1. Acab A, Muotri AR. {{The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment}}. {Neurotherapeutics};2015 (Apr 8)
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders sharing a core set of symptoms, including impaired social interaction, language deficits, and repetitive behaviors. While ASDs are highly heritable and demonstrate a clear genetic component, the cellular and molecular mechanisms driving ASD etiology remain undefined. The unavailability of live patient-specific neurons has contributed to the difficulty in studying ASD pathophysiology. The recent advent of induced pluripotent stem cells (iPSCs) has provided the ability to generate patient-specific human neurons from somatic cells. The iPSC field has quickly grown, as researchers have demonstrated the utility of this technology to model several diseases, especially neurologic disorders. Here, we review the current literature around using iPSCs to model ASDs, and discuss the notable findings, and the promise and limitations of this technology. The recent report of a nonsyndromic ASD iPSC model and several previous ASD models demonstrating similar results points to the ability of iPSC to reveal potential novel biomarkers and therapeutics.
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2. Anketell PM, Saunders KJ, Gallagher SM, Bailey C, Little JA. {{Brief Report: Vision in Children with Autism Spectrum Disorder: What Should Clinicians Expect?}}. {J Autism Dev Disord};2015 (Apr 7)
Anomalous visual processing has been described in individuals with autism spectrum disorder (ASD) but relatively few studies have profiled visual acuity (VA) in this population. The present study describes presenting VA in children with ASD (n = 113) compared to typically developing controls (n = 206) and best corrected visual acuity (BCVA) in a sub-group of children with ASD (n = 29). There was no statistically significant difference in presenting VA between groups (z = -1.75, p = 0.08); ASD group median VA (interquartile range, IQR) -0.05 logMAR (IQR: -0.125 to 0.025 logMAR) and typically developing control group -0.075 logMAR (IQR: -0.150 to -0.025 logMAR). Median BCVA was -0.175 logMAR (IQR: -0.200 to -0.125 logMAR) for the ASD sub-group. Clinicians should not anticipate reduced VA when assessing children with ASD.
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3. Begeer S, Howlin P, Hoddenbach E, Clauser C, Lindauer R, Clifford P, Gevers C, Boer F, Koot HM. {{Effects and Moderators of a Short Theory of Mind Intervention for Children with Autism Spectrum Disorder: A Randomized Controlled Trial}}. {Autism Res};2015 (Apr 6)
Limited perspective taking or « Theory of Mind » (ToM) abilities are a core deficit of autism, and many interventions are aimed to improve ToM abilities. In this study, we investigated the effectiveness of a ToM treatment for children with autism spectrum disorders (ASD) and, for the first time, the moderating roles of social interaction style (SIS) and disruptive behavior (DB), to determine which children are most likely to respond to this intervention. The trial protocol is registered at www.trialregister.nl, trial number 2327 and published before the data collection was finished (www.trialsjournal.com). Children with autism aged 7-12 years (n = 97) were randomized over a waitlist control or a treatment condition. Outcome measures included ToM and emotion understanding, parent and teacher questionnaires on children’s social skills, ToM-related social behavior, and autistic traits. Six-month follow-up parent reported data were collected for the treatment group. The treatment had a positive effect on ToM understanding, parent-reported ToM behavior, and autistic traits, but not on parent or teacher-reported social behavior. Passive SIS was associated with diminished treatment effects on autistic traits, but DB was unrelated to outcomes. The ToM intervention improved conceptual social understanding and ToM-related behavior of children with ASD. However, broader application of learned skills to other domains of functioning was limited. Individual differences with regard to treatment response are discussed. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Brown SS, Stanfield AC. {{Fragile X premutation carriers: A systematic review of neuroimaging findings}}. {J Neurol Sci};2015 (Mar 27)
BACKGROUND: Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the fragile X premutation. Carriers of the fragile X premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). Recent evidence suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. METHODS: Medline, EMBASE and PsychINFO were searched for all appropriate English language studies published between January 1990 and December 2013. 419 potentially relevant articles were identified and screened. 19 articles were included in the analysis. RESULTS: We discuss key structural magnetic resonance imaging (MRI) findings such as the MCP sign and white matter atrophy. Additionally, we discuss how functional MRI results have progressed our knowledge of how FXTAS may manifest, including reduced brain activation during social and memory tasks in multiple regions. LIMITATIONS: This systematic review may have been limited by the search for articles on just 3 scientific databases. Differing techniques and methods of analyses between research groups and primary research articles may have caused differences in results between studies. CONCLUSION: Current MRI studies into the fragile X premutation have been important in the diagnosis of FXTAS and identifying potential pathophysiological mechanisms. Associations with blood based measures have also demonstrated that neurodevelopmental and neurodegenerative aspects of the fragile X premutation could be functionally and pathologically separate. Larger longitudinal studies will be required to investigate these conclusions.
