1. Alò R, Olivito I, Fazzari G, Zizza M, Di Vito A, Avolio E, Mandalà M, Bruno R, Tullio B, Canonaco M, Facciolo RM. Correlation of Distinct Behaviors to the Modified Expression of Cerebral Shank1,3 and BDNF in Two Autistic Animal Models. Behav Brain Res. 2021 : 113165.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder featuring altered neuronal circuitry and consequently impaired social interactions, restrictive interests plus repetitive stereotypic activities. In the present study, differentiated behaviors of valproic (VPA) and propionic (PPA) acid-mediated autism rats were correlated to cerebral scaffolding proteins (Shank1,3) and BDNF expression variations. Sprague-Dawley offspring that received VPA during pregnancy displayed a notably diminished permanence (-78%, p < 0.01) in light chamber of light dark (LD) test, reduced exploratory tasks, i.e. grooming (-90%) and rearing (-65%). Moreover, they executed extremely greater climbing intervals (+300%, p < 0.001) in novel cage (NC) test, plus exhibited an extremely reduced (-331%) discrimination index in novel object recognition (NOR) test when compared to controls. PPA-treated postnatal days (PND) 12-16 rats also displayed anxiety-like behaviors, although in a less evident manner, as indicated by a moderate time (+55% ; p < 0.05) spent in dark chamber along with notable and moderate decreases in digging (-78%) plus grooming (-52%), respectively. Contextually, VPA- more than PPA supplied opposite Shank1,3 expression changes in cerebellum (CB ; -62% ; +78%), dorsomedial prefrontal cortex (DM-PFC ; +95% -76%), respectively, while resulting extremely upregulated in hippocampus (HIP ; +125% - +155%). Even BDNF resulted to be substantially and notably diminished in HIP (-85%) and DM-PFC (-72%), respectively, of VPA rats while it was only moderately reduced (-35% to -45%) in these same areas of PPA rats. The early altered brain-specific expression levels accounting for different behavioral performances may provide useful diagnostic indications and constitute valuable therapeutic strategies for autistic patients.

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2. Ding Y, O’Brien A, de la Cruz BM, Yang M, Fitzgerald J, Yang G, Li W, McInerney V, Krawczyk J, Lynch SA, Howard L, Allen NM, O’Brien T, Gallagher L, Shen S. Derivation of iPSC lines from two patients with autism spectrum disorder carrying NRXN1α deletion (NUIGi041-A, NUIG041-B ; NUIGi045-A) and one sibling control (NUIGi042-A, NUIGi042-B). Stem cell research. 2021 ; 52 : 102222.

NRXN1 encodes thousands of splicing variants categorized into long NRXN1α, short NRXN1β and extremely short NRXN1γ, which exert differential roles in neuronal excitation/inhibition. NRXN1α deletions are common in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. We derived induced pluripotent stem cells (iPSCs) from one sibling control and two ASD probands carrying NRXN1α(+/-), using non-integrating Sendai viral method. All iPSCs highly expressed pluripotency markers and could be differentiated into ectodermal/mesodermal/endodermal cells. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. The availability of the iPSCs offers an opportunity for understanding NRXN1α function in human neurons and in ASD.

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3. Droboniku MJ, Mychailyszyn MP. Animal Interaction Affecting Core Deficit Domains Among Children with Autism : A Meta-Analysis. J Autism Dev Disord. 2021.

Animal-assisted intervention (AAI) has garnered public interest and has been implemented for youth with autism spectrum disorders-a practice supported by anecdotal evidence. While investigations of AAI for children with autism have been conducted, the extant literature is characterized by significant variability in methodology and practice. The present meta-analysis examines the aggregated effects of equine AAI on adaptive functioning among children with autism. Results indicated that interacting with an equine specifically during AAI produced small-to-medium effects (g = 0.40) on the adaptive functioning of children with autism. Recommendations are made for future research on this topic.

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4. Hong E, Matson JL. Factors Associated with Restricted, Repetitive Behaviors and Interests and Diagnostic Severity Level Ratings in Young Children with Autism Spectrum Disorder. J Autism Dev Disord. 2021.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, repetitive patterns of behavior and interests (RRBIs). With the latest update to the Diagnostic and Statistical Manual of Mental Disorders, a severity level rating is assigned to the two core features of ASD (American Psychiatric Association in Diagnostic and statistical manual of mental disorders 5 American Psychiatric Association Washington, D.C., 2013). Previous studies have identified factors associated with RRBI severity ; however, the relationship among RRBIs, adaptive functioning, and diagnostic severity level remains unclear. The present study investigated whether adaptive functioning and parent-reported ASD symptoms predict RRBI severity in young children with ASD. Additionally, a fine-grained analysis was conducted to examine the factors associated with diagnostic severity level ratings. Several significant associations were found. Study findings and implications for assessment and treatment of RRBIs are discussed.

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5. Lorah E, Holyfield C, Kucharczyk S. Typical preschoolers’ perceptions of augmentative and alternative communication modes of a preschooler with autism spectrum disorder. Augmentative and alternative communication (Baltimore, Md : 1985). 2021 : 1-20.

Understanding typical preschoolers’ perceptions of communication modes could help guide augmentative and alternative communication (AAC) intervention for preschoolers with autism spectrum disorder (ASD). This study explored the perceptions of 16 typically developing preschoolers toward an (a) AAC application (app) on a tablet, (b) picture exchange using a binder with printed Picture Communication Symbols(TM), and (c) prelinguistic communication used by a preschooler with ASD in a series of videos the preschoolers watched. Using a multi-method design, the study implemented both quantitative (rank ordering and preference selection) and qualitative (interview) methodologies. Quantitative results revealed the typical preschoolers had a clear overall preference for the AAC app, but variation in preference existed when selecting a communication mode to use in specific social scenarios. Qualitative data show the children more easily understood the child with ASD when he used the AAC app and associated tablets with fun, which may have accounted for positive perceptions of this AAC mode. The study is exploratory in nature and limited by its size and scope. However, it provides insights useful for clinicians’ understanding not just how typical preschoolers perceive various modes of communication, but also why they may perceive some more favorably than others, in order to tailor intervention accordingly.

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6. Roberta B, Riva V, Cantiani C, Riboldi EM, Molteni M, Macchi Cassia V, Bulf H. Dysfunctions in Infants’ Statistical Learning are Related to Parental Autistic Traits. J Autism Dev Disord. 2021.

Statistical learning refers to the ability to extract the statistical relations embedded in a sequence, and it plays a crucial role in the development of communicative and social skills that are impacted in the Autism Spectrum Disorder (ASD). Here, we investigated the relationship between infants’ SL ability and autistic traits in their parents. Using a visual habituation task, we tested infant offspring of adults (non-diagnosed) who show high (HAT infants) versus low (LAT infants) autistic traits. Results demonstrated that LAT infants learned the statistical structure embedded in a visual sequence, while HAT infants failed. Moreover, infants’ SL ability was related to autistic traits in their parents, further suggesting that early dysfunctions in SL might contribute to variabilities in ASD symptoms.

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7. Sorenson Duncan T, Karkada M, Deacon SH, Smith IM. Building Meaning : Meta-analysis of Component Skills Supporting Reading Comprehension in Children with Autism Spectrum Disorder. Autism Res. 2021.

The ability to understand what one reads, or reading comprehension, is central to academic success. For many children with autism spectrum disorder (ASD), reading comprehension is a noted area of challenge. For children with typical development, it is well established that successful reading comprehension requires two broad skills : word reading and oral language. For children with ASD, word reading is often believed to be relatively intact, even in the face of poor reading comprehension, suggesting that deficits in oral language, more than in word reading, underlie reading comprehension deficits. Yet, extant research has suggested the importance of both skills. To clarify the role of these skills in the reading comprehension of children with ASD, we conducted a meta-analysis. ERIC, PsycINFO, PubMed, and Proquest Dissertation & Theses were searched for studies of reading comprehension in children with ASD, published up to May 2019. We identified 26 relevant studies about children with ASD (aged 6-18 years) that included both a measure of word reading and reading comprehension. Hunt-Schmidt Random Effects Models showed similar mean correlations between reading comprehension and the component skills of word reading (M r = 0.65 [0.27-1.03]) and oral language (M r = 0.61 [0.33-0.88]). These findings demonstrate that these skills are essential for reading comprehension in children with ASD, making contributions of similar size. This study advances our understanding of the mechanisms by which children with ASD understand what they read, providing a foundation on which to build programmatic research into each of these mechanisms. LAY SUMMARY : Academic progress is closely tied to children’s ability to understand what they read. Yet reading comprehension is difficult for many children with autism spectrum disorder (ASD). We used a statistical method to summarize existing research on the skills that children with ASD use to understand what they read. We found that the reading comprehension of children with ASD was related to a similar extent to both their ability to read individual words and their oral language skills. These findings suggest that both areas should be assessed in order to determine appropriate interventions to support reading comprehension for children with ASD.

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8. Tomoiaga D, Aguiar-Pulido V, Shrestha S, Feinstein P, Levy SE, Mason CE, Rosenfeld JA. Single-cell sperm transcriptomes and variants from fathers of children with and without autism spectrum disorder. NPJ genomic medicine. 2020 ; 5(1) : 14.

The human sperm is one of the smallest cells in the body, but also one of the most important, as it serves as the entire paternal genetic contribution to a child. Investigating RNA and mutations in sperm is especially relevant for diseases such as autism spectrum disorders (ASD), which have been correlated with advanced paternal age. Historically, studies have focused on the assessment of bulk sperm, wherein millions of individual sperm are present and only high-frequency variants can be detected. Using 10× Chromium single-cell sequencing technology, we assessed the transcriptome from >65,000 single spermatozoa across six sperm donors (scSperm-RNA-seq), including two who fathered multiple children with ASD and four fathers of neurotypical children. Using RNA-seq methods for differential expression and variant analysis, we found clusters of sperm mutations in each donor that are indicative of the sperm being produced by different stem cell pools. Finally, we have shown that genetic variations can be found in single sperm.

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9. Zhao X, Kumari D, Miller CJ, Kim GY, Hayward B, Vitalo AG, Pinto RM, Usdin K. Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders : Implications for the Mechanism of Somatic Expansion in Huntington’s Disease. Journal of Huntington’s disease. 2021 ; 10(1) : 149-63.

Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

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