A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders

There is growing interest in the role of gastrointestinal (GI) pathology and clinical expression of autism. Recent studies have demonstrated differences in the faecal clostridial populations harboured by autistic and non-autistic children. The potential of Lactobacillus plantarum WCSF1 (a probiotic) to modulate the gut microbiota of autistic subjects was investigated during a double-blind, placebo-controlled, crossover-designed feeding study. The faecal microbiota, gut function and behaviour scores of subjects were examined throughout the 12-week study. Lactobacillus plantarum WCFS1 feeding significantly increased Lab158 counts (lactobacilli and enterococci group) and significantly reduced Erec482 counts (Clostridium cluster XIVa) compared to placebo. Probiotic feeding also resulted in significant differences in the stool consistency compared to placebo and behaviour scores (total score and scores for some subscales) compared to baseline. The major finding of this work was the importance of study protocol in relation to the specific considerations of this subject population, with an extremely high dropout rate seen (predominantly during the baseline period). Furthermore, the relatively high inter-individual variability observed suggests that subsequent studies should use defined subgroups of autistic spectrum disorders, such as regressive or late-onset autism. In summary, the current study has highlighted the potential benefit of L. plantarum WCFS1 probiotic feeding in autistic individuals.

Securing provision for children with autistic spectrum disorders: the views of parents

An original questionnaire was designed to seek the perspectives of parents about the process of securing appropriate educational provision for their child with autism spectrum disorder. In total, 738 responses were analysed using both quantative and qualitative data. Although a broad range of opinion was evidenced and a clear majority of families were happy with the end decision of placement, most families were significantly less happy with the process to determine that provision. Most families found this process difficult to navigate and frustrating. This caused a high level of stress for a significant proportion of families. Implications for practice are discussed.

Autism spectrum disorder in a girl with a de novo x;19 balanced translocation

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

A complex chromosomal rearrangement involving chromosomes 2, 5, and X in autism spectrum disorder

Here, we describe a female patient with autism spectrum disorder and dysmorphic features that harbors a complex genetic alteration, involving a de novo balanced translocation t(2;X)(q11;q24), a 5q11 segmental trisomy and a maternally inherited isodisomy on chromosome 5. All the possibly damaging genetic effects of such alterations are discussed. In light of recent findings on ASD genetic causes, the hypothesis that all these alterations might be acting in orchestration and contributing to the phenotype is also considered. (C) 2012 Wiley Periodicals, Inc.

Analysis of Copy Number Variants identifies new candidate genes for Autism Spectrum Disorder and Intellectual Disability

Autism spectrum disorder (ASD) and Intellectual Disability (ID) are complex neuropsychiatric disorders characterized by extensive clinical and genetic heterogeneity and with overlapping risk factors. The aim of my project was to further investigate the role of Copy Numbers Variants (CNVs), identified through genome-wide studies performed by the Autism Geome Project (AGP) and the CHERISH consortium in large cohorts of ASD and ID cases, respectively. Specifically, I focused on four rare genic CNVs, selected on the basis of their impact on interesting ASD/ID candidate genes: a) a compound heterozygous deletion involving CTNNA3, predicted to cause the lack of functional protein; b) a 15q13.3 duplication containing CHRNA7; c) a 2q31.1 microdeletion encompassing KLHL23, SSB and METTL5; d) Lastly, I investigated the putative imprinting regulation of the CADPS2 gene, disrupted by a maternal deletion in two siblings with ASD and ID. This study provides further evidence for the role of CTNNA3, CHRNA7, KLHL23 and CADPS2 as ASD and/or ID susceptibility genes, and highlights that rare genetic variation contributes to disease risk in different ways: some rare mutations, such as those impacting CTNNA3, act in a recessive mode of inheritance, while other CNVs, such as those occurring in the 15q13.3 region, are implicated in multiple developmental and/or neurological disorders possibly interacting with other susceptibility variants elsewhere in the genome. On the other hand, the discovery of a tissue-specific monoallelic expression for the CADPS2 gene, implicates the involvement of epigenetic regulatory mechanisms as risk factors conferring susceptibility to ASD/ID.

