TACA-24 线粒体功能障碍和自闭症谱系障碍：一种简化方法

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TACA-24 线粒体功能障碍和自闭症谱系障碍：一种简化方法

Mitochondrial Dysfunction and Autism Spectrum Disorders: A Simplified Approach

作者：Daniel A. Rossignol, MD, FAAFP 和 Richard E. Frye, MD, PhD

原文链接：https://tacanow.org/family-resou ... -spectrum-disorder/

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关于作者

Daniel A. Rossignol, MD, FAAFP
在弗吉尼亚医学院获得医学博士学位，并在弗吉尼亚大学完成了家庭医学住院医师培训。他目前是佛罗里达州墨尔本国际儿童发展资源中心(ICDRC)的医生。来自学术背景，Rossignol医生在他的两个孩子被诊断为自闭症后，搜索医学文献寻找解决方案，他将其使命定为研究和发表自闭症相关文章。在过去的5年中，他发表了16篇关于自闭症的文章和3个书籍章节。

Richard E. Frye, MD, PhD
在乔治城大学获得医学博士/哲学博士学位。他在迈阿密大学完成了儿科住院医师培训，并在波士顿儿童医院完成了儿童神经科住院医师培训和行为神经科与学习障碍 fellowship。Frye医生在普通儿科和神经科（具有儿童神经科特殊能力）获得委员会认证。目前在德克萨斯大学休斯顿健康科学中心，Frye医生研究神经发育障碍中的脑结构和功能、自闭症中的线粒体功能障碍和代谢障碍，以及新型自闭症治疗方法。他发表了许多关于自闭症儿童的论文和书籍章节。

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引言

英文原文：
Recently, evidence has accumulated that some children with autism spectrum disorders (ASDs) have mitochondrial disease (also known as mitochondrial disorders) or mitochondrial dysfunction. Mitochondrial dysfunction generally refers to mitochondria that are impaired in function but not severely impaired enough to fulfill the criteria necessary for the diagnosis of mitochondrial disease. In essence, mitochondrial disease can be thought of as a severe form of mitochondrial dysfunction, and mitochondrial dysfunction can be thought of as a less severe form of mitochondrial disease. If mitochondrial dysfunction can be represented by an engine that is sputtering, mitochondrial disease would be represented by an engine that is constantly in the repair shop.

中文翻译：
最近，证据积累表明一些自闭症谱系障碍(ASD)儿童患有线粒体疾病（也称为线粒体障碍）或线粒体功能障碍。线粒体功能障碍通常指功能受损但未严重到足以满足线粒体疾病诊断标准的线粒体。本质上，线粒体疾病可以被认为是线粒体功能障碍的严重形式，而线粒体功能障碍可以被认为是线粒体疾病的较轻形式。如果线粒体功能障碍可以用一台正在喘息的发动机来表示，那么线粒体疾病就是一台经常在修理店的发动机。

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英文原文：
The evidence for mitochondrial dysfunction in ASD has expanded over the last several years based on multiple published papers on this topic. This article reviews the role of mitochondria in health and disease, the proper functioning of mitochondria, possible causes of mitochondrial dysfunction in ASD, laboratory testing and criteria that can help identify mitochondrial dysfunction, and potential treatments. Before beginning any workup for mitochondrial dysfunction and before performing laboratory testing or starting any treatment (including over-the-counter nutritional supplements), please consult with your or your child's physician.

中文翻译：
基于多篇发表的相关论文，ASD中线粒体功能障碍的证据在过去几年中有所扩展。本文综述了线粒体在健康和疾病中的作用、线粒体的正常功能、ASD中线粒体功能障碍的可能原因、有助于识别线粒体功能障碍的实验室检测和标准，以及潜在的治疗方法。在开始任何线粒体功能障碍的检查之前，在进行实验室检测或开始任何治疗（包括非处方营养补充剂）之前，请咨询您或您孩子的医生。

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线粒体的作用

英文原文：
In the simplest terms, mitochondria are the powerhouses of the cell, generating energy from the breakdown of food. Figure 1 depicts a mitochondrion and shows the pathways involved when mitochondria break down food and use oxygen to create ATP (the energy source for the body, analogous to gasoline for a car).

中文翻译：
用最简单的话来说，线粒体是细胞的发电站，从食物分解中产生能量。图1描绘了一个线粒体，显示了线粒体分解食物并利用氧气产生ATP（身体的能量来源，类似于汽车的汽油）所涉及的途径。

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线粒体结构

英文原文：
As seen in Figure 1, the structure of the mitochondrion consists of outer and inner membranes, with a space (the intermembrane space) in between. The matrix is the innermost part of the mitochondria where many biochemical reactions occur, including the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle. The inner mitochondrial membrane contains five complexes (known as complexes I through V) that make up the electron transport chain.

中文翻译：
如图1所示，线粒体的结构由外膜和内膜组成，中间有一个空间（膜间空间）。基质是线粒体的最内层部分，许多生化反应在这里发生，包括三羧酸(TCA)循环，也称为克雷布斯循环或柠檬酸循环。线粒体内膜包含五个复合物（称为复合物I至V），构成电子传递链。

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能量产生过程

英文原文：
On the bottom of the figure, you can see glucose, which is eventually broken down into pyruvate through the process of glycolysis. Pyruvate is then transported into the mitochondria and eventually is broken down into acetyl-CoA, which enters the TCA cycle. In the case of mitochondrial dysfunction, pyruvate transportation can be slowed, and, therefore, pyruvate can convert into lactate (also known as lactic acid) and alanine, leading to elevations in these markers.

中文翻译：
在图的底部，您可以看到葡萄糖，它最终通过糖酵解过程分解为丙酮酸。丙酮酸然后被转运到线粒体中，最终分解为乙酰辅酶A，进入TCA循环。在线粒体功能障碍的情况下，丙酮酸转运可能减慢，因此丙酮酸可以转化为乳酸（也称为乳酸）和丙氨酸，导致这些标志物升高。

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英文原文：
Fatty acid metabolism is shown on the bottom right-hand corner of the figure. Short chain fatty acids (SCFA) and medium chain fatty acids (MCFA) can diffuse directly into the mitochondria, whereas long chain fatty acids (LCFA) are transported into the mitochondria by attaching to carnitine, which shuttles these fatty acids across the inner and outer mitochondrial membranes. Once inside the mitochondria, the fatty acids, like pyruvate, are broken down and converted into acetyl-CoA, which feeds into the TCA cycle.

中文翻译：
脂肪酸代谢显示在图的右下角。短链脂肪酸(SCFA)和中链脂肪酸(MCFA)可以直接扩散到线粒体中，而长链脂肪酸(LCFA)通过附着在肉碱上被转运到线粒体中，肉碱将这些脂肪酸穿梭通过线粒体内膜和外膜。一旦进入线粒体，脂肪酸像丙酮酸一样被分解并转化为乙酰辅酶A，进入TCA循环。

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电子传递链

英文原文：
The three dotted lines with arrows coming off of the TCA cycle are electrons (negatively charged particles) that are transferred through NADH into complex I. Complex I then transfers these electrons to coenzyme Q10 (CoQ10) which, in turn, transfers the electrons to complex III. When the electrons pass through complex I, NADH is converted to NAD+. Hydrogen protons (positively charged hydrogen particles, H+) are pumped from the matrix through the inner membrane and into the intermembrane space, where they build up and form an electrochemical gradient.

中文翻译：
从TCA循环出来的三条带箭头的虚线是通过NADH转移到复合物I的电子（带负电的粒子）。复合物I然后将这些电子转移给辅酶Q10(CoQ10)，后者又将电子转移给复合物III。当电子通过复合物I时，NADH转化为NAD+。氢质子（带正电的氢粒子，H+）从基质通过内膜被泵入膜间空间，在那里积累并形成电化学梯度。

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英文原文：
The electrons that passed to complex III are now transferred by cytochrome C (Cyt C) to complex IV. This process also pumps more hydrogen protons into the intermembrane space through complexes III and IV. During this process, oxygen is converted into water in complex IV. The hydrogen protons in the intermembrane space then diffuse back into the matrix through complex V (ATP synthase), and this generates ATP through a process known as oxidative phosphorylation.

中文翻译：
传递到复合物III的电子现在被细胞色素C(Cyt C)转移到复合物IV。这个过程也通过复合物III和IV将更多的氢质子泵入膜间空间。在这个过程中，氧气在复合物IV中转化为水。膜间空间中的氢质子然后通过复合物V（ATP合酶）扩散回基质，这通过称为氧化磷酸化的过程产生ATP。

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线粒体功能障碍的标志

英文原文：
If the electron transport chain does not work properly (is "blocked"), metabolites begin to "back up" and elevations can then occur in TCA cycle metabolites, fatty acids, pyruvate, lactate (lactic acid) and alanine. Elevations in these metabolites are laboratory markers of mitochondrial dysfunction. Generally, the higher the elevations and the more metabolites affected, the more likely that mitochondrial dysfunction exists.

中文翻译：
如果电子传递链不能正常工作（被"阻塞"），代谢物开始"回流"，TCA循环代谢物、脂肪酸、丙酮酸、乳酸和丙氨酸可能出现升高。这些代谢物的升高是线粒体功能障碍的实验室标志物。一般来说，升高越多，受影响的代谢物越多，线粒体功能障碍存在的可能性就越大。

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病史和实验室检测

英文原文：
To evaluate possible mitochondrial dysfunction, it is important to examine the patient's clinical history. Sometimes there will be a family history of mitochondrial disease. Other clinical history that is often observed in mitochondrial dysfunction includes developmental regression (loss of previously acquired skills), seizures, fatigue or lethargy, ataxia (lack of coordination of muscle movements), motor delays, gastrointestinal (GI) abnormalities (such as reflux, constipation, dysmotility, diarrhea and inflammation), and cardiomyopathy (significant heart problems). After a clinical history and examination of the patient, laboratory testing can also be helpful (ideally performed in the morning after fasting for 8-10 hours).

中文翻译：
要评估可能的线粒体功能障碍，检查患者的临床病史很重要。有时会有线粒体疾病的家族史。线粒体功能障碍中经常观察到的其他临床病史包括发育倒退（失去以前获得的技能）、癫痫、疲劳或嗜睡、共济失调（肌肉运动协调障碍）、运动发育迟缓、胃肠道(GI)异常（如反流、便秘、运动障碍、腹泻和炎症）和心肌病（严重的心脏问题）。在临床病史和患者检查后，实验室检测也可能有帮助（最好在空腹8-10小时后的早晨进行）。

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推荐实验室检测

英文原文：
The labs include:
• Lactate (lactic acid)
• Pyruvate
• Carnitine (free and total)
• Acylcarnitine panel (fatty acids attached to carnitine)
• Quantitative plasma amino acids
• Ubiquinone (also known as coenzyme Q10)
• Ammonia
• Creatine kinase (CK)
• AST and ALT
• CO2 and glucose

中文翻译：
实验室检查包括：
• 乳酸（lactic acid）
• 丙酮酸
• 肉碱（游离和总量）
• 酰基肉碱面板（附着在肉碱上的脂肪酸）
• 定量血浆氨基酸
• 泛醌（也称为辅酶Q10）
• 氨
• 肌酸激酶(CK)
• AST和ALT
• CO2和葡萄糖

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线粒体障碍的诊断标准（Morava标准）

第一部分：临床体征和症状（本部分最多4分）

类别	症状	分数
(a) 肌肉表现	眼肌麻痹、肌病面容、运动不耐受、肌肉无力、横纹肌溶解、异常EMG	最多2分
(b) 中枢神经系统表现	发育迟缓、技能丧失、中风样发作、偏头痛、癫痫、肌阵挛、皮质盲、脑干受累、锥体束征、锥体外系体征	最多2分
(c) 多系统疾病	血液、内分泌/生长、胃肠道、肾脏、听力、视力、神经病变、复发/家族性	最多3分

第二部分：代谢/影像学检查（本部分最多4分）

检查项目	分数
乳酸升高	2分
乳酸/丙酮酸比值升高	-
丙氨酸升高	2分
脑脊液乳酸升高	2分
脑脊液蛋白升高	-
脑脊液丙氨酸升高	2分
尿三羧酸排泄	2分
乙基丙二酸尿	-
MRI中风样图像	-
MRI Leigh综合征	2分
MRS乳酸升高	-

第三部分：形态学（肌肉活检）（本部分最多4分）

发现	分数
破碎红/蓝纤维	4分
COX阴性纤维	4分
COX染色减少	4分
SDH染色减少	-
SDH阳性血管	2分
电镜下异常线粒体	2分

总分解释：
• 1分：线粒体障碍不太可能
• 2-4分：可能线粒体障碍
• 5-7分：很可能线粒体障碍
• 8-12分：确诊线粒体障碍

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线粒体功能障碍与ASD的关系

英文原文：
Children with ASD are more likely to have deficits in their ability to produce cellular energy than are typically developing children. Cumulative damage and oxidative stress in mitochondria might influence both the onset and severity of autism, suggesting a significant link between autism and mitochondrial problems. Some individuals with mitochondrial disease will have a genetic cause (termed primary mitochondrial disease). However, in our recent systematic review and meta-analysis, most children (79%) who had ASD and mitochondrial disease did not have a genetic reason that could explain their mitochondrial dysfunction. Therefore, the mitochondrial problems reported in these children may have been due to a biochemical abnormality (termed secondary mitochondrial disease).

中文翻译：
与典型发育的儿童相比，ASD儿童更可能存在产生细胞能量的能力缺陷。线粒体的累积损伤和氧化应激可能影响自闭症的发病和严重程度，表明自闭症与线粒体问题之间存在显著联系。一些线粒体疾病患者会有遗传原因（称为原发性线粒体疾病）。然而，在我们最近的系统综述和荟萃分析中，大多数（79%）患有ASD和线粒体疾病的儿童没有可以解释其线粒体功能障碍的遗传原因。因此，这些儿童报告的线粒体问题可能是由于生化异常（称为继发性线粒体疾病）。

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继发性线粒体功能障碍与ASD

英文原文：
Several studies have documented a significantly lower mean glutathione (GSH) concentration and a lower mitochondrial GSH reserve in children with ASD compared to controls. GSH is the major antioxidant in humans, and GSH depletion is associated with impaired mitochondrial function as well as increased free radical production. An example of a free radical is an oxygen molecule that has an unpaired electron (this free radical is called a "reactive oxygen species"), which can then remove an electron from enzymes and DNA/RNA and cause damage. This damage is termed oxidative stress. Antioxidants can donate an electron to the free radical to allow all of its electrons to be paired, which quenches the free radical and prevents oxidative stress.

中文翻译：
几项研究记录了与对照相比，ASD儿童的平均谷胱甘肽(GSH)浓度显著降低，线粒体GSH储备也较低。GSH是人类的主要抗氧化剂，GSH耗竭与线粒体功能受损以及自由基产生增加有关。自由基的一个例子是一个氧分子有一个未配对的电子（这种自由基被称为"活性氧物种"），然后它可以从酶和DNA/RNA中夺取一个电子并造成损害。这种损害称为氧化应激。抗氧化剂可以向自由基捐赠一个电子，使其所有电子配对，从而熄灭自由基并防止氧化应激。

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环境毒素与线粒体功能障碍

英文原文：
These findings suggest that mitochondria from children with ASD may be more vulnerable to damage from environmental toxicants than mitochondria from typically developing children. In this context, exposures to environmental toxicants could contribute to secondary mitochondrial dysfunction in some children with ASD. For example, in vitro exposure to diesel exhaust particles (DEP) has been shown to inhibit mitochondrial function, and elevated environmental concentrations of DEP have been associated with ASD. Other environmental toxicants that inhibit mitochondrial function and have been associated with ASD include mercury, lead, cadmium, PCBs, and pesticides.

