BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay...BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay;thus,they can be considered within a clinical continuum of neurodevelopmental disorders.Given the high heterogeneity of ASD,the subjective nature of diagnostic criteria,and the presence of phenocopies,identifying genetic determinants of these disorders remains a challenge.AIM To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children.METHODS 110 patients from 106 families were recruited into the study mean age at diagnosis 6 years;boy-to-girl ratio 3:1.Most of the patients(84%)demonstrated a combination of ASD with developmental delay(DD)or ID.Patients with syndromic features were subjected to the chromosomal microarray analysis.The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD.The study focused on rare(minor allele frequency≤0.001)variants affecting high-confidence ASD-associated genes.RESULTS Pathogenic copy number variations were detected in three(7%)of the patients examined.Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases(11%),indicating the presence of monogenic syndromes with established clinical significance(Pitt-Hopkins syndrome,ZTTK syndrome,syndromic X-linked ID of Billuart type,Snijders-Blok-Campeau,Helsmoortel-van der Aa,Coffin-Siris,Clark-Baraitser,Keefstra syndromes,etc.).In addition,27 patients(26%)had 37 rare variants of unknown clinical significance in DSCAM,SHANK2,AUTS2,ADNP,ANKRD11,APBA2,ARID1B,ASTN2,ATRX,SCN1A,CHD2,DEAF1,EHMT1,GRIN2B,NBEA,NR4A2,TRIO,TRIP12,POGZ,EP300,FOXP1,PCDH19,GRIN2A,NCKAP1,and CHD8 genes.No specific variant was detected more than once in unrelated patients.Among the genes with rare variants found in 2 or more patients were TRIP12(n=4),AUTS2(n=3),ARID1B(n=3),PCDH19(n=3),EP300(n=3),TRIO(n=2),ASTN2(n=2),EHMT1(n=2),and CHD2(n=2).Of note,5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants,confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities.These variants did not cause epilepsy restricted to females in patients’mothers or sisters.CONCLUSION These data confirm a tremendous diversity of genetic causes of ASD.Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.展开更多
BACKGROUND Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder(ASD),and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an e...BACKGROUND Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder(ASD),and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies.Stem cells have yielded so far mixed results in clinical trials,and at patient level the results varied from impressive to no improvement.In this context we have administered autologous cord blood(ACB)and a non-placebo,material intervention repre-sented by an individualized combination of supplements(ICS)to ASD children.METHODS CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children;ACB was infused as an inpatient procedure.Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist,Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score,after interviewing the children’s parents and therapists.Before and after each intervention participants had a set of blood tests including inflammatory,metabolic and oxidative markers,and the neuronal specific enolase.RESULTS No serious adverse reactions were noted during and after cord blood or supplement administration.ACB improved evaluation scores in 78%of children with age 3–7-years(n=28),but was much less effective in kids older than 8 years or with body weight of more than 35 kg(n=28;only 11%of children improved scores).ICS yielded better results than ACB in 5 cases out of 28,while in 23 kids ACB brought more improvement than ICS(P<0.05);high initial levels of inflammation and ferritin were associated with no improvement.Ample individual differences were noted in children's progress,and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction,but not on irritability or aggressive behavior.CONCLUSION ACB has superior efficacy to ICS in ASD;high inflammation,ferritin,age and body weight predict less improvement;more clinical studies are needed for studying ACB efficacy in ASD.展开更多
Studies on the evaluation by therapists of parental behavior towards their children with Autistic Spectrum Disorder(ASD)and towards the therapists of their children are scarce.They are necessary,however,for enabling p...Studies on the evaluation by therapists of parental behavior towards their children with Autistic Spectrum Disorder(ASD)and towards the therapists of their children are scarce.They are necessary,however,for enabling parents to become co-therapists.The present study’s purpose was the evaluation by therapists of the behavior of parents towards their children,of their relationship to therapists,and therapy outcome.The sample consisted of 178 parents of 89 children(72 boys)with ASD,who underwent intensive early intervention at a day centre for developmental disabilities.The professional team completed a questionnaire,separately for the mother and father,evaluating the parental attitude towards their children and towards the therapists.The behavior of parents was less satisfactory than expected.The fathers had difficulties in understanding their child’s problems,and had unrealistic expectations;mothers’behavior towards their children and therapists was better than the fathers’.Mothers had difficulty mostly in the management of the child’s behavior,and did not do well with feeding.It might be difficult for every parent to become co-therapist.Understanding the child’s difficulties by the mother,adequate handling of feeding and homework,were statistically significant in the good outcome of therapy.展开更多
Autistic spectrum disorder(ASD)is a male-biased,heterogeneous neurodevelopmental disorder that affects approximately 1%e2%of the population.Prenatal exposure to valproic acid(VPA)is a recognized risk factor for ASD,bu...Autistic spectrum disorder(ASD)is a male-biased,heterogeneous neurodevelopmental disorder that affects approximately 1%e2%of the population.Prenatal exposure to valproic acid(VPA)is a recognized risk factor for ASD,but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear.Here,we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level.The transcriptomes of more than 45,000 cells are assigned to 12 major cell types,including neurons,glial cells,vascular cells,and immune cells.Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed,and the largest number of differentially expressed genes(DEGs)are found in neurons,choroid plexus epithelial cells,and microglia.In microglia,several pathways related to inflammation are found in both males and females,including the tumor necrosis factor(TNF),nuclear factor kappa B(NF-kB),toll-like receptor(TLR),and mitogen-activated protein kinase(MAPK)signaling pathways,which are important for the induction of autistic-like behavior.Additionally,we note that several X-linked genes,including Bex1,Bex3,and Gria3,were among the male-specific DEGs of neurons.This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice.The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.展开更多
Attention deficit disorder is a frequently observed symptom in individuals with autism spectrum disorder(ASD).This condition can present significant obstacles for those affected,manifesting in challenges such as susta...Attention deficit disorder is a frequently observed symptom in individuals with autism spectrum disorder(ASD).This condition can present significant obstacles for those affected,manifesting in challenges such as sustained focus,task completion,and the management of distractions.These issues can impede learning,social interactions,and daily functioning.This complexity of symptoms underscores the need for tailored approaches in both educational and therapeutic settings to support individuals with ASD effectively.In this study,we have expanded upon our initial virtual reality(VR)prototype,originally created for attention therapy,to conduct a detailed statistical analysis.Our objective was to precisely identify and measure any significant differences in attention-related outcomes between sessions and groups.Our study found that heart rate(HR)and electrodermal activity(EDA)were more responsive to attention shifts than temperature.The‘Noise’and‘Score’strategies significantly affected eye openness,with the ASD group showing more responsiveness.The control group had smaller pupil sizes,and the ASD group’s pupil size increased notably when switching strategies in Session 1.Distraction log data showed that both‘Noise’and‘Object Opacity’strategies influenced attention patterns,with the‘Red Vignette’strategy showing a significant effect only in the ASD group.The responsiveness of HR and EDA to attention shifts and the changes in pupil size could serve as valuable physiological markers to monitor and guide these interventions.These findings further support evidence that VR has positive implications for helping those with ASD,allowing for more tailored personalized interventions with meaningful impact.展开更多
基金Supported by the Russian Science Foundation Grant,No.24-45-00067.
文摘BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay;thus,they can be considered within a clinical continuum of neurodevelopmental disorders.Given the high heterogeneity of ASD,the subjective nature of diagnostic criteria,and the presence of phenocopies,identifying genetic determinants of these disorders remains a challenge.AIM To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children.METHODS 110 patients from 106 families were recruited into the study mean age at diagnosis 6 years;boy-to-girl ratio 3:1.Most of the patients(84%)demonstrated a combination of ASD with developmental delay(DD)or ID.Patients with syndromic features were subjected to the chromosomal microarray analysis.The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD.The study focused on rare(minor allele frequency≤0.001)variants affecting high-confidence ASD-associated genes.RESULTS Pathogenic copy number variations were detected in three(7%)of the patients examined.Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases(11%),indicating the presence of monogenic syndromes with established clinical significance(Pitt-Hopkins syndrome,ZTTK syndrome,syndromic X-linked ID of Billuart type,Snijders-Blok-Campeau,Helsmoortel-van der Aa,Coffin-Siris,Clark-Baraitser,Keefstra syndromes,etc.).In addition,27 patients(26%)had 37 rare variants of unknown clinical significance in DSCAM,SHANK2,AUTS2,ADNP,ANKRD11,APBA2,ARID1B,ASTN2,ATRX,SCN1A,CHD2,DEAF1,EHMT1,GRIN2B,NBEA,NR4A2,TRIO,TRIP12,POGZ,EP300,FOXP1,PCDH19,GRIN2A,NCKAP1,and CHD8 genes.No specific variant was detected more than once in unrelated patients.Among the genes with rare variants found in 2 or more patients were TRIP12(n=4),AUTS2(n=3),ARID1B(n=3),PCDH19(n=3),EP300(n=3),TRIO(n=2),ASTN2(n=2),EHMT1(n=2),and CHD2(n=2).Of note,5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants,confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities.These variants did not cause epilepsy restricted to females in patients’mothers or sisters.CONCLUSION These data confirm a tremendous diversity of genetic causes of ASD.Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.
文摘BACKGROUND Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder(ASD),and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies.Stem cells have yielded so far mixed results in clinical trials,and at patient level the results varied from impressive to no improvement.In this context we have administered autologous cord blood(ACB)and a non-placebo,material intervention repre-sented by an individualized combination of supplements(ICS)to ASD children.METHODS CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children;ACB was infused as an inpatient procedure.Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist,Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score,after interviewing the children’s parents and therapists.Before and after each intervention participants had a set of blood tests including inflammatory,metabolic and oxidative markers,and the neuronal specific enolase.RESULTS No serious adverse reactions were noted during and after cord blood or supplement administration.ACB improved evaluation scores in 78%of children with age 3–7-years(n=28),but was much less effective in kids older than 8 years or with body weight of more than 35 kg(n=28;only 11%of children improved scores).ICS yielded better results than ACB in 5 cases out of 28,while in 23 kids ACB brought more improvement than ICS(P<0.05);high initial levels of inflammation and ferritin were associated with no improvement.Ample individual differences were noted in children's progress,and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction,but not on irritability or aggressive behavior.CONCLUSION ACB has superior efficacy to ICS in ASD;high inflammation,ferritin,age and body weight predict less improvement;more clinical studies are needed for studying ACB efficacy in ASD.
文摘Studies on the evaluation by therapists of parental behavior towards their children with Autistic Spectrum Disorder(ASD)and towards the therapists of their children are scarce.They are necessary,however,for enabling parents to become co-therapists.The present study’s purpose was the evaluation by therapists of the behavior of parents towards their children,of their relationship to therapists,and therapy outcome.The sample consisted of 178 parents of 89 children(72 boys)with ASD,who underwent intensive early intervention at a day centre for developmental disabilities.The professional team completed a questionnaire,separately for the mother and father,evaluating the parental attitude towards their children and towards the therapists.The behavior of parents was less satisfactory than expected.The fathers had difficulties in understanding their child’s problems,and had unrealistic expectations;mothers’behavior towards their children and therapists was better than the fathers’.Mothers had difficulty mostly in the management of the child’s behavior,and did not do well with feeding.It might be difficult for every parent to become co-therapist.Understanding the child’s difficulties by the mother,adequate handling of feeding and homework,were statistically significant in the good outcome of therapy.
基金supported by the National Natural Science Foundation of China(82074162 and 82274344)Project for Capacity Promotion of Putuo District Clinical Special Disease“Stroke”,Science and Technology Innovation Project of Putuo District Health System(ptkwws201902 and ptkwws202301)+2 种基金Training Plan of“100 professionals”of Shanghai Putuo District Central Hospital(2022-RCJC-05)Project of“XingLin Scholars Training”of Chengdu University of Traditional Chinese Medicine(YYZX2022170)Shanghai Putuo District Health System Clinical Characteristic Special Disease Construction Project(2023tszb04).
文摘Autistic spectrum disorder(ASD)is a male-biased,heterogeneous neurodevelopmental disorder that affects approximately 1%e2%of the population.Prenatal exposure to valproic acid(VPA)is a recognized risk factor for ASD,but the cellular and molecular basis of VPA-induced ASD at the single-cell resolution is unclear.Here,we aim to compare the cellular and molecular differences in the hippocampus between male and female prenatal mice with ASD at the single-cell transcriptomic level.The transcriptomes of more than 45,000 cells are assigned to 12 major cell types,including neurons,glial cells,vascular cells,and immune cells.Cell type-specific genes with altered expression after prenatal VPA exposure are analyzed,and the largest number of differentially expressed genes(DEGs)are found in neurons,choroid plexus epithelial cells,and microglia.In microglia,several pathways related to inflammation are found in both males and females,including the tumor necrosis factor(TNF),nuclear factor kappa B(NF-kB),toll-like receptor(TLR),and mitogen-activated protein kinase(MAPK)signaling pathways,which are important for the induction of autistic-like behavior.Additionally,we note that several X-linked genes,including Bex1,Bex3,and Gria3,were among the male-specific DEGs of neurons.This pioneering study describes the landscape of the transcriptome in the hippocampus of autistic mice.The elucidation of sexual differences could provide innovative strategies for the prevention and treatment of ASD.
基金supported by the US National Science Foundation(2244221 and 2315595).
文摘Attention deficit disorder is a frequently observed symptom in individuals with autism spectrum disorder(ASD).This condition can present significant obstacles for those affected,manifesting in challenges such as sustained focus,task completion,and the management of distractions.These issues can impede learning,social interactions,and daily functioning.This complexity of symptoms underscores the need for tailored approaches in both educational and therapeutic settings to support individuals with ASD effectively.In this study,we have expanded upon our initial virtual reality(VR)prototype,originally created for attention therapy,to conduct a detailed statistical analysis.Our objective was to precisely identify and measure any significant differences in attention-related outcomes between sessions and groups.Our study found that heart rate(HR)and electrodermal activity(EDA)were more responsive to attention shifts than temperature.The‘Noise’and‘Score’strategies significantly affected eye openness,with the ASD group showing more responsiveness.The control group had smaller pupil sizes,and the ASD group’s pupil size increased notably when switching strategies in Session 1.Distraction log data showed that both‘Noise’and‘Object Opacity’strategies influenced attention patterns,with the‘Red Vignette’strategy showing a significant effect only in the ASD group.The responsiveness of HR and EDA to attention shifts and the changes in pupil size could serve as valuable physiological markers to monitor and guide these interventions.These findings further support evidence that VR has positive implications for helping those with ASD,allowing for more tailored personalized interventions with meaningful impact.
