Fritz Poustka

A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p

Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes.

Abnormal neural responses to emotional visual stimuli in adolescents with conduct disorder

BACKGROUND It is widely held that aggression and antisocial behavior arise as a consequence of a deficiency in responding to emotional cues in the social environment. We asked whether neural responses evoked by affect-laden pictures would be abnormal in adolescents with conduct disorder (CD). METHODS Functional magnetic resonance imaging during passive viewing of pictures with neutral or strong negative affective valence was performed in 13 male adolescents with severe CD aged 9 to 15 years and in 14 healthy age-matched control subjects. RESULTS Main effects for negative-neutral affective valence included activations in the amygdala and hippocampus, ventral extrastriate visual cortex, and intraparietal sulcus bilaterally. There was a significant group-by-condition interaction in the right dorsal anterior cingulate cortex that was due to a pronounced deactivation in the patient group during viewing of negative pictures. When correcting for anxiety and depressive symptoms, we additionally found a reduced responsiveness of the left amygdala to negative pictures in patients compared with control subjects. CONCLUSIONS We suggest that these findings reflect an impairment of both the recognition of emotional stimuli and the cognitive control of emotional behavior in patients with CD, resulting in a propensity for aggressive behavior.

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: Alternative biallelic variation in rhesus monkeys

SummaryBy conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter genes 5′-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio. years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and nonhuman primate populations.

Functional imbalance of visual pathways indicates alternative face processing strategies in autism

Objective: To investigate whether autistic subjects show a different pattern of neural activity than healthy individuals during processing of faces and complex patterns. Methods: Blood oxygen level–dependent (BOLD) signal changes accompanying visual processing of faces and complex patterns were analyzed in an autistic group (n = 7; 25.3 [6.9] years) and a control group (n = 7; 27.7 [7.8] years). Results: Compared with unaffected subjects, autistic subjects demonstrated lower BOLD signals in the fusiform gyrus, most prominently during face processing, and higher signals in the more object-related medial occipital gyrus. Further signal increases in autistic subjects vs controls were found in regions highly important for visual search: the superior parietal lobule and the medial frontal gyrus, where the frontal eye fields are located. Conclusions: The cortical activation pattern during face processing indicates deficits in the face-specific regions, with higher activations in regions involved in visual search. These findings reflect different strategies for visual processing, supporting models that propose a predisposition to local rather than global modes of information processing in autism.

A structural neural deficit in adolescents with conduct disorder and its association with lack of empathy

The goal of this study was to determine whether brain regions implicated in emotion processing show structural alterations in adolescents with conduct disorder (CD). Using an optimized voxel-based morphometry protocol, we compared grey matter volume in 12 patients with CD and 12 age-, sex-, and intelligence-matched control subjects. Grey matter volume in bilateral anterior insular cortex and the left amygdala was significantly reduced in CD patients compared to healthy control subjects. The insular grey matter abnormalities could be attributed to aggressive behaviour. Moreover, bilateral anterior insular grey matter volume in CD patients correlated significantly with empathy scores. These novel findings point at a joint neuroanatomical substrate underpinning aggressive behaviour and impaired capacity of empathy and suggest a critical role for the anterior insula in regulating social behaviour.

The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives

BACKGROUND Autism and schizophrenia are considered to be substantially influenced by genetic factors. The endophenotype of both disorders probably also includes deficits in affect perception. The objective of this study was to examine the capacity to detect facially expressed emotion in autistic and schizophrenic subjects, their parents and siblings. METHOD Thirty-five subjects with autism and 102 of their relatives, 21 schizophrenic subjects and 46 relatives from simplex (one child affected) and multiplex (more than one child affected) families, as well as an unaffected control sample consisting of 22 probands completed a 50-item computer-based test to assess the ability to recognize basic emotions. RESULTS The autistic subjects showed a poorer performance on the facial recognition test than did the schizophrenic and the unaffected individuals. In addition, there was a tendency for subjects from multiplex families with autistic loading to score lower on the test than individuals from simplex families with autistic loading. Schizophrenic subjects and their relatives as well as siblings and parents of autistic subjects did not differ from the sample of unaffected subjects in their ability to judge facial affect. CONCLUSIONS Findings corroborate the assumption that emotion detection deficits are part of the endophenotype of autism. In families with autistic children, the extent of facial recognition deficits probably indexes an elevation in familial burden. It seems unlikely that problems in emotion perception form a consistent part of the endophenotype of schizophrenia or the broader phenotype in relatives of patients with psychosis or autism.

Assessing autistic traits: cross‐cultural validation of the social responsiveness scale (SRS)

The Social Responsiveness Scale (SRS) is a quantitative measure of autistic traits in 4‐ to 18‐year‐olds, which has been used in behavior‐genetic, epidemiological and intervention studies. The US standardization demonstrated a single‐factor structure and good to excellent psychometric properties. The cross‐cultural validity of the German adaptation of the parent‐report SRS in a sample of N=1,436 children and adolescents: 838 typically developing and 527 clinical participants (160 with autism spectrum disorders (ASDs)) was examined. Internal consistency (0.91–0.97), test–retest reliability (0.84–0.97), interrater reliability (0.76 and 0.95) and convergent validity with the Autism Diagnostic Observation Schedule as well as the Autism Diagnostic Interview—Revised and Social Communication Questionnaire (0.35–0.58) were satisfactory to good. The SRS total score discriminated between ASD and other mental disorders. SRS scores proved to be sufficiently independent of general psychopathology. Principal component analyses yielded single‐factor solutions for the normative and clinical subsamples. In addition, construct validity was ensured by consistent correlations with the Vineland Adaptive Behavior Scales, the Child Behavior Checklist and the Junior Temperament and Character Inventory. Normative SRS total scores for girls and boys as well as values for ASD were lower in the German sample, while scores for conduct disorder and attention deficit hyperactivity/conduct disorder combined were higher. Generally, cross‐cultural validity of the SRS seems to be sufficiently assured for a large European sample. However, some discrepancies regarding SRS normative and clinical raw score distributions, reliability and validity findings are critically discussed.

Autism spectrum disorders: sex differences in autistic behaviour domains and coexisting psychopathology

The purpose of the present study was to examine possible differences between high‐functioning males and females with autism spectrum disorder (ASD) regarding the core symptoms of autism and coexisting psychopathology. A total of 23 females and 23 males matched for age, IQ, and ASD diagnoses were recruited(mean age 11y 9mo [SD 4y 5mo], range 5y‐20y 2mo) with an IQ above the range of learning disability (mean IQ 88.8 [SD 18.5], range 70–128). They were compared using the Autism Diagnostic Interview‐Revised, the Autism Diagnostic Observation Schedule, and the Child Behavior Checklist/4–18. We did not identify striking differences between males and females for the triad of autism core dysfunctions (deficits in reciprocal social interaction, communication, and repetitive, stereotyped behaviours) as assessed by expert ratings. However, with regard to several domains of coexisting psychopathology, parent reports revealed significantly more symptoms in females than males, particularly social problems (t=4.47, p<0.01, d=1.20), attention problems (t=3.39, p<0.01, d=0.80), and thought problems (t=3.24, p<0.01, d=0.84). These results are discussed with possible interpreting bias by parents who may expect more socially desired behaviour from daughters than from sons. The severity of social and attention problems in high‐functioning females with autism emphasizes the need for thorough assessments and interventions in these domains. Future research should compare the cognitive phenotype of autism between sexes.

Genotype)phenotype relationship in female carriers of the premutation and full mutation of FMR-1

The present French-German cooperative study focuses on the genotype-phenotype relationship of mutations of the FMR-1 gene and psychiatric conditions in mothers with a full mutation in the FMR-1 gene of fra-X children (n=13), mothers with a premutation in the FMR-1 gene of fra-X children (n=61), as well as premutated siblings of these mothers without affected children (n=17) and two non-mutated control groups: (1) siblings of these mothers with normal CGG repeat (n=18); and (2) mothers of non-fra-X autistic children (n=42). Mothers with a full mutation in the FMR-1 gene and mothers with a premutation in the FMR-1 gene did not differ in the frequency of any axis I disorder; however, both groups were diagnosed with social phobia more often than the control group of mothers of autistic children. Moreover, mothers with a premutation in the FMR-1 gene of fra-X children and their siblings with the premutation (without affected offspring) revealed a similar frequency of social phobia. Furthermore avoidant personality disorder was more common in groups of carriers of the full premutation than in siblings without mutation or than the control group of mothers with autistic children. On the basis of our data, we therefore suggest that social avoidance (expressed as social phobia or avoidant personality disorder) has been underestimated in previous studies of carriers with the FMR-1 full mutation or premutation. Comorbidity of axis I and axis II psychiatric diagnoses was mainly restricted to the group of carriers of the full mutation and carriers of the premutation of FMR-1. Correlations between size of CGG repeat and IQ as well as CGG and age of onset of axis I diagnosis were non-significant. IQ of subjects had no impact on presence or absence of axis I and/or axis II diagnoses.