1. Achermann S, Falck-Ytter T, Bölte S, Nyström P. Updating Expectations About Unexpected Object Motion in Infants Later Diagnosed with Autism Spectrum Disorder. J Autism Dev Disord. 2021.

In typical development, infants form predictions about future events based on incoming sensory information, which is essential for perception and goal-directed action. It has been suggested that individuals with autism spectrum disorder (ASD) make predictions differently compared to neurotypical individuals. We investigated how infants who later received an ASD diagnosis and neurotypical infants react to temporarily occluded moving objects that violate initial expectations about object motion. Our results indicate that infants regardless of clinical outcome react similarly to unexpected object motion patterns, both in terms of gaze shift latencies and pupillary responses. These findings indicate that the ability to update representations about such regularities in light of new information may not differ between typically developing infants and those with later ASD.

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2. Batiha O, Shaaban ST, Al-Smadi M, Jarun Y, Maswadeh A, Alahmad NA, Al-Talib MM. A study on the role of FMR1 CGG trinucleotide repeats in Jordanian poor ovarian responders. Gene. 2021 ; 767 : 145174.

The expansion of trinucleotide CGG repeats in the promoter of fragile X mental retardation 1 (FMR1) gene is associated with fragile X and fragile X associated tremor/ataxia syndromes. While the expansion of CGG repeats has been associated with such neuro/psychiatric diseases, the contraction of CGG repeats has been recently suggested as an indication of ovarian dysfunction. This study aimed to evaluate a possible association of the short CGG repeats with poor ovarian responders (POR) and to test for a possible correlation between the CGG size and different known markers of the ovarian reserve, namely FSH, AMH, and the number of retrieved oocytes from Jordanian females. We found a significant difference between the CGG median allele size between the cases and the controls (p < 0.001), where poor ovarian responders had shorter CGG repeats compared to the healthy controls. Also, females with alleles <26 had twice the odds to be presented in the POR compared to the controls. However, we did not find a significant correlation between CGG sizes and the markers of ovarian reserve. We conclude that although low CGG repeats appear to be linked to POR, the clinical utility of FMR1 for predicting ovarian response needs further investigation.

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3. Cakar NE, Yilmazbas P. Cases of inborn errors of metabolism diagnosed in children with autism. Ideggyogyaszati szemle. 2021 ; 74(1-2) : 67-72.

BACKGROUND AND PURPOSE : Autism spectrum disorder is a neurodevelopmental disorder with a heterogeneous presentation, the etiology of which is not clearly elucidated. In recent years, comorbidity has become more evident with the increase in the frequency of autism and diagnostic possibilities of inborn errors of metabolism. METHODS : One hundred and seventy-nine patients with diagnosis of autism spectrum disorder who presented to the Pediatric Metabolism outpatient clinic between 01/September/2018-29/February/2020 constituted the study population. The personal information, routine and specific metabolic tests of the patients were analyzed retrospectively. RESULTS : Out of the 3261 patients who presented to our outpatient clinic, 179 (5.48%) were diagnosed with autism spectrum disorder and were included in the study. As a result of specific metabolic examinations performed, 6 (3.3%) patients were diagnosed with inborn errors of metabolism. Two of our patients were diagnosed with classical phenylketonuria, two with classical homocystinuria, one with mucopolysaccharidosis type 3D (Sanfilippo syndrome) and one with 3-methylchrotonyl Co-A carboxylase deficiency. CONCLUSION : Inborn errors of metabolism may rarely present with autism spectrum disorder symptoms. Careful evaluation of the history, physical examination and additional findings in patients diagnosed with autism spectrum disorder will guide the clinician in the decision-making process and chose the appropriate specific metabolic investigation. An underlying inborn errors of metabolism may be a treatable cause of autism.

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4. Courraud J, Ernst M, Svane Laursen S, Hougaard DM, Cohen AS. Studying Autism Using Untargeted Metabolomics in Newborn Screening Samples. Journal of molecular neuroscience : MN. 2021.

Main risk factors of autism spectrum disorder (ASD) include both genetic and non-genetic factors, especially prenatal and perinatal events. Newborn screening dried blood spot (DBS) samples have great potential for the study of early biochemical markers of disease. To study DBS strengths and limitations in the context of ASD research, we analyzed the metabolomic profiles of newborns later diagnosed with ASD. We performed LC-MS/MS-based untargeted metabolomics on DBS from 37 case-control pairs randomly selected from the iPSYCH sample. After preprocessing using MZmine 2.41, metabolites were putatively annotated using mzCloud, GNPS feature-based molecular networking, and MolNetEnhancer. A total of 4360 mass spectral features were detected, of which 150 (113 unique) could be putatively annotated at a high confidence level. Chemical structure information at a broad level could be retrieved for 1009 metabolites, covering 31 chemical classes. Although no clear distinction between cases and controls was revealed, our method covered many metabolites previously associated with ASD, suggesting that biochemical markers of ASD are present at birth and may be monitored during newborn screening. Additionally, we observed that gestational age, age at sampling, and month of birth influence the metabolomic profiles of newborn DBS, which informs us on the important confounders to address in future studies.

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5. Hartig R, Wolf D, Schmeisser MJ, Kelsch W. Genetic influences of autism candidate genes on circuit wiring and olfactory decoding. Cell and tissue research. 2021 ; 383(1) : 581-95.

Olfaction supports a multitude of behaviors vital for social communication and interactions between conspecifics. Intact sensory processing is contingent upon proper circuit wiring. Disturbances in genetic factors controlling circuit assembly and synaptic wiring can lead to neurodevelopmental disorders, such as autism spectrum disorder (ASD), where impaired social interactions and communication are core symptoms. The variability in behavioral phenotype expression is also contingent upon the role environmental factors play in defining genetic expression. Considering the prevailing clinical diagnosis of ASD, research on therapeutic targets for autism is essential. Behavioral impairments may be identified along a range of increasingly complex social tasks. Hence, the assessment of social behavior and communication is progressing towards more ethologically relevant tasks. Garnering a more accurate understanding of social processing deficits in the sensory domain may greatly contribute to the development of therapeutic targets. With that framework, studies have found a viable link between social behaviors, circuit wiring, and altered neuronal coding related to the processing of salient social stimuli. Here, the relationship between social odor processing in rodents and humans is examined in the context of health and ASD, with special consideration for how genetic expression and neuronal connectivity may regulate behavioral phenotypes.

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6. Keller A, Rimestad ML, Friis Rohde J, Holm Petersen B, Bruun Korfitsen C, Tarp S, Briciet Lauritsen M, Händel MN. The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders : A Systematic Review and Meta-Analysis. Nutrients. 2021 ; 13(2).

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) -0.31 (95% Cl. -0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl -5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl -6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

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7. Lee RR, Ward AR, Lane DM, Aman MG, Loveland KA, Mansour R, Pearson DA. Executive Function in Autism : Association with ADHD and ASD Symptoms. J Autism Dev Disord. 2021.

There is substantial comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD), and there are well-documented executive functioning (EF) deficits in both populations. An important question concerns whether EF deficits in children with ASD are related to severity of ASD, ADHD, or both. We examined ADHD and ASD symptoms in relation to ratings of EF in the home and classroom. The sample comprised 64 children (55 males) diagnosed with ASD (mean age = 9.26 years ; mean FSIQ = 92). Analyses indicated that parent and teacher ratings of EF (except Shift and Emotional Control) were consistently related to ADHD symptom severity, but not to ASD severity. Thus, functioning in the domains of Shift and Emotional control appear relatively spared, whereas performance in all other EF was impaired in relation to ADHD symptoms.

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8. Loesch DZ, Tassone F, Atkinson A, Stimpson P, Trost N, Pountney DL, Storey E. Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement. Frontiers in molecular biosciences. 2020 ; 7 : 577246.

Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called « Fragile X-Associated Tremor Ataxia Syndrome » (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40-50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities : all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.

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9. Reindal L, Nærland T, Weidle B, Lydersen S, Andreassen OA, Sund AM. Structural and Pragmatic Language Impairments in Children Evaluated for Autism Spectrum Disorder (ASD). J Autism Dev Disord. 2021.

Pragmatic language impairments are common in neurodevelopmental disorders, especially in autism spectrum disorder (ASD). The relationship between structural language skills and pragmatic competence in children with autistic symptoms, however, is largely unknown. We investigated this relationship based on the Children’s Communication Checklist-2 and early language delay among children (N = 177, 19% females) clinically evaluated for ASD, differentiated into ASD (n = 148) and non-ASD (n = 29). Structural language deficits were common and associated with reduced pragmatic competence in both groups. Pragmatic language impairments were most profound in children with ASD. Early language delay and structural language deficits were less common in females. Our findings suggest that assessment of structural language skills should be included in the evaluation of children with suspected ASD.

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10. Wang M, Doenyas C, Wan J, Zeng S, Cai C, Zhou J, Liu Y, Yin Z, Zhou W. Virulence factor-related gut microbiota genes and immunoglobulin A levels as novel markers for machine learning-based classification of autism spectrum disorder. Computational and structural biotechnology journal. 2021 ; 19 : 545-54.

Autism spectrum disorder (ASD) is a neurodevelopmental condition for which early identification and intervention is crucial for optimum prognosis. Our previous work showed gut Immunoglobulin A (IgA) to be significantly elevated in the gut lumen of children with ASD compared to typically developing (TD) children. Gut microbiota variations have been reported in ASD, yet not much is known about virulence factor-related gut microbiota (VFGM) genes. Upon determining the VFGM genes distinguishing ASD from TD, this study is the first to utilize VFGM genes and IgA levels for a machine learning-based classification of ASD. Sequence comparisons were performed of metagenome datasets from children with ASD (n = 43) and TD children (n = 31) against genes in the virulence factor database. VFGM gene composition was associated with ASD phenotype. VFGM gene diversity was higher in children with ASD and positively correlated with IgA content. As Group B streptococcus (GBS) genes account for the highest proportion of 24 different VFGMs between ASD and TD and positively correlate with gut IgA, GBS genes were used in combination with IgA and VFGMs diversity to distinguish ASD from TD. Given that VFGM diversity, increases in IgA, and ASD-enriched VFGM genes were independent of sex and gastrointestinal symptoms, a classification method utilizing them will not pertain only to a specific subgroup of ASD. By introducing the classification value of VFGM genes and considering that VFs can be isolated in pregnant women and newborns, these findings provide a novel machine learning-based early risk identification method for ASD.

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11. Westerveld MF, Paynter J, Adams D. Brief Report : Associations Between Autism Characteristics, Written and Spoken Communication Skills, and Social Interaction Skills in Preschool-Age Children on the Autism Spectrum. J Autism Dev Disord. 2021.

We used parent-report data from a prospective longitudinal study to better understand the early strengths in written skills often observed in preschoolers on the spectrum. Consistent with previous research, children demonstrated relative strengths in standardized written communication compared to spoken communication scores on the VABS-II. We found no significant links between children’s performance on the written communication subdomain and their autism characteristics or the Social Interaction Deviance Composite score on the CCC-2. Our results emphasize the need for further research into the early strengths in written skills of preschoolers on the spectrum. From a clinical viewpoint, we highlight the need for a comprehensive emergent literacy assessment in this group of children who are at high risk of persistent literacy difficulties.

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12. Wu YT, Tsao CH, Huang HC, Yang TA, Li YJ. Relationship between Motor Skills and Language Abilities in Children with Autism Spectrum Disorder. Physical therapy. 2021.

OBJECTIVES : Few studies have examined the relationship between language abilities and specific motor skills in toddlers with autism spectrum disorder (ASD). The aim of this study was to compare the relationship of receptive language (RL) and expressive language (EL) abilities with motor functioning between toddlers with ASD aged 24-36 months and their typically developing (TD) peers. Furthermore, the study compared multidimensional motor functioning between toddlers with ASD with delayed RL and EL development and toddlers with ASD and typical RL and EL development. The predictive powers of the motor skills were examined for the group with delayed RL and EL development. METHODS : The language abilities of 38 toddlers with ASD and 38 age-matched TD toddlers were evaluated using the Receptive and Expressive Language Subscales of the Mullen Scale of Early Learning, and their motor skills were assessed using the Peabody Developmental Motor Scales, 2nd Edition. RESULTS : Significant correlations between language ability and motor functioning were observed in the ASD and TD groups. The ASD group with delayed RL and EL development had lower scores for multidimensional motor functioning than the ASD group with typical RL and EL development and the TD group. Moreover, the risks of delayed EL and RL development could be predicted by the lower motor scores among toddlers with ASD. CONCLUSIONS : The positive correlation between language abilities and motor functioning among toddlers with ASD indicated potential connections between the early onsets of motor and speech-language impairments among these toddlers. IMPACT : The results may have implications for the development of motor-based interventions targeting language development among young children with ASD.

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