儿童孤独症的高危因素及早期特征、血浆谷氨酸和γ-氨基丁酸浓度、Reelin基因多态性的研究
|
摘要
目的
(1)研究儿童孤独症发病的高危因素及孤独症儿童的早期发育特征。
(2)研究血浆谷氨酸和丫-氨基丁酸浓度变化与儿童孤独症的关系,及其在儿童孤独症易发癫痫病理机制中的作用。
(3)通过对Reelin基因上四个单核苷酸多态(SNP)位点rs736707、rs2229864、rs362691、rs2073559的检测,探讨Reelin基因多态性与儿童孤独症的关系。
方法
(1)共入组儿童孤独症核心家系278例及正常对照儿童核心家系200例,调查一般人口学资料、母孕期情况、围产期情况、发育性标志出现时间、养育情况、既往史、家族史及体格检查情况;对于孤独症儿童,尚需调查早期症状表现、评定儿童孤独症评定量表(CARS)及孤独症行为检查量表(ABC)。
(2)27例伴癫痫的孤独症患者作为观察组,30例不伴癫痫的孤独症患者为另一观察组,36例正常儿童作为对照组。采用高效液相色谱法测定三组血浆谷氨酸和γ-氨基丁酸浓度,进行组间比较。
(3)在中国汉族孤独症核心家系(孤独症患者234人,父母399人)及正常对照人群(286人)中,检测Reelin基因上四个单核苷酸多态位点rs736707、rs2229864、rs362691、rs2073559,采用TaqMan—PCR的方法确定样本各位点的基因型,进行以核心家系为基础的传递不平衡检验及病例对照的关联研究。
(4)采用DNA测序和序列分析的方法,验证TaqMan-PCR等位基因鉴别分析技术的准确性。
(5)使用GENEHUNTER(version 2.1)软件对孤独症核心家系进行传递不平衡分析,使用SAS软件包构建单倍体模型,以x~2检验比较组间差异。统计分析采用SPSS14.0软件包,根据资料特征分别进行独立样本t检验、x~2检验、方差分析、Logistic回归分析以及计算暴露因素的优势比(OR值)。
结果
(1)儿童孤独症先证者中男性233人,女性45人,男女比例为5.18:1;患者起病年龄为22.36±8.29月。家长感觉到孩子异常最早是在10个月时,最晚在48个月。
(2)与正常儿童相比,孤独症患者的多项围产期和母孕期高危因素差异具有显著性。Logistic回归发现:母亲受教育年限(P=0.009)、父亲生育年龄(P=0.001)、家庭负担(P=-0.001)、抚育者(P=0.001)、妊娠反应(P=0.025)、孕期服药史(P=0.014)、分娩方式(P=-0.045)、养育方式(P＜0.001)、主要教导者(P＜0.001)、阳性家族史(P=0.002)进入回归方程。
(3)计算回归方程中有临床意义的6项指标的组间优势比(OR值),从强到弱依次为父亲生育年龄＞30岁(OR=6.715)、家族史阳性(OR=5.798)、孕期服用药物(OR=4.653)、非自然分娩(OR=4.147)、母亲受教育年限＞11年(OR=1.373)、妊娠反应中/重度(OR=1.044)。
(4)与对照组儿童相比,孤独症儿童的各项发育性标志出现时间、孤独症早期表现总分、头围等指标,差异具有统计学意义(P＜0.001)。
(5)不伴癫痫的孤独症组(A组)血浆谷氨酸浓度为653.95±545.87pmol/L,伴有癫痫的孤独症组(B组)血浆谷氨酸浓度为1608.81±1478.22pmol/L,正常对照儿童(C组)血浆谷氨酸浓度为653.70±589.86pmol/L。A组与B组相比,差异具有显著性(P＜0.05);B组与C组相比,差异具有显著性(P＜0.05);A组与C组相比,无显著性差异(P＞0.05)。A组血浆γ-氨基丁酸浓度为71.46±65.98pmol/L,B组为111.19±85.27pmol/L,C组为70.13±51.36pmol/L。A组与B组相比,差异具有显著性(P＜0.05);B组与C组相比,差异具有显著性(P＜0.05);A组与C组相比,无显著性差异(P＞0.05)。
(6)孤独症核心家系单位点SNP传递不平衡分析,四个位点均无显著性差异(P＞0.05);四个位点组成的单倍体中GTCC 5条全部未传递,未传递存在显著性差异,其余各单倍体未发现不平衡传递。
对照组样本在四个SNPs多态位点上全部符合H-W平衡。病例对照关联研究中,孤独症组与对照组四个SNPs多态位点基因型及等位基因频率比较均未发现显著性差异(P＞0.05)。
孤独症组与对照组单倍体分型比较中,rs362691-rs2073559相邻两位点的CC、CT、GC三种单倍体,每一单倍体频率在两组之间比较,差异均无显著性(P＞0.05);而GT单倍体频率在两组之间差异具有显著性(x~2=5.805,P=0.020)。两组单倍体频率构成具有显著性差异(x~2=9.682,P=0.021)。其余相邻两位点、三位点以及四个位点组合的每一单倍体频率、以及单倍体频率构成均无显著性差异(P＞0.05)。
结论
(1)儿童孤独症在母孕期、围产期高危因素明显增多,前三位的高危因素分别是父亲生育年龄大于30岁、家族史阳性、孕期服用药物史。
(2)孤独症儿童整体发育落后于正常对照儿童,而且在发育过程中具有某些特征性的早期表现,有望被早期识别。
(3)血浆谷氨酸/γ-氨基丁酸浓度异常在孤独症儿童中并不具有普遍性,仅在伴有癫痫的孤独症儿童中有异常升高。谷氨酸/γ-氨基丁酸系统功能异常可能是孤独症易发癫痫的病理机制之一。
(4)以孤独症核心家系为基础的传递不平衡检验未发现Reelin等位基因的优势传递。病例对照关联研究发现仅rs362691-rs2073559的GT单倍体频率在两组之间存在显著性差异,提示Reelin基因与孤独症无关联。
Objective
(1) To study on risk factors and early manifestation in autism.
(2) To explore whether plasma level of glutamate and gamma-aminobutyric acid were related with autism, as well as the high prevalence of epilepsy in autism.
(3) To explore the relationship between Reelin gene polymorphisms and autism by detecting four single-nucleotide polymorphisms (SNPs) including rs736707、rs2229864、rs362691、rs2073559 located on RELN.
Method
(1) 278 autism trioes and 200 control trioes were recruited. At the screening, all the children would fulfill clinical questionnaires, including demography, conditions of pregnancy and perinatal period, postnatal development, raising patterns, previous history and family history, physical examination. Autism children were assessed with CARS and ABC and their early manifestation were recorded.
(2) The plasma level of glumatic acid and gamma-aminobutyric acid was measured with high efficiency liquid chromatography in 27 autism children with epilepsy, compared with that of 30 autism children without epilepsy and 36 control children.
(3) The four SNPs, rs736707、rs2229864、rs362691、rs2073559, on Reelin gene were genotyped by Taqman-PCR in 234 autistic children, 399 parents, and 286 controls in Chinese Han. And the family-based transmission disequilibrium test (TDT) and case-control association anlysis were performed at the same time.
(4) To check the accuracy of the allele identified technique inTaqMan-PCR by DNA sequencing.
(5) GENEHUNTER (version 2.1) was used in transmission disequilibrium test. The haplotype model was constructed with SAS and all analyses were conducted with SPSS14.0 for Windows. We used t-test, chi-square test, analysis of variance, logistic regression analysis, and odds ratio according to the type of the data.
Results
(1) Childhood autism probands consisted of 233 males and 45 females (male/female = 5.18/1) . The mean onset age of autism was 22.36±8.29 months. The emergence time of abnormality being detectedby their caregivers was different, ranging from 10 to 48 months.
(2) There were significant difference in many pregnancy and perinatal period risk factors between autistic children and control. Logistic regression found that many items entered regression equation as the following: mother's school life (P=0.009) , father's reproductive age(P=0.001), family burden (P=0.001), dry nurse (P=0.001), pregnancy reaction (P=0.025) ,drug history during mother's pregnancy period (P=0.014), delivery modality (P=0.045 ), nurture modality (P<0.001), main instructor (P<0.001) , positive family history (P=0.002) .
(3) We calculated odds ratios of six items with clinical signific -ance in regression equation: father's reproductive age more than 30years(OR=6.715), positive family history (OR=5.798 ), drug history during mother's pregnancy period (OR=4.653 ) ,un-spontaneous delivery (O R = 4.147) , mother's school life more than 11 years (OR=1.373) ,moderate /severe pregnancy reaction (OR= 1.044) .
(4) There were significant differences between autism patients and control in the following items: the emergence time of early developmental sign, the total score of early manifestation, and head circumference (P<0.001) .
(5) Plasma level of glutamic acid was 653.95 pmol/L (SD =545.87) in autism children (group A), 1608.81 pmol/L (SD=1478.22) in autism children with epilepsy (group B ) and 653.70 pmol/L(SD=589.86) in control group (group C). Compared with Group B, the average plasma level of glutamic acid in group A and group C was significantly lower (p<0.05) , but there was no significant difference between group A and group C (p>0.05) . In terms of plasma level of gamma-aminobutyric acid (GABA) , group A was 71.46 pmol/L(SD=65.98 ) , group B was 111.19 pmol/L ( SD=85.27 ) and group C was 70.13 pmol/L (SD=51.36) . The plasma level of GABA in group B was significantly higher than group A and group C (p<0.05 ) . But there was no significant difference between group A and Group C (p>0.05 ) .
(6) No significant differences were found on family-based TDT for single-locus marker in four SNPs in autism. There was no significant transmission disequilibrium but haplotype GTCC, in which 5 haplotypes were non-transmission.
All these 4 SNPs (rs736707, rs2229864, rs362691, rs2073559) among control samples met Hardy-Weinberg equilibrium. In case-control association analysis, no significant difference were found in allelic and genotypic distribution of the 4 SNPs between autism group and control group (P>0.05) .
There were no significant difference in frequency of CC,CT,GC of rs362691-rs2073559 between autism and control (P>0.05 ) , but that of GT showed significant difference between the two groups ( x~2=5.805, P =0.020) . The frequency composition of haplotypes between the two groups was significantly different (x~2=9.682, P=0.021) . No significant differences were found in other multiple-locus haplotypes frequencies and frequency compositions between autism and control (P>0.05 ) .
Conclusion
( 1 ) Autistic children have more risk factors in duration of pregnancy and peripartum. The first three risk factors were father's reproductive age exceeding 30, positive family history, taking medicine in duration of pregnancy.
(2) The global development in autism children is behind control. There are some characteristic early manifestation in the development of autistic children, which can be identified earlier.
(3) The increasing of plasma level of glutamate and gamma-aminobutyric acid is not general in all autistic children but only in those with epilepsy. It suggests that disfunction of glutamatergic and GABAergic system make a role in high prevalence of epilepsy in autism.
(4) Transmission disequilibrium test based on autism trios found no preferential transmission in alleles of Reelin. Case-control association study showed that only frequency of GT in rs362691-rs2073559 was significantly different between the two groups, which suggested that Reelin gene may have no association with autism.
(1)研究儿童孤独症发病的高危因素及孤独症儿童的早期发育特征。
(2)研究血浆谷氨酸和丫-氨基丁酸浓度变化与儿童孤独症的关系,及其在儿童孤独症易发癫痫病理机制中的作用。
(3)通过对Reelin基因上四个单核苷酸多态(SNP)位点rs736707、rs2229864、rs362691、rs2073559的检测,探讨Reelin基因多态性与儿童孤独症的关系。
方法
(1)共入组儿童孤独症核心家系278例及正常对照儿童核心家系200例,调查一般人口学资料、母孕期情况、围产期情况、发育性标志出现时间、养育情况、既往史、家族史及体格检查情况;对于孤独症儿童,尚需调查早期症状表现、评定儿童孤独症评定量表(CARS)及孤独症行为检查量表(ABC)。
(2)27例伴癫痫的孤独症患者作为观察组,30例不伴癫痫的孤独症患者为另一观察组,36例正常儿童作为对照组。采用高效液相色谱法测定三组血浆谷氨酸和γ-氨基丁酸浓度,进行组间比较。
(3)在中国汉族孤独症核心家系(孤独症患者234人,父母399人)及正常对照人群(286人)中,检测Reelin基因上四个单核苷酸多态位点rs736707、rs2229864、rs362691、rs2073559,采用TaqMan—PCR的方法确定样本各位点的基因型,进行以核心家系为基础的传递不平衡检验及病例对照的关联研究。
(4)采用DNA测序和序列分析的方法,验证TaqMan-PCR等位基因鉴别分析技术的准确性。
(5)使用GENEHUNTER(version 2.1)软件对孤独症核心家系进行传递不平衡分析,使用SAS软件包构建单倍体模型,以x~2检验比较组间差异。统计分析采用SPSS14.0软件包,根据资料特征分别进行独立样本t检验、x~2检验、方差分析、Logistic回归分析以及计算暴露因素的优势比(OR值)。
结果
(1)儿童孤独症先证者中男性233人,女性45人,男女比例为5.18:1;患者起病年龄为22.36±8.29月。家长感觉到孩子异常最早是在10个月时,最晚在48个月。
(2)与正常儿童相比,孤独症患者的多项围产期和母孕期高危因素差异具有显著性。Logistic回归发现:母亲受教育年限(P=0.009)、父亲生育年龄(P=0.001)、家庭负担(P=-0.001)、抚育者(P=0.001)、妊娠反应(P=0.025)、孕期服药史(P=0.014)、分娩方式(P=-0.045)、养育方式(P＜0.001)、主要教导者(P＜0.001)、阳性家族史(P=0.002)进入回归方程。
(3)计算回归方程中有临床意义的6项指标的组间优势比(OR值),从强到弱依次为父亲生育年龄＞30岁(OR=6.715)、家族史阳性(OR=5.798)、孕期服用药物(OR=4.653)、非自然分娩(OR=4.147)、母亲受教育年限＞11年(OR=1.373)、妊娠反应中/重度(OR=1.044)。
(4)与对照组儿童相比,孤独症儿童的各项发育性标志出现时间、孤独症早期表现总分、头围等指标,差异具有统计学意义(P＜0.001)。
(5)不伴癫痫的孤独症组(A组)血浆谷氨酸浓度为653.95±545.87pmol/L,伴有癫痫的孤独症组(B组)血浆谷氨酸浓度为1608.81±1478.22pmol/L,正常对照儿童(C组)血浆谷氨酸浓度为653.70±589.86pmol/L。A组与B组相比,差异具有显著性(P＜0.05);B组与C组相比,差异具有显著性(P＜0.05);A组与C组相比,无显著性差异(P＞0.05)。A组血浆γ-氨基丁酸浓度为71.46±65.98pmol/L,B组为111.19±85.27pmol/L,C组为70.13±51.36pmol/L。A组与B组相比,差异具有显著性(P＜0.05);B组与C组相比,差异具有显著性(P＜0.05);A组与C组相比,无显著性差异(P＞0.05)。
(6)孤独症核心家系单位点SNP传递不平衡分析,四个位点均无显著性差异(P＞0.05);四个位点组成的单倍体中GTCC 5条全部未传递,未传递存在显著性差异,其余各单倍体未发现不平衡传递。
对照组样本在四个SNPs多态位点上全部符合H-W平衡。病例对照关联研究中,孤独症组与对照组四个SNPs多态位点基因型及等位基因频率比较均未发现显著性差异(P＞0.05)。
孤独症组与对照组单倍体分型比较中,rs362691-rs2073559相邻两位点的CC、CT、GC三种单倍体,每一单倍体频率在两组之间比较,差异均无显著性(P＞0.05);而GT单倍体频率在两组之间差异具有显著性(x~2=5.805,P=0.020)。两组单倍体频率构成具有显著性差异(x~2=9.682,P=0.021)。其余相邻两位点、三位点以及四个位点组合的每一单倍体频率、以及单倍体频率构成均无显著性差异(P＞0.05)。
结论
(1)儿童孤独症在母孕期、围产期高危因素明显增多,前三位的高危因素分别是父亲生育年龄大于30岁、家族史阳性、孕期服用药物史。
(2)孤独症儿童整体发育落后于正常对照儿童,而且在发育过程中具有某些特征性的早期表现,有望被早期识别。
(3)血浆谷氨酸/γ-氨基丁酸浓度异常在孤独症儿童中并不具有普遍性,仅在伴有癫痫的孤独症儿童中有异常升高。谷氨酸/γ-氨基丁酸系统功能异常可能是孤独症易发癫痫的病理机制之一。
(4)以孤独症核心家系为基础的传递不平衡检验未发现Reelin等位基因的优势传递。病例对照关联研究发现仅rs362691-rs2073559的GT单倍体频率在两组之间存在显著性差异,提示Reelin基因与孤独症无关联。
Objective
(1) To study on risk factors and early manifestation in autism.
(2) To explore whether plasma level of glutamate and gamma-aminobutyric acid were related with autism, as well as the high prevalence of epilepsy in autism.
(3) To explore the relationship between Reelin gene polymorphisms and autism by detecting four single-nucleotide polymorphisms (SNPs) including rs736707、rs2229864、rs362691、rs2073559 located on RELN.
Method
(1) 278 autism trioes and 200 control trioes were recruited. At the screening, all the children would fulfill clinical questionnaires, including demography, conditions of pregnancy and perinatal period, postnatal development, raising patterns, previous history and family history, physical examination. Autism children were assessed with CARS and ABC and their early manifestation were recorded.
(2) The plasma level of glumatic acid and gamma-aminobutyric acid was measured with high efficiency liquid chromatography in 27 autism children with epilepsy, compared with that of 30 autism children without epilepsy and 36 control children.
(3) The four SNPs, rs736707、rs2229864、rs362691、rs2073559, on Reelin gene were genotyped by Taqman-PCR in 234 autistic children, 399 parents, and 286 controls in Chinese Han. And the family-based transmission disequilibrium test (TDT) and case-control association anlysis were performed at the same time.
(4) To check the accuracy of the allele identified technique inTaqMan-PCR by DNA sequencing.
(5) GENEHUNTER (version 2.1) was used in transmission disequilibrium test. The haplotype model was constructed with SAS and all analyses were conducted with SPSS14.0 for Windows. We used t-test, chi-square test, analysis of variance, logistic regression analysis, and odds ratio according to the type of the data.