中文翻译：
这些发现表明，与典型发育的儿童相比，ASD儿童的线粒体可能更容易受到环境毒素的损害。在这种情况下，暴露于环境毒素可能导致一些ASD儿童的继发性线粒体功能障碍。例如，体外暴露于柴油排气颗粒(DEP)已被证明会抑制线粒体功能，而DEP的环境浓度升高与ASD有关。其他抑制线粒体功能且与ASD有关的环境毒素包括汞、铅、镉、多氯联苯(PCBs)和农药。

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梭菌与线粒体功能障碍

英文原文：
Finally, Clostridia, an anaerobic, spore-forming Gram-positive rod bacterium, is known to produce propionic acid, and a derivative of propionic acid recovered in the urine of ASD individuals has been reported as a marker of Clostridia. A recent rat model of ASD demonstrated that the administration of propionic acid induced mitochondrial dysfunction and led to certain behavioral and biochemical features of ASD such as repetitive behaviors, social interaction problems, hyperactivity, oxidative stress, lowered GSH levels and altered carnitine levels. Furthermore, significantly elevated concentrations of Clostridia in the GI tract have been reported in some ASD children compared to controls, with improvements noted with vancomycin treatment in some children. Therefore, Clostridia may be a contributor to mitochondrial dysfunction in some children with ASD.

中文翻译：
最后，梭菌是一种厌氧、产孢子的革兰氏阳性杆菌，已知产生丙酸，在ASD个体尿液中回收的丙酸衍生物已被报告为梭菌的标志物。最近的一个ASD大鼠模型表明，给予丙酸会诱导线粒体功能障碍，并导致ASD的某些行为和生化特征，如重复行为、社交互动问题、多动、氧化应激、GSH水平降低和肉碱水平改变。此外，与对照相比，一些ASD儿童胃肠道中梭菌浓度显著升高，一些儿童在万古霉素治疗后有改善。因此，梭菌可能是一些ASD儿童线粒体功能障碍的原因之一。

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线粒体功能障碍的治疗

英文原文：
Several studies have reported that nutritional supplements and/or antioxidants may be beneficial in some children with ASD who have mitochondrial dysfunction. Six studies have reported various improvements (including language and coordination) with the use of carnitine in children with ASD and mitochondrial disease. Recently, another study reported improvements in children with ASD using carnitine compared to placebo, although it was not reported if the children had concomitant mitochondrial dysfunction. Along with carnitine, some investigators report clinical improvements with coenzyme Q10 and high doses of B vitamins, including thiamine or riboflavin.

中文翻译：
几项研究报告称，营养补充剂和/或抗氧化剂可能对一些有线粒体功能障碍的ASD儿童有益。六项研究报告了在ASD和线粒体疾病儿童中使用肉碱的各种改善（包括语言和协调）。最近，另一项研究报告了与安慰剂相比，使用肉碱的ASD儿童有改善，尽管没有报告这些儿童是否同时患有线粒体功能障碍。除肉碱外，一些研究者报告辅酶Q10和高剂量B族维生素（包括硫胺素或核黄素）有临床改善。

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脑叶酸缺乏症

英文原文：
Cerebral folate deficiency (CFD) has been described in one child with ASD and mitochondrial disease. In some studies, treatment with folinic acid and a milk-free diet has been reported to result in significant improvements in ASD symptoms in children with CFD.

中文翻译：
脑叶酸缺乏症(CFD)在一例ASD和线粒体疾病儿童中被描述。在一些研究中，使用亚叶酸和无奶饮食治疗已被报告能显著改善CFD儿童的ASD症状。

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治疗注意事项

英文原文：
Treatment of mitochondrial dysfunction also consists of specific precautions to avoid prolonged fasting, implement dietary recommendations (ensuring an adequate number of calories), avoid certain medications, adