氧化应激、叶酸受体自身免疫和脑脊液在重度婴儿自闭症中的表现。

Autism Research and Treatment Pub Date : 2020-11-18 eCollection Date: 2020-01-01 DOI:10.1155/2020/9095284
Vincent T Ramaekers, Jeffrey M Sequeira, Beat Thöny, Edward V Quadros
{"title":"氧化应激、叶酸受体自身免疫和脑脊液在重度婴儿自闭症中的表现。","authors":"Vincent T Ramaekers,&nbsp;Jeffrey M Sequeira,&nbsp;Beat Thöny,&nbsp;Edward V Quadros","doi":"10.1155/2020/9095284","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Biomarkers such as oxidative stress, folate receptor alpha (FR<i>α</i>) autoimmunity, and abnormal brain serotonin turnover are common in autism.</p><p><strong>Methods: </strong>Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism (<i>n</i> = 38) and controls (<i>n</i> = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N<sup>5</sup>-methyltetrahydrofolate (MTHF). Statistical analysis assessed correlations between variables. Genetic analysis included the SLC6A4 and SLC29A4 genes encoding synaptic serotonin reuptake proteins.</p><p><strong>Results: </strong>Compared to controls, the autism group showed a significant increase in oxidative DNA damage in lymphocytes, plasma ceruloplasmin and copper levels with a high copper/zinc ratio, thiol proteins, and superoxide dismutase (SOD) activity. Vitamin C levels were significantly diminished. In most autistic patients, the vitamin A (64%) and D (70%) levels were low. Serum FR autoantibodies fluctuating over 5-7 week periods presented in 68% of all autistic children, 41% of parents vs. 3.3% of control children and their parents. CSF showed lowered serotonin 5-hydroxyindole acetic acid (5HIAA) metabolites in 13 (34%), a low 5HIAA to HVA (dopamine metabolite) ratio in 5 (13%), low 5HIAA and MTHF in 2 (5%), and low MTHF in 8 patients (21%). A known SLC6A4 mutation was identified only in 1 autistic child with low CSF 5HIAA and a novel SLC29A4 mutation was identified in identical twins. Low CSF MTHF levels among only 26% of subjects can be explained by the fluctuating FR antibody titers. Two or more aberrant pro-oxidant and/or antioxidant factors predisposed to low CSF serotonin metabolites. Three autistic children having low CSF 5HIAA and elevated oxidative stress received antioxidative supplements followed by CSF 5HIAA normalisation.</p><p><strong>Conclusion: </strong>In autism, we found diverse combinations for FR autoimmunity and/or oxidative stress, both amenable to treatment. Parental and postnatal FR autoantibodies tend to block folate passage to the brain affecting folate-dependent pathways restored by folinic acid treatment, while an abnormal redox status tends to induce reduced serotonin turnover, corrected by antioxidant therapy. <i>Trial Registration</i>. The case-controlled study was approved in 2008 by the IRB at Liège University (Belgian Number: B70720083916). <i>Lay Summary</i>. Children with severe infantile autism frequently have serum folate receptor autoantibodies that block the transport of the essential vitamin folate across the blood-brain barrier to the brain. Parents are often asymptomatic carriers of these serum folate receptor autoantibodies, which in mothers can block folate passage across the placenta to their unborn child. This folate deficiency during the child's intrauterine development may predispose to neural tube defects and autism. Oxidative stress represents a condition with the presence of elevated toxic oxygen derivatives attributed to an imbalance between the formation and protection against these toxic reactive oxygen derivatives. Oxidative stress was found to be present in autistic children where these reactive oxygen derivatives can cause damage to DNA, which changes DNA function and regulation of gene expression. In addition, excessive amounts of these toxic oxygen derivatives are likely to damage the enzyme producing the neuromessenger serotonin in the brain, diminished in about 1/3 of the autistic children. Testing children with autism for oxidative stress and its origin, as well as testing for serum folate receptor autoantibodies, could open new approaches towards more effective treatments.</p>","PeriodicalId":8659,"journal":{"name":"Autism Research and Treatment","volume":"2020 ","pages":"9095284"},"PeriodicalIF":0.0000,"publicationDate":"2020-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/9095284","citationCount":"15","resultStr":"{\"title\":\"Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.