1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Al-Ayadhi LY, Alsaad AMS, Assiri MA, Al-Mazroua HA, Attia SM. {{Upregulation of interleukin (IL)-31, a cytokine producing CXCR1 peripheral immune cells, contributes to the immune abnormalities of autism spectrum disorder}}. {J Neuroimmunol}. 2020; 349: 577430.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by communication deficits, impaired social interactions, and restricted stereotypical behaviors. Several immune cells are associated with immune dysfunction in ASD; however, IL-31 has not been explored in ASD. This study aims to investigate the role of inflammatory cytokines and transcription factors of the CXCR1 cells in children with ASD. In the current study, we investigated the cytokines and transcription factors produced by CXCR1(+) cells (IL-31, IL-9, IL-21R, IL-21, NF-κB p65, RORγT, STAT1, and FoxP3) in peripheral blood mononuclear cells (PBMCs), from children with ASD and typically developing (TD) control children, using flow cytometric analysis. In addition, we measured mRNA and protein expression levels of IL-31 using quantitative real-time PCR and western blot analyses in PBMCs. In our study, children with ASD had increased CXCR1(+)IL-31(+), CXCR1(+)IL-9(+), CXCR1(+)IL-21R(+), CXCR1(+)IL-21(+), CXCR1(+)NF-κB(+) p65, CXCR1(+)RORγT(+), and CXCR1(+)STAT1(+), and decreased CXCR1(+)FoxP3(+) cells as compared with cells from the TD control samples. Similarly, children with ASD showed increased IL-31 mRNA and protein expression levels as compared to those of TD control samples. Our results suggest that upregulated production of inflammatory cytokines and transcription factors in CXCR1(+) cells cause immunological imbalance in children with ASD. Therefore, attenuation of inflammatory cytokines/mediators and transcription factors could have a therapeutic potential in the treatment of ASD.
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2. Arun Rao AC, Goel H. {{Pathogenic nonsense variant in NFIB in another patient with dysmorphism, Autism Spectrum Disorder, agenesis of the corpus callosum, and intellectual disability}}. {European journal of medical genetics}. 2020: 104092.
The Nuclear Factor I (NFI) transcription family (NFIA, NFIB and NFIX) have been implicated in a range of developmental pathologies, including corpus callosum, craniofacial, urinary tract abnormalities, as well in the development of a number of neurodevelopmental developmental phenotypes including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioural abnormalities. NFIB haploinsufficiency has only recently been presented as a cause for macrocephaly-intellectual disability syndrome, with comparable phenotypes to NFIA related disorder. We add another patient with a previously reported nonsense variant in the NFIB who has Autism Spectrum Disorder level 2, agenesis of the corpus callosum, ADHD, obsessive compulsive Disorder and an intellectual disability. A clinical exome analysis identified a nonsense variant, c.265C>T, p.(Arg89*) involving exon 2 of NFIB (ClinVar variation ID: 424344). A brain MRI demonstrated agenesis of the corpus callosum.
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3. Gulisano M, Barone R, Mosa MR, Milana MC, Saia F, Scerbo M, Rizzo R. {{Incidence of Autism Spectrum Disorder in Youths Affected by Gilles de la Tourette Syndrome Based on Data from a Large Single Italian Clinical Cohort}}. {Brain Sci}. 2020; 10(11).