Complex syntax in autistic spectrum disorders: A study with relative clauses

Background The few studies that have evaluated syntax in autism spectrum disorder (ASD) have yielded conflicting findings: some suggest that once matched on mental age, ASD and typically developing controls do not differ for grammar, while others report that morphosyntactic deficits are independent of cognitive skills in ASD. There is a need for a better understanding of syntax in ASD and its relation to, or dissociation from, nonverbal abilities. Aims Syntax in ASD was assessed by evaluating subject and object relative clause comprehension in adolescents and adults diagnosed with ASD with a performance IQ within the normal range, and with or without a history of language delay. Methods & Procedures Twenty-eight participants with ASD (mean age 21.8) and 28 age-matched controls (mean age 22.07) were required to point to a character designated by relative clauses that varied in syntactic complexity. Outcomes & Results Scores indicate that participants with ASD regardless of the language development history perform significantly worse than age-matched controls with object relative clauses. In addition, participants with ASD with a history of language delay (diagnosed with high-functioning autism in the DSM-IV-TR) perform worse on subject relatives than ASD participants without language delay (diagnosed with Asperger syndrome in the DSM-IV-TR), suggesting that these two groups do not have equivalent linguistic abilities. Performance IQ has a positive impact on the success of the task for the population with ASD. Conclusions & Implications This study reveals subtle grammatical difficulties remaining in adult individuals with ASD within normal IQ range as compared with age-matched peers. Even in the absence of a history of language delay in childhood, the results suggest that a slight deficit may nevertheless be present and go undetected by standardized language assessments. Both groups with and without language delay have a similar global performance on relative clause comprehension; however, the study also indicates that the participants with reported language delay show more difficulty with subject relatives than the participants without language delay, suggesting the presence of differences in linguistic abilities between these subgroups of ASD.

From complexity to category: Responding to diagnostic uncertainties of autistic spectrum disorders

Objective: Recent data from Education Queensland has identified rising numbers of children receiving diagnoses of autistic spectrum disorder (ASD). Faced with funding diagnostic pressures, in clinical situations that are complex and inherently uncertain, it is possible that specialists err on the side of a positive diagnosis. This study examines the extent to which possible overinclusion of ASD diagnosis may exist in the presence of uncertainty and factors potentially related to this practice in Queensland. Methods: Using anonymous self-report, all Queensland child psychiatrists and paediatricians who see paediatric patients with development/behavioural problems were surveyed and asked whether they had ever specified an ASD diagnosis in the presence of diagnostic uncertainty. Using logistic regression, elicited responses to the diagnostic uncertainty questions were related to other clinical- and practice-related characteristics. Results: Overall, 58% of surveyed psychiatrists and paediatricians indicated that, in the face of diagnostic uncertainty, they had erred on the side of providing an ASD diagnosis for educational ascertainment and 36% of clinicians had provided an autism diagnosis for Carer's Allowance when Centrelink diagnostic specifications had not been met. Conclusion: In the absence of definitive biological markers, ASD remains a behavioural diagnosis that is often complex and uncertain. In response to systems that demand a categorical diagnostic response, specialists are providing ASD diagnoses, even when uncertain. The motivation for this practice appears to be a clinical risk/benefit analysis of what will achieve the best outcomes for children. It is likely that these practices will continue unless systems change eligibility to funding based on functional impairment rather than medical diagnostic categories.

Diagnosis of autistic spectrum disorders in Queensland: Variations in practice

Objective: For both paediatricians and child psychiatrists, referrals to assess possible autistic spectrum disorders (ASD) are increasing. This study examines current practices of medical specialists in the assessment of these disorders. Methods: An anonymous, self-report questionnaire was sent to all Queensland paediatricians and child psychiatrists. The survey elicited frequencies of consultation for ASD, diagnostic method, advice provided and perceived adequacy of training for this work. Results: Responses were received from 79 (85%) eligible paediatricians and 26 (58%) eligible child psychiatrists. For one-third of all clinicians, new consultations for possible ASD occurred as often as 2-3 times per week. Most specialists approached the clinical diagnosis of ASD by considering history from different sources and professional assessments. Paediatricians (86%) were more likely than child psychiatrists (62%) to request genetic studies for children with severe autism (P = 0.01). Both general paediatricians and developmental paediatricians perceived level of training for possible ASD consultations was significantly worse than child psychiatrists (P < 0.001 and P = 0.02, respectively), but no difference was found between paediatric groups (P = 0.27). Perceived adequacy of specialist training was not associated with length of experience in clinical practice. Conclusion: Medical practice in Queensland around diagnosis of ASD is characterized by considerable variability. There is still a long way to go if we are to achieve consistency around medical issues of organic diagnosis and practices impacting on health as well as consideration of differential developmental diagnoses. The finding that recently trained paediatricians felt just as unprepared for this work as their older colleagues suggests that the graduate training response to this 'new morbidity' has not been adequate.

Characteristics of visual function in Asperger’s syndrome and the autism spectrum

Autism is a pervasive developmental disorder and Asperger’s syndrome is part of the spectrum of autism disorders. This thesis aims to: • Review and investigate current theories concerning visual function in individuals with Asperger’s syndrome and high functioning autism spectrum disorder and to translate the findings into clinical practice by developing a specific protocol for the eye examination of individuals of this population. • Investigate whether those with Asperger’s syndrome are more likely to suffer from Meares-Irlen syndrome and/or dyslexia. • Assess the integrity of the M-cell pathway in Asperger’s syndrome using perimetric tests available in optometric practice to investigate and also to describe the nature of any defects. • Evaluate eye movement strategies in Asperger’s whilst viewing both text and images. Also to evaluate the most appropriate methodology for investigating eye movements; namely optical digital eye tracking and electrophysiology methodologies. Findings of the investigations include • Eye examinations for individuals with Asperger’s syndrome should contain the same testing methods as for the general population, with special consideration for clear communication. • There is a depression of M-pathway visual field sensitivity in 57% (8/14) of people with Asperger’s syndrome, supporting previous evidence for an M-cell deficit in some individuals. • There is a raised prevalence of dyslexia in Asperger’s syndrome (26% of a sample of 31) but not necessarily of Meares-Irlen syndrome. • Gaze strategies are abnormal in Asperger’s syndrome, for both reading and viewing of images. With increased saccadic movement and decreased viewing of faces in comparison to background detail.

