Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions.

BACKGROUND: The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. METHODS: We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). RESULTS: We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10(-7); OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). CONCLUSIONS: Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment.

Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis.

BACKGROUND: Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. AIMS: To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). METHOD: Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD-ASD (n = 16) and healthy controls (n = 78). RESULTS: Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures. CONCLUSIONS: Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.

Specificity of impaired facial identity recognition in children with suspected developmental prosopagnosia.

Adults experiencing face recognition difficulties in the absence of known brain injury are described as cases of developmental prosopagnosia (DP), under the assumption that specific face recognition impairments have always been present. However, only five childhood cases of DP have been reported, and the majority had additional socio-communicative impairments consistent with an autism spectrum disorder (ASD). We tested face recognition skills of six 4- to 8-year-old children, who were suspected of having DP, and tested for ASD using established diagnostic tools. Two children met criteria for ASD. One child did not exhibit consistent face recognition impairments. The remaining three children were severely impaired on multiple tasks of unfamiliar face recognition despite normal cognitive functioning and no evidence of ASD. Two of these children were also impaired at object recognition suggesting more general visual recognition problems. The final child showed normal object recognition demonstrating apparently specific problems with facial identity recognition.

Face recognition impairments despite normal holistic processing and face space coding: evidence from a case of developmental prosopagnosia.

Holistic processing and face space coding are widely considered primary perceptual mechanisms behind good face recognition. Here, however, we present the case of S.P., a developmental prosopagnosic who demonstrated severe impairments in face memory and face perception, yet showed normal holistic processing and face space coding. Across three composite experiments, S.P. showed normal-strength holistic processing for upright faces and no composite effect for inverted faces. Across five aftereffect experiments, S.P. showed normal-sized face aftereffects, which derived normally from face space rather than shape-generic mechanisms. The case of S.P. implies: (a) normal holistic processing and face space coding can be insufficient for good face recognition even when present in combination; and (b) the focus of recent literature on holistic processing and face space should be expanded to include other potential face processing mechanisms (e.g., part-based processing). Our article also highlights the importance of internal task reliability in drawing inferences from single-case studies.

Impaired P1 Habituation and Mismatch Negativity in Children with Autism Spectrum Disorder.

Passive testing of auditory function is an important objective in individuals with ASD due to known difficulties in understanding and/or following task instructions. In present study the habituation to standard tones following deviants and the auditory discriminative processes were examined in two conditions: electronic and human sounds, in a sample of 16 ASD children. ASD children presented a reduced habituation in the P1 component and a decrease in the amplitude of the mismatch negativity indicating a lower auditory discrimination with respect to controls. MMN amplitude was related to sensory sensitivity. Results suggest an increased activation to repeatedly auditory stimulus and a poor auditory discrimination, for both: electronic and human sounds with consequences on the impaired sensory behavior of ASD subjects.

Diagnosing prosopagnosia: effects of ageing, sex, and participant-stimulus ethnic match on the Cambridge Face Memory Test and Cambridge Face Perception Test.

The Cambridge Face Memory Test (CFMT) and Cambridge Face Perception Test (CFPT) have provided the first theoretically strong clinical tests for prosopagnosia based on novel rather than famous faces. Here, we assess the extent to which norms for these tasks must take into account ageing, sex, and testing country. Data were from Australians aged 18 to 88 years (N = 240 for CFMT; 128 for CFPT) and young adult Israelis (N = 49 for CFMT). Participants were unselected for face recognition ability; most were university educated. The diagnosis cut-off for prosopagnosia (2 SDs poorer than mean) was affected by age, participant-stimulus ethnic match (within Caucasians), and sex for middle-aged and older adults on the CFPT. We also report internal reliability, correlation between face memory and face perception, correlations with intelligence-related measures, correlation with self-report, distribution shape for the CFMT, and prevalence of developmental prosopagnosia.

No evidence of atypical attentional disengagement in autism: A study across the spectrum.

The ability to disengage attention and reengage elsewhere has been proposed as a fundamental deficit in the autism spectrum, potentially disrupting development of higher cognitive domains. Eye-movements were recorded while 16 autism spectrum children of mixed ability, and 18 typically developing age-matched controls, completed the Gap-Overlap paradigm. A significant difference in latency to fixate target was found between Gap and Overlap conditions. A significant interaction with group was due to autism spectrum participants' shorter latencies to fixate target in the Gap condition, but similar group responses in the Overlap condition. Considerable within-group variability emerged. We predicted that attentional disengaging would be related to specific features of the phenotype; however, there was no evidence of an association with receptive language, non-verbal IQ, sensory behaviors, or autistic severity in autism spectrum or typically developing groups. In conclusion, while atypical visual attention mechanisms may be a feature of autism spectrum, this is not explained by impaired visual disengaging but is more likely due to increased susceptibility of visual fixation offset cueing. Despite best efforts, nine additional autism spectrum children could not complete testing, and data from a further six were unusable; more work is needed to develop research methods that enable individuals across the spectrum to participate.

Processing of observed pupil size modulates perception of sadness and predicts empathy.

Facial autonomic responses may contribute to emotional communication and reveal individual affective style. In this study, the authors examined how observed pupillary size modulates processing of facial expression, extending the finding that incidentally perceived pupils influence ratings of sadness but not those of happy, angry, or neutral facial expressions. Healthy subjects rated the valence and arousal of photographs depicting facial muscular expressions of sadness, surprise, fear, and disgust. Pupil sizes within the stimuli were experimentally manipulated. Subjects themselves were scored with an empathy questionnaire. Diminishing pupil size linearly enhanced intensity and valence judgments of sad expressions (but not fear, surprise, or disgust). At debriefing, subjects were unaware of differences in pupil size across stimuli. These observations complement an earlier study showing that pupil size directly influences processing of sadness but not other basic emotional facial expressions. Furthermore, across subjects, the degree to which pupil size influenced sadness processing correlated with individual differences in empathy score. Together, these data demonstrate a central role of sadness processing in empathetic emotion and highlight the salience of implicit autonomic signals in affective communication.

Autism spectrum disorder in adults: diagnosis, management, and health services development.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by pervasive difficulties since early childhood across reciprocal social communication and restricted, repetitive interests and behaviors. Although early ASD research focused primarily on children, there is increasing recognition that ASD is a lifelong neurodevelopmental disorder. However, although health and education services for children with ASD are relatively well established, service provision for adults with ASD is in its infancy. There is a lack of health services research for adults with ASD, including identification of comorbid health difficulties, rigorous treatment trials (pharmacological and psychological), development of new pharmacotherapies, investigation of transition and aging across the lifespan, and consideration of sex differences and the views of people with ASD. This article reviews available evidence regarding the etiology, legislation, diagnosis, management, and service provision for adults with ASD and considers what is needed to support adults with ASD as they age. We conclude that health services research for adults with ASD is urgently warranted. In particular, research is required to better understand the needs of adults with ASD, including health, aging, service development, transition, treatment options across the lifespan, sex, and the views of people with ASD. Additionally, the outcomes of recent international legislative efforts to raise awareness of ASD and service provision for adults with ASD are to be determined. Future research is required to identify high-quality, evidence-based, and cost-effective models of care. Furthermore, future health services research is also required at the beginning and end of adulthood, including improved transition from youth to adult health care and increased understanding of aging and health in older adults with ASD.

Cortical and subcortical glutathione levels in adults with autism spectrum disorder.

Increased oxidative stress has been postulated to contribute to the pathogenesis of autism spectrum disorder (ASD). However, reports of alterations in oxidation markers including glutathione (GSH), the major endogenous antioxidant, are indirect, coming from blood plasma level measurements and postmortem studies. Therefore we used in-vivo 3 Tesla proton magnetic resonance spectroscopy ([1H]MRS) to directly measure GSH concentrations in the basal ganglia (BG) and the dorsomedial prefrontal cortex of 21 normally intelligent adult males with ASD and 29 controls who did not differ in age or IQ. There was no difference in brain GSH between patients and controls in either brain area; neither did GSH levels correlate with measures of clinical severity in patients. Thus [1H]MRS measures of cortical and subcortical GSH are not a biomarker for ASD in intellectually able adult men.

Does sex influence the diagnostic evaluation of autism spectrum disorder in adults?

It is unknown whether sex influences the diagnostic evaluation of autism spectrum disorder, or whether male and female adults within the spectrum have different symptom profiles. This study reports sex differences in clinical outcomes for 1244 adults (935 males and 309 females) referred for autism spectrum disorder assessment. Significantly, more males (72%) than females (66%) were diagnosed with an autism spectrum disorder of any subtype (x(2) = 4.09; p = 0.04). In high-functioning autism spectrum disorder adults (IQ > 70; N = 827), there were no significant sex differences in severity of socio-communicative domain symptoms. Males had significantly more repetitive behaviours/restricted interests than females (p = 0.001, d = 0.3). A multivariate analysis of variance indicated a significant interaction between autism spectrum disorder subtype (full-autism spectrum disorder/partial-autism spectrum disorder) and sex: in full-autism spectrum disorder, males had more severe socio-communicative symptoms than females; for partial-autism spectrum disorder, the reverse was true. There were no sex differences in prevalence of co-morbid psychopathologies. Sex influenced diagnostic evaluation in a clinical sample of adults with suspected autism spectrum disorder. The sexes may present with different manifestations of the autism spectrum disorder phenotype and differences vary by diagnostic subtype. Understanding and awareness of adult female repetitive behaviours/restricted interests warrant attention and sex-specific diagnostic assessment tools may need to be considered.

Obsessive-Compulsive Disorder in Adults with High-Functioning Autism Spectrum Disorder: What Does Self-Report with the OCI-R Tell Us?

Little is known about the symptom profile of obsessive-compulsive disorder (OCD) in individuals who have autism spectrum disorders (ASD). It is also unknown whether self-report questionnaires are useful in measuring OCD in ASD. We sought to describe the symptom profiles of adults with ASD, OCD, and ASD + OCD using the Obsessive Compulsive Inventory-Revised (OCI-R), and to assess the utility of the OCI-R as a screening measure in a high-functioning adult ASD sample. Individuals with ASD (n = 171), OCD (n = 108), ASD + OCD (n = 54) and control participants (n = 92) completed the OCI-R. Individuals with ASD + OCD reported significantly higher levels of obsessive-compulsive symptoms than those with ASD alone. OCD symptoms were not significantly correlated with core ASD repetitive behaviors as measured on the ADI-R or ADOS-G. The OCI-R showed good psychometric properties and corresponded well with clinician diagnosis of OCD. Receiver operating characteristic analysis suggested cut-offs for OCI-R Total and Checking scores that discriminated well between ASD + versus -OCD, and fairly well between ASD-alone and OCD-alone. OCD manifests separately from ASD and is characterized by a different profile of repetitive thoughts and behaviors. The OCI-R appears to be useful as a screening tool in the ASD adult population.

Autistic traits and abnormal sensory experiences in adults.

Sensory processing abnormalities are common in autism spectrum disorders (ASD), and now form part of the Diagnostic and Statistical Manual 5th Edition (DSM-5) diagnostic criteria, but it is unclear whether they characterize the 'broader phenotype' of the disorder. We recruited adults (n = 772) with and without an ASD and administered the Autism Quotient (AQ) along with the Adult/Adolescent Sensory Profile (AASP), the Cardiff Anomalous Perceptions Scale (CAPS), and the Glasgow Sensory Questionnaire (GSQ), all questionnaire measures of abnormal sensory responsivity. Autism traits were significantly correlated with scores on all three sensory scales (AQ/GSQ r = 0.478; AQ/AASP r = 0.344; AQ/CAPS r = 0.333; all p < 0.001). This relationship was linear across the whole range of AQ scores and was true both in those with, and without, an ASD diagnosis. It survived correction for anxiety trait scores, and other potential confounds such as mental illness and migraine.

The neuropsychology of male adults with high-functioning autism or asperger syndrome.

Autism Spectrum Disorder (ASD) is diagnosed on the basis of behavioral symptoms, but cognitive abilities may also be useful in characterizing individuals with ASD. One hundred seventy-eight high-functioning male adults, half with ASD and half without, completed tasks assessing IQ, a broad range of cognitive skills, and autistic and comorbid symptomatology. The aims of the study were, first, to determine whether significant differences existed between cases and controls on cognitive tasks, and whether cognitive profiles, derived using a multivariate classification method with data from multiple cognitive tasks, could distinguish between the two groups. Second, to establish whether cognitive skill level was correlated with degree of autistic symptom severity, and third, whether cognitive skill level was correlated with degree of comorbid psychopathology. Fourth, cognitive characteristics of individuals with Asperger Syndrome (AS) and high-functioning autism (HFA) were compared. After controlling for IQ, ASD and control groups scored significantly differently on tasks of social cognition, motor performance, and executive function (P's < 0.05). To investigate cognitive profiles, 12 variables were entered into a support vector machine (SVM), which achieved good classification accuracy (81%) at a level significantly better than chance (P < 0.0001). After correcting for multiple correlations, there were no significant associations between cognitive performance and severity of either autistic or comorbid symptomatology. There were no significant differences between AS and HFA groups on the cognitive tasks. Cognitive classification models could be a useful aid to the diagnostic process when used in conjunction with other data sources-including clinical history.

Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic.

An Autism Spectrum Disorder (ASD) diagnosis is often used to access services. We investigated whether ASD diagnostic outcome varied when DSM-5 was used compared to ICD-10R and DSM-IV-TR in a clinical sample of 150 intellectually able adults. Of those diagnosed with an ASD using ICD-10R, 56 % met DSM-5 ASD criteria. A further 19 % met DSM-5 (draft) criteria for Social Communication Disorder. Of those diagnosed with Autistic Disorder/Asperger Syndrome on DSM-IV-TR, 78 % met DSM-5 ASD criteria. Sensitivity of DSM-5 was significantly increased by reducing the number of criteria required for a DSM-5 diagnosis, or by rating 'uncertain' criteria as 'present', without sacrificing specificity. Reduced rates of ASD diagnosis may mean some ASD individuals will be unable to access clinical services.

Visual scan paths and recognition of facial identity in autism spectrum disorder and typical development.

BACKGROUND: Previous research suggests that many individuals with autism spectrum disorder (ASD) have impaired facial identity recognition, and also exhibit abnormal visual scanning of faces. Here, two hypotheses accounting for an association between these observations were tested: i) better facial identity recognition is associated with increased gaze time on the Eye region; ii) better facial identity recognition is associated with increased eye-movements around the face. METHODOLOGY AND PRINCIPAL FINDINGS: Eye-movements of 11 children with ASD and 11 age-matched typically developing (TD) controls were recorded whilst they viewed a series of faces, and then completed a two alternative forced-choice recognition memory test for the faces. Scores on the memory task were standardized according to age. In both groups, there was no evidence of an association between the proportion of time spent looking at the Eye region of faces and age-standardized recognition performance, thus the first hypothesis was rejected. However, the 'Dynamic Scanning Index'--which was incremented each time the participant saccaded into and out of one of the core-feature interest areas--was strongly associated with age-standardized face recognition scores in both groups, even after controlling for various other potential predictors of performance. CONCLUSIONS AND SIGNIFICANCE: In support of the second hypothesis, results suggested that increased saccading between core-features was associated with more accurate face recognition ability, both in typical development and ASD. Causal directions of this relationship remain undetermined.

Adaptive face space coding in congenital prosopagnosia: typical figural aftereffects but abnormal identity aftereffects.

People with congenital prosopagnosia (CP) report difficulty recognising faces in everyday life and perform poorly on face recognition tests. Here, we investigate whether impaired adaptive face space coding might contribute to poor face recognition in CP. To pinpoint how adaptation may affect face processing, a group of CPs and matched controls completed two complementary face adaptation tasks: the figural aftereffect, which reflects adaptation to general distortions of shape, and the identity aftereffect, which directly taps the mechanisms involved in the discrimination of different face identities. CPs displayed a typical figural aftereffect, consistent with evidence that they are able to process some shape-based information from faces, e.g., cues to discriminate sex. CPs also demonstrated a significant identity aftereffect. However, unlike controls, CPs impression of the identity of the neutral average face was not significantly shifted by adaptation, suggesting that adaptive coding of identity is abnormal in CP. In sum, CPs show reduced aftereffects but only when the task directly taps the use of face norms used to code individual identity. This finding of a reduced face identity aftereffect in individuals with severe face recognition problems is consistent with suggestions that adaptive coding may have a functional role in face recognition.

Recognition of own- and other-race faces in autism spectrum disorders.

Empirical data regarding the extent of face recognition abnormalities in autism spectrum disorder (ASD) is inconsistent. Here, 27 ASD and 47 typically developing (TD) children completed an immediate two-alternative forced-choice identity matching task. We contrasted recognition of own- and other-race faces, and, counter to prediction, we found a typical advantage for recognizing own- over other-race faces in both the ASD and TD groups. In addition, ASD and TD groups responded similarly to stimulus manipulations (use of identical or different photographs for identity matching and cropping stimuli to remove hair information). However, age-standardized scores varied widely within the ASD sample, and a subgroup of ASD participants with impaired face recognition did not exhibit a significant own-race recognition advantage. An explanation regarding early experience with faces is considered, and implications for research of individual variation within ASD are discussed.

Impaired holistic coding of facial expression and facial identity in congenital prosopagnosia.

We test 12 individuals with congenital prosopagnosia (CP), who replicate a common pattern of showing severe difficulty in recognising facial identity in conjunction with normal recognition of facial expressions (both basic and 'social'). Strength of holistic processing was examined using standard expression composite and identity composite tasks. Compared to age- and sex-matched controls, group analyses demonstrated that CPs showed weaker holistic processing, for both expression and identity information. Implications are (a) normal expression recognition in CP can derive from compensatory strategies (e.g., over-reliance on non-holistic cues to expression); (b) the split between processing of expression and identity information may take place after a common stage of holistic processing; and (c) contrary to a recent claim, holistic processing of identity is functionally involved in face identification ability.

Learning new faces in typically developing children and children on the autistic spectrum.

As faces become familiar, recognition becomes easier but the style of processing also changes. Here, twenty-one typically developing (TD) children and twenty-one children with autism spectrum disorder (ASD) were familiarised with 6 identities over 3 days. Next, they completed a 4-alternative forced-choice matching test in which targets were the 6 familiarised faces and 6 unfamiliar faces. The TD group showed a significant advantage for familiarised faces when matching whole faces and both internal and external facial regions. The ASD group showed similar familiarisation effects for whole and external faces, but not for internal regions. The ASD group was also impaired at matching eyes and mouths of familiarised faces. Results suggest the process of acquiring familiarity with faces differs from ASD and TD children.