\",\"authors\":\"Vincent T Ramaekers,&nbsp;Jeffrey M Sequeira,&nbsp;Beat Thöny,&nbsp;Edward V Quadros\",\"doi\":\"10.1155/2020/9095284\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Biomarkers such as oxidative stress, folate receptor alpha (FR<i>α</i>) autoimmunity, and abnormal brain serotonin turnover are common in autism.</p><p><strong>Methods: </strong>Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism (<i>n</i> = 38) and controls (<i>n</i> = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N<sup>5</sup>-methyltetrahydrofolate (MTHF). Statistical analysis assessed correlations between variables. Genetic analysis included the SLC6A4 and SLC29A4 genes encoding synaptic serotonin reuptake proteins.</p><p><strong>Results: </strong>Compared to controls, the autism group showed a significant increase in oxidative DNA damage in lymphocytes, plasma ceruloplasmin and copper levels with a high copper/zinc ratio, thiol proteins, and superoxide dismutase (SOD) activity. Vitamin C levels were significantly diminished. In most autistic patients, the vitamin A (64%) and D (70%) levels were low. Serum FR autoantibodies fluctuating over 5-7 week periods presented in 68% of all autistic children, 41% of parents vs. 3.3% of control children and their parents. CSF showed lowered serotonin 5-hydroxyindole acetic acid (5HIAA) metabolites in 13 (34%), a low 5HIAA to HVA (dopamine metabolite) ratio in 5 (13%), low 5HIAA and MTHF in 2 (5%), and low MTHF in 8 patients (21%). A known SLC6A4 mutation was identified only in 1 autistic child with low CSF 5HIAA and a novel SLC29A4 mutation was identified in identical twins. Low CSF MTHF levels among only 26% of subjects can be explained by the fluctuating FR antibody titers. Two or more aberrant pro-oxidant and/or antioxidant factors predisposed to low CSF serotonin metabolites. Three autistic children having low CSF 5HIAA and elevated oxidative stress received antioxidative supplements followed by CSF 5HIAA normalisation.</p><p><strong>Conclusion: </strong>In autism, we found diverse combinations for FR autoimmunity and/or oxidative stress, both amenable to treatment. Parental and postnatal FR autoantibodies tend to block folate passage to the brain affecting folate-dependent pathways restored by folinic acid treatment, while an abnormal redox status tends to induce reduced serotonin turnover, corrected by antioxidant therapy. <i>Trial Registration</i>. The case-controlled study was approved in 2008 by the IRB at Liège University (Belgian Number: B70720083916). <i>Lay Summary</i>. Children with severe infantile autism frequently have serum folate receptor autoantibodies that block the transport of the essential vitamin folate across the blood-brain barrier to the brain. Parents are often asymptomatic carriers of these serum folate receptor autoantibodies, which in mothers can block folate passage across the placenta to their unborn child. This folate deficiency during the child's intrauterine development may predispose to neural tube defects and autism. Oxidative stress represents a condition with the presence of elevated toxic oxygen derivatives attributed to an imbalance between the formation and protection against these toxic reactive oxygen derivatives. Oxidative stress was found to be present in autistic children where these reactive oxygen derivatives can cause damage to DNA, which changes DNA function and regulation of gene expression. In addition, excessive amounts of these toxic oxygen derivatives are likely to damage the enzyme producing the neuromessenger serotonin in the brain, diminished in about 1/3 of the autistic children. Testing children with autism for oxidative stress and its origin, as well as testing for serum folate receptor autoantibodies, could open new approaches towards more effective treatments.</p>\",\"PeriodicalId\":8659,\"journal\":{\"name\":\"Autism Research and Treatment\",\"volume\":\"2020 \",\"pages\":\"9095284\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2020-11-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1155/2020/9095284\",\"citationCount\":\"15\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Autism Research and Treatment\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1155/2020/9095284\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2020/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Autism Research and Treatment","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1155/2020/9095284","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2020/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 15

摘要

背景:氧化应激、叶酸受体α (FRα)自身免疫和脑血清素转换异常等生物标志物在自闭症中很常见。方法:对重度自闭症患儿(n = 38)和对照组(n = 24)的氧化应激生物标志物进行检测。儿童和家长反复检测血清FR自身抗体、脊髓液多巴胺和血清素代谢物、蝶呤和n5 -甲基四氢叶酸(MTHF)。统计分析评估变量之间的相关性。遗传分析包括编码突触血清素再摄取蛋白的SLC6A4和SLC29A4基因。结果:与对照组相比,自闭症组淋巴细胞DNA氧化损伤显著增加,血浆铜蓝蛋白和铜水平升高,铜锌比高,硫醇蛋白和超氧化物歧化酶(SOD)活性升高。维生素C水平显著降低。在大多数自闭症患者中,维生素A(64%)和D(70%)水平较低。在所有自闭症儿童中,血清FR自身抗体波动超过5-7周的比例为68%,家长为41%,对照组儿童及其父母为3.3%。脑脊液显示血清素- 5-羟吲哚乙酸(5HIAA)代谢物降低13例(34%),5HIAA / HVA(多巴胺代谢物)低5例(13%),5HIAA和MTHF低2例(5%),MTHF低8例(21%)。已知的SLC6A4突变仅在1例脑脊液5HIAA低的自闭症儿童中发现,而在同卵双胞胎中发现了一种新的SLC29A4突变。只有26%的受试者脑脊液中MTHF水平较低,这可以通过FR抗体滴度的波动来解释。两种或多种异常的促氧化和/或抗氧化因素易导致脑脊液血清素代谢产物降低。三名脑脊液5HIAA低和氧化应激升高的自闭症儿童接受抗氧化剂补充,随后脑脊液5HIAA正常化。结论:在自闭症中,我们发现FR自身免疫和/或氧化应激的不同组合,两者都可以治疗。亲代和出生后FR自身抗体倾向于阻断叶酸进入大脑的通道,影响叶酸治疗恢复的叶酸依赖途径,而异常氧化还原状态倾向于诱导血清素转换减少,通过抗氧化治疗纠正。试验注册。该病例对照研究于2008年获得法国里昂热大学IRB批准(比利时编号:B70720083916)。总结。患有严重自闭症的儿童通常有血清叶酸受体自身抗体,这种抗体会阻止必需维生素叶酸通过血脑屏障进入大脑。父母通常是这些血清叶酸受体自身抗体的无症状携带者,在母亲身上可以阻止叶酸通过胎盘到达未出生的孩子。儿童在宫内发育期间叶酸缺乏可能导致神经管缺陷和自闭症。氧化应激是指由于有毒活性氧衍生物的形成和对这些有毒活性氧衍生物的保护之间的不平衡而导致有毒氧衍生物含量升高的一种状态。氧化应激被发现存在于自闭症儿童中,这些活性氧衍生物会对DNA造成损害,从而改变DNA功能和基因表达的调节。此外,过量的这些有毒的氧衍生物可能会损害大脑中产生神经信使血清素的酶,在大约三分之一的自闭症儿童中,这种酶会减少。测试自闭症儿童的氧化应激及其来源,以及测试血清叶酸受体自身抗体,可以为更有效的治疗开辟新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Background: Biomarkers such as oxidative stress, folate receptor alpha (FRα) autoimmunity, and abnormal brain serotonin turnover are common in autism.

Methods: Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism (n = 38) and controls (n = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N5-methyltetrahydrofolate (MTHF). Statistical analysis assessed correlations between variables. Genetic analysis included the SLC6A4 and SLC29A4 genes encoding synaptic serotonin reuptake proteins.

Results: Compared to controls, the autism group showed a significant increase in oxidative DNA damage in lymphocytes, plasma ceruloplasmin and copper levels with a high copper/zinc ratio, thiol proteins, and superoxide dismutase (SOD) activity. Vitamin C levels were significantly diminished. In most autistic patients, the vitamin A (64%) and D (70%) levels were low. Serum FR autoantibodies fluctuating over 5-7 week periods presented in 68% of all autistic children, 41% of parents vs. 3.3% of control children and their parents. CSF showed lowered serotonin 5-hydroxyindole acetic acid (5HIAA) metabolites in 13 (34%), a low 5HIAA to HVA (dopamine metabolite) ratio in 5 (13%), low 5HIAA and MTHF in 2 (5%), and low MTHF in 8 patients (21%). A known SLC6A4 mutation was identified only in 1 autistic child with low CSF 5HIAA and a novel SLC29A4 mutation was identified in identical twins. Low CSF MTHF levels among only 26% of subjects can be explained by the fluctuating FR antibody titers. Two or more aberrant pro-oxidant and/or antioxidant factors predisposed to low CSF serotonin metabolites. Three autistic children having low CSF 5HIAA and elevated oxidative stress received antioxidative supplements followed by CSF 5HIAA normalisation.

Conclusion: In autism, we found diverse combinations for FR autoimmunity and/or oxidative stress, both amenable to treatment. Parental and postnatal FR autoantibodies tend to block folate passage to the brain affecting folate-dependent pathways restored by folinic acid treatment, while an abnormal redox status tends to induce reduced serotonin turnover, corrected by antioxidant therapy. Trial Registration. The case-controlled study was approved in 2008 by the IRB at Liège University (Belgian Number: B70720083916). Lay Summary. Children with severe infantile autism frequently have serum folate receptor autoantibodies that block the transport of the essential vitamin folate across the blood-brain barrier to the brain. Parents are often asymptomatic carriers of these serum folate receptor autoantibodies, which in mothers can block folate passage across the placenta to their unborn child. This folate deficiency during the child's intrauterine development may predispose to neural tube defects and autism. Oxidative stress represents a condition with the presence of elevated toxic oxygen derivatives attributed to an imbalance between the formation and protection against these toxic reactive oxygen derivatives. Oxidative stress was found to be present in autistic children where these reactive oxygen derivatives can cause damage to DNA, which changes DNA function and regulation of gene expression. In addition, excessive amounts of these toxic oxygen derivatives are likely to damage the enzyme producing the neuromessenger serotonin in the brain, diminished in about 1/3 of the autistic children. Testing children with autism for oxidative stress and its origin, as well as testing for serum folate receptor autoantibodies, could open new approaches towards more effective treatments.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
4
审稿时长
21 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信