Results
(1) Childhood autism probands consisted of 233 males and 45 females (male/female = 5.18/1) . The mean onset age of autism was 22.36±8.29 months. The emergence time of abnormality being detectedby their caregivers was different, ranging from 10 to 48 months.
(2) There were significant difference in many pregnancy and perinatal period risk factors between autistic children and control. Logistic regression found that many items entered regression equation as the following: mother's school life (P=0.009) , father's reproductive age(P=0.001), family burden (P=0.001), dry nurse (P=0.001), pregnancy reaction (P=0.025) ,drug history during mother's pregnancy period (P=0.014), delivery modality (P=0.045 ), nurture modality (P<0.001), main instructor (P<0.001) , positive family history (P=0.002) .
(3) We calculated odds ratios of six items with clinical signific -ance in regression equation: father's reproductive age more than 30years(OR=6.715), positive family history (OR=5.798 ), drug history during mother's pregnancy period (OR=4.653 ) ,un-spontaneous delivery (O R = 4.147) , mother's school life more than 11 years (OR=1.373) ,moderate /severe pregnancy reaction (OR= 1.044) .
(4) There were significant differences between autism patients and control in the following items: the emergence time of early developmental sign, the total score of early manifestation, and head circumference (P<0.001) .
(5) Plasma level of glutamic acid was 653.95 pmol/L (SD =545.87) in autism children (group A), 1608.81 pmol/L (SD=1478.22) in autism children with epilepsy (group B ) and 653.70 pmol/L(SD=589.86) in control group (group C). Compared with Group B, the average plasma level of glutamic acid in group A and group C was significantly lower (p<0.05) , but there was no significant difference between group A and group C (p>0.05) . In terms of plasma level of gamma-aminobutyric acid (GABA) , group A was 71.46 pmol/L(SD=65.98 ) , group B was 111.19 pmol/L ( SD=85.27 ) and group C was 70.13 pmol/L (SD=51.36) . The plasma level of GABA in group B was significantly higher than group A and group C (p<0.05 ) . But there was no significant difference between group A and Group C (p>0.05 ) .
(6) No significant differences were found on family-based TDT for single-locus marker in four SNPs in autism. There was no significant transmission disequilibrium but haplotype GTCC, in which 5 haplotypes were non-transmission.
All these 4 SNPs (rs736707, rs2229864, rs362691, rs2073559) among control samples met Hardy-Weinberg equilibrium. In case-control association analysis, no significant difference were found in allelic and genotypic distribution of the 4 SNPs between autism group and control group (P>0.05) .
There were no significant difference in frequency of CC,CT,GC of rs362691-rs2073559 between autism and control (P>0.05 ) , but that of GT showed significant difference between the two groups ( x~2=5.805, P =0.020) . The frequency composition of haplotypes between the two groups was significantly different (x~2=9.682, P=0.021) . No significant differences were found in other multiple-locus haplotypes frequencies and frequency compositions between autism and control (P>0.05 ) .
Conclusion
( 1 ) Autistic children have more risk factors in duration of pregnancy and peripartum. The first three risk factors were father's reproductive age exceeding 30, positive family history, taking medicine in duration of pregnancy.
(2) The global development in autism children is behind control. There are some characteristic early manifestation in the development of autistic children, which can be identified earlier.
(3) The increasing of plasma level of glutamate and gamma-aminobutyric acid is not general in all autistic children but only in those with epilepsy. It suggests that disfunction of glutamatergic and GABAergic system make a role in high prevalence of epilepsy in autism.
(4) Transmission disequilibrium test based on autism trios found no preferential transmission in alleles of Reelin. Case-control association study showed that only frequency of GT in rs362691-rs2073559 was significantly different between the two groups, which suggested that Reelin gene may have no association with autism.
引文
[1]Kanner L.Follow-up study of eleven autistic children originally reported in 1943.Psychiatr Enfant,1995,38(2):421-461.
[2]李雪荣,陈劲梅.孤独症诊疗学.长沙:中南大学出版社,2004.1-2.
[3]罗维力,林力.福建省儿童孤独症流行病学调查.上海精神医学,2000,12(1):3-5.
[4]郭荣.天津市5000名0～6岁儿童中儿童孤独症的流行病学调查.中国临床康复,2004,8(6):1122-1123.
[5]Hyman S.Mental illness:genetically complex disorders of neural circuitry and neural communication.Neuron,2000,28(2),321-323.
[6]Volkmar FR,Nelson DS.Seizure disorders in autism.J Am Acad Child Adolesc Psychiatry,1990,29(1):127-129.
[7]Fatemi SH,Halt AR,Realmuto G,et al.Purkinje cell size is reduced in cerebellum of patients with autism.Cell Mol Neurobiol,2002,22(2):171-175.
[8]Lahuis BE,Durston S,Nederveen H,et al.MRI-based morphometry in children with multiple complex developmental disorder,a phenotypically defined subtype of pervasive developmental disorder not otherwise specified.Psychol Meal.2007 10(9):1-7.
[9]Bolte S,Hubl D,Dierks T,et al.An fMRI-study of locally oriented perception in autism:altered early visual processing of the block design test.J Neural Transm,2008,115(3):545-552.
[10]Amaral DG,Schumann CM,Nordahl CW.Neuroanatomy of autism.Trends Neurosci,2008,31(3):137-145.
[11]Brieber S,Neufang $,Bruning N,et al.Structural brain abnormalities in adolescents with autism spectrum disorder and patients with attention deficit/hyperactivity disorder.J Child Psychol Psychiatry,2007,48(12):1251-1258.
[12]Degirmenci B,Miral S,Kaya GC,et al.Technetium-99m HMPAO brain SPECT in autistic children and their families.Psychiatry Res,2008,162(3):236-243.
[13] Vorstman JA, Staal WG, van Daalen E,et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry,2006,11 (1) .1,18-28.
[14] Samaco RC,Hogart A,LasaIle JM.Epigenetic overlap in autism-spectrum neurodevelopment disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3.Hum Mol Genet,2005,14 (4) :483-492.
[15] Hussman JP. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism.J Autism Dev Disord,2001,31(2): 247-248.
[16] Carlsson ML. Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate - serotonin interactions for pharmacotherapy.J Neural Transm, 1998,105 (4-5) :525-535.
[17] Purcell AE, Jeon OH, Zimmerman AW,et al. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 2001,57 (9) .1618-1628.
[18] Segurado R, Conroy J, Meally E.Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31 .Am J Psychiatry,2005,162 (11) :2182-2184.
[19] McGale EH, Pye IF, Stonier C, et al. Studies of the interrelationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem,1977,29:291-297.
[20] Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry, 1988,23 (7) :689-697.
[21] Rolf LH, Haarmann FY, Grotemeyer KH,et al. Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand, 1993,87 (5) .312-316.
[22] Aldred S, Moore KM, Fitzgerald M,et al. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord,2003,33 (1) :93-97.
[23] Impagnatiello F, Guidotti AR, Pesold C,et al. A decrease of Reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U.S.A.,1998,95(26):15718-15723.
[24]Fatemi SH,Stary JM,Egan EA.Reduced Blood Levels of Reelin as a Vulnerability Factor in Pathophysiology of Autistic Disorder.Cell Mol Neurobiol,2002,22(2):171-175.
[25]Nelson KB.Prenatal and perinatal factors in the etiology of autism.Pediatrics,1991,87(5 Pt 2):761-766.
[26]Piven J,Simon J,Chase GA,et al.The etiology of autism:pre-,peri-and neonatal factors.J Am Acad Child Adolesc Psychiatry,1993,32(6):1256-1263.
[27]Zeanah CH,Boris NW,Larrieu JA.Infant development and developmental risk:A review of the past 10 years.J Am Acad Child Adolesc Psychiatry,1997,36(2):165-178.
[28]Bolton PF,Murphy M,Macdonald H,et al.Obstetric complications in autism:consequences or causes of the condition ?J Am Acad Child Adolesc Psychiatry,1997,36(2):272-281.
[29]李思特,李雪荣,张献共等.儿童孤独症高危因素和早期特征的回顾性分析.中国心理卫生杂志,2002,16(8):552-554.
[30]黄春香,陈劲梅,苏林雁等.婴儿孤独症的临床特征.中国临床心理学杂志,1999,7(1):53-54.
[31]Kobayashi R,Murata T.Setback phenomenon in autism and long-term prognosis.Acta Psychiatr Scand,1998,98(4):296-303.
[32]陶国泰.儿童少年精神医学.南京:江苏科学技术出版社,1999.207-214.
[33]杨晓玲,贾美香.儿童孤独症30例临床分析.中国心理卫生杂志,1990,4(4):250-254.
[34]Baron-Cohen S,Cox A,Baird G,et al.Psychological markers in the detection of autism in infancy in a large population.Br J Psychiatry,1996,168(2):158-163.
[35]Baron-Cohen S,Allen J,Gillberg C.Can autism be detected at 18 months?The needle,the haystack,and the CHAT.Br J Psychiatry,1992,161:839-843.
[36]Kawasaki Y,Yokota K,Shinomiya M,et al.Electroenchephalographicparo xysmal activities in the frontal area emerged in middle childhoodand during adolescence in a follow-up study of autism.J Autism DevDisord,1997,27(5):605-620.
[37]Mouridsen SE,Rich B,Isager T.Epilepsy in disintegrative psychosis and infantile autism:a long-term validation study.Dev Med Child Neurol,1999,41(2):110-114.