Atypical connectivity in autistic spectrum disorders

Autism is a developmental disorder that is currently defined in terms of a triad of impairments in social interaction, communication, and behavioural flexibility. Psychological models have focussed on deficits in high level social and cognitive processes, such as ‘weak central coherence’ and deficits in ‘theory of mind’. Converging evidence from different fields of neuroscience research indicates that the underlying neural dysfunction is associated with atypical patterns of cortical connectivity (Rippon et al., 2007). This arises very early in development and results in sensory, perceptual and cognitive deficits at a much earlier and more fundamental level than previously suggested, but with cascading effects on higher level psychological and social processes. Earlier research in this sphere has focussed mainly on patterns of underconnectivity in distributed cortical networks underpinning process such as language and executive function. (Just et al., 2007). Such research mainly utilises imaging techniques with high spatial resolution. This paper focuses on evidence associated with local over-connectivity, evident in more low level and transitory processes and hence more easily measurable with techniques with high temporal resolution, such as MEG and EEG. Results are described which provide evidence of such local over-connectivity, characterised by atypical results in the gamma frequency range (Brown et al., 2005) together with discussions about the future directions of such research and its implications for remediation.

DSM-5 Autism Spectrum Disorder:in search of essential behaviours for diagnosis

Background: Despite initial concerns about the sensitivity of the proposed diagnostic criteria for DSM-5 Autism Spectrum Disorder (ASD; e.g. Gibbs et al., 2012; McPartland et al., 2012), evidence is growing that the DSM-5 criteria provides an inclusive description with both good sensitivity and specificity (e.g. Frazier et al., 2012; Kent, Carrington et al., 2013). The capacity of the criteria to provide high levels of sensitivity and specificity comparable with DSM-IV-TR however relies on careful measurement to ensure that appropriate items from diagnostic instruments map onto the new DSM-5 descriptions.Objectives: To use an existing DSM-5 diagnostic algorithm (Kent, Carrington et .al., 2013) to identify a set of ‘essential’ behaviors sufficient to make a reliable and accurate diagnosis of DSM-5 Autism Spectrum Disorder (ASD) across age and ability level. Methods: Specific behaviors were identified and tested from the recently published DSM-5 algorithm for the Diagnostic Interview for Social and Communication Disorders (DISCO). Analyses were run on existing DISCO datasets, with a total participant sample size of 335. Three studies provided step-by-step development towards identification of a minimum set of items. Study 1 identified the most highly discriminating items (p<.0001). Study 2 used a lower selection threshold than in Study 1 (p<.05) to facilitate better representation of the full DSM-5 ASD profile. Study 3 included additional items previously reported as significantly more frequent in individuals with higher ability. The discriminant validity of all three item sets was tested using Receiver Operating Characteristic curves. Finally, sensitivity across age and ability was investigated in a subset of individuals with ASD (n=190).Results: Study 1 identified an item set (14 items) with good discriminant validity, but which predominantly measured social-communication behaviors (11/14). The Study 2 item set (48 items) better represented the DSM-5 ASD and had good discriminant validity, but the item set lacked sensitivity for individuals with higher ability. The final Study 3 adjusted item set (54 items) improved sensitivity for individuals with higher ability and performance and was comparable to the published DISCO DSM-5 algorithm.Conclusions: This work represents a first attempt to derive a reduced set of behaviors for DSM-5 directly from an existing standardized ASD developmental history interview. Further work involving existing ASD diagnostic tools with community-based and well characterized research samples will be required to replicate these findings and exploit their potential to contribute to a more efficient and focused ASD diagnostic process.

Diagnosing autism spectrum disorder:who will get a DSM-5 diagnosis?

Background Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels. Methods A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190). Results Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level. Conclusions This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

Brief report:effects of sensory sensitivity and intolerance of uncertainty on anxiety in mothers of children with autism spectrum disorder

This study examined the relations between anxiety and individual characteristics of sensory sensitivity (SS) and intolerance of uncertainty (IU) in mothers of children with ASD. The mothers of 50 children completed the Hospital Anxiety and Depression Scale, the Highly Sensitive Person Scale and the IU Scale. Anxiety was associated with both SS and IU and IU was also associated with SS. Mediation analyses showed direct effects between anxiety and both IU and SS but a significant indirect effect was found only in the model in which IU mediated between SS. This is the first study to characterize the nature of the IU and SS interrelation in predicting levels of anxiety.

The effects of aging on the BTBR mouse model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including "Neural synaptic plasticity regulation" and "Neurotransmitter secretion regulation." Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype.