 msec before the target appeared. RESULTS: Although no differences between the groups in either condition was observed, the gap effect (i.e., the difference in saccadic reaction time between the overlap condition and the gap condition) was smaller in the autistic group than in the control group. CONCLUSIONS: We concluded that autistic children show a lower level of attentional engagement.

The use of adrenocorticotrophic hormone (4-9) analog ORG 2766 in autistic children: effects on the organization of behavior.

In a double-blind placebo-controlled crossover trial, 14 autistic children were treated with the neuropeptide ORG 2766, a synthetic analog of adrenocorticotrophic hormone (ACTH) (4-9). ORG 2766 treatment (20 mg per day during 4 weeks) was associated with an increased amount and an improved quality of the social interaction of the autistic children with a familiar experimenter. These changes in interaction were clinically relevant. Following treatment with ORG 2766 gaze and smile behaviors of child and experimenter showed stronger temporal contingencies. Further, after ORG 2766, stereotypies were temporally disconnected from verbal initiatives. The data supported the notion of a stimulating effect of ORG 2766 on social interaction. The implications of these findings for the endogenous opioid theory of autism are discussed.

Event-related potentials and performance of attention-deficit hyperactivity disorder: children and normal controls in auditory and visual selective attention tasks.

Attention-deficit hyperactivity disorder (ADHD) children and normal controls (7-13 yrs old) performed an auditory and visual selective attention task. Subjects were instructed to respond to the infrequent (10%) stimuli in the relevant channel. Processing negativity (PN) and several other ERP peaks were scored at the midline electrodes. In the auditory task, controls had more correct detections (hits), less false alarms, larger P3b amplitudes to nontarget stimuli (but not to hits), a larger central PN and larger early frontal positivity (100-250 ms) to target stimuli than ADHD subjects. In the visual modality, controls had more correct detections, less false alarms, larger P3b amplitudes to nontarget stimuli (but not to hits), and larger frontal P3(1) amplitudes to infrequent than to frequent stimuli. It was hypothesized that in ADHD children in both the auditory and the visual task, there is a deficit in the activation of the P3b process. Incorrect triggering of the P3b process might be caused by disturbances in other aspects of the attention process, preceding the P3b.