1. Adachi M, Takahashi M, Takayanagi N, Yoshida S, Yasuda S, Tanaka M, Osato-Kaneda A, Saito M, Kuribayashi M, Kato S, Nakamura K. {{Adaptation of the Autism Spectrum Screening Questionnaire (ASSQ) to preschool children}}. {PLoS One}. 2018; 13(7): e0199590.
The Autism Spectrum Screening Questionnaire (ASSQ) is equipped with good properties for screening the broader phenotype of autistic traits, but it is standardized for a limited age range-from 7 to 16 years. To contribute to the early detection of Autism Spectrum Disorder (ASD), particularly in high functioning children with ASD, likely to cause maladjustments during school age, the present study examined psychometric properties to apply the ASSQ to a younger age. We tested parents’ ASSQ ratings for preschool children in clinical (N = 154, average age 60.77 months, range 55-72 months) and community settings (N = 1390, average age 60.53 months, range 57-68 months) in Japan. The results showed, just as in school-aged children, the ASSQ had reliability and validity as a screening instrument for preschool children in community settings. A cut-off of 7 with sensitivity of 0.93 and specificity of 0.84 is recommended for community screening. Still, based on the current study with a clinical group, an optimal cut-off score with high sensitivity and high specificity for parents’ ASSQ ratings could not be established. The clinicians should be reminded that the ASSQ is a screening instrument, not a diagnosing instrument. Also, this result suggest multi-faceted evaluation is necessary in clinical settings, for example, the addition of teachers’ ratings.
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2. Amal H, Barak B, Bhat V, Gong G, Joughin BA, Wishnok JS, Feng G, Tannenbaum SR. {{Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function}}. {Mol Psychiatry}. 2018.
Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO(*))-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions. SNO-proteins in two ASD-related brain regions, cortex and striatum of young and adult InsG3680(+/+) mice (a human mutation-based Shank3 mouse model), were identified by an innovative mass spectrometric method, SNOTRAP. We found changes of the SNO-proteome in the mutant compared to WT in both ages. Pathway analysis showed enrichment of processes affected in ASD. SNO-Calcineurin in mutant led to a significant increase of phosphorylated Synapsin1 and CREB, which affect synaptic vesicle mobilization and gene transcription, respectively. A significant increase of 3-nitrotyrosine was found in the cortical regions of the adult mutant, signaling both oxidative and nitrosative stress. Neuronal NO(*) Synthase (nNOS) was examined for levels and localization in neurons and no significant difference was found in WT vs. mutant. S-nitrosoglutathione concentrations were higher in mutant mice compared to WT. This is the first study on NO(*)-related molecular changes and SNO-signaling in the brain of an ASD mouse model that allows the characterization and identification of key proteins, cellular pathways, and neurobiological mechanisms that might be affected in ASD.
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3. Andrews SV, Sheppard B, Windham GC, Schieve LA, Schendel DE, Croen LA, Chopra P, Alisch RS, Newschaffer CJ, Warren ST, Feinberg AP, Fallin MD, Ladd-Acosta C. {{Case-control meta-analysis of blood DNA methylation and autism spectrum disorder}}. {Mol Autism}. 2018; 9: 40.
Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 x 10(- 7). Seven CpGs showed differences at p < 1 x 10(- 5) and 48 at 1 x 10(- 4). Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. Lien vers le texte intégral (Open Access ou abonnement)
4. Askari E, Setarehdan SK, Sheikhani A, Mohammadi MR, Teshnehlab M. {{Modeling the connections of brain regions in children with autism using cellular neural networks and electroencephalography analysis}}. {Artificial intelligence in medicine}. 2018.
The brain connections in the different regions demonstrate the characteristics of brain activities. In addition, in various conditions and with neuropsychological disorders, the brain has special patterns in different regions. This paper presents a model to show and compare the connection patterns in different brain regions of children with autism (53 boys and 36 girls) and control children (61 boys and 33 girls). The model is designed by cellular neural networks and it uses the proper features of electroencephalography. The results show that there are significant differences and abnormalities in the left hemisphere, (p<0.05) at the electrodes AF3, F3, P7, T7, and O1 in the children with autism compared with the control group. Also, the evaluation of the obtained connections values between brain regions demonstrated that there are more abnormalities in the connectivity of frontal and parietal lobes and the relations of the neighboring regions in children with autism. It is observed that the proposed model is able to distinguish the autistic children from the control subjects with an accuracy rate of 95.1% based on the obtained values of CNN using the SVM method. Lien vers le texte intégral (Open Access ou abonnement)
5. Cooper RA, Simons JS. {{Exploring the neurocognitive basis of episodic recollection in autism}}. {Psychonomic bulletin & review}. 2018.
Increasing evidence indicates that the subjective experience of recollection is diminished in autism spectrum disorder (ASD) compared to neurotypical individuals. The neurocognitive basis of this difference in how past events are re-experienced has been debated and various theoretical accounts have been proposed to date. Although each existing theory may capture particular features of memory in ASD, recent research questions whether any of these explanations are alone sufficient or indeed fully supported. This review first briefly considers the cognitive neuroscience of how episodic recollection operates in the neurotypical population, informing predictions about the encoding and retrieval mechanisms that might function atypically in ASD. We then review existing research on recollection in ASD, which has often not distinguished between different theoretical explanations. Recent evidence suggests a distinct difficulty engaging recollective retrieval processes, specifically the ability to consciously reconstruct and monitor a past experience, which is likely underpinned by altered functional interactions between neurocognitive systems rather than brain region-specific or process-specific dysfunction. This integrative approach serves to highlight how memory research in ASD may enhance our understanding of memory processes and networks in the typical brain. We make suggestions for future research that are important for further specifying the neurocognitive basis of episodic recollection in ASD and linking such difficulties to social developmental and educational outcomes.
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6. Hoofs V, Princen MM, Poljac E, Stolk A, Poljac E. {{Task switching in autism: An EEG study on intentions and actions}}. {Neuropsychologia}. 2018; 117: 398-407.
One of the main symptoms of Autism Spectrum Conditions (ASC) is experiencing cognitive inflexibility when adjustments of behaviour are required. While this so-called behavioural rigidity is broadly recognised in ASC, finding evidence for the underlying neurocognitive mechanisms remains challenging. In this electroencephalographic (EEG) study, participants with ASC and matched controls were instructed to choose between two cognitive tasks in each trial, and to respond to the subsequently presented target stimulus according to their task choice. While doing so, we tracked the frontally distributed contingent negative variation (CNV) during the task preparation interval as a measure of intentional control, and the posteriorly measured P3 during the task execution interval to monitor the translation of intentions into actions. The results support the notion of intentional control difficulties in ASC, where the CNV was attenuated in the ASC group compared to the control group. Furthermore, the CNV was differentiated between the tasks and transition types in the control group only, suggesting that the ASC group was less fine-tuning the required amount of intentional control to contextual circumstances. In contrast, the P3 showed no significant differences between the groups. Together, these findings highlight the importance of intentional control mechanisms as a crucial future route for a better understanding of cognitive flexibility and behavioural rigidity in ASC.
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7. Huang Y, Chang Z, Li X, Liang S, Yi Y, Wu L. {{Integrated multifactor analysis explores core dysfunctional modules in autism spectrum disorder}}. {International journal of biological sciences}. 2018; 14(8): 811-8.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease in early childhood, and growing up to be a major cause of disability in children. However, the underlying molecular mechanism of ASD remains elusive. Hence, we represented integrated multifactor analysis exploring dysfunctional modules based on RNA-Seq data from corpus callosum in 6 patients with ASD and 6 normal individuals. According to protein-protein interactions (PPIs) and WGCNA, we performed co-expression modules analysis for ASD-associated genes, and identified 25 modules with differentially expressed genes (DEGs), observing that genes in these modules were significantly involved in various biological processes in nervous system, sensory system, phylogenetic system and variety of signaling pathways. Then, based on transcriptional and post-transcriptional regulations, integrating transcription factor (TF)-target and RNA-associated interactions, significant regulators of co-expression modules were identified as pivot regulators, including 67 pivot TFs, 13 pivot miRNAs and 6 pivot lncRNAs. GO and KEGG pathway enrichment analysis demonstrated that the pivot miRNAs significantly enriched in neural or mental-associated biological progresses. The pivot TFs were mainly involved in various regulation of transcription, immune system and organs development. Finally, our work deciphered a multifactor dysfunctional co-expression subnetwork involved in ASD, helps uncover core dysfunctional modules for this disease and improves our understanding of its underlying molecular mechanism.
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8. Maneeton N, Maneeton B, Putthisri S, Woottiluk P, Narkpongphun A, Srisurapanont M. {{Risperidone for children and adolescents with autism spectrum disorder: a systematic review}}. {Neuropsychiatr Dis Treat}. 2018; 14: 1811-20.
Background: Various clinical trials suggested that risperidone was beneficial in the treatment of autism spectrum disorder (ASD) in children and adolescents. Objective: The aim of this systematic review was to determine the efficacy, acceptability and tolerability of risperidone in the treatment of children and adolescents with ASD. Data sources: The databases of Scopus, PubMed, CINAHL and Cochrane Controlled Trials Register were searched in February 2017. Study eligibility criteria participants and interventions: Eligible RCTs of risperidone in the treatment of child and adolescent patients with ASD. Languages were not restricted. Study appraisal and synthesis methods: The full-text versions of relevant studies were thoroughly assessed and extracted. The primary efficacy of outcome was the pooled response rate and the pooled mean changed scores of the standardized rating scales for ASD. Results: A total of 372 randomized subjects from seven RCTs were included in this review. In acute treatment, the pooled mean change score of the Aberrant Behavior Checklist for irritability subscale (ABC-I) and response rate for the risperidone-treated group had a greater significance than that of the placebo-treated group. In the long-term treatment, the pooled mean change score of the CARS in the risperidone-treated group was significantly greater than that in the placebo-treated group. According to the discontinuation phase, the overall pooled relapse rate of the risperidone-treated group was significantly less than that of the placebo-treated group. The rates of pooled overall discontinuation and discontinuation due to adverse events rates were not different between the two groups in acute and long-term treatments. Limitations: A small study was included in the current review. Conclusion: In relation to the current systematic review, risperidone is efficacious in the treatment of symptoms in children and adolescents with ASD. Although its acceptability is comparable to placebo, treatment with risperidone is well tolerated in children and adolescents with ASD.
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9. Parikshak NN, Swarup V, Belgard TG, Irimia M, Ramaswami G, Gandal MJ, Hartl C, Leppa V, de la Torre Ubieta L, Huang J, Lowe JK, Blencowe BJ, Horvath S, Geschwind DH. {{Author Correction: Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism}}. {Nature}. 2018.
Change history: In this Letter, the labels for splicing events A3SS and A5SS were swapped in column D of Supplementary Table 3a and b. This has been corrected online.
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10. Saldanha Tschinkel PF, Bjorklund G, Conon LZZ, Chirumbolo S, Nascimento VA. {{Plasma concentrations of the trace elements copper, zinc and selenium in Brazilian children with autism spectrum disorder}}. {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}. 2018; 106: 605-9.
The association between the plasma levels of trace elements, such as copper (Cu), zinc (Zn) and selenium (Se), in people with autism spectrum disorder (ASD), has attracted the interest of many physicians in the very recent years, because the impaired homeostatic regulation of trace elements, including their levels in the bloodstream and their potential neurotoxicity, contribute to the onset and exacerbation of ASD. In this study, we investigated 23 pediatric subjects (Lien vers le texte intégral (Open Access ou abonnement)
11. Shovlin S, Tropea D. {{Transcriptome level analysis in Rett syndrome using human samples from different tissues}}. {Orphanet journal of rare diseases}. 2018; 13(1): 113.
The mechanisms of neuro-genetic disorders have been mostly investigated in the brain, however, for some pathologies, transcriptomic analysis in multiple tissues represent an opportunity and a challenge to understand the consequences of the genetic mutation. This is the case for Rett Syndrome (RTT): a neurodevelopmental disorder predominantly affecting females that is characterised by a loss of purposeful movements and language accompanied by gait abnormalities and hand stereotypies. Although the genetic aetiology is largely associated to Methyl CpG binding protein 2 (MECP2) mutations, linking the pathophysiology of RTT and its clinical symptoms to direct molecular mechanisms has been difficult.One approach used to study the consequences of MECP2 dysfunction in patients, is to perform transcriptomic analysis in tissues derived from RTT patients or Induced Pluripotent Stem cells. The growing affordability and efficiency of this approach has led to a far greater understanding of the complexities of RTT syndrome but is also raised questions about previously held convictions such as the regulatory role of MECP2, the effects of different molecular mechanisms in different tissues and role of X Chromosome Inactivation in RTT.In this review we consider the results of a number of different transcriptomic analyses in different patients-derived preparations to unveil specific trends in differential gene expression across the studies. Although the analyses present limitations- such as the limited sample size- overlaps exist across these studies, and they report dysregulations in three main categories: dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity.These observations have a direct application to the disorder and give insights on the altered mechanisms in RTT, with implications on potential diagnostic criteria and treatments.
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12. Walsh EC, Lee JM, Terzakis K, Zhou DW, Burns S, Buie TM, Firth PG, Shank ES, Houle TT, Brown EN, Purdon PL. {{Age-Dependent Changes in the Propofol-Induced Electroencephalogram in Children With Autism Spectrum Disorder}}. {Frontiers in systems neuroscience}. 2018; 12: 23.
Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2-30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2-30 years old. The primary outcome was changes in propofol-induced alpha (8-13 Hz) and slow (0.1-1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD. Lien vers le texte intégral (Open Access ou abonnement)
13. Wang Y, Xiao Y, Li Y, Chu K, Feng M, Li C, Qiu N, Weng J, Ke X. {{Exploring the relationship between fairness and ‘brain types’ in children with high-functioning autism spectrum disorder}}. {Prog Neuropsychopharmacol Biol Psychiatry}. 2018; 88: 151-8.
BACKGROUND: Existing research typically focuses on only one domain of cognition with regard to fairness-theory of mind or executive function. However, children with High-functioning autism spectrum disorder (HF-ASD) are cognitively impaired in both domains. Moreover, little is known about fairness characteristics in children with HF-ASD in relation to both domains of cognition. METHODS: Thirty children with HF-ASD as well as 39 children with typical development (TD) were evaluated in this study. We investigated the development of children’s fairness characteristics as a responder in a mini ultimatum game (UG). The different ‘brain types,’ i.e., with or without HF-ASD, were evaluated using the Empathy Questionnaire-Systemizing Questionnaire (E/SC-Q). Furthermore, we explored the relationship between fairness and brain types using Pearson correlation analyses. RESULTS: Children in the HF-ASD group were more likely to accept unfair offers than were children in the TD group (chi(2)=17.513, p=.025). In the HF-ASD group, the acceptance rate of unfair offers was correlated with the discrepancy score (r=0.363, p=.048), while there were no significant correlations in the TD group. In HF-ASD group, compared with Type S, acceptance rate of unfair offer was significant higher in Extreme Type S ‘brain type’ (F=28.584, p<.001). While dividing TD participants by 'brain type', there was no significant difference in acceptance rate of unfair offer among five difference 'brain types' (F=1.131, p=.358). Stepwise regression revealed that Extreme Type S positively predicted acceptance of unfair offers (F [1, 68]=8.695, p<.001). DISCUSSION: Our findings show that children with HF-ASD were more likely to accept an unfair offer; in particular, the more unbalanced the development of empathy and systemizing was, the more significant the unfairness preference observed. Extreme Type S positively predicted the acceptance of unfair offers by children with HF-ASD. REGISTRATION OF CLINICAL TRIALS: World Health Organization class I registered international clinical trial platform, ChiCTR-ROC-17012877. Lien vers le texte intégral (Open Access ou abonnement)
14. Yang Q, Huang P, Li C, Fang P, Zhao N, Nan J, Wang B, Gao W, Cui LB. {{Mapping alterations of gray matter volume and white matter integrity in children with autism spectrum disorder: evidence from fMRI findings}}. {Neuroreport}. 2018.
This study aimed to identify the neuroanatomical substrates and white matter connectivity in children with autism spectrum disorder (ASD) and the association between gray matter and structural connectivity. A total of 36 children including patients with ASD and healthy controls between 6 and 15 years of age were enrolled in this study. High-resolution structural MRI and functional MRI were performed and analyzed using voxel-based morphometry and tract-based spatial statistics. The relationship between gray matter volume and structural connectivity was generated using Pearson correlation analysis. Voxel-based morphometry analysis showed significantly reduced areas of gray matter in the left cerebellum. Tract-based spatial statistics analysis showed white matter abnormalities in several distinct clusters within the right inferior frontal gyrus (opercular part), the left inferior parietal lobule, and the right mentary motor area. Neither ASD nor healthy controls showed a significant correlation between gray matter volume and white matter integrity. Our study confirmed the presence of several structural and regional abnormalities in ASD children. These findings suggest that there are significant differences in some brain regions in children with autism relative to healthy children, but no association between them.
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15. Yuen T, Penner M, Carter MT, Szatmari P, Ungar WJ. {{Assessing the accuracy of the Modified Checklist for Autism in Toddlers: a systematic review and meta-analysis}}. {Dev Med Child Neurol}. 2018.
AIM: The Modified Checklist for Autism in Toddlers (M-CHAT) could be appropriate for universal screening for autism spectrum disorder (ASD) at 18 months and 24 months. Validation studies, however, reported differences in psychometric properties across sample populations. This meta-analysis summarized its accuracy measures and quantified their change in relation to patient and study characteristics. METHOD: Four electronic databases (MEDLINE, PsycINFO, CINAHL, and Embase) were searched to identify articles published between January 2001 and May 2016. Bayesian regression models pooled study-specific measures. Meta-regressions covariates were age at screening, study design, and proportion of males. RESULTS: On the basis of the 13 studies included, the pooled sensitivity was 0.83 (95% credible interval [CI] 0.75-0.90), specificity was 0.51 (95% CI 0.41-0.61), and positive predictive value was 0.53 (95% CI 0.43-0.63) in high-risk children and 0.06 (95% CI <0.01-0.14) in low-risk children. Sensitivity was higher for screening at 30 months compared with 24 months. INTERPRETATION: Findings indicate that the M-CHAT performs with low to moderate accuracy in identifying ASD among children with developmental concerns, but there was a lack of evidence on its performance in low-risk children or at age 18 months. Clinicians should account for a child's age and presence of developmental concern when interpreting their M-CHAT score. WHAT THIS PAPER ADDS: The Modified Checklist for Autism in Toddlers (M-CHAT) performs with low-to-moderate accuracy in children with developmental concerns. There is limited evidence supporting its use at 18 months or in low-risk children. Lien vers le texte intégral (Open Access ou abonnement)
16. Zhao G, Walsh K, Long J, Gui W, Denisova K. {{Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder}}. {PLoS One}. 2018; 13(7): e0196964.
The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13-10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47-10.52). We focus on an age range within the ‘middle and late childhood’ period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD.
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17. Zhao XN, Usdin K. {{FAN1 protects against repeat expansions in a Fragile X mouse model}}. {DNA repair}. 2018; 69: 1-5.
The Fragile X-related disorders (FXDs) are members of a large group of human neurological or neurodevelopmental conditions known as the Repeat Expansion Diseases. The mutation responsible for all of these diseases is an expansion in the size of a disease-specific tandem repeat tract. However, the underlying cause of this unusual mutation is unknown. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the vicinity of the FAN1 (MIM* 613534) gene that are associated with variations in the age at onset of a number of Repeat Expansion Diseases. FAN1 is a nuclease that has both 5′-3′ exonuclease and 5′ flap endonuclease activities. Here we show in a model for the FXDs that Fan1(-/-) mice have expansions that, in some tissues including brain, are 2-3 times as extensive as they are in Fan1(+/+) mice. However, no effect of the loss of FAN1 was apparent for germ line expansions. Thus, FAN1 plays an important role in protecting against somatic expansions but is either not involved in protecting against intergenerational repeat expansions or is redundant with other related enzymes. However, since loss of FAN1 results in increased expansions in brain and other somatic tissue, FAN1 polymorphisms may be important disease modifiers in those Repeat Expansion Diseases in which somatic expansion contributes to age at onset or disease severity.
