1. Ann Abraham D, Narasimhan U, Christy S, Muhasaparur Ganesan R. {{Effect of L-Carnosine as adjunctive therapy in the management of children with autism spectrum disorder: a randomized controlled study}}. {Amino acids}. 2020.
L-Carnosine is an amino acid that acts as an anti-oxidant, anti-toxic and neuroprotective agent. There is a paucity of data about the effectiveness of L-Carnosine in the management of autism spectrum disorder (ASD) in children. This study aimed at investigating the effectiveness of L-Carnosine as adjunctive therapy in the management of ASD. This was a randomized controlled trial. Children aged 3-6 years with a diagnosis of mild to moderate ASD were assigned to standard care arm (occupational and speech therapy) and intervention care arm (L-Carnosine, 10-15 mg/kg in 2 divided doses) plus standard care treatment. The children were assessed at the baseline and the end of 2 months for the scores of Childhood Autism Rating Scale, Second Edition-Standard Version (CARS2-ST), Autism Treatment Evaluation Checklist (ATEC), BEARS sleep screening tool and 6-item Gastrointestinal Severity Index (6-GSI). Of the sixty-seven children enrolled, sixty-three children had completed the study. No statistically significant difference (p > 0.05) was observed for any of the outcome measures assessed. Supplementation of L-Carnosine did not improve the total score of CARS2-ST, ATEC, BEARS sleep screening tool and 6-GSI scores of children with ASD. Further investigations are needed with more objective assessments to critically validate the effectiveness of L-Carnosine on ASD children for more decisive results.
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2. Ash RT, Park J, Suter B, Zoghbi HY, Smirnakis SM. {{Excessive formation and stabilization of dendritic spine clusters in the MECP2 duplication syndrome mouse model of autism}}. {eNeuro}. 2020.
Autism-associated genetic mutations may perturb the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the formation and stabilization of dendritic spines in the cerebral cortex of the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. Increased stabilization is mediated entirely by spines that form cooperatively in 10-micron clusters and is observable across multiple cortical areas both spontaneously and following motor training. Excessive stability of dendritic spine clusters could contribute to behavioral rigidity and other phenotypes in syndromic autism.Significance Statement The inflexible repetitive behaviors, « insistence on sameness, » and at times exceptional learning abilities seen in autism imply a defect in the neural processes underlying learning and memory, potentially affecting the balance between stability and plasticity of synaptic connections in the brain. Here we report a pathological bias toward stability of newly formed dendritic spines in the MECP2-duplication mouse model of autism. Enhanced spine stability is mediated entirely by spines aggregating within 10 µm of each other, in clusters. Enhanced clustered spine stability is observable in multiple brain areas both at rest and during motor training. The results suggest that some phenotypes of autism could arise from abnormal consolidation of clustered synaptic connections.
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3. Chiurazzi P, Kiani AK, Miertus J, Paolacci S, Barati S, Manara E, Stuppia L, Gurrieri F, Bertelli M. {{Genetic analysis of intellectual disability and autism}}. {Acta bio-medica : Atenei Parmensis}. 2020; 91(13-s): e2020003.
BACKGROUND AND AIM: Intellectual disability (ID) and autism spectrum disorders (ASD) are neurodevelopmental conditions that often co-exist and affect children from birth, impacting on their cognition and adaptive behaviour. Social interaction and communication ability are also severely impaired in ASD. Almost 1-3% of the population is affected and it has been estimated that approximately 30% of intellectual disability and autism is caused by genetic factors. The aim of this review is to summarize monogenic conditions characterized by intellectual disability and/or autism for which the causative genes have been identified. METHODS AND RESULTS: We identified monogenic ID/ASD conditions through PubMed and other NCBI databases. Many such genes are located on the X chromosome (>150 out of 900 X-linked protein-coding genes), but at least 2000 human genes are estimated to be involved in ID/ASD. We selected 174 genes (64 X-linked and 110 autosomal) for an NGS panel in order to screen patients with ID and/or ASD, after fragile X syndrome and significant Copy Number Variants have been excluded. CONCLUSIONS: Accurate clinical and genetic diagnosis is required for precise treatment of these disorders, but due to their genetic heterogeneity, most cases remain undiagnosed. Next generation sequencing technologies have greatly enhanced the identification of new genes associated with intellectual disability and autism, ultimately leading to the development of better treatment options.
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4. Jacobs GR, Voineskos AN, Hawco C, Stefanik L, Forde NJ, Dickie EW, Lai MC, Szatmari P, Schachar R, Crosbie J, Arnold PD, Goldenberg A, Erdman L, Ameis SH. {{Integration of brain and behavior measures for identification of data-driven groups cutting across children with ASD, ADHD, or OCD}}. {Neuropsychopharmacology}. 2020.
Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network was used including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Future work is needed to build on this early attempt through replication of the current findings in independent samples and testing longitudinally for prognostic value.
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5. Jamal W, Cardinaux A, Haskins AJ, Kjelgaard M, Sinha P. {{Reduced Sensory Habituation in Autism and Its Correlation with Behavioral Measures}}. {J Autism Dev Disord}. 2020.
Autism is strongly associated with sensory processing difficulties. We investigate sensory habituation, given its relevance for understanding important phenotypic traits like hyper- and hypo-sensitivities. We collected electroencephalography data from 22 neuro-typical(NT) and 13 autistic(ASD) children during the presentation of visual and auditory sequences of repeated stimuli. Our data show that the ASD children have significantly reduced habituation relative to the NT children for both auditory and visual stimuli. These results point to impaired habituation as a modality-general phenomenon in ASD. Additionally, the rates of habituation are correlated with several clinical scores associated with competence along diverse phenotypic dimensions. These data suggest that the sensory difficulties in autism are likely to be associated with reduced habituation and are related to clinical symptomology.
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6. Kara T, Alpgan Ö. {{Nursing personality and features in children with autism spectrum disorder aged 0-2: an exploratory case-control study}}. {Nutr Neurosci}. 2020: 1-9.
AIM: Although studies have investigated relationships between autism spectrum disorder (ASD) and breastfeeding duration, information concerning these children’s nursing styles is limited. This study investigated nursing personality and features and ASD. METHOD: One hundred forty-one children aged 24-72 months diagnosed with ASD and 128 healthy children were included. Information concerning the family’s sociodemographic characteristics and the child’s developmental stages was obtained through forms prepared by the authors and from hospital records. The Childhood Autism Rating Scale (CARS) was used to determine symptom severity in ASD. Development levels of children with ASD were determined using the Denver Developmental Screening Test 2nd Edition (DDST II). RESULTS: Mothers of children with ASD reported higher rates of unintended pregnancies (p = 0.029) [2.380*(1.093-5.182)]. Children with ASD exhibited less nursing strike (NS) behavior (p = 0.042) [0.388(0.156-0.967)] and less eye contact during breastfeeding (ECDB) (p = 0.009) [2.300(1.236-4.282)]. NS reduced the risk of ASD 2.6-fold, while absence of ECDB increased the risk 2.3-fold, and unintended pregnancy increased the risk 2.4-fold. Higher CARS scores were determined in children with ASD with vaginal delivery histories (p = 0.041) and histories of incubation (p = 0.025). Lack of ECDB was associated with decreased social and gross motor scores at DDST-II (p = 0.005). CONCLUSION: Babies with ASD began breastfeeding at least as early as typically developing peers and for similar lengths of time. However, babies with ASD exhibited less NS behavior and less eye contact during breastfeeding. Babies with ASD perceive no emotional cues even in the first months, and may therefore not exhibit NS behavior.
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7. Kim SS. {{Recent Trends in Autism Spectrum Disorder Research using Text Mining of PubMed: Importance of Early Detection}}. {Clinical and experimental pediatrics}. 2020.
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8. Kurtz-Nelson EC, Tham SW, Ahlers K, Cho D, Wallace AS, Eichler EE, Bernier RA, Earl RK. {{Brief Report: Associations Between Self-injurious Behaviors and Abdominal Pain Among Individuals with ASD-Associated Disruptive Mutations}}. {J Autism Dev Disord}. 2020.
Self-injurious behaviors (SIB) are elevated in autism spectrum disorder (ASD) and related genetic disorders, but the genetic and biological mechanisms that contribute to SIB in ASD are poorly understood. This study examined rates and predictors of SIB in 112 individuals with disruptive mutations to ASD-risk genes. Current SIB were reported in 30% of participants and associated with poorer cognitive and adaptive skills. History of severe abdominal pain predicted higher rates of SIB and SIB severity after controlling for age and adaptive behavior; individuals with a history of severe abdominal pain were eight times more likely to exhibit SIB than those with no history. Future research is needed to examine associations between genetic risk, pain, and SIB in this population.
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9. Masini E, Loi E, Vega-Benedetti AF, Carta M, Doneddu G, Fadda R, Zavattari P. {{An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity}}. {International journal of molecular sciences}. 2020; 21(21).
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects social interaction and communication, with restricted interests, activity and behaviors. ASD is highly familial, indicating that genetic background strongly contributes to the development of this condition. However, only a fraction of the total number of genes thought to be associated with the condition have been discovered. Moreover, other factors may play an important role in ASD onset. In fact, it has been shown that parental conditions and in utero and perinatal factors may contribute to ASD etiology. More recently, epigenetic changes, including DNA methylation and micro RNA alterations, have been associated with ASD and proposed as potential biomarkers. This review aims to provide a summary of the literature regarding ASD candidate genes, mainly focusing on synapse formation and functionality and relevant epigenetic and environmental aspects acting in concert to determine ASD onset.
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10. Raghavan R, Selhub J, Paul L, Ji Y, Wang G, Hong X, Zuckerman B, Fallin MD, Wang X. {{A prospective birth cohort study on cord blood folate subtypes and risk of autism spectrum disorder}}. {The American journal of clinical nutrition}. 2020; 112(5): 1304-17.
BACKGROUND: We previously reported that extremely high concentrations of maternal plasma folate were associated with increased risk of autism spectrum disorder (ASD) in children. This study explored whether specific types of folate in cord blood have differential association with ASD. OBJECTIVES: In the Boston Birth Cohort (BBC), we assessed the association between cord blood unmetabolized folic acid (UMFA), 5-methyl tetrahydrofolate (THF), and total folate and a child’s ASD risk. In a subset, we explored whether the association between UMFA and ASD risk can be affected by the dihydrofolate reductase (DHFR) genotype and cord plasma creatinine. We also examined prenatal correlates of cord UMFA concentrations. METHODS: This report included 567 BBC children (92 ASD, 475 neurotypical), who were recruited at birth and prospectively followed at the Boston Medical Center. ASD was defined from International Classification of Diseases (ICD)-9 and ICD-10 codes documented in electronic medical records. RESULTS: Children with cord UMFA in the highest, versus lowest quartile, had a greater ASD risk (adjusted OR, aORquartile4: 2.26; 95% CI: 1.08, 4.75). When stratified by race/ethnicity, the association was limited to 311 (45 ASD) Black children (aORquartile4: 9.85; 95% CI: 2.53, 38.31); a test of interaction between race/ethnicity and cord UMFA concentrations was significant (P = 0.007). The UMFA-ASD association in Black children slightly attenuated after adjusting for cord plasma creatinine (P = 0.05). There was no significant association between cord 5-methyl THF, total folate, DHFR genotype, and ASD risk. Cord total folate and maternal supplement intake during second trimester were associated with higher cord UMFA. CONCLUSIONS: Higher concentrations of cord UMFA, but not 5-methyl THF or total folate, were associated with a greater risk of ASD in Black children. This study in a preterm-birth-enriched cohort raises more questions than it could answer and underscores the need for additional investigations on the sources and role of cord UMFA in children’s neurodevelopmental outcomes and underlying mechanisms.
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11. Rohatgi RK, Qureshi MY, Taggart NW. {{Limited Utility of Surveillance Echocardiograms in Pediatric Patients with Isolated Secundum ASDs}}. {Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography}. 2020.
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12. Sandgreen H, Frederiksen LH, Bilenberg N. {{Digital Interventions for Autism Spectrum Disorder: A Meta-analysis}}. {J Autism Dev Disord}. 2020.
This study aimed to review digital interventions in the treatment of autism spectrum disorder (ASD). A systematic review and meta-analysis was conducted. Nineteen studies were included. The interventions aimed to improve social skills (n = 11), developmental skills (n = 2) and 6 other different targets. Technology used were computer programs (n = 14), tablet apps (n = 3), a robot (n = 1) and an interactive DVD (n = 1). The meta-analysis resulted in an overall effect size (Cohen’s d) of 0.32 [0.12-0.51], indicating a small effect. Heterogeneity between studies was high (I(2) = 100%), limiting the generalization of results. Therefore, we recommend larger RCT studies, and guidelines for the development of trials evaluating digital interventions for ASD, for making comparison of future studies possible.Registration can be found online at Prospero: https://www.crd.york.ac.uk/prospero/ , registration no. CRD42020146542.
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13. Shih PY, Hsieh BY, Tsai CY, Lo CA, Chen BE, Hsueh YP. {{Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms}}. {Acta neuropathologica communications}. 2020; 8(1): 185.
Abnormal synaptic formation and signaling is one of the key molecular features of autism spectrum disorders (ASD). Cortactin binding protein 2 (CTTNBP2), an ASD-linked gene, is known to regulate the subcellular distribution of synaptic proteins, such as cortactin, thereby controlling dendritic spine formation and maintenance. However, it remains unclear how ASD-linked mutations of CTTNBP2 influence its function. Here, using cultured hippocampal neurons and knockin mouse models, we screen seven ASD-linked mutations in the short form of the Cttnbp2 gene and identify that M120I, R533* and D570Y mutations impair CTTNBP2 protein-protein interactions via divergent mechanisms to reduce dendritic spine density in neurons. R533* mutation impairs CTTNBP2 interaction with cortactin due to lack of the C-terminal proline-rich domain. Through an N-C terminal interaction, M120I mutation at the N-terminal region of CTTNBP2 also negatively influences cortactin interaction. D570Y mutation increases the association of CTTNBP2 with microtubule, resulting in a dendritic localization of CTTNBP2, consequently reducing the distribution of CTTNBP2 in dendritic spines and impairing the synaptic function of CTTNBP2. Finally, we generated heterozygous M120I knockin mice to mimic the genetic variation of patients and found they exhibit reduced social interaction. Our study elucidates that different ASD-linked mutations of CTTNBP2 result in diverse molecular deficits, but all have the similar consequence of synaptic impairment.
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14. Tschida JE, Yerys BE. {{A Systematic Review of the Positive Valence System in Autism Spectrum Disorder}}. {Neuropsychology review}. 2020.
This review synthesized current literature of behavioral and cognitive studies targeting reward processing in autism spectrum disorder (ASD). The National Institute of Mental Health’s Research Domain Criteria (RDoC) Positive Valence System (PVS) domain was used as an overarching framework. The objectives were to determine which component operations of reward processing may be atypical in ASD and consequently postulate a heuristic model of reward processing in ASD that could be evaluated with future research. 34 studies were identified from the Embase, PubMed, PsycINFO, and Web of Science databases and included in the review using guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (also known as PRISMA guidelines). The extant literature suggested potential relationships between social symptoms of ASD and PVS sub-constructs of reward anticipation, probabilistic and reinforcement learning, reward prediction error, reward (probability), delay, and effort as well as between restricted and repetitive behaviors and interests (RRBIs) and PVS-sub constructs of initial response to reward, reward anticipation, reward (probability), delay, and effort. However, these findings are limited by a sparse and mixed literature for some sub-constructs. We put forward a developmentally informed heuristic model that posits how these component reward processes may be implicated in early ASD behaviors as well as later emerging and more intransigent symptoms. Future research is needed to comprehensively evaluate the proposed model.
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15. Vita A, Barlati S, Deste G, Rocca P, Rossi A, Bertolino A, Aguglia E, Amore M, Bellomo A, Biondi M, Carpiniello B, Collantoni E, Cuomo A, D’Ambrosio E, dell’Osso L, di Giannantonio M, Giordano GM, Marchesi C, Monteleone P, Montemagni C, Oldani L, Pompili M, Roncone R, Rossi R, Siracusano A, Zeppegno P, Nibbio G, Galderisi S, Maj M. {{The influence of autistic symptoms on social and non-social cognition and on real-life functioning in people with schizophrenia: evidence from the Italian Network for Research on Psychoses multicenter study}}. {European psychiatry : the journal of the Association of European Psychiatrists}. 2020: 1-24.
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16. Xing H, Cui N, Johnson CM, Faisthalab Z, Jiang C. {{Dual synaptic inhibitions of brainstem neurons by GABA and glycine with impact on Rett syndrome}}. {Journal of cellular physiology}. 2020.
Rett syndrome (RTT) is a neurodevelopmental disease caused mostly by mutations in the MECP2 gene. People with RTT show breathing dysfunction attributable to the high rate of sudden death. Previous studies have shown that insufficient GABA synaptic inhibition contributes to the breathing abnormalities in mouse models of RTT, while it remains elusive how the glycine system is affected. We found that optogenetic stimulation of GAD-expressing neurons in mice produced GABAergic and glycinergic postsynaptic inhibitions of neurons in the hypoglossal nucleus (XII) and the dorsal motor nucleus of vagus (DMNV). By sequential applications of bicuculline and strychnine, such inhibition appeared approximately 44% GABA(A) ergic and 52% glycinergic in XII neurons, and approximately 49% GABA(A) ergic and 46% glycinergic in DMNV neurons. Miniature inhibitory postsynaptic potentials (mIPSCs) in these neurons were approximately 47% GABA(A) ergic and 49% glycinergic in XII neurons, and approximately 48% versus 50% in DMNV neurons, respectively. Consistent with the data, our single-cell polymerase chain reaction studies indicated that transcripts of GABA(A) receptor γ2 subunit (GABA(A) Rγ2) and glycine receptor β subunit (GlyRβ) were simultaneously expressed in these cells. In MeCP2(R168X) mice, proportions of GABA(A) ergic and glycinergic mIPSCs became approximately 28% versus 69% in XII neurons, and approximately 31% versus 66% in DMNV cells. In comparison with control mice, the GABA(A) ergic and glycinergic mIPSCs decreased significantly in the XII and DMNV neurons from the MeCP2(R168X) mice, so did the transcripts of GABA(A) Rγ2 and GlyRβ. These results suggest that XII and DMNV neurons adopt dual GABA(A) ergic and glycinergic synaptic inhibitions, and with Mecp2 disruption these neurons rely more on glycinergic synaptic inhibition.