Gilles de la Tourette syndrome (GTS) and autism spectrum disorder (ASD) are etiologically related neurodevelopmental disorders with an onset age before 18 years and a reported comorbidity of 2.9-20%. The aim of the present study was to identify the incidence of ASD in a large clinical sample of individuals affected by GTS and to compare our results with previously reported incidences. We retrospectively analyzed clinical data (n = 1200) from January 2010 to March 2019 obtained from the outpatient Catania Tourette Clinic, part of the Child and Adolescent Neurology and Psychiatry of the Medical and Experimental Department of Catania University. We used internationally validated evaluation tools. The neuropsychological evaluation was carried out by an expert and a certificated team of child and adolescent neurologists, supervised by two expert child neurologists (R.R. and M.G.). We investigated 975 GTS-affected individuals of various socioeconomic levels aged 5-18 years, and 8.9% (n = 87) were affected by ASD. The incidence of GTS with ASD was significantly lower (p < 0.001) in children than in adolescents. No statistically significant differences were found in the sex distribution and age of onset of tics between individuals with GTS alone and those with GTS and ASD. The incidence of GTS and ASD comorbidity in this study was high, and this has several implications in terms of treatment and prognosis. Lien vers le texte intégral (Open Access ou abonnement)
4. Jokiranta-Olkoniemi E, Gyllenberg D, Sucksdorff D, Suominen A, Kronström K, Chudal R, Sourander A. {{Risk for Premature Mortality and Intentional Self-harm in Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2020.
To examine the risk for premature mortality and intentional self-harm in autism spectrum disorders (ASD). Based on a national birth cohort. Children born in 1987-2005, diagnosed with ASD by 2007 (n = 4695) were matched with four non-ASD subjects (n = 18,450) and followed until 2015 for mortality and intentional self-harm. The risk among ASD subjects was elevated only for natural cause of death. The risk for intentional self-harm was increased in the unadjusted analyses, but decreased to non-significant after adjusting for comorbid psychiatric disorders. ASD subjects are at increased risk for premature mortality due to natural causes of death. While ASD subjects die of suicide and present with more self-harm, the association is explained by comorbid psychiatric disorders.
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5. Kozono N, Okamura A, Honda S, Matsumoto M, Mihara T. {{Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome}}. {Sci Rep}. 2020; 10(1): 18799.
Fragile X syndrome (FXS) is characteristically displayed intellectual disability, hyperactivity, anxiety, and abnormal sensory processing. Electroencephalography (EEG) abnormalities are also observed in subjects with FXS, with many researchers paying attention to these as biomarkers. Despite intensive preclinical research using Fmr1 knock out (KO) mice, an effective treatment for FXS has yet to be developed. Here, we examined Fmr1-targeted transgenic rats (Fmr1-KO rats) as an alternative preclinical model of FXS. We characterized the EEG phenotypes of Fmr1-KO rats by measuring basal EEG power and auditory steady state response (ASSR) to click trains of stimuli at a frequency of 10-80 Hz. Fmr1-KO rats exhibited reduced basal alpha power and enhanced gamma power, and these rats showed enhanced locomotor activity in novel environment. While ASSR clearly peaked at around 40 Hz, both inter-trial coherence (ITC) and event-related spectral perturbation (ERSP) were significantly reduced at the gamma frequency band in Fmr1-KO rats. Fmr1-KO rats showed gamma power abnormalities and behavioral hyperactivity that were consistent with observations reported in mouse models and subjects with FXS. These results suggest that gamma power abnormalities are a translatable biomarker among species and demonstrate the utility of Fmr1-KO rats for investigating drugs for the treatment of FXS.
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6. McDonnell CG, DeLucia EA, Hayden EP, Penner M, Curcin K, Anagnostou E, Nicolson R, Kelley E, Georgiades S, Liu X, Stevenson RA. {{Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder}}. {J Clin Child Adolesc Psychol}. 2020: 1-11.
OBJECTIVE: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time. METHOD: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70). RESULTS: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls. CONCLUSIONS: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed. Abbreviations: ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.
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7. McDonnell CG, Speidel R, Lawson M, Valentino K. {{Reminiscing and Autobiographical Memory in ASD: Mother-Child Conversations About Emotional Events and How Preschool-Aged Children Recall the Past}}. {J Autism Dev Disord}. 2020.
Autobiographical memory (AM) is a socially-relevant cognitive skill. Little is known regarding AM during early childhood in ASD. Parent-child reminiscing conversations predict AM in non-ASD populations but have rarely been examined in autism. To address this gap, 17 preschool-aged children (ages 4-6 years) with ASD and 21 children without ASD matched on age, sex, and expressive language completed assessments of AM, executive functioning, self-related variables, and a parent-child reminiscing task. Children with ASD had less specific AM, which related to theory of mind, self-concept, and working memory. AM specificity also related to child observed autism traits. Mothers of children with ASD made more closed-ended and off-topic utterances during reminiscing, although only maternal open-ended elaborations predicted better AM in ASD.
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8. Miron O, Delgado RE, Delgado CF, Simpson EA, Yu KH, Gutierrez A, Zeng G, Gerstenberger JN, Kohane IS. {{Prolonged Auditory Brainstem Response in Universal Hearing Screening of Newborns with Autism Spectrum Disorder}}. {Autism Res}. 2020.
Previous studies report prolonged auditory brainstem response (ABR) in children and adults with autism spectrum disorder (ASD). Despite its promise as a biomarker, it is unclear whether healthy newborns who later develop ASD also show ABR abnormalities. In the current study, we extracted ABR data on 139,154 newborns from their Universal Newborn Hearing Screening, including 321 newborns who were later diagnosed with ASD. We found that the ASD newborns had significant prolongations of their ABR phase and V-negative latency compared with the non-ASD newborns. Newborns in the ASD group also exhibited greater variance in their latencies compared to previous studies in older ASD samples, likely due in part to the low intensity of the ABR stimulus. These findings suggest that newborns display neurophysiological variation associated with ASD at birth. Future studies with higher-intensity stimulus ABRs may allow more accurate predictions of ASD risk, which could augment the universal ABR test that currently screens millions of newborns worldwide. LAY SUMMARY: Children with autism spectrum disorder (ASD) have slow brain responses to sounds. We examined these brain responses from newborns’ hearing tests and found that newborns who were later diagnosed with autism also had slower brain responses to sounds. Future studies might use these findings to better predict autism risk, with a hearing test that is already used on millions of newborns worldwide.
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9. Myers L, Karp SM, Dietrich MS, Looman WS, Lutenbacher M. {{Family-Centered Care: How Close Do We Get When Talking to Parents of Children Undergoing Diagnosis for Autism Spectrum Disorders?}}. {J Autism Dev Disord}. 2020.
Autism spectrum disorder (ASD) affects 1:59 children, yet little is known about parents’ perceptions of family-centered care (FCC) during the diagnostic process leading up to diagnosis. This mixed-methods study explored key elements of FCC from 31 parents of children recently diagnosed with ASD using parallel qualitative and quantitative measures. Parents rated highly their receipt of FCC and discussed ways providers demonstrated FCC. However, the majority of parents indicated that the period when their child was undergoing diagnosis was stressful and reported symptoms of depression and anxiety. The study points to ways in which health care providers can enhance FCC provided to families when a child is undergoing ASD diagnosis.
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10. Olesova D, Galba J, Piestansky J, Celusakova H, Repiska G, Babinska K, Ostatnikova D, Katina S, Kovac A. {{A Novel UHPLC-MS Method Targeting Urinary Metabolomic Markers for Autism Spectrum Disorder}}. {Metabolites}. 2020; 10(11).
Autism spectrum disorder is a heterogeneous neurodevelopmental disease. Currently, no biomarker of this disease is known. Diagnosis is performed through observation, standardized behavioral scales, and interviews with parents. In practice, diagnosis is often delayed to the average age of four years or even more which adversely affects a child’s perspective. A laboratory method allowing to detect the disorder at earlier stages is of a great need, as this could help the patients to start with treatment at a younger age, even prior to the clinical diagnosis. Recent evidence indicates that metabolomic markers should be considered as diagnostic markers, also serving for further differentiation and characterization of different subgroups of the autism spectrum. In this study, we developed an ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry method for the simultaneous determination of six metabolites in human urine. These metabolites, namely methylguanidine, N-acetyl arginine, inosine, indole-3-acetic acid, indoxyl sulfate and xanthurenic acid were selected as potential biomarkers according to prior metabolomic studies. The analysis was carried out by means of reversed-phase liquid chromatography with gradient elution. Separation of the metabolites was performed on a Phenomenex Luna(®) Omega Polar C18 (100 × 1.0 mm, 1.6 µm) column at a flow rate of 0.15 mL/min with acetonitrile/water 0.1% formic acid aqueous as the mobile phase. The analysis was performed on a group of children with autism spectrum disorder and age-matched controls. In school children, we have detected disturbances in the levels of oxidative stress markers connected to arginine and purine metabolism, namely methylguanidine and N-acetylargine. Also, products of gut bacteria metabolism, namely indoxyl sulfate and indole-3-acetic acid, were found to be elevated in the patients’ group. We can conclude that this newly developed method is fast, sensitive, reliable, and well suited for the quantification of proposed markers.
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11. Vandewouw MM, Choi E, Hammill C, Arnold P, Schachar R, Lerch JP, Anagnostou E, Taylor MJ. {{Emotional face processing across neurodevelopmental disorders: a dynamic faces study in children with autism spectrum disorder, attention deficit hyperactivity disorder and obsessive-compulsive disorder}}. {Translational psychiatry}. 2020; 10(1): 375.
Autism spectrum disorder (ASD) is classically associated with poor face processing skills, yet evidence suggests that those with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) also have difficulties understanding emotions. We determined the neural underpinnings of dynamic emotional face processing across these three clinical paediatric groups, including developmental trajectories, compared with typically developing (TD) controls. We studied 279 children, 5-19 years of age but 57 were excluded due to excessive motion in fMRI, leaving 222: 87 ASD, 44 ADHD, 42 OCD and 49 TD. Groups were sex- and age-matched. Dynamic faces (happy, angry) and dynamic flowers were presented in 18 pseudo-randomized blocks while fMRI data were collected with a 3T MRI. Group-by-age interactions and group difference contrasts were analysed for the faces vs. flowers and between happy and angry faces. TD children demonstrated different activity patterns across the four contrasts; these patterns were more limited and distinct for the NDDs. Processing happy and angry faces compared to flowers yielded similar activation in occipital regions in the NDDs compared to TDs. Processing happy compared to angry faces showed an age by group interaction in the superior frontal gyrus, increasing with age for ASD and OCD, decreasing for TDs. Children with ASD, ADHD and OCD differentiated less between dynamic faces and dynamic flowers, with most of the effects seen in the occipital and temporal regions, suggesting that emotional difficulties shared in NDDs may be partly attributed to shared atypical visual information processing.
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12. Windham GC, Pearl M, Poon V, Berger K, Soriano JW, Eyles D, Lyall K, Kharrazi M, Croen LA. {{Maternal Vitamin D Levels During Pregnancy in Association With Autism Spectrum Disorders (ASD) or Intellectual Disability (ID) in Offspring; Exploring Non-linear Patterns and Demographic Sub-groups}}. {Autism Res}. 2020.
Increasing vitamin D deficiency and evidence for vitamin D’s role in brain and immune function have recently led to studies of neurodevelopment; however, few are specific to autism spectrum disorder (ASD) and vitamin D in pregnancy, a likely susceptibility period. We examined this in a case-control study of 2000-2003 Southern Californian births; ASD and intellectual disability (ID) were identified through the Department of Developmental Services and controls from birth certificates (N = 534, 181, and 421, respectively, in this analysis). Total 25-Hydroxyvitamin D (25(OH)D) was measured in mid-pregnancy serum, categorized as deficient (<50 nmol/L), insufficient (50-74 nmol/L), or sufficient (≥75 nmol/L, referent category), and examined continuously (per 25 nmol/L). Crude and adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) were calculated. Non-linearity was examined with cubic splines. AORs (95% CI) for ASD were 0.79 (0.49-1.3) for maternal deficiency (9.5%), 0.93 (0.68-1.3) for insufficiency (25.6%), and 0.95 (0.86, 1.05) for linear continuous 25(OH)D. Results were similarly null for ASD with or without ID, and ID only. Interactions were observed; non-Hispanic whites (NHW) (AOR = 0.82, 95% CI = 0.69-0.98) and males (AOR = 0.89, 95% CI = 0.80-0.99) had protective associations for ASD with continuous 25(OH)D. A positive association with ASD was observed in females (AOR = 1.40, 95% CI = 1.06-1.85). With splines, a non-linear inverted j-shaped pattern was seen overall (P = 0.009 for non-linearity), with the peak around 100 nmol/L; a non-linear pattern was not observed among NHW, females, nor for ID. Our findings from a large study of ASD and prenatal vitamin D levels indicate that further research is needed to investigate non-linear patterns and potentially vulnerable sub-groups. LAY SUMMARY: We studied whether mothers' vitamin D levels during pregnancy were related to their children having autism (or low IQ) later. Low vitamin D levels were not related to greater risk of autism or low IQ in children overall. With higher levels of mothers' vitamin D, risk of autism went down in boys, but went up in girls. Risk of autism also went down in children of non-Hispanic white mothers with higher vitamin D levels, but we did not find a relation in other race/ethnic groups. Lien vers le texte intégral (Open Access ou abonnement)
13. Wood-Downie H, Wong B, Kovshoff H, Cortese S, Hadwin JA. {{Research Review: A systematic review and meta-analysis of sex/gender differences in social interaction and communication in autistic and nonautistic children and adolescents}}. {J Child Psychol Psychiatry}. 2020.
BACKGROUND: Evidence increasingly suggests that ASD manifests differently in females than males. Previous reviews investigating sex/gender differences in social interaction and social communication have focused at the level of broad constructs (e.g. comparing algorithm scores from pre-existing diagnostic instruments) and have typically reported no significant differences between males and females. However, a number of individual studies have found sex/gender differences in narrow construct domains. METHODS: We conducted a systematic review and random effects model meta-analyses (in January 2019 and updated January 2020) that investigated sex/gender differences in narrow construct measures of social communication and interaction in autistic and nonautistic children and adolescents, and adults. Study quality was appraised using the Appraisal Tool for Cross-Sectional Studies (AXIS, BMJ Open, 6, 2016, 1). RESULTS: Across 16 studies (including 2,730 participants), the analysis found that female (vs. male) individuals with ASD had significantly better social interaction and social communication skills (SMD = 0.39, p < .001), which was reflective of a similar sex/gender profile in nonautistic individuals (SMD = 0.35, p < .001). Nonautistic males had significantly better social interaction and communication than males with ASD (SMD = 0.77, p < .001). Nonautistic females also had significantly better social interaction and communication than females with ASD (SMD = 0.72, p <.001). Nonautistic males had better social interaction and communication than females with ASD, though this difference was not significant (SMD = 0.30, p = .07). CONCLUSIONS: This systematic review and meta-analysis highlighted important sex/gender differences in social interaction and communication for individuals with ASD, likely not captured by pre-existing diagnostic instruments, which potentially contribute to the under recognition of autism in females, and may need to be reflected in the diagnostic process. Lien vers le texte intégral (Open Access ou abonnement)
14. Zafarullah M, Palczewski G, Rivera SM, Hessl DR, Tassone F. {{Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)}}. {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}. 2020.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. It is currently unknown when, and if, individual premutation carriers will develop FXTAS. Thus, with the aim of identifying biomarkers for early diagnosis, development, and progression of FXTAS, we performed global metabolomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct categories: those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not (non-converters, NCON) and we compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. In this study we found 47 metabolites were significantly dysregulated between HC and the premutation groups (PM). Importantly, we identified 24 metabolites that showed significant changes in expression in the CON as compared to the NCON both at V1 and V2, and 70 metabolites in CON as compared to NCON but only at V2. These findings suggest the potential role of the identified metabolites as biomarkers for early diagnosis and for FXTAS disease progression, respectively. Interestingly, the majority of the identified metabolites were lipids, followed by amino acids. To our knowledge, this the first report of longitudinal metabolic profiling and identification of unique biomarkers of FXTAS. The lipid metabolism and specifically the sub pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered in FXTAS.
