1. Allen EG, Grus WE, Narayan S, Espinel W, Sherman SL. {{Approaches to identify genetic variants that influence the risk for onset of fragile X-associated primary ovarian insufficiency (FXPOI): a preliminary study}}. {Front Genet}. 2014; 5: 260.
Fragile X-associated primary ovarian insufficiency (FXPOI) is due to an X-linked mutation that results from the expansion of a CGG repeat sequence located in the 5′ untranslated region of the FMR1 gene (premutation, PM). About 20% of women who carry the PM have cessation of menses before age 40, a clinical condition known as premature ovarian failure (POF). This leads to a 20-fold increased risk over women in the general population. Thus, this single gene mutation has a major effect on reducing a woman’s reproductive life span. Based on survival analysis of about 1300 women, we showed that the mean age at menopause among PM carriers is reduced compared with noncarriers, even after removing women who reported POF. This suggests that the majority of women with the PM, not just a subset, experience ovarian insufficiency earlier than noncarriers. To better understand the underlying mechanism of the PM and to identify genes that modify the variable expressivity of FXPOI, we conducted two pilot studies. The first focused on five common variants known to reduce age at menopause. We genotyped these SNPs in 72 women with a PM who experienced menopause and found a significant association with the total SNP risk burden and age at menopause. This suggests that these SNPs influence onset of FXPOI, after adjusting for the effect of the PM allele. In the second approach, we conducted whole genome sequencing on 10 PM carriers, five with onset of FXPOI prior to age 30 and five who experienced menopause after age 47 years. Although only a pilot study, we describe our preliminary approach to identify potential variants that may play a role in modifying onset of FXPOI and potentially play a role in idiopathic primary ovarian insufficiency. The overarching goal of both approaches is to identify predictor variants that may identify women predisposed to early onset FXPOI and to further identify genes involved in defining a woman’s reproductive life span.
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2. Aoki Y, Yahata N, Watanabe T, Takano Y, Kawakubo Y, Kuwabara H, Iwashiro N, Natsubori T, Inoue H, Suga M, Takao H, Sasaki H, Gonoi W, Kunimatsu A, Kasai K, Yamasue H. {{Oxytocin improves behavioural and neural deficits in inferring others’ social emotions in autism}}. {Brain}. 2014.
Recent studies have suggested oxytocin’s therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others’ social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person’s social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others’ social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others’ social emotions (P = 0.018) but not in inferring others’ beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others’ social emotions, and in the dorsomedial prefrontal cortex during inferring others’ beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others’ social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others’ social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others’ beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others’ social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.
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3. Bhat S, Acharya UR, Adeli H, Bairy GM, Adeli A. {{Automated diagnosis of autism: in search of a mathematical marker}}. {Rev Neurosci}. 2014.
Abstract Autism is a type of neurodevelopmental disorder affecting the memory, behavior, emotion, learning ability, and communication of an individual. An early detection of the abnormality, due to irregular processing in the brain, can be achieved using electroencephalograms (EEG). The variations in the EEG signals cannot be deciphered by mere visual inspection. Computer-aided diagnostic tools can be used to recognize the subtle and invisible information present in the irregular EEG pattern and diagnose autism. This paper presents a state-of-the-art review of automated EEG-based diagnosis of autism. Various time domain, frequency domain, time-frequency domain, and nonlinear dynamics for the analysis of autistic EEG signals are described briefly. A focus of the review is the use of nonlinear dynamics and chaos theory to discover the mathematical biomarkers for the diagnosis of the autism analogous to biological markers. A combination of the time-frequency and nonlinear dynamic analysis is the most effective approach to characterize the nonstationary and chaotic physiological signals for the automated EEG-based diagnosis of autism spectrum disorder (ASD). The features extracted using these nonlinear methods can be used as mathematical markers to detect the early stage of autism and aid the clinicians in their diagnosis. This will expedite the administration of appropriate therapies to treat the disorder.
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4. Bray N. {{Neurodevelopmental disorders: Righting Rett syndrome with IGF1}}. {Nat Rev Drug Discov}. 2014.
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5. Cheak-Zamora NC, Farmer JE. {{The Impact of the Medical Home on Access to Care for Children with Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2014.
Children with autism spectrum disorders (ASD) experience difficulty accessing health care services. Using parent-reported data from the 2009-2010 National Survey of Children with Special Health Care Needs, we examined whether having a medical home reduces unmet need for specialty care services for children with ASD (n = 3,055). Descriptive statistics and Chi square tests identified sample characteristics and examined the relationship between unmet needs and a standardized measure of medical home. Logistic regression models explored the individual impact of demographic, condition-specific and medical home variables on unmet need. Parents reported that nearly all children had a need for specialty services, 36 % had an unmet need, and 23.9 % had a medical home. Children who had fewer unmet needs were more likely to have received family-centered and coordinated care through a medical home, and this relationship remained significant even when demographic and condition-specific variables were taken into account. These findings suggest ways to improve access to care for children with ASD through enhanced family-centered and coordinated care within the medical home.
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6. Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, Erb JL, Churchill SE, Kaimal AJ, Doyle AE, Robinson EB, Smoller JW, Kohane IS, Perlis RH. {{Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system}}. {Mol Psychiatry}. 2014.
Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70-1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22-2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.Molecular Psychiatry advance online publication, 26 August 2014; doi:10.1038/mp.2014.90.
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7. Diehl JJ, Friedberg C, Paul R, Snedeker J. {{The use of prosody during syntactic processing in children and adolescents with autism spectrum disorders}}. {Dev Psychopathol}. 2014: 1-18.
In this study, we employed an eye-gaze paradigm to explore whether children (ages 8-12) and adolescents (ages 12-18) with autism spectrum disorders (ASDs) are able to use prosodic cues to determine the syntactic structure of an utterance. Persons with ASD were compared to typically developing (TD) peers matched on age, IQ, gender, and receptive language abilities. The stimuli were syntactically ambiguous but had a prosodic break that indicated the appropriate interpretation (feel the frog … with the feather vs. feel … the frog with the feather). We found that all groups were equally sensitive to the initial prosodic cues that were presented. Children and teens with ASD used prosody to interpret the ambiguous phrase as rapidly and efficiently as their TD peers. However, when a different cue was presented in subsequent trials, the younger ASD group was more likely to respond in a manner consistent with the initial prosodic cue rather than the new one. Eye-tracking data indicated that both younger groups (ASD and TD) had trouble shifting their interpretation as the prosodic cue changed, but the younger TD group was able to overcome this interference and produce an action consistent with the prosodic cue.
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8. Dumas G, Soussignan R, Hugueville L, Martinerie J, Nadel J. {{Revisiting mu suppression in autism spectrum disorder}}. {Brain Res}. 2014.
Two aspects of the EEG literature lead us to revisit mu suppression in Autism Spectrum Disorder (ASD). First and despite the fact that the mu rhythm can be functionally segregated in two discrete sub-bands, 8-10Hz and 10-12/13Hz, mu-suppression in ASD has been analyzed as a homogeneous phenomenon covering the 8-13Hz frequency. Second and although alpha-like activity is usually found across the entire scalp, ASD studies of action observation have focused on the central electrodes (C3/C4). The present study was aimed at testing on the whole brain the hypothesis of a functional dissociation of mu and alpha responses to the observation of human actions in ASD according to bandwidths. Electroencephalographic (EEG) mu and alpha responses to execution and observation of hand gestures were recorded on the whole scalp in high functioning subjects with ASD and typical subjects. When two bandwidths of the alpha-mu 8-13Hz were distinguished, a different mu response to observation appeared for subjects with ASD in the upper sub-band over the sensorimotor cortex, whilst the lower sub-band responded similarly in the two groups. Source reconstructions demonstrated that this effect was related to a joint mu-suppression deficit over the occipito-parietal regions and an increase over the frontal regions. These findings suggest peculiarities in top-down response modulation in ASD and question the claim of a global dysfunction of the MNS in autism. This research also advocates for the use of finer grained analyses at both spatial and spectral levels for future directions in neurophysiological accounts of autism.
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9. Forgeot d’Arc B, Ramus F, Lefebvre A, Brottier D, Zalla T, Moukawane S, Amsellem F, Letellier L, Peyre H, Mouren MC, Leboyer M, Delorme R. {{Atypical Social Judgment and Sensitivity to Perceptual Cues in Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2014.
Evaluation of faces is an important dimension of social relationships. A degraded sensitivity to facial perceptual cues might contribute to atypical social interactions in autism spectrum disorder (ASD). The current study investigated whether face based social judgment is atypical in ASD and if so, whether it could be related to a degraded sensitivity to facial perceptual cues. Individuals with ASD (n = 33) and IQ- and age-matched controls (n = 38) were enrolled in this study. Watching a series of photographic or synthetic faces, they had to judge them for « kindness ». In synthetic stimuli, the amount of perceptual cues available could be either large or small. We observed that social judgment was atypical in the ASD group on photographic stimuli, but, contrarily to the prediction based on the degraded sensitivity hypothesis, analyses on synthetic stimuli found a similar performance and a similar effect of the amount of perceptual cues in both groups. Further studies on perceptual differences between photographs and synthetic pictures of faces might help understand atypical social judgment in ASD.
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10. Gothelf D. {{Measuring prodromal symptoms in youth with developmental disabilities: a lesson from 22q11 deletion syndrome}}. {J Am Acad Child Adolesc Psychiatry}. 2014; 53(9): 945-7.
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11. Guillon Q, Hadjikhani N, Baduel S, Kruck J, Arnaud M, Roge B. {{Both dog and human faces are explored abnormally by young children with autism spectrum disorders}}. {Neuroreport}. 2014.
When looking at faces, typical individuals tend to have a right hemispheric bias manifested by a tendency to look first toward the left visual hemifield. Here, we tested for the presence of this bias in young children with autism spectrum disorders (ASD) for both human and dog faces. We show that children with ASD do not show a left visual hemifield (right hemispheric) bias for human faces. In addition, we show that this effect extends to faces of dogs, suggesting that the absence of bias is not specific to human faces, but applies to all faces with the first-order configuration, pointing to an anomaly at an early stage of visual analysis of faces. The lack of right hemispheric dominance for face processing may reflect a more general disorder of cerebral specialization of social functions in ASD.
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12. Handt M, Epplen A, Hoffjan S, Mese K, Epplen JT, Dekomien G. {{Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening}}. {Mol Cell Probes}. 2014.
Fragile X syndrome (FXS) is a common cause of intellectual disability, developmental delay and autism spectrum disorders. This syndrome is due to a functional loss of the FMR1 gene product FMRP, and, in most cases, it is caused by CGG repeat expansion in the FMR1 promoter. Yet, also other FMR1 mutations may cause a FXS-like phenotype. Since standard molecular testing does not include the analysis of the FMR1 coding region, the prevalence of point mutations causing FXS is not well known. Here, high resolution melting (HRM) was used to screen for FMR1 gene mutations in 508 males with clinical signs of mental retardation and developmental delay, but without CGG and GCC repeat expansions in the FMR1 gene and AFF2 genes, respectively. Sequence variations were identified by HRM analysis and verified by direct DNA sequencing. Two novel missense mutations (p.Gly482Ser in one patient and p.Arg534His in two unrelated patients), one intronic and two 3′-untranslated region (UTR) variations were identified in the FMR1 gene. Missense mutations in the FMR1 gene might account for a considerable proportion of cases in male patients with FXS-related symptoms, such as those linked to mental retardation and developmental delay.
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13. Hirjak D, Wolf RC, Koch SC, Mehl L, Kelbel JK, Kubera KM, Traeger T, Fuchs T, Thomann PA. {{Neurological abnormalities in recent-onset schizophrenia and asperger-syndrome}}. {Front Psychiatry}. 2014; 5: 91.
BACKGROUND: Neurological abnormalities including a variety of subtle deficits such as discrete impairments in sensory integration, motor coordination (MOCO), and sequencing of complex motor acts are frequently found in patients with schizophrenia (SZ) and commonly referred to as neurological soft signs (NSS). Asperger-syndrome (AS) is characterized by sensory-motor difficulties as well. However, the question whether the two disorders share a common or a disease-specific pattern of NSS remains unresolved. METHOD: A total of 78 age- and education-matched participants [26 patients with recent-onset SZ, 26 individuals with AS, and 26 healthy controls (HC)] were recruited for the study. Analyses of covariance (ANCOVAs), with age, years of education, and medication included as covariates, were used to examine group differences on total NSS and the five subscale scores. Discriminant analyses were employed to identify the NSS subscales that maximally discriminate between the three groups. RESULTS: Significant differences among the three groups were found in NSS total score and on the five NSS subscales. The clinical groups differed significantly in the NSS subscale MOCO. The correct discriminant rate between patients with SZ and individuals with AS was 61.5%. The correct discriminant rate was 92.3% between individuals with AS and HC, and 80.8% between SZ patients and HC, respectively. CONCLUSION: Our findings provide new evidence for the presence of NSS in AS and lend further support to previously reported difficulties in movement control in this disorder. According to the present results, SZ and AS seem to be characterized by both quantitative and qualitative NSS expression.
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14. Imitola J, Walleigh D, Anderson CE, Jethva R, Carvalho KS, Legido A, Khurana DS. {{Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis}}. {Semin Pediatr Neurol}. 2014; 21(2): 167-71.
A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene (NRXN1). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the alpha-NRXN1 isoform, which has a role in the Ca(2+)-dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic alpha NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.
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15. Keidan I, Ben-Menachem E, Tzadok M, Ben-Zeev B, Berkenstadt H. {{Electroencephalography for children with autistic spectrum disorder: a sedation protocol}}. {Paediatr Anaesth}. 2014.
OBJECTIVES: To report the effectiveness and efficiency of a predetermined sedation protocol for providing sedation for electroencephalograph (EEG) studies in children with autism. METHODS: Sleep EEG has been advocated for the majority of children with autism spectrum disorder. In most cases, sedation is required to allow adequate studies. Most sedation drugs have negative effects on the EEG pattern. The sedation protocol we adopted included chloral hydrate, dexmedetomidine, and ketamine and was evaluated prospectively for 2 years. RESULTS: One hundred and eighty-three children with autistic spectrum disorder were sedated with the described drug protocol that was efficient, provided adequate EEG readings, and was not associated with serious adverse events. CONCLUSIONS: Our protocol kept costs to a minimum but provided appropriate escalation in care when required.
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16. Kretschmer A, Altgassen M, Rendell PG, Bolte S. {{Prospective memory in adults with high-functioning autism spectrum disorders: Exploring effects of implementation intentions and retrospective memory load}}. {Res Dev Disabil}. 2014; 35(11): 3108-18.
This study examined, for the first time, the impact of implementation intentions on prospective memory (PM) performance in adults with autism spectrum disorders (ASD) and further explored the role of retrospective memory for PM in ASD. PM was assessed with Virtual Week, a computerized game simulating upcoming everyday-life tasks. Twenty-seven adults with ASD and 27 age- and ability-matched controls were included. Half of the participants were instructed to form implementation intentions (i.e., encoding PM tasks in form of if-then statements), while the rest received simple PM instructions. Results provide first tentative evidence for beneficial effects of implementation intentions and PM tasks with low demands on retrospective memory for adults with ASD’s PM. Overall, results point to the importance of planning and retrospective memory for successful prospective remembering in ASD.
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17. Kron M, Lang M, Adams IT, Sceniak M, Longo F, Katz DM. {{A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome}}. {Dis Model Mech}. 2014; 7(9): 1047-55.
Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice.
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18. Li SO, Wang JL, Bjorklund G, Zhao WN, Yin CH. {{Serum copper and zinc levels in individuals with autism spectrum disorders}}. {Neuroreport}. 2014.
Trace elements play a critical role in the pathogenesis of autism spectrum disorders (ASD). The aim of this study was to investigate the serum levels of zinc (Zn) and copper (Cu) in Chinese children with ASD. Sixty patients (48 males, 12 females) diagnosed with ASD and 60 healthy sex-matched and age-matched control participants were assessed for serum Zn and Cu content at admission. The severity of ASD was also evaluated using the Childhood Autism Rating Scale (CARS) score. The results indicated that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases (P<0.001, respectively), whereas serum Cu levels were significantly higher (P<0.001). There was a significant negative association between Zn/Cu and CARS scores (r=-0.345, P=0.007). On the basis of the receiver operating characteristic curve, the optimal cut-off value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943-0.993). In conclusion, these results suggested an association between serum levels of Zn and Cu and ASD among Chinese patients, and the Zn/Cu ratio could be considered a biomarker of ASD.
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19. Marsh LE, Pearson A, Ropar D, Hamilton AF. {{Predictive Gaze During Observation of Irrational Actions in Adults with Autism Spectrum Conditions}}. {J Autism Dev Disord}. 2014.
Understanding irrational actions may require the observer to make mental state inferences about why an action was performed. Individuals with autism spectrum conditions (ASC) have well documented difficulties with mentalizing; however, the degree to which rationality understanding is impaired in autism is not yet clear. The present study uses eye-tracking to measure online understanding of action rationality in individuals with ASC. Twenty adults with ASC and 20 typically developing controls, matched for age and IQ watched movies of rational and irrational actions while their eye movements were recorded. Measures of looking time, scan path and saccade latency were calculated. Results from looking time and scan path analyses demonstrate that participants with ASC have reduced visual attention to salient action features such as the action goal and the hand performing the action, regardless of action rationality. However, when participants with ASC do attend to these features, they are able to make anticipatory goal saccades as quickly as typically developing controls. Taken together these results indicate that individuals with autism have reduced attention to observed actions, but when attention is maintained, goal prediction is typical. We conclude that the basic mechanisms of action understanding are intact in individuals with ASC although there may be impairment in the top-down, social modulation of eye movements.
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20. Mayer EA, Padua D, Tillisch K. {{Altered brain-gut axis in autism: Comorbidity or causative mechanisms?}}. {Bioessays}. 2014.
The concept that alterated communications between the gut microbiome and the brain may play an important role in human brain disorders has recently received considerable attention. This is the result of provocative preclinical and some clinical evidence supporting early hypotheses about such communication in health and disease. Gastrointestinal symptoms are a common comorbidity in patients with autism spectrum disorders (ASD), even though the underlying mechanisms are largely unknown. In addition, alteration in the composition and metabolic products of the gut microbiome has long been implicated as a possible causative mechanism contributing to ASD pathophysiology, and this hypothesis has been supported by several recently published evidence from rodent models of autism induced by prenatal insults to the mother. Recent evidence in one such model involving maternal infection, that is characterized by alterations in behavior, gut physiology, microbial composition, and related metabolite profile, suggests a possible benefit of probiotic treatment on several of the observed abnormal behaviors.
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21. McLean RL, Johnson Harrison A, Zimak E, Joseph RM, Morrow EM. {{Executive Function in Probands With Autism With Average IQ and Their Unaffected First-Degree Relatives}}. {J Am Acad Child Adolesc Psychiatry}. 2014; 53(9): 1001-9.