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5. Bryn V, Halvorsen B, Ueland T, Isaksen J, Kolkova K, Ravn K, Skjeldal OH. {{Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood}}. {Eur J Paediatr Neurol};2015 (Mar 18)
BACKGROUND: Neurotrophic factors are essential regulators of neuronal maturation including synaptic synthesis. Among those, Brain derived neurotrophic factor (BDNF) has been in particular focus in the understanding of autism spectrum disorders (ASD). PURPOSE: The aim of our study was to investigate whether BNDF could be used as diagnostic/biological marker for ASD. For this purpose we examined the plasma levels of BDNF and the precursors pro- BDNF in patients with ASD and compared it with non-autistic controls; determined whether there was a correlation between the BDNF and proBDNF levels and clinical severity. We also investigated the coding region of BDNF identify for well-variations which could be associated to ASD. METHODS: The 65 ASD patients (51 boys) were enrolled from a recent completed epidemiological survey covering two counties (Oppland and Hedmark) in Norway. The mean age of the total number of children who participated in this study was 11,7 years. 30 non-autistic children were included as controls, 14 boys and 16 girls. The mean age was 11.3 years. Exclusion criteria for control group were individuals suffering from either neurological, endocrine, or immune insuffiency. RESULTS AND CONCLUSIONS: Patients with ASD were characterized by moderately but significantly elevated plasma levels of BDNF compared to matched controls. No differences were observed in the proBDNF level between patients and controls. Within the ASD group, children with intellectual disability demonstrated increased BDNF, but not proBDNF levels, while the presence of ADHD had no impact on circulating proBDNF or BDNF. No further associations between plasma proBDNF or BDNF and other clinical demographics were observed.
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6. Byrge L, Dubois J, Tyszka JM, Adolphs R, Kennedy DP. {{Idiosyncratic brain activation patterns are associated with poor social comprehension in autism}}. {J Neurosci};2015 (Apr 8);35(14):5837-5850.
Autism spectrum disorder (ASD) features profound social deficits but neuroimaging studies have failed to find any consistent neural signature. Here we connect these two facts by showing that idiosyncratic patterns of brain activation are associated with social comprehension deficits. Human participants with ASD (N = 17) and controls (N = 20) freely watched a television situation comedy (sitcom) depicting seminaturalistic social interactions (« The Office », NBC Universal) in the scanner. Intersubject correlations in the pattern of evoked brain activation were reduced in the ASD group-but this effect was driven entirely by five ASD subjects whose idiosyncratic responses were also internally unreliable. The idiosyncrasy of these five ASD subjects was not explained by detailed neuropsychological profile, eye movements, or data quality; however, they were specifically impaired in understanding the social motivations of characters in the sitcom. Brain activation patterns in the remaining ASD subjects were indistinguishable from those of control subjects using multiple multivariate approaches. Our findings link neurofunctional abnormalities evoked by seminaturalistic stimuli with a specific impairment in social comprehension, and highlight the need to conceive of ASD as a heterogeneous classification.
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7. Crawford JD, Chandley MJ, Szebeni K, Szebeni A, Waters B, Ordway GA. {{Elevated GFAP Protein in Anterior Cingulate Cortical White Matter in Males With Autism Spectrum Disorder}}. {Autism Res};2015 (Apr 6)
Based on evidence of abnormalities in axon thickness and neuronal disorganization, autism spectrum disorder (ASD) is commonly considered to be a condition resulting from neuronal dysfunction. Yet, recent findings suggest that non-neuronal cell types also contribute to ASD pathology. To investigate the role of glial cells in ASD, a combination of protein and gene expression analyses were used to determine levels of two glial markers, glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG), in the postmortem brain tissue from control and ASD donors. Levels of GFAP immunoreactivity (ir) were significantly elevated (P = 0.008) in anterior cingulate cortex (Brodmann area 24; BA24) white matter of ASD donors compared to control donors. In contrast, GFAP-ir levels were similar in BA24 gray matter from ASD and control donors. MOG-ir was also similar in both BA24 white and gray matter from ASD and control donors. In anterior prefrontal cortex (BA10), there were no significant differences in GFAP-ir or MOG-ir in either white or gray matter comparing ASD to control donors. Levels of expression of the genes GFAP and MOG also showed no differences between control and ASD donors in BA24 and BA10 white and gray matter. Collectively, these data imply that ASD is associated with an activation of white matter astrocytes in the anterior cingulate cortex as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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8. Dickinson A, Bruyns-Haylett M, Jones M, Milne E. {{Increased peak gamma frequency in individuals with higher levels of autistic traits}}. {Eur J Neurosci};2015 (Apr 8)
Individual differences in orientation discrimination threshold are related to both visually-induced peak gamma frequency and the presence of autistic traits. The relationship between peak gamma frequency and orientation discrimination thresholds may be due to both of these factors being mediated by levels of neural inhibition. No study has previously measured the relationship between peak gamma frequency and levels of autistic traits. Thus, this was the aim of the present study. We measured orientation discrimination thresholds and autistic traits in a neurotypical human sample (N = 33), and separately recorded electroencephalography to measure visually induced gamma activity. In line with our prediction, we found a significant relationship between peak gamma frequency and level of autistic traits. Consistent with previous work we also found significant relationships between orientation discrimination thresholds and level of autistic traits and between orientation discrimination thresholds and peak gamma frequency. Our results demonstrate that individuals with individuals with higher levels of autistic personality traits have a higher peak-gamma frequency and are better at discriminating between visual stimuli based on orientation. As both higher peak gamma frequency and lower orientation discrimination thresholds have been linked to higher levels of neural inhibition, this suggests that autistic traits co-occur with increased neural inhibition. This discovery is significant as it challenges the currently-held view that autism spectrum conditions are associated with increased neural excitation.
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9. Fakhoury M. {{Autistic spectrum disorders: A review of clinical features, theories and diagnosis}}. {Int J Dev Neurosci};2015 (Apr 8)
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders that is among the most severe in terms of prevalence, morbidity and impact to the society. It is characterized by complex behavioral phenotype and deficits in both social and cognitive functions. Although the exact cause of ASD is still not known, the main findings emphasize the role of genetic and environmental factors in the development of autistic behavior. Environmental factors are also likely to interact with the genetic profile and cause aberrant changes in brain growth, neuronal development, and functional connectivity. The past few years have seen an increase in the prevalence of ASD, as a result of enhanced clinical tests and diagnostic tools. Despite growing evidence for the involvement of endogenous biomarkers in the pathophysiology of ASD, early detection of this disorder remains a big challenge. This paper describes the main behavioral and cognitive features of ASD, as well as the symptoms that differentiate autism from other developmental disorders. An attempt will be made to integrate all the available evidence which point to reduced brain connectivity, mirror neurons deficits, and inhibition-excitation imbalance in individuals with ASD. Finally, this review discusses the main factors involved in the pathophysiology of ASD, and illustrates some of the most important markers used for the diagnosis of this debilitating disorder.
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10. Foulkes L, Bird G, Gokcen E, McCrory E, Viding E. {{Common and distinct impacts of autistic traits and alexithymia on social reward}}. {PLoS One};2015;10(4):e0121018.
According to the social motivation hypothesis of autism, individuals with high levels of autistic traits experience reduced levels of reward from social interactions. However, empirical evidence to date has been mixed, with some studies reporting lower levels of social reward in individuals with Autism Spectrum Disorder (ASD), and others finding no difference when compared to typically developing controls. Alexithymia, a subclinical condition associated with the reduced ability to identify and describe one’s own emotions, has been found to account for other affective difficulties observed inconsistently in individuals with ASD. The current study used a nonclinical sample (N = 472) to explore the associations between autistic traits and the value of six types of social reward, as measured by the Social Reward Questionnaire. In addition, we measured alexithymia to assess if this accounted for associations between autistic traits and social reward. There were three main findings. Firstly, higher levels of autistic traits were associated with significantly less enjoyment of admiration and sociability, and adding alexithymia to these models did not account for any additional variance. Secondly, both autistic traits and alexithymia were uniquely associated with reduced levels of enjoyment of prosocial interactions and sexual relationships. Thirdly, autistic traits were associated with higher levels of enjoyment of passivity and negative social potency, but these associations were no longer significant once alexithymia was taken into account, suggesting that co-occurring alexithymia accounted for these apparent associations. Overall, the current findings provide a novel and more nuanced picture of the relationship between autistic traits and social reward.
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11. Fu X, Zheng D, Liao J, Li Q, Lin Y, Zhang D, Yan A, Lan F. {{Alternatively spliced products lacking exon 12 dominate the expression of fragile X mental retardation 1 gene in human tissues}}. {Mol Med Rep};2015 (Mar 31)
Fragile X mental retardation 1 gene (FMR1) expression is associated with fragile X syndrome (FXS) and exhibits several splicing products. However, the proportion of spliced isoforms that are expressed in different tissues remains unclear. In the present study, longchain reverse transcriptionpolymerase chain reaction with a T cloningsequencing method was conducted in order to analyze the entire coding region of the FMR1 gene in human tissues. In particular, FXSassociated tissues were analyzed, including the brain and testis. Twenty alternatively spliced isoforms were observed among 271 recombinants, including six novel ones. The isoform that consisted of the entire FMR1 coding region (ISO1) accounted for a small proportion of all isoforms. Isoforms lacking exon 12 were the most abundant. In particular, spliced isoforms ISO7 and ISO17 were the most abundant. However, their relative abundance varied between the peripheral blood cells, and the testis and brain tissues. Bioinformatic analyses suggested that exon 12 may be the sole exon undergoing positive selection. The results of the present study suggested that the mechanisms underlying alternative splicing (AS) of the FMR1 gene may be more complex. Furthermore, the functions of alternatively spliced products lacking exon 12 require further investigation. The results of the present study provide novel insights into the association between AS and the structure and function of the FMR1 gene.
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12. Furman JM, Osorio MJ, Minshew NJ. {{Visual and Vestibular Induced Eye Movements in Verbal Children and Adults with Autism}}. {Autism Res};2015 (Apr 6)
This study assessed the functionality of vestibular, pursuit, and saccade circuitry in autism across a wide age range. Subjects were 79 individuals with autism (AUT) and 62 controls (CON) aged 5 to 52 years with IQ scores > 70. For vestibular testing, earth-vertical axis rotation was performed in darkness and in a lighted visual surround with a fixation target. Ocular motor testing included assessment of horizontal saccades and horizontal smooth pursuit. No between-group differences were found in vestibular reflexes or in mean saccade velocity or accuracy. Saccade latency was increased in the AUT group with significant age-related effects in the 8-18 year old subgroups. There was a trend toward decreased pursuit gain without age effects. Normal vestibular-induced eye movements and normal saccade accuracy and velocity provide the most substantial evidence to date of the functional integrity of brainstem and cerebellar pathways in autism, suggesting that the histopathological abnormalities described in these structures may not be associated with intrinsic dysfunction but rather reflect developmental alterations related to forebrain cortical systems formation. Increased saccade latency with age effects adds to the extensive existing evidence of altered function and maturation of cortical systems in autism. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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13. Ghacibeh GA, Fields C. {{Interictal epileptiform activity and autism}}. {Epilepsy Behav};2015 (Apr 3)
Many individuals with autism have epileptiform discharges on their EEG without having definite clinical seizures. The clinical significance of epileptiform activity in patients with autism is controversial. Some consider it an epiphenomenon of the underlying condition that should be ignored, and others believe that frequent spikes may contribute to the cognitive impairment and advocate treatment. Several studies have reported variable rates of epileptiform activity and variable response to treatment. There is an urgent need to conduct controlled clinical trials to assess the true incidence of epileptiform activity in children with autism, develop a risk assessment model, and study the effectiveness of treatment. This article is part of a Special Issue entitled « Autism and Epilepsy ».
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14. Hwang SR, Kim CY, Shin KM, Jo JH, Kim HA, Heo Y. {{Altered Expression Levels of Neurodevelopmental Proteins in Fetal Brains of BTBR T+tf/J Mice with Autism-Like Behavioral Characteristics}}. {J Toxicol Environ Health A};2015;78(8):516-523.
Autism is a brain developmental disorder with characteristics of social interaction defects, language and communication dysfunction, and repetitive behavior. Occurrence of autism is continuously increasing, but the cause of autism is not clearly defined. Genetic linkage or environmental factors were proposed as sources for pathogenesis of autism. BTBR T+tf/J (BTBR) mice were reported as an appropriate animal model for autism investigation because of their similarities in behavioral abnormalities with human autistic subjects. The aim of this study was to evaluate expression levels of proteins involved with brain development at fetal stage of BTBR mice. FVB/NJ mice were used as a control strain because of their social behaviors. Level of fetal brain immunoglobulin (Ig) G deposit was also evaluated. Fetal brains were obtained at d 18 of gestational period. Thirty-one and 27 fetuses were obtained from 3 pregnant BTBR and FVB dams, respectively. The level of glial fibrillary acidic protein expression was significantly lower in fetal brains of BTBR than FVB/NJ mice. Expression of brain-derived neurotrophic factor and myelin basic protein was significantly more upregulated in BTBR than in FVB/NJ mice. No significant difference was obtained for nerve growth factor between the two strains. Levels of IgG isotypes deposited in fetal brain of BTBR mice were significantly higher than in FVB mice except for IgG1. Overall, these results suggest that prenatal alterations in expression of various fetal brain proteins may be implicated in aberrant behavioral characteristics of BTBR mice.
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15. Kalinowska M, Castillo C, Francesconi A. {{Quantitative profiling of brain lipid raft proteome in a mouse model of fragile x syndrome}}. {PLoS One};2015;10(4):e0121464.
Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.
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16. Kamien B, Harraway J, Lundie B, Smallhorne L, Gibbs V, Heath A, Fullerton JM. {{Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: Additional information}}. {Am J Med Genet A};2015 (Apr 2)
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17. Koolschijn PC, Geurts HM, van der Leij AR, Scholte HS. {{Are Autistic Traits in the General Population Related to Global and Regional Brain Differences?}}. {J Autism Dev Disord};2015 (Apr 7)
There is accumulating evidence that autistic-related traits in the general population lie on a continuum, with autism spectrum disorders representing the extreme end of this distribution. Here, we tested the hypothesis of a possible relationship between autistic traits and brain morphometry in the general population. Participants completed the short autism-spectrum quotient-questionnaire (AQ); T1-anatomical and DWI-scans were acquired. Associations between autistic traits and gray matter, and white matter microstructural-integrity were performed on the exploration-group (N = 204; 105 males, M-age = 22.85), and validated in the validation-group (N = 304; 155 males, M-age = 22.82). No significant associations were found between AQ-scores and brain morphometry in the exploration-group, or after pooling the data. This questions the assumption that autistic traits and their morphological associations do lie on a continuum in the general population.
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18. Lombardo MV, Pierce K, Eyler LT, Carter Barnes C, Ahrens-Barbeau C, Solso S, Campbell K, Courchesne E. {{Different Functional Neural Substrates for Good and Poor Language Outcome in Autism}}. {Neuron};2015 (Apr 8)
Autism (ASD) is vastly heterogeneous, particularly in early language development. While ASD language trajectories in the first years of life are highly unstable, by early childhood these trajectories stabilize and are predictive of longer-term outcome. Early neural substrates that predict/precede such outcomes are largely unknown, but could have considerable translational and clinical impact. Pre-diagnosis fMRI response to speech in ASD toddlers with relatively good language outcome was highly similar to non-ASD comparison groups and robustly recruited language-sensitive superior temporal cortices. In contrast, language-sensitive superior temporal cortices were hypoactive in ASD toddlers with poor language outcome. Brain-behavioral relationships were atypically reversed in ASD, and a multimodal combination of pre-diagnostic clinical behavioral measures and speech-related fMRI response showed the most promise as an ASD prognosis classifier. Thus, before ASD diagnoses and outcome become clinically clear, distinct functional neuroimaging phenotypes are already present that can shed insight on an ASD toddler’s later outcome. VIDEO ABSTRACT.
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19. Lozano R, Vino A, Lozano C, Fisher SE, Deriziotis P. {{A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment}}. {Eur J Hum Genet};2015 (Apr 8)
FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.European Journal of Human Genetics advance online publication, 8 April 2015; doi:10.1038/ejhg.2015.66.
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20. Mukherjee SB, Malhotra MK, Aneja S, Chakraborty S, Deshpande S. {{Diagnostic Accuracy of Indian Scale for Assessment of Autism (ISAA) in Chidren Aged 2-9 Years}}. {Indian Pediatr};2015 (Mar 8);52(3):212-216.
OBJECTIVE: To determine the diagnostic accuracy of Indian Scale for Assessment of Autism (ISAA) in children aged 2-9 year at high risk of autism, and to ascertain the level of agreement with Childhood Autism Rating Scale (CARS). DESIGN: Diagnostic Accuracy study. SETTING: Tertiary-level hospital. PARTICIPANTS: Children aged between 2 and 9 year and considered to be at a high risk for autism (delayed development, and age-inappropriate cognition, speech, social interaction, behavior or play) were recruited. Those with diagnosed Hearing impairment, Cerebral palsy, Attention deficit hyperactivity disorder or Pervasive developmental disorders (PDD) were excluded. METHODS: Eligible children underwent a comprehensive assessment by an expert. The study group comprising of PDD, Global developmental delay (GDD) or Intellectual disability was administered ISAA by an investigator after one week. Both evaluators were blinded. ISAA results were compared to the Experts diagnosis and CARS scores. RESULTS: Out of 102 eligible children, 90 formed the study group (63 males, mean age 4.5y). ISAA had a sensitivity 93.3, specificity of 97.4, positive and negative likelihood ratios 85.7 and 98.7 and positive and negative predictive values of 35.5 and 0.08, respectively. Reliability was good and validity sub-optimal (r low, in 4/6 domains). The optimal threshold point demarcating Autism from No autism according to Receiver Operating Characteristic curve was ISAA score of 70. Level of agreement with CARS measured by Kappa coefficient was low (0.14). CONCLUSIONS: The role of ISAA in 3-9 year old children at high risk for Autism is limited to identifying and certifying Autism at ISAA score of 70. It requires re-examination in 2-3 year olds.
21. Seung H, Ji J, Kim SJ, Sung I, Youn YA, Hong G, Lee H, Lee YH, Youm HK. {{Examination of the Korean Modified Checklist of Autism in Toddlers: Item Response Theory}}. {J Autism Dev Disord};2015 (Apr 7)
The study examined the clinical utility and psychometric properties of the Korean Modified Checklist of Autism in Toddlers (K-M-CHAT)-2. A sample of 2300 parents of 16- to 36-month-old children was recruited across South Korea. A phone interview was utilized to follow up with participants who initially screened positive for autism spectrum disorder (ASD). Item response theory was applied to assess the psychometric properties of the K-M-CHAT-2. Parents’ responses were substantially changed after the follow-up, and the final screen-positive rate was 2.3 %. Results indicated that the psychometric properties of items 1, 3, 11, 18 and 22 were not as strong as the other items. The K-M-CHAT-2 is a useful ASD screening test when implemented with a follow-up.
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22. Thomas MS, Davis R, Karmiloff-Smith A, Knowland VC, Charman T. {{The over-pruning hypothesis of autism}}. {Dev Sci};2015 (Apr 6)
This article outlines the over-pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub-type (Thomas, Knowland & Karmiloff-Smith, 2011a, 2011b). Here we develop a more general version of the over-pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co-inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at-risk of ASD. We review evidence consistent with the over-pruning hypothesis, its relation to other current theories (including C. Frith’s under-pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.
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23. Walton KM, Ingersoll BR. {{Psychosocial Adjustment and Sibling Relationships in Siblings of Children with Autism Spectrum Disorder: Risk and Protective Factors}}. {J Autism Dev Disord};2015 (Apr 7)
This study compared sibling adjustment and relationships in siblings of children with Autism Spectrum Disorder (ASD-Sibs; n = 69) and siblings of children with typical development (TD-Sibs; n = 93). ASD-Sibs and TD-Sibs demonstrated similar emotional/behavioral adjustment. Older male ASD-Sibs were at increased risk for difficulties. Sibling relationships of ASD-Sibs involved less aggression, less involvement, and more avoidance than those of TD-Sibs. Partial support for a diathesis-stress conceptualization of sibling difficulties was found for ASD-Sibs. For TD-Sibs, broader autism phenotype (BAP) was related to psychosocial difficulties regardless of family stressors. For ASD-Sibs, BAP was related to difficulties only when family stressors were present. This suggests that having a sibling with ASD may be a protective factor that attenuates the negative impact of sibling BAP.
