| ObjectiveAutism spectrum disorders(ASD)are a group of complex neurodevelopmental disorders characterized by deficits in social communication and interaction,and by restricted and repetitive behaviors,interests,or activities,and the ratio of males and females is about 4~5: 1.Over the past four decades,the global prevalence of ASD keeps rising,but its exact etiology and effective treatments have not yet been clarified.The purpose of this study includes three aspects:(1)Exploring the associations between serum oxytocin(OT)levels,oxytocin receptors(OXTR)gene single nucleotide polymorphism(SNP)rs2254298 and the etiology of ASD,the symptom-based and early behavioral developmental phenotypes of child and adolescent patients with ASD,so as to elucidate the pathogenesis of ASD and provide a theoretical basis for key points in the rehabilitation and treatment for ASD child and adolescent patients with different abnormalities of oxytocinergic system.(2)Exploring the relationships between GABRB3 SNP rs2081648,GABRB3 SNP rs1426217,GABRA5 SNP rs35586628,and GABRG3 SNP rs208129 of gamma-aminobutyric acid type A receptor(GABAA)and the etiology of ASD,the symptom-based and early behavioral developmental phenotypes of child and adolescent patients with ASD,in order to demonstrate the pathogenesis of ASD and provide a theoretical basis for key points in the rehabilitation and treatment for ASD child and adolescent patients with different genotypes of GABRB3,GABRA5 and GABRG3.(3)Evaluating the rehabilitation effects of preschool children with ASD who had completed three professional assessments in community-based rehabilitation project,so as to know the relevant factors that may affect the rehabilitation effects of them,and provide a theoretical basis for effectively improving related defects in children with ASD.To sum up,this study aims to study on the etiology and rehabilitation of child and/or adolescent patients with ASD so as to reveal the factors that may affect their pathogenesis,symptoms,early behaviors and rehabilitation effects,and provide guides for the key points of diagnosis,rehabilitation and treatment of child and/or adolescent patients with ASD.Methods1.Applying the method of epidemiological survey,the situations of early behavioral development of child and/or adolescent patients with ASD were collected by the ‘Early Childhood Behavioral Development Questionnaire'.The suspected symptoms,diagnosis,and intervention of preschool children with ASD in community-based rehabilitation project were collected by the ‘Parents' Questionnaire on the Situation of Rehabilitation Intervention for Children with ASD'.2.The symptom-based phenotypes of all ASD child and/or adolescent patients with ASD were assessed by Autism Behavior Checklist(ABC)and Childhood Autism Rating Scale(CARS).Clancy Autism Behavior Scale(CABS),Psychoeducational Profile-Revised(PEP-R)and Peabody Picture Vocabulary Test(PPVT)were additionally added for preschool children with ASD in community-based rehabilitation project.3.Serum OT levels were tested in 55 ASD and 110 typical developing(TD)children and adolescents by enzyme linked immunosorbent assay(ELISA),and we compared the serum OT levels between two groups a nd analyzed the the correlations between serum OT levels and symptom-based phenotypes of children and adolescents with ASD.4.The polymorphism of OXTR SNP rs2254298 was measured in 100 ASD and 232 TD children and adolescents by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP),and we compared the distributions of genotypic and allelic frequencies between two groups and analyzed the associations between its genotypes and serum OT levels,symptom-based and early behavioral developmental phenotypes in children and adolescents with ASD.With the same method,we detected the polymorphism of this locus in 16 preschool children with ASD who had completed three professional assessments in community-based rehabilitation project and analyzed the relationships between its genotypes and the rehabilitation effects.5.The polymorphisms of GABRB3 SNPs rs2081648 and rs1426217?GABRA5 SNP rs35586628 and GABRG3 SNP rs208129 were tested in 99 ASD and 231 TD children and adolescents by Taqman-PCR,and we compared the distributions of genotypic and allelic frequencies between two groups and analyzed the associations between their genotypes and symptom-based and early behavioral developmental phenotypes in children and adolescents with ASD.With the same method,we detected the polymorphism of these four loci in 16 preschool children with ASD who had completed three professional assessments in community-based rehabilitation project and analyzed the relationships between their genotypes and the rehabilitation effects.6.Hardy-Weinberg equilibrium test was performed by Haploview 4.2.With the application of SPSS17.0 and SAS 9.3.2 software package,we respectively chose the ?2 test,ordinal ploytomous logistic regression analysis(adjusting for covariates),independent-samples t test,rank-sum test,one-way analysis of covariance(ANCOVA)(adjusting for covariates),Pearson correlation and Spearman partial correlation(adjusting for covariates),and repeated measurement analysis of variance for statistical processing according to the features of data.Bonferroni correction for multigroup pairwise comparisons was performed.The test level is ? = 0.05.Results1.Serum OT levels of ASD group were higher than that of TD group(P < 0.05),and serum OT levels of ASD group were positively correlated with the ‘adaptation to change' score and total score of CARS(P < 0.05).2.There were no significant differences in the distributions of genotypic and allelic frequencies of OXTR SNP rs2254298 between ASD and TD groups,and genotypes of ASD group were not related to early behavioral developmental phenotypes(P > 0.05).However,genotypes of ASD group were correlated with serum OT levels,the ‘body and object use' score of ABC and the ‘adaptation to change' score of CARS(P < 0.05).3.There were no significant differences in the distributions of genotypic and allelic frequencies of GABRB3 SNPs rs2081648 and rs1426217,GABRA5 SNP rs35586628 and GABRG3 SNP rs208129 between ASD and TD groups(P > 0.05).However,in the ASD group,genotypes of GABRB3 SNP rs2081648 were associated with the ‘visual response' score of CARS,the time of ‘smiling to his/her mother' and ‘grasping things by himself/herself' in early behavioral developmental phenotypes(P < 0.05),genotypes of GABRA5 SNP rs35586628 were associated with the ‘verbal communication' score of CARS(P < 0.05),and genotypes of GABRG3 SNP rs208129 were associated with the ‘imitative behavior' and ‘activity level' scores of CARS,as well as the time of ‘controlling defecate and urinate' in early behavioral developmental phenotypes(P < 0.05).4.The time interval between the first and second assessments of preschool children with ASD who had completed three professional assessments in community-based rehabilitation project was 8.05±0.84 months,and the time interval between the second and third assessments of preschool children with ASD who had completed three professional assessments in community-based rehabilitation project was 7.05±0.70 months.All months of P(actual developmental months)were less than months of E(possible to achieved months)and the actual months at three assessments,and the differences between months of P and the actual months were statistically significant(P < 0.05).5.The ‘cognitive performance' was with the best improvement in the ‘developmental rehabilitation effects' of preschool children with ASD in community-based rehabilitation project.The ‘symptom-based rehabilitation effects' were more obvious,during three evaluations,the ‘relating',‘language' and total scores of ABC showed downward trends,and the differences between the first assessment and the second assessment,as well as the third assessment were statistically significant(P < 0.05).The CARS total score and the ‘play and interest in materials' score of PEP-R also showed decreasing trends and the difference between the first assessment and the third assessment was statistically significant(P < 0.05).Moreover,intelligence quotient showed a increasing trend and the difference between the first assessment and the third assessment was statistically significant(P < 0.05).6.‘Developmental rehabilitation effects' were positively correlated to different domains(P < 0.05)and negatively correlated to the ‘age of the earliest intervention',the ‘age of the first assessment',‘CABS total score',as well as the ‘language' and total scores of PEP-R behavioral part(P < 0.05).Except for negative associations between genotypes of OXTR SNP rs2254298 and the ‘developmental rehabilitation effects',the genotypes of GABRB3 SNP rs2081648 were related to the ‘developmental rehabilitation effects' of ‘imitation',‘perception' and ‘cognitive performance',the genotypes of GABRB3 SNP rs1426217 were related to the ‘developmental rehabilitation effect' of ‘eye-hand integration',the genotypes of GABRA5 SNP rs35586628 were related to the ‘developmental rehabilitation effects' of ‘perception' and ‘cognitive verbal',and the genotypes of GABRG3 SNP rs208129 were related to the ‘developmental rehabilitation effects' of ‘perception',‘fine motor' and ‘cognitive verbal'(all P < 0.05).7.‘Symptom-based rehabilitation effects' were positively correlated to different domains(P < 0.05)and negatively correlated to the ‘age of the earliest intervention',the ‘sensory' and ‘body and object use' scores of ABC and ‘CARS total score' at first assessment(P < 0.05).But there were no associations with 5 loci(P > 0.05).Conclusions1.Children and adolescents with ASD exist a metabolic disturbance of OT,and this anomaly may be affected by the changes of OXTR gene expression,the stimulation of external environments and the severity of symptoms.2.Polymorphism of OXTR SNP rs2254298 was not found to associated with the etiology,early behavioral developmental phenotypes,and the rehabilitation effects of child and adolescent patients with ASD,but was found to associated with the symptom-based phenotypes in children and adolescents with ASD.These provide the hint that we should pay attention to the special role of this locus in symptoms and develop personalized intervention program for child and adolescent patients with ASD in the rehabilitation work.3.Polymorphisms of four GABAA receptor gene loci were found irrelevant to the etiology of child and adolescent patients with ASD.However,in children and adolescents with ASD,genotypes of GABRB3 SNP rs2081648,GABRA5 SNP rs35586628 and GABRG3 SNP rs208129 were related to the symptom-based phenotypes,and phenotypes of GABRB3 SNP rs2081648 and GABRG3 SNP rs208129 were related to the early behavioral developmental phenotypes.In preschool children with ASD of community-based rehabilitation project,genotypes of all four loci were associated with their ‘developmental rehabilitation effects'.These provide the hints that we should pay attention to the special roles of genotypes of four GABAA receptor gene loci and develop personalized intervention program for child and adolescent patients with ASD in the rehabilitation work.4.Preschool children with ASD in community-based rehabilitation project had developmental retardation,and the ‘developmental rehabilitation effects' were not more obvious than ‘symptom-based rehabilitation effects',which may be affected by their own development,genes,the intensity and focus of rehabilitation intervention,the time of early interventions and assessments,as well as the sevevity of symptoms. |
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