OBJECTIVE: This study aimed to characterize executive function (EF) in pedigrees of children with autism spectrum disorder (ASD) and average IQ. The authors examined the hypothesis that deficits in EF relate to lower levels of adaptive functioning, and they assessed evidence for a cognitive extended phenotype in unaffected relatives in a large, well-characterized sample. METHOD: Proband EF was assessed by parent-report questionnaires (Behavior Rating Inventory of Executive Functioning [BRIEF], n = 109) and child neuropsychological tests (Delis-Kaplan Executive Functioning System [D-KEFS], n = 35). EF also was examined in parents (D-KEFS, n = 335) and unaffected siblings (BRIEF, n = 114; D-KEFS, n = 57). Adaptive functioning was assessed by the Vineland Adaptive Behavior Scales-II (n = 155). All data were obtained from the Autism Consortium Clinical Genetics Database. RESULTS: Individuals with ASD showed important EF weaknesses. Multiple regression analyses showed that parent-reported EF deficits were related to profound decreases in adaptive functioning even after controlling for age, IQ, and severity of ASD symptoms. Parent-reported EF also was related to adaptive skills in preschoolers. First-degree unaffected relatives did not demonstrate difficulties with EF compared with normative data. CONCLUSION: In this study, EF impairments do not appear to relate to broad familial risk factors for ASD but may be associated with factors relevant to the expression of ASD in probands. Results support the benefits of EF assessment as a way to identify potential therapeutic targets that could lead to improved adaptive behavior in children with ASD and average IQ.
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22. McStay RL, Trembath D, Dissanayake C. {{Maternal stress and family quality of life in response to raising a child with autism: From preschool to adolescence}}. {Res Dev Disabil}. 2014; 35(11): 3119-30.
While the impact of raising a child with an Autism Spectrum Disorder (ASD) is well documented, with mothers reporting higher levels of stress than mothers of children with other disabilities, positive maternal outcomes have also been identified. What remains unclear, however, is the role of child age on maternal outcomes. We sought to clarify the role of child age in maternal stress and family quality of life (FQoL) in mothers raising a child with ASD. Participants included 140 mothers of children aged 3-16 years grouped to represent four key stages of childhood (preschool, early school years, middle school, early high school). Using a cross-sectional design, mothers completed questionnaires assessing potential risk (e.g., child problem behaviour, symptom severity) and protective (e.g., family characteristics) factors attributed to maternal outcomes. The results revealed significant age related group differences in child internalising behaviour and ASD symptomatology between the early and middle school years. Lower levels of adaptive social behaviour in older age groups were also found. Although mothers of older children reported significantly less support from professionals than mothers of younger children, no significant age effects were found to contribute to maternal reports of stress or FQoL. The current findings support the view that mothers appear to demonstrate stable levels of stress and FQoL despite fluctuations in key child variables and a reduction in supports, across age, highlighting the ongoing nature of maternal needs and heightened levels of child symptomatology during adolescence.
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23. O’Dowd A. {{Antidepressants in pregnancy are linked to ADHD but not to autism, says study}}. {BMJ}. 2014; 349: g5315.
24. Pineda JA, Friedrich EV, LaMarca K. {{Neurorehabilitation of social dysfunctions: a model-based neurofeedback approach for low and high-functioning autism}}. {Front Neuroeng}. 2014; 7: 29.
Autism Spectrum Disorder (ASD) is an increasingly prevalent condition with core deficits in the social domain. Understanding its neuroetiology is critical to providing insights into the relationship between neuroanatomy, physiology and social behaviors, including imitation learning, language, empathy, theory of mind, and even self-awareness. Equally important is the need to find ways to arrest its increasing prevalence and to ameliorate its symptoms. In this review, we highlight neurofeedback studies as viable treatment options for high-functioning as well as low-functioning children with ASD. Lower-functioning groups have the greatest need for diagnosis and treatment, the greatest barrier to communication, and may experience the greatest benefit if a treatment can improve function or prevent progression of the disorder at an early stage. Therefore, we focus on neurofeedback interventions combined with other kinds of behavioral conditioning to induce neuroplastic changes that can address the full spectrum of the autism phenotype.
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25. Rahbar MH, Samms-Vaughan M, Dickerson AS, Loveland KA, Ardjomand-Hessabi M, Bressler J, Shakespeare-Pellington S, Grove ML, Pearson DA, Boerwinkle E. {{Blood manganese concentrations in Jamaican children with and without autism spectrum disorders}}. {Environ Health}. 2014; 13(1): 69.
BACKGROUND: Manganese is an essential element for human health and development. Previous studies have shown neurotoxic effects in children exposed to higher levels of manganese. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. Several studies have hypothesized that ASD is caused through environmental exposures during crucial stages in brain development. We investigated the possible association between blood manganese concentrations (BMC) and ASD. We also identified factors associated with BMC in typically developing (TD) Jamaican children. METHODS: We used data from 109 ASD cases with their 1:1 age- and sex-matched TD controls to compare mean BMC in Jamaican children (2-8 years of age) with and without ASD. We administered a pre-tested questionnaire to assess demographic and socioeconomic information, medical history, and potential exposure to manganese. Finally, we collected 2 mL of whole blood from each child for analysis of manganese levels. Using General Linear Models (GLM), we assessed the association between BMC and ASD status. Furthermore, we used two independent sample t-tests to identify factors associated with BMC in TD children. RESULTS: In univariable GLM analysis, we found no significant association between BMC and ASD, (10.9 mug/L for cases vs. 10.5 mug/L for controls; P = 0.29). In a multivariable GLM adjusting for paternal age, parental education, place of child’s birth (Kingston parish), consumption of root vegetables, cabbage, saltwater fish, and cakes/buns, there was still no significant association between BMC and ASD status, (11.5 mug/L for cases vs. 11.9 mug/L for controls; P = 0.48). Our findings also indicated TD children who ate fresh water fish had a higher BMC than children who did not (11.0 mug/L vs. 9.9 mug/L; P = 0.03) as younger TD children (i.e., 2 <= age <=4), (12.0 mug/L vs. 10.2 mug/L; P = 0.01). CONCLUSIONS: While these results cannot be used to assess early exposure at potentially more susceptible time period, our findings suggest that there is no significant association between manganese exposures and ASD case status in Jamaica. Our findings also indicate that BMC in Jamaican children resemble those of children in the developed world and are much lower than those in the developing countries.
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26. Rais TB, Rais A. {{Association Between Antidepressants Use During Pregnancy and Autistic Spectrum Disorders: A Meta-analysis}}. {Innov Clin Neurosci}. 2014; 11(5-6): 18-22.
OBJECTIVE: Antidepressants have been reported in several studies in the literature to be associated with the development of autistic disorder symptoms in children exposed to them during the time of their mothers’ pregnancies. There have also been reports of neurodevelopment delays associated with exposure to antidepressants in the same conditions. DESIGN: We searched the PUBMED, MEDLINE, PsycARTICLES, and ERIC for original articles published between January 1983 and May 2013 to identify studies on the association between autistic spectrum disorders (ASD) and neurodevelopment delays in children and exposure to antidepressants during pregnancy. CONCLUSION: At the end of our preliminary work, we retained only three articles that were pertinent to the purpose of our study. We extracted the available data in Excel files and then did a meta-analysis. The final results showed a positive association between the exposure to antidepressants in utero and autistic spectrum disorders.
27. Roser ME, Aslin RN, McKenzie R, Zahra D, Fiser J. {{Enhanced Visual Statistical Learning in Adults With Autism}}. {Neuropsychology}. 2014.
Objective: Individuals with autism spectrum disorder (ASD) are often characterized as having social engagement and language deficiencies, but a sparing of visuospatial processing and short-term memory (STM), with some evidence of supranormal levels of performance in these domains. The present study expanded on this evidence by investigating the observational learning of visuospatial concepts from patterns of covariation across multiple exemplars. Method: Child and adult participants with ASD, and age-matched control participants, viewed multishape arrays composed from a random combination of pairs of shapes that were each positioned in a fixed spatial arrangement. Results: After this passive exposure phase, a posttest revealed that all participant groups could discriminate pairs of shapes with high covariation from randomly paired shapes with low covariation. Moreover, learning these shape-pairs with high covariation was superior in adults with ASD than in age-matched controls, whereas performance in children with ASD was no different than controls. Conclusions: These results extend previous observations of visuospatial enhancement in ASD into the domain of learning, and suggest that enhanced visual statistical learning may have arisen from a sustained bias to attend to local details in complex arrays of visual features. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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28. Rossignol R, Ranchon-Cole I, Paris A, Herzine A, Perche A, Laurenceau D, Bertrand P, Cercy C, Pichon J, Mortaud S, Briault S, Menuet A, Perche O. {{Visual sensorial impairments in neurodevelopmental disorders: evidence for a retinal phenotype in fragile x syndrome}}. {PLoS One}. 2014; 9(8): e105996.
Visual sensory impairments are common in Mental Deficiency (MD) and Autism Spectrum Disorder (ASD). These defects are linked to cerebral dysfunction in the visual cortical area characterized by the deregulation of axon growth/guidance and dendrite spine immaturity of neurons. However, visual perception had not been addressed, although the retina is part of the central nervous system with a common embryonic origin. Therefore, we investigated retinal perception, the first event of vision, in a murine model of MD with autistic features. We document that retinal function is altered in Fmr1 KO mice, a model of human Fragile X Syndrome. Indeed, In Fmr1 KO mice had a lower retinal function characterized by a decreased photoreceptors neuron response, due to a 40% decrease in Rhodopsin content and to Rod Outer Segment destabilization. In addition, we observed an alteration of the visual signal transmission between photoreceptors and the inner retina which could be attributed to deregulations of pre- and post- synaptic proteins resulting in retinal neurons synaptic destabilization and to retinal neurons immaturity. Thus, for the first time, we demonstrated that retinal perception is altered in a murine model of MD with autistic features and that there are strong similarities between cerebral and retinal cellular and molecular defects. Our results suggest that both visual perception and integration must be taken into account in assessing visual sensory impairments in MD and ASD.
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29. Rowberry J, Macari S, Chen G, Campbell D, Leventhal JM, Weitzman C, Chawarska K. {{Screening for Autism Spectrum Disorders in 12-Month-Old High-Risk Siblings by Parental Report}}. {J Autism Dev Disord}. 2014.
This study examines whether parental report of social-communicative and repetitive behaviors at 12 months can be helpful in identifying autism spectrum disorder (ASD) in younger siblings of children with ASD [high-risk (HR)-siblings]. Parents of HR-siblings and infants without a family history of ASD completed the First Year Inventory at 12 months. Developmental outcomes were based on 24- or 36-month assessments. HR-siblings later diagnosed with ASD showed greater impairments in social communication than those with other developmental outcomes based on parental and clinician ratings. Parental report of decline in play and communication and impaired vocal imitation correctly classified a majority of ASD cases with high specificity. These preliminary findings have important implications for the development of early screening instruments for ASD in HR-siblings.
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30. Ruzzano L, Borsboom D, Geurts HM. {{Repetitive Behaviors in Autism and Obsessive-Compulsive Disorder: New Perspectives from a Network Analysis}}. {J Autism Dev Disord}. 2014.
The association between autism and obsessive-compulsive disorder (OCD) seems largely dependent upon observed similarities in the repetitive behaviors that manifest in both disorders. The aim of this study was to use a network approach to explore the interactions between these behaviors. We constructed a network based on clinician’s perceptions as well as a network based on 213 clinically diagnosed children. In all networks, autism and OCD emerged as two distinct symptom clusters and obsessions and compulsions showed few direct associations with autism symptoms. Further, sensory interests were identified as behaviors that may contribute to the link between autism and OCD. Through network analysis, we expose the symptom pathways that may lead to the perceived association between autism and OCD.
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31. Santiesteban I, Shah P, White S, Bird G, Heyes C. {{Mentalizing or submentalizing in a communication task? Evidence from autism and a camera control}}. {Psychon Bull Rev}. 2014.
In the director task (DT), participants are instructed to move objects within a grid of shelves while ignoring those objects that cannot be seen by a human figure, the « director, » located beyond the shelves. It is widely assumed that, since they are explicitly instructed to do, participants use mentalizing in this communicative task; they represent what the director can see, and therefore the DT provides important information about how and when mentalizing is used in adult life. We tested this view against a « submentalizing » hypothesis suggesting that DT performance depends on object-centered spatial coding, without mentalizing. As predicted by the submentalizing account, we found that DT performance was unchanged when the director was replaced by an inanimate object, a camera, and that participants with autism spectrum disorders were unimpaired, relative to matched control participants, in both the director and camera conditions. In combination with recent critical analyses of « implicit mentalizing, » these findings support the view that adults use mentalizing sparingly in psychological experiments and in everyday life.
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32. Schaefer GB. {{Editorial comment: fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis}}. {Semin Pediatr Neurol}. 2014; 21(2): 172.
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33. Sherman SL, Curnow EC, Easley CA, Jin P, Hukema RK, Tejada MI, Willemsen R, Usdin K. {{Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)}}. {J Neurodev Disord}. 2014; 6(1): 26.
Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5′ untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP’s function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI.
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34. Shire SY, Kasari C. {{Train the trainer effectiveness trials of behavioral intervention for individuals with autism: a systematic review}}. {Am J Intellect Dev Disabil}. 2014; 119(5): 436-51.
Abstract This systematic review examines train the trainer (TTT) effectiveness trials of behavioral interventions for individuals with autism spectrum disorder (ASD). Published methodological quality scales were used to assess studies including participant description, research design, intervention, outcomes, and analysis. Twelve studies including 9 weak quality quasi-experimental studies, 2 single-subject experimental design studies of moderate and weak quality, and 1 high quality randomized control trial were included. Overall, author reported effect sizes and calculation of improvement rate difference for SSRDs indicate positive effects of intervention across participant outcomes including cognition, language, and autism symptoms postcommunity delivered interventions primarily based in applied behavior analysis. Effects varied by children’s developmental level.
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35. Sokhadze EM, El-Baz AS, Sears LL, Opris I, Casanova MF. {{rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism}}. {Front Syst Neurosci}. 2014; 8: 134.
OBJECTIVES: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. MATERIALS AND METHODS: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. RESULTS: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. CONCLUSION: RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.
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36. Solomon M, Frank MJ, Ragland JD, Smith AC, Niendam TA, Lesh TA, Grayson DS, Beck JS, Matter JC, Carter CS. {{Feedback-Driven Trial-by-Trial Learning in Autism Spectrum Disorders}}. {Am J Psychiatry}. 2014.
Objective: Impairments in learning are central to autism spectrum disorders. The authors investigated the cognitive and neural basis of these deficits in young adults with autism spectrum disorders using a well-characterized probabilistic reinforcement learning paradigm. Method: The probabilistic selection task was implemented among matched participants with autism spectrum disorders (N=22) and with typical development (N=25), aged 18-40 years, using rapid event-related functional MRI. Participants were trained to choose the correct stimulus in high-probability (AB), medium-probability (CD), and low-probability (EF) pairs, presented with valid feedback 80%, 70%, and 60% of the time, respectively. Whole-brain voxel-wise and parametric modulator analyses examined early and late learning during the stimulus and feedback epochs of the task. Results: The groups exhibited comparable performance on medium- and low-probability pairs. Typically developing persons showed higher accuracy on the high-probability pair, better win-stay performance (selection of the previously rewarded stimulus on the next trial of that type), and more robust recruitment of the anterior and medial prefrontal cortex during the stimulus epoch, suggesting development of an intact reward-based working memory for recent stimulus values. Throughout the feedback epoch, individuals with autism spectrum disorders exhibited greater recruitment of the anterior cingulate and orbito-frontal cortices compared with individuals with typical development, indicating continuing trial-by-trial activity related to feedback processing. Conclusions: Individuals with autism spectrum disorders exhibit learning deficits reflecting impaired ability to develop an effective reward-based working memory to guide stimulus selection. Instead, they continue to rely on trial-by-trial feedback processing to support learning dependent upon engagement of the anterior cingulate and orbito-frontal cortices.
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37. Stern JA, Gadgil MS, Blakeley-Smith A, Reaven JA, Hepburn SL. {{Psychometric Properties of the SCARED in Youth with Autism Spectrum Disorder}}. {Res Autism Spectr Disord}. 2014; 8(9): 1225-34.
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38. Tsuchiya KJ, Matsumoto K, Suda S, Miyachi T, Itoh H, Kanayama N, Hirano K, Ohzeki T, Takei N. {{Searching for very early precursors of autism spectrum disorders: the Hamamatsu Birth Cohort for Mothers and Children (HBC)}}. {J Dev Orig Health Dis}. 2010; 1(3): 158-73.
Autism spectrum disorders (ASD) are life-long neurodevelopmental conditions. The pathophysiology is poorly understood, and the clinical diagnosis can only be made through behavioural assessments. The prevalence of ASD has increased eight-fold over the last three decades. Paralleling this rise, research interest in the disorder has been accumulating, centering on two aspects: risk factors that would explain the increase in prevalence, and precursors that could predict an emergence of ASD prior to 2 years of age. As regard factors responsible for the increased prevalence, an increasing trend of low birthweight (4.2% in 1980 v. 9.6% in 2006 at Japan) and advanced paternal age at birth are potentially implicated. To explore these issues, and to yield an early diagnostic algorithm for ASD, the authors initiated the ongoing Hamamatsu Birth Cohort for Mothers and Children (HBC) in 2007. The strengths of the HBC include frequent, direct face-to-face assessments of all the participating mothers and children during the first 4 years of life (12 assessments); this depth of assessments will disclose subtle changes in the developmental domains of individuals with ASD, which might otherwise be overlooked. A total of 1200 pregnant women are to be recruited by the end of 2010. Assembled information comprises a range of variables related to the mother’s characteristics and child development. The comprehensiveness of the HBC will provide an informative data source that will elucidate early trajectories of children with ASD in addition to revealing detailed, developmental properties of typically developing children.
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39. Woodbury-Smith M, Dein K. {{Autism Spectrum Disorder (ASD) and Unlawful Behaviour: Where Do We Go from Here?}}. {J Autism Dev Disord}. 2014.
There exists now a body of research that describes case studies of individuals with autism spectrum disorder (ASD) who have engaged, or are alleged to have engaged, in a range of illegal behaviours, and that attempts to estimate the prevalence of ASD at different stages of the criminal justice process. Taken together, this research does suggest that some individuals with ASD will come into contact with the criminal justice system, but many questions regarding this apparent association remain unanswered. The purpose of this review is to propose a direction for research to address some of these unanswered questions and potentially inform the development of treatments and service provision.
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40. Zhang L, Ou J, Xu X, Peng Y, Guo H, Pan Y, Chen J, Wang T, Peng H, Liu Q, Tian D, Pan Q, Zou X, Zhao J, Hu Z, Xia K. {{AMPD1 functional variants associated with autism in Han Chinese population}}. {Eur Arch Psychiatry Clin Neurosci}. 2014.
Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients’ lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.