[38]Giovanardi Rossi P,Posar A,Parmeggiani A.Epilepsy in adolescents and young adults with autistic disorder.Brain Dev,2000,22(2):102-106.
[39]Danielsson S,Gillberg IC,Billstedt E,et al.Epilepsy in young adults with autism:a prospective populationbased follow-up study of 120 individuals diagnosed in childhood.Epilepsia,2005,46(6):918-923.
[40]ILAE Commission Report.The epidemiology of the epilepsies:future directions.International League Against Epilepsy.Epilepsia,1997,38(5):614-618.
[41]Jallon P,ILAE.Workshop Report:Epilepsy in developing countries.Epilepsia,1997,38(10):1143-1151.
[42]李世绰,王忠诚,周树宾,等.中国六城市居民癫痫的流行病学调查.中华神经精神科杂志,1986,19(4):193-196.
[43]四川医学院流行病学教研室.四川42万人口癫痫发病情况调查报告.中华神经精神科杂志,1981,14(3):135-138.
[44]王志文,吴建中,王德生,等.中国五省农村人群癫痫流行病学抽样调查.中华医学杂志,2002,82(7):449-452.
[45]Coyle JT,Leski ML,Morrison JH.The diverse roles of L-glutamic acid in brain signal transduction.Neuropsychopharmacology—the fifth genera- tion of progress,2002,71-90.
[46]McDougle CJ,Edckson CA,Stigler KA,et al.Neurochemistry inthe pathophysiology of autism.J Clin Psychiatry,2005,66(suppl 10):9-18.
[47]Page LA,Daly E,Schmitz N,et al.In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism.Am J Psychiatry 2006;163(12):2189-2192.
[48]Dhossche D,Applegate H,Abraham A,et al.Elevated plasma gammaaminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monit ,2002,8 (8) :PR1-R6.
[49] Blatt GJ, Fitzgerald CM, Guptill JT,et al. Density and distribution of hippocampalneurotransmitter receptors in autism: an autoradiographic study.J Autism Dev Disord ,2001,31 (6) :537-543.
[50] Ueda Y,Tsuru N.Simultaneous monitoring of the seizure-related changes in extracellular glutamate and gamma-aminobutyric acid concentration in bilateral hippocampi following development of amygdaloid kindling.Epilepsy Res, 1995,20 (3) :213-219.
[51] Fried I,Wilson CL,Mridment NT,et al.Cerebral microialysis combined with single neuron and electroencephalographic recording in neurosurgical patients. Technical note. JNeurosurg, 1999,91 (4) :697-705.
[52] Sherwin AL,Neuroactive amino acids in focally epileptic human brain:A review. Neurochem Res, 1999,24 (11) : 1387-1395.
[53] Hirao T,Morimoto K,Yamamoto Y,et al.Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats.Brain Res Mol Brain Res, 1998,54 (1) :49-55.
[54] Shinohe A, Hashimoto K, Nakamura K, et al. Increased serum levels of glutamate in adult patients with autism.Neuropsychopharmacology Biol Psychiatry , 2006,30 (8) 1472-1477.
[55] Hrdlicka M, Komarek V, Propper L, et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry ,2004,13 (4) :209-213.
[56] Kobayashi R, Murata T. Setback phenomenon in autism and longterm prognosis. Acta Psychiatr Scand ,1998,98 (4) :296-303.
[57] Hara H. Autism and epilepsy: A retrospective follow-up study. Brain Dev,2007,29 (8) :486-490.
[58] Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry, 2000,48 (6) : 518-530.
[59] Chuang DM. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol, 2004,16 (1-2) :83-90.
[60] Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol, 2002, 1 (6) : 352-358.
[61] Hollander E, Dolgoff-Kaspar R, Cartwright C, et al. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry, 2001,62 (7) :530-534.
[62] Gabis L , Pomeroy J, Andriola MR. Autism and epilepsy: Cause, consequence, comorbidity, or coincidence? Epilepsy Behav,2005,7 (4) : 652-656.
[63] Pickles A ,Bolton P, Macdonald H, et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet, 1995, 57 (3) :717-726.
[64] Folstein SE, Piven J. Etiology of autism: genetic influences. Pediatrics, 1991,87 (5 Pt 2) : 767-773.
[65] Bailey A,Le Couteur A,Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study.Psychol Med, 1995,25 (1) :63- 77.
[66] Auranen M ,Vanhala R , Varilo T ,et al. A genome wide screen for autism-spectrum disorders:evidence for a major susceptibility locus on chromosome 3q25-27. Am J Hum Genet,2002,71 (4) :777-790.
[67] Buxbaum,JD ,Silverman JM,Smith CJ,et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet, 2001,68 (6) : 1514-1520.
[68] Shao Y, Raiford KL, Wolpert CM, et al.Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet,2002,70 (4) : 1058-1061.
[69] A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet, 1998,7 (3) :571-578.
[70] Philippe A,Martinez M,Guilloud-Bataille M,et al. Genome-wide scan for autism susceptibility genes.Paris Autism Research International Sibpair Study.Hum Mol Genet, 1999,8 (5) :805-812.
[71] Ashley-Koch A,Wolpert CM,Menold MM, et al. Genetic studies of autistic disorder and chromosome 7.Genomics ,1999,61 (3) :227-236.
[72] Liu J, Nyholt DR,Magnussen P,et al. A genomewide screen for autism susceptibility loci.Am J Hum Genet,2001,69 (2) : 327-340.
[73] Risch N,Spiker D,Lotspeich L, et al. A genomic screen of autism: evidence for a multilocus etiology.Am J Hum Genet, 1999,65 (2) : 493-507.
[74] Barrett S,Beck JC,Bernier R, et al. An autosomal genomic screen for autism.Collaborative linkage study of autism. Am J Med Genet, 1999,88 (6) :609-615.
[75] Shao Y, Wolpert CM,Raiford KL, et al.Genomic screen and follow-up analysis for autistic disorder.Am J Med Genet, 2002,114 (1) :99-105.
[76] International Molecular Genetic Study of Autism Consortium (IMGSAC) . Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q.Hum Mol Genet,2001,10 (9) : 973-982.
[77] International Molecular Genetic Study of Autism Consortium (IMGSAC) . A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q and 16q.Am J Hum Genet,2001,69 (3) :570-581.
[78] Collaborative Linkage Study of Autism. An autosomal genomic screen for autism. Am J Med Genet,2001,105 (8) :609-615.
[79] Yonan AL,Alarcon M,Cheng R,et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet,2003,73 (4) .886-897.
[80] Tissir F, Goffinet AM. Reelin and brain development.Nat Rev Neurosci, 2003,4 (6) :496-505.
[81] Hiesberger T, Trommsdorff M, Howell BW,et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphory- lation of disabled-1 and modulates tau phosphorylation.Neuron, 1999,24 (2) :481-489.
[82] Fatemi SH, Stary JM, Halt AR,et al.Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum.J Autism Dev Disord,2001,31 (6) :529-535.
[83] Persico AM,D' Aqruma L,Maiorano N,et al.Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.Mol Psychiatry, 2001,6 (2) : 150-159.
[84] Krebs MO, Betancur C, Leroy S, et al.Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.Mol Psychiatry, 2002,7 (7) :801-804.
[85] Zhang H,Liu X,Zhang C, et al.Reelin gene alleles and susceptibility to autism spectrum disorders.Mol Psychiatry,2002,7 (9) :1012-1017.
[86] Bonora E,Beyer KS,Lamb JA,et al. Analysis of reelin as a candidate gene for autism.Mol Psychiatry, 2003,8 (10) :885-892.
[87] Li J,Nquyen L,Gleason C,et al.Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.Am J Med Genet B Neuropsychiatr Genet, 2004,126 (1) -.51-57.
[88] Devlin B,Bennett P,Dawson G,et al.Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.Am J Med Genet B Neuropsychiatr Genet, 2004,126 (1) : 46-50.
[89] Skaar DA, Shao Y,Haines JL,et al.Analysis of the RELN gene as a genetic risk factor for autism.Mol Psychiatry, 2005,10 (6) .563-571.
[90] Bauman M,Kemper TL.Histoanatomic observations of the brain in early infantile autism. Neurology, 1985, 35 (6) :866-874.
[91] Ritvo ER,Freeman BJ,Scheibel AB,et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report.Am J Psychiatry, 1986,143 (7) .862-866.
[92] Courchesne E.Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism.Curr Opin Neurobiol, 1997,7 (2) .269-278.
[93] Levitt JG,Blanton R,Capetillo-Cunliffe L,et al. Cerebellar vermis lobules VIII-X in autism.Prog Neuropsychopharmacol Biol Psychiatry, 1999,23(4):625-633.
[94] Fatemi SH.Reelin mutations in mouse and man: from reeler mouse to schizophrenia,mood disorders,autism and lissencephaly.Mol Psychiatry, 2001,6 (2) :129-133.
[95] Sparks BF,Friedman SD, Shaw DW,et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology,2002,59 (2) : 184-192.
[96] Salinger WL,Ladrow P, Wheeler C. Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation.Behav Neurosci,2003,117 (6) :1257-1275.
[97] Dutta S,Guhathakurta S,Sinha S,et al.Reelin gene polymorphisms in the Indian population: a possible paternal 5'UTR-CGG-repeat-allele effect on autism. Am J Med Genet B Neuropsychiatr Genet,2007,144 (1) : 106-112.
[98] Serajee FJ,Zhong H,Mahbubul Huq AH.Association of Reelin gene polymorphisms with autism.Genomics, 2006,87 (1) :75-83.
[1] Szatmari P , Jones MB , Zwaigenbaum L, et al. Genetics of autism: overview and new directions.J Autism Dev Disord ,1998 ,28 (5) :351-368.
[2] Rapin I, Tuchman RF. What is new in autism?Curr Opin Neurol,2008, 21 (2) :143-149.
[3] Rutter M. Genetic studies of autism: from the 1970s into the millennium. J Abnorm Child Psychol,2000,28 (1) :3-14.
[4] Sedlacek Z,Havlovicova M,Hrdlicka M. Genetics of autism.Cas Lek Cesk, 2002,141 (12) : 376-380.
[5] Koch A,Windeler J. Statistical models and analysis of observational studies. Med Klin (Munich) ,1999,94 (10) :587-593.
[6] Cook EH Jr, Lindgren V , Leventhal BL , et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet , 1997,60 (4) :928-934.
[7] Koochek M, Harvard C, Hildebrand MJ,et al. 15q duplication associated with autism in a multiplex family with a familial cryptic translocation t ( 14; 15 ) (q11.2;q13.3) detected using array-CGH. Clin Genet,2006,69 (2) :124-134.
[8] Maestrini E , Marlow AJ , Weeks DE, et al. Molecular genetic investigations of autism. J Autism Dev Disord , 1998 ,28 (5 ) :427-437.
[9] Chudley AE.Genetic landmarks through philately - autism spectrum disorders: a genetic update.Clin Genet,2004,65 (5) :352-357.
[10] Gillberg C. Chromosomal disorders and autism. J Autism Dev Disord , 1998,28 (5) :415-425.
[11] Hodapp RM, Urbano RC. Adult siblings of individuals with Down syndrome versus with autism: findings from a large-scale US survey.J Intellect Disabil Res,2007,51 (Pt 12) : 1018-1029.
[12] Thomas NS,Sharp AJ,Browne CE,et al. Xp deletions associated with autism in three females. Hum Genet, 1999,104 (1) : 43-48.
[13] Chocholska S, Rossier E, Barbi G,et al.Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers. Am J Med Genet A,2006,140 (6) :604-610.
[14] International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q and 16q.Am J Hum Genet,2001,69 (3) :570-581.
[15] Nurmi EL , Bradford Y, Chen Y, et al. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics,2001,77 (1-2) : 105-113.
[16] Wassink TH , Piven J , Vieland VJ , et al . Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet, 2001,105 (5) :406-413.
[17] Folstein SE , Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet,2001,2 (12) :943-955.
[18] Vincent JB,Neves-Pereira ML,Paterson AD, et al. An unstable trinucleotide -repeat region on chromosome 13 implicated in spinocere- bellar ataxia: a common expansion locus .Am J Hum Genet, 2000,66 (3) : 510-514.
[19] McCoy PA,Shao Y,Wolpert CM, et al. No association between the WNT2 gene and autistic disorder. Am J Med Genet, 2002,114 (1) : 106-109.
[20] Li J, Nguyen L, Gleason C, et al.Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.Am J Med Genet B Neuropsychiatr Genet,2004,126 (1) :51-57.
[21] Tager-Flusberg H,Joseph R,Folstein S.Current directions in research on autism.Ment Retard Dev Disabil Res Rev,2001,7 (1) :21-29.
[22] Beeghly M.Translational research on early language development: current challenges and future directions.Dev Psychopathol, 2006,18 (3) : 737-757.
[23] Cook EH Jr,Courchesne RY,CoxNJ, et al. Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet, 1998, 62 (5) : 1077-1083.
[24] Kwasnicka-Crawford DA, Roberts W, Scherer SW.Characterization of an autism-associated segmental maternal heterodisomy of the chromosome 15q11-13 region.J Autism Dev Disord,2007,37 (4) -.694-702.
[25] Buxbaum JD,Silverman JM,Smith CJ,et al.Association between a GABRB3 polymorphism and autism.Mol Psychiatry,2002,7 (3) :311 -316.
[26] Solis-Anez E, Delgado-Luengo W, Borjas-Fuentes L, et al. Molecular analysis of the GABRB3 gene in autistic patients: an exploratory study. Invest Clin,2007,48 (2) :225-242.
[27]Veenstra-VanderWeele J,Gonen D,Leventhal BL,et al. Mutation screening of the UBE3A/E6-AP gene in autistic disorder. Mol Psychiatry, 1999,4 (1) : 64-67.
[28] Herzing LB,Cook EH Jr,Ledbetter DH. Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications. Hum Mol Genet,2002,11 (15) : 1707-1718.
[29] Borg I,Squire M,Menzel C,et al. A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation. J Med Genet, 2002, 39 (6) : 391-399.
[30] Veenstra-VanderWeele J,Anderson GM,Cook EH Jr.Pharmacogenetics and the serotonin system:initial studies and future directions.Eur J Pharmacol,2000,410 (2-3) :165-181.
[31] Leboyer M,Philippe A,Bouvard M,et al.Whole blood serotonin and plasma beta-endourphin in autistic probands and their first-degree relatives.Biol Psychiatry, 1999,45 (2) :158-163.
[32] Veenstra-VanderWeele J,Kim SJ,Lord C,et al.Transmission disequil-ibrium studies of the serotonin 5-HT2A receptor gene (HTR2A) in autism.Am J Med Genet,2002,114 (3) :277-283.
[33] Cho IH, Yoo HJ, Park M,et al.Family-based association study of 5-HTTLPR and the 5-HT2A receptor gene polymorphisms with autism spectrum disorder in Korean trios.Brain Res,2007 ,1139:34-41.
[34] Di Bella D,Catalano M,Balling U, et al. Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE. Am J Med Genet, 1996,67 (6) : 541-545.
[35] Cook EH Jr,Courchesne R,Lord C,et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry, 1997,2 (3) : 247-250.
[36] Cross S, Kim SJ, Weiss LA, et al.Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychophar macology,2008,33 (2) :353-360.
[37] Tordjman S,Gutknecht L,Carlier M,et al.Role of the serotoniin transporter gene in the behavioral expression of autism.Mol Psych- iatry,2001,6 (4) :434-439.
[38] Kim SJ,Cox N,Courchesne R,et al.Transmission disequilbrium mapping at the serotonin transporter gene ( SLC6A4 ) region in autistic disorder.Mol Psychiatry,2002,7 (3) :278-288.
[39] Ingram JL,Stodgell CJ,Hyman SL, et al . Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology, 2000,62 (6) : 393-405.
[40] Li J,Tabor HK,Nguyen L,et al. Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families.Am J Med Genet, 2002, 114 (1) : 24-30.
[41] Meldrum BS.Glutamate as a neurotransmitter in the brain:review of physiology and pathology.J Nutr,2000,130 (4S Suppl) :1007S-1015S.
[42] Munoz-Yunta JA, Palau-Baduell M, Salvado-Salvado B,et al.Autism, epilepsy and genetics.Rev Neurol,2008,46 Suppl1:S71-77.
[43] Jamain S,Betancur C,Quach H,et al.Linkage and association of the glutamate receptor 6 gene with autism.Mol Psychiatry,2002,7 (3) :302-310.
[44] Dutta S, Das S, Guhathakurta S,et al.Glutamate Receptor 6 Gene (GluR6 or GRIK2) Polymorphisms in the Indian Population: A Genetic Association Study on Autism Spectrum Disorder.Cell Mol Neurobiol,2007,27 (8) : 1035-1047.
[45] Warren RP,Singh VK,Averett RE, et al. Immunogenetic studies in autism and related disorders. Mol Chem Neuropathol, 1996,28 (1 -3) : 77-81.
[46] Samano ES, Ribeiro Lde M, Gorescu RG, et al.Involvement of C4 allotypes in the pathogenesis of human diseases.Rev Hosp Clin Fac Med Sao Paulo,2004,59 (3):138-144.
[47]Warren RP,Odell JD,Warren WL,et al.Strong association of the third hypervariable region of HLA-DR beta 1 with autism.J Neuroimmunol,1996,67(2):97-102.
[48]胡冬贵,黎青.FMR-1基因分子遗传学研究进展.国外医学遗传学分册,1997,20(4):202-207.
[49]Hallmayer J,Pintado E,Lotspeich L,et al.Molecular analysis and test of linkage between the FMR-1 gene and infantile autism in multiplex families.Am J HumGenet,1994,55(5):951-959.
[50]Klauck SM,Munstermann E,Bieber-Martig B,et al.Molecular genetic analysis of the FMR-1 gene in a large collection of autistic patients.Hum Genet,1997,100(2):224-229.
[51]Vincent JB,Konecki DS,Munstermann E,et al.Point mutation analysis of the FMR-1 gene in autism.Mol Psychiatry,1996,1(3):227-231.
[52]Hallmayer J,Hebert JM,Spiker D,et al.Autism and the X chromosome.Multipoint sib-pair analysis.Arch Gen Psychiatry,1996,53(11):985-989.
[53]Iourov IY,Yurov YB,Vorsanova SG.Mosaic X chromosome aneuploidy can help to explain the male-to-female ratio in autism.Med Hypotheses,2008,70(2):456.
[54]Petit E,Herault J,Raynaud M,et al.X chromosome and infantile autism.Biol Psychiatry,1996,40(6):457-464.
[55]Miyazaki K,Narita N,Sakuta R,et al.Serum neurotrophin concentrations in autism and mental retardation:a pilot study.Brain Dev,2004,26(5):292-295.
[56]Nelson KB,Grether JK,Croen LA,et al.Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation.Ann Neurol,2001,49(5):597-606.
[57]Philippe A,Guilloud-Bataille M,Martinez M,et al.Analysis of ten candidate genes in autism by association and linkage.Am J Med Genet,2002,114(2):125-128.
[58]Yrigollen CM,Han SS,Kochetkova A,et al.Genes Controlling Affiliative Behavior as Candidate Genes for Autism.Biol Psychiatry,2008,[Epub ahead of print].
[59]Fatemi SH.Reelin mutations in mouse and man:from reeler mouse to schizophrenia,mood disorders, autism and lissencephaly. Mol Psychiatry, 2001, 6 (2) :129-133.
[60] Persico AM,D' Aqruma L,Maiorano N,et al.Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.Mol Psychiatry, 2001,6 (2) : 150-159.
[61] Impagnatiello F, Guidotti AR, Pesold C,et al. A decrease of Reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A,1998,95 (26) :15718-15723.
[62] Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression.Mol Psychiatry,2000, 5 (6) :654-663,571.
[63] Fatemi SH, Kroll JL, Stary JM. Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport,2001,12 (5) : 3209-3215.
[64] Fatemi SH, Stary JM, Halt AR,et al. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord,2001,31 (6) : 529 - 535.
[65] Fatemi SH,Stary JM,Egan EA.Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder.Cell Mol Neurobiol, 2002, 22 (2) :139-152.
[2]李雪荣,陈劲梅.孤独症诊疗学.长沙:中南大学出版社,2004.1-2.
[3]罗维力,林力.福建省儿童孤独症流行病学调查.上海精神医学,2000,12(1):3-5.
[4]郭荣.天津市5000名0～6岁儿童中儿童孤独症的流行病学调查.中国临床康复,2004,8(6):1122-1123.
[5]Hyman S.Mental illness:genetically complex disorders of neural circuitry and neural communication.Neuron,2000,28(2),321-323.
[6]Volkmar FR,Nelson DS.Seizure disorders in autism.J Am Acad Child Adolesc Psychiatry,1990,29(1):127-129.
[7]Fatemi SH,Halt AR,Realmuto G,et al.Purkinje cell size is reduced in cerebellum of patients with autism.Cell Mol Neurobiol,2002,22(2):171-175.
[8]Lahuis BE,Durston S,Nederveen H,et al.MRI-based morphometry in children with multiple complex developmental disorder,a phenotypically defined subtype of pervasive developmental disorder not otherwise specified.Psychol Meal.2007 10(9):1-7.
[9]Bolte S,Hubl D,Dierks T,et al.An fMRI-study of locally oriented perception in autism:altered early visual processing of the block design test.J Neural Transm,2008,115(3):545-552.
[10]Amaral DG,Schumann CM,Nordahl CW.Neuroanatomy of autism.Trends Neurosci,2008,31(3):137-145.
[11]Brieber S,Neufang $,Bruning N,et al.Structural brain abnormalities in adolescents with autism spectrum disorder and patients with attention deficit/hyperactivity disorder.J Child Psychol Psychiatry,2007,48(12):1251-1258.
[12]Degirmenci B,Miral S,Kaya GC,et al.Technetium-99m HMPAO brain SPECT in autistic children and their families.Psychiatry Res,2008,162(3):236-243.
[13] Vorstman JA, Staal WG, van Daalen E,et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry,2006,11 (1) .1,18-28.
[14] Samaco RC,Hogart A,LasaIle JM.Epigenetic overlap in autism-spectrum neurodevelopment disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3.Hum Mol Genet,2005,14 (4) :483-492.
[15] Hussman JP. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism.J Autism Dev Disord,2001,31(2): 247-248.
[16] Carlsson ML. Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate - serotonin interactions for pharmacotherapy.J Neural Transm, 1998,105 (4-5) :525-535.
[17] Purcell AE, Jeon OH, Zimmerman AW,et al. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology, 2001,57 (9) .1618-1628.
[18] Segurado R, Conroy J, Meally E.Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31 .Am J Psychiatry,2005,162 (11) :2182-2184.
[19] McGale EH, Pye IF, Stonier C, et al. Studies of the interrelationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem,1977,29:291-297.
[20] Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry, 1988,23 (7) :689-697.
[21] Rolf LH, Haarmann FY, Grotemeyer KH,et al. Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand, 1993,87 (5) .312-316.
[22] Aldred S, Moore KM, Fitzgerald M,et al. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord,2003,33 (1) :93-97.
[23] Impagnatiello F, Guidotti AR, Pesold C,et al. A decrease of Reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U.S.A.,1998,95(26):15718-15723.
[24]Fatemi SH,Stary JM,Egan EA.Reduced Blood Levels of Reelin as a Vulnerability Factor in Pathophysiology of Autistic Disorder.Cell Mol Neurobiol,2002,22(2):171-175.
[25]Nelson KB.Prenatal and perinatal factors in the etiology of autism.Pediatrics,1991,87(5 Pt 2):761-766.
[26]Piven J,Simon J,Chase GA,et al.The etiology of autism:pre-,peri-and neonatal factors.J Am Acad Child Adolesc Psychiatry,1993,32(6):1256-1263.
[27]Zeanah CH,Boris NW,Larrieu JA.Infant development and developmental risk:A review of the past 10 years.J Am Acad Child Adolesc Psychiatry,1997,36(2):165-178.
[28]Bolton PF,Murphy M,Macdonald H,et al.Obstetric complications in autism:consequences or causes of the condition ?J Am Acad Child Adolesc Psychiatry,1997,36(2):272-281.
[29]李思特,李雪荣,张献共等.儿童孤独症高危因素和早期特征的回顾性分析.中国心理卫生杂志,2002,16(8):552-554.
[30]黄春香,陈劲梅,苏林雁等.婴儿孤独症的临床特征.中国临床心理学杂志,1999,7(1):53-54.
[31]Kobayashi R,Murata T.Setback phenomenon in autism and long-term prognosis.Acta Psychiatr Scand,1998,98(4):296-303.
[32]陶国泰.儿童少年精神医学.南京:江苏科学技术出版社,1999.207-214.
[33]杨晓玲,贾美香.儿童孤独症30例临床分析.中国心理卫生杂志,1990,4(4):250-254.
[34]Baron-Cohen S,Cox A,Baird G,et al.Psychological markers in the detection of autism in infancy in a large population.Br J Psychiatry,1996,168(2):158-163.
[35]Baron-Cohen S,Allen J,Gillberg C.Can autism be detected at 18 months?The needle,the haystack,and the CHAT.Br J Psychiatry,1992,161:839-843.
[36]Kawasaki Y,Yokota K,Shinomiya M,et al.Electroenchephalographicparo xysmal activities in the frontal area emerged in middle childhoodand during adolescence in a follow-up study of autism.J Autism DevDisord,1997,27(5):605-620.
[37]Mouridsen SE,Rich B,Isager T.Epilepsy in disintegrative psychosis and infantile autism:a long-term validation study.Dev Med Child Neurol,1999,41(2):110-114.
[38]Giovanardi Rossi P,Posar A,Parmeggiani A.Epilepsy in adolescents and young adults with autistic disorder.Brain Dev,2000,22(2):102-106.
[39]Danielsson S,Gillberg IC,Billstedt E,et al.Epilepsy in young adults with autism:a prospective populationbased follow-up study of 120 individuals diagnosed in childhood.Epilepsia,2005,46(6):918-923.
[40]ILAE Commission Report.The epidemiology of the epilepsies:future directions.International League Against Epilepsy.Epilepsia,1997,38(5):614-618.
[41]Jallon P,ILAE.Workshop Report:Epilepsy in developing countries.Epilepsia,1997,38(10):1143-1151.
[42]李世绰,王忠诚,周树宾,等.中国六城市居民癫痫的流行病学调查.中华神经精神科杂志,1986,19(4):193-196.
[43]四川医学院流行病学教研室.四川42万人口癫痫发病情况调查报告.中华神经精神科杂志,1981,14(3):135-138.
[44]王志文,吴建中,王德生,等.中国五省农村人群癫痫流行病学抽样调查.中华医学杂志,2002,82(7):449-452.
[45]Coyle JT,Leski ML,Morrison JH.The diverse roles of L-glutamic acid in brain signal transduction.Neuropsychopharmacology—the fifth genera- tion of progress,2002,71-90.
[46]McDougle CJ,Edckson CA,Stigler KA,et al.Neurochemistry inthe pathophysiology of autism.J Clin Psychiatry,2005,66(suppl 10):9-18.
[47]Page LA,Daly E,Schmitz N,et al.In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism.Am J Psychiatry 2006;163(12):2189-2192.
[48]Dhossche D,Applegate H,Abraham A,et al.Elevated plasma gammaaminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monit ,2002,8 (8) :PR1-R6.
[49] Blatt GJ, Fitzgerald CM, Guptill JT,et al. Density and distribution of hippocampalneurotransmitter receptors in autism: an autoradiographic study.J Autism Dev Disord ,2001,31 (6) :537-543.
[50] Ueda Y,Tsuru N.Simultaneous monitoring of the seizure-related changes in extracellular glutamate and gamma-aminobutyric acid concentration in bilateral hippocampi following development of amygdaloid kindling.Epilepsy Res, 1995,20 (3) :213-219.
[51] Fried I,Wilson CL,Mridment NT,et al.Cerebral microialysis combined with single neuron and electroencephalographic recording in neurosurgical patients. Technical note. JNeurosurg, 1999,91 (4) :697-705.
[52] Sherwin AL,Neuroactive amino acids in focally epileptic human brain:A review. Neurochem Res, 1999,24 (11) : 1387-1395.
[53] Hirao T,Morimoto K,Yamamoto Y,et al.Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats.Brain Res Mol Brain Res, 1998,54 (1) :49-55.
[54] Shinohe A, Hashimoto K, Nakamura K, et al. Increased serum levels of glutamate in adult patients with autism.Neuropsychopharmacology Biol Psychiatry , 2006,30 (8) 1472-1477.
[55] Hrdlicka M, Komarek V, Propper L, et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry ,2004,13 (4) :209-213.
[56] Kobayashi R, Murata T. Setback phenomenon in autism and longterm prognosis. Acta Psychiatr Scand ,1998,98 (4) :296-303.
[57] Hara H. Autism and epilepsy: A retrospective follow-up study. Brain Dev,2007,29 (8) :486-490.
[58] Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry, 2000,48 (6) : 518-530.
[59] Chuang DM. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol, 2004,16 (1-2) :83-90.
[60] Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol, 2002, 1 (6) : 352-358.
[61] Hollander E, Dolgoff-Kaspar R, Cartwright C, et al. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry, 2001,62 (7) :530-534.
[62] Gabis L , Pomeroy J, Andriola MR. Autism and epilepsy: Cause, consequence, comorbidity, or coincidence? Epilepsy Behav,2005,7 (4) : 652-656.
[63] Pickles A ,Bolton P, Macdonald H, et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet, 1995, 57 (3) :717-726.
[64] Folstein SE, Piven J. Etiology of autism: genetic influences. Pediatrics, 1991,87 (5 Pt 2) : 767-773.
[65] Bailey A,Le Couteur A,Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study.Psychol Med, 1995,25 (1) :63- 77.
[66] Auranen M ,Vanhala R , Varilo T ,et al. A genome wide screen for autism-spectrum disorders:evidence for a major susceptibility locus on chromosome 3q25-27. Am J Hum Genet,2002,71 (4) :777-790.
[67] Buxbaum,JD ,Silverman JM,Smith CJ,et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet, 2001,68 (6) : 1514-1520.
[68] Shao Y, Raiford KL, Wolpert CM, et al.Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet,2002,70 (4) : 1058-1061.
[69] A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet, 1998,7 (3) :571-578.
[70] Philippe A,Martinez M,Guilloud-Bataille M,et al. Genome-wide scan for autism susceptibility genes.Paris Autism Research International Sibpair Study.Hum Mol Genet, 1999,8 (5) :805-812.
[71] Ashley-Koch A,Wolpert CM,Menold MM, et al. Genetic studies of autistic disorder and chromosome 7.Genomics ,1999,61 (3) :227-236.
[72] Liu J, Nyholt DR,Magnussen P,et al. A genomewide screen for autism susceptibility loci.Am J Hum Genet,2001,69 (2) : 327-340.
[73] Risch N,Spiker D,Lotspeich L, et al. A genomic screen of autism: evidence for a multilocus etiology.Am J Hum Genet, 1999,65 (2) : 493-507.
[74] Barrett S,Beck JC,Bernier R, et al. An autosomal genomic screen for autism.Collaborative linkage study of autism. Am J Med Genet, 1999,88 (6) :609-615.
[75] Shao Y, Wolpert CM,Raiford KL, et al.Genomic screen and follow-up analysis for autistic disorder.Am J Med Genet, 2002,114 (1) :99-105.
[76] International Molecular Genetic Study of Autism Consortium (IMGSAC) . Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q.Hum Mol Genet,2001,10 (9) : 973-982.
[77] International Molecular Genetic Study of Autism Consortium (IMGSAC) . A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q and 16q.Am J Hum Genet,2001,69 (3) :570-581.
[78] Collaborative Linkage Study of Autism. An autosomal genomic screen for autism. Am J Med Genet,2001,105 (8) :609-615.
[79] Yonan AL,Alarcon M,Cheng R,et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet,2003,73 (4) .886-897.
[80] Tissir F, Goffinet AM. Reelin and brain development.Nat Rev Neurosci, 2003,4 (6) :496-505.
[81] Hiesberger T, Trommsdorff M, Howell BW,et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphory- lation of disabled-1 and modulates tau phosphorylation.Neuron, 1999,24 (2) :481-489.
[82] Fatemi SH, Stary JM, Halt AR,et al.Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum.J Autism Dev Disord,2001,31 (6) :529-535.
[83] Persico AM,D' Aqruma L,Maiorano N,et al.Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.Mol Psychiatry, 2001,6 (2) : 150-159.
[84] Krebs MO, Betancur C, Leroy S, et al.Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism.Mol Psychiatry, 2002,7 (7) :801-804.
[85] Zhang H,Liu X,Zhang C, et al.Reelin gene alleles and susceptibility to autism spectrum disorders.Mol Psychiatry,2002,7 (9) :1012-1017.
[86] Bonora E,Beyer KS,Lamb JA,et al. Analysis of reelin as a candidate gene for autism.Mol Psychiatry, 2003,8 (10) :885-892.
[87] Li J,Nquyen L,Gleason C,et al.Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.Am J Med Genet B Neuropsychiatr Genet, 2004,126 (1) -.51-57.
[88] Devlin B,Bennett P,Dawson G,et al.Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.Am J Med Genet B Neuropsychiatr Genet, 2004,126 (1) : 46-50.
[89] Skaar DA, Shao Y,Haines JL,et al.Analysis of the RELN gene as a genetic risk factor for autism.Mol Psychiatry, 2005,10 (6) .563-571.
[90] Bauman M,Kemper TL.Histoanatomic observations of the brain in early infantile autism. Neurology, 1985, 35 (6) :866-874.
[91] Ritvo ER,Freeman BJ,Scheibel AB,et al. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report.Am J Psychiatry, 1986,143 (7) .862-866.
[92] Courchesne E.Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism.Curr Opin Neurobiol, 1997,7 (2) .269-278.
[93] Levitt JG,Blanton R,Capetillo-Cunliffe L,et al. Cerebellar vermis lobules VIII-X in autism.Prog Neuropsychopharmacol Biol Psychiatry, 1999,23(4):625-633.
[94] Fatemi SH.Reelin mutations in mouse and man: from reeler mouse to schizophrenia,mood disorders,autism and lissencephaly.Mol Psychiatry, 2001,6 (2) :129-133.
[95] Sparks BF,Friedman SD, Shaw DW,et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology,2002,59 (2) : 184-192.
[96] Salinger WL,Ladrow P, Wheeler C. Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation.Behav Neurosci,2003,117 (6) :1257-1275.
[97] Dutta S,Guhathakurta S,Sinha S,et al.Reelin gene polymorphisms in the Indian population: a possible paternal 5'UTR-CGG-repeat-allele effect on autism. Am J Med Genet B Neuropsychiatr Genet,2007,144 (1) : 106-112.
[98] Serajee FJ,Zhong H,Mahbubul Huq AH.Association of Reelin gene polymorphisms with autism.Genomics, 2006,87 (1) :75-83.
[1] Szatmari P , Jones MB , Zwaigenbaum L, et al. Genetics of autism: overview and new directions.J Autism Dev Disord ,1998 ,28 (5) :351-368.
[2] Rapin I, Tuchman RF. What is new in autism?Curr Opin Neurol,2008, 21 (2) :143-149.
[3] Rutter M. Genetic studies of autism: from the 1970s into the millennium. J Abnorm Child Psychol,2000,28 (1) :3-14.
[4] Sedlacek Z,Havlovicova M,Hrdlicka M. Genetics of autism.Cas Lek Cesk, 2002,141 (12) : 376-380.
[5] Koch A,Windeler J. Statistical models and analysis of observational studies. Med Klin (Munich) ,1999,94 (10) :587-593.
[6] Cook EH Jr, Lindgren V , Leventhal BL , et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet , 1997,60 (4) :928-934.
[7] Koochek M, Harvard C, Hildebrand MJ,et al. 15q duplication associated with autism in a multiplex family with a familial cryptic translocation t ( 14; 15 ) (q11.2;q13.3) detected using array-CGH. Clin Genet,2006,69 (2) :124-134.
[8] Maestrini E , Marlow AJ , Weeks DE, et al. Molecular genetic investigations of autism. J Autism Dev Disord , 1998 ,28 (5 ) :427-437.
[9] Chudley AE.Genetic landmarks through philately - autism spectrum disorders: a genetic update.Clin Genet,2004,65 (5) :352-357.
[10] Gillberg C. Chromosomal disorders and autism. J Autism Dev Disord , 1998,28 (5) :415-425.
[11] Hodapp RM, Urbano RC. Adult siblings of individuals with Down syndrome versus with autism: findings from a large-scale US survey.J Intellect Disabil Res,2007,51 (Pt 12) : 1018-1029.
[12] Thomas NS,Sharp AJ,Browne CE,et al. Xp deletions associated with autism in three females. Hum Genet, 1999,104 (1) : 43-48.
[13] Chocholska S, Rossier E, Barbi G,et al.Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers. Am J Med Genet A,2006,140 (6) :604-610.
[14] International Molecular Genetic Study of Autism Consortium (IMGSAC). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q and 16q.Am J Hum Genet,2001,69 (3) :570-581.
[15] Nurmi EL , Bradford Y, Chen Y, et al. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics,2001,77 (1-2) : 105-113.
[16] Wassink TH , Piven J , Vieland VJ , et al . Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet, 2001,105 (5) :406-413.
[17] Folstein SE , Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet,2001,2 (12) :943-955.
[18] Vincent JB,Neves-Pereira ML,Paterson AD, et al. An unstable trinucleotide -repeat region on chromosome 13 implicated in spinocere- bellar ataxia: a common expansion locus .Am J Hum Genet, 2000,66 (3) : 510-514.
[19] McCoy PA,Shao Y,Wolpert CM, et al. No association between the WNT2 gene and autistic disorder. Am J Med Genet, 2002,114 (1) : 106-109.
[20] Li J, Nguyen L, Gleason C, et al.Lack of evidence for an association between WNT2 and RELN polymorphisms and autism.Am J Med Genet B Neuropsychiatr Genet,2004,126 (1) :51-57.
[21] Tager-Flusberg H,Joseph R,Folstein S.Current directions in research on autism.Ment Retard Dev Disabil Res Rev,2001,7 (1) :21-29.
[22] Beeghly M.Translational research on early language development: current challenges and future directions.Dev Psychopathol, 2006,18 (3) : 737-757.
[23] Cook EH Jr,Courchesne RY,CoxNJ, et al. Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet, 1998, 62 (5) : 1077-1083.
[24] Kwasnicka-Crawford DA, Roberts W, Scherer SW.Characterization of an autism-associated segmental maternal heterodisomy of the chromosome 15q11-13 region.J Autism Dev Disord,2007,37 (4) -.694-702.
[25] Buxbaum JD,Silverman JM,Smith CJ,et al.Association between a GABRB3 polymorphism and autism.Mol Psychiatry,2002,7 (3) :311 -316.
[26] Solis-Anez E, Delgado-Luengo W, Borjas-Fuentes L, et al. Molecular analysis of the GABRB3 gene in autistic patients: an exploratory study. Invest Clin,2007,48 (2) :225-242.
[27]Veenstra-VanderWeele J,Gonen D,Leventhal BL,et al. Mutation screening of the UBE3A/E6-AP gene in autistic disorder. Mol Psychiatry, 1999,4 (1) : 64-67.
[28] Herzing LB,Cook EH Jr,Ledbetter DH. Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications. Hum Mol Genet,2002,11 (15) : 1707-1718.
[29] Borg I,Squire M,Menzel C,et al. A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation. J Med Genet, 2002, 39 (6) : 391-399.
[30] Veenstra-VanderWeele J,Anderson GM,Cook EH Jr.Pharmacogenetics and the serotonin system:initial studies and future directions.Eur J Pharmacol,2000,410 (2-3) :165-181.
[31] Leboyer M,Philippe A,Bouvard M,et al.Whole blood serotonin and plasma beta-endourphin in autistic probands and their first-degree relatives.Biol Psychiatry, 1999,45 (2) :158-163.
[32] Veenstra-VanderWeele J,Kim SJ,Lord C,et al.Transmission disequil-ibrium studies of the serotonin 5-HT2A receptor gene (HTR2A) in autism.Am J Med Genet,2002,114 (3) :277-283.
[33] Cho IH, Yoo HJ, Park M,et al.Family-based association study of 5-HTTLPR and the 5-HT2A receptor gene polymorphisms with autism spectrum disorder in Korean trios.Brain Res,2007 ,1139:34-41.
[34] Di Bella D,Catalano M,Balling U, et al. Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE. Am J Med Genet, 1996,67 (6) : 541-545.
[35] Cook EH Jr,Courchesne R,Lord C,et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry, 1997,2 (3) : 247-250.
[36] Cross S, Kim SJ, Weiss LA, et al.Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism. Neuropsychophar macology,2008,33 (2) :353-360.
[37] Tordjman S,Gutknecht L,Carlier M,et al.Role of the serotoniin transporter gene in the behavioral expression of autism.Mol Psych- iatry,2001,6 (4) :434-439.
[38] Kim SJ,Cox N,Courchesne R,et al.Transmission disequilbrium mapping at the serotonin transporter gene ( SLC6A4 ) region in autistic disorder.Mol Psychiatry,2002,7 (3) :278-288.
[39] Ingram JL,Stodgell CJ,Hyman SL, et al . Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology, 2000,62 (6) : 393-405.
[40] Li J,Tabor HK,Nguyen L,et al. Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families.Am J Med Genet, 2002, 114 (1) : 24-30.
[41] Meldrum BS.Glutamate as a neurotransmitter in the brain:review of physiology and pathology.J Nutr,2000,130 (4S Suppl) :1007S-1015S.
[42] Munoz-Yunta JA, Palau-Baduell M, Salvado-Salvado B,et al.Autism, epilepsy and genetics.Rev Neurol,2008,46 Suppl1:S71-77.
[43] Jamain S,Betancur C,Quach H,et al.Linkage and association of the glutamate receptor 6 gene with autism.Mol Psychiatry,2002,7 (3) :302-310.
[44] Dutta S, Das S, Guhathakurta S,et al.Glutamate Receptor 6 Gene (GluR6 or GRIK2) Polymorphisms in the Indian Population: A Genetic Association Study on Autism Spectrum Disorder.Cell Mol Neurobiol,2007,27 (8) : 1035-1047.
[45] Warren RP,Singh VK,Averett RE, et al. Immunogenetic studies in autism and related disorders. Mol Chem Neuropathol, 1996,28 (1 -3) : 77-81.
[46] Samano ES, Ribeiro Lde M, Gorescu RG, et al.Involvement of C4 allotypes in the pathogenesis of human diseases.Rev Hosp Clin Fac Med Sao Paulo,2004,59 (3):138-144.
[47]Warren RP,Odell JD,Warren WL,et al.Strong association of the third hypervariable region of HLA-DR beta 1 with autism.J Neuroimmunol,1996,67(2):97-102.
[48]胡冬贵,黎青.FMR-1基因分子遗传学研究进展.国外医学遗传学分册,1997,20(4):202-207.
[49]Hallmayer J,Pintado E,Lotspeich L,et al.Molecular analysis and test of linkage between the FMR-1 gene and infantile autism in multiplex families.Am J HumGenet,1994,55(5):951-959.
[50]Klauck SM,Munstermann E,Bieber-Martig B,et al.Molecular genetic analysis of the FMR-1 gene in a large collection of autistic patients.Hum Genet,1997,100(2):224-229.
[51]Vincent JB,Konecki DS,Munstermann E,et al.Point mutation analysis of the FMR-1 gene in autism.Mol Psychiatry,1996,1(3):227-231.
[52]Hallmayer J,Hebert JM,Spiker D,et al.Autism and the X chromosome.Multipoint sib-pair analysis.Arch Gen Psychiatry,1996,53(11):985-989.
[53]Iourov IY,Yurov YB,Vorsanova SG.Mosaic X chromosome aneuploidy can help to explain the male-to-female ratio in autism.Med Hypotheses,2008,70(2):456.
[54]Petit E,Herault J,Raynaud M,et al.X chromosome and infantile autism.Biol Psychiatry,1996,40(6):457-464.
[55]Miyazaki K,Narita N,Sakuta R,et al.Serum neurotrophin concentrations in autism and mental retardation:a pilot study.Brain Dev,2004,26(5):292-295.
[56]Nelson KB,Grether JK,Croen LA,et al.Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation.Ann Neurol,2001,49(5):597-606.
[57]Philippe A,Guilloud-Bataille M,Martinez M,et al.Analysis of ten candidate genes in autism by association and linkage.Am J Med Genet,2002,114(2):125-128.
[58]Yrigollen CM,Han SS,Kochetkova A,et al.Genes Controlling Affiliative Behavior as Candidate Genes for Autism.Biol Psychiatry,2008,[Epub ahead of print].
[59]Fatemi SH.Reelin mutations in mouse and man:from reeler mouse to schizophrenia,mood disorders, autism and lissencephaly. Mol Psychiatry, 2001, 6 (2) :129-133.
[60] Persico AM,D' Aqruma L,Maiorano N,et al.Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder.Mol Psychiatry, 2001,6 (2) : 150-159.
[61] Impagnatiello F, Guidotti AR, Pesold C,et al. A decrease of Reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A,1998,95 (26) :15718-15723.
[62] Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression.Mol Psychiatry,2000, 5 (6) :654-663,571.
[63] Fatemi SH, Kroll JL, Stary JM. Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport,2001,12 (5) : 3209-3215.
[64] Fatemi SH, Stary JM, Halt AR,et al. Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord,2001,31 (6) : 529 - 535.
[65] Fatemi SH,Stary JM,Egan EA.Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder.Cell Mol Neurobiol, 2002, 22 (2) :139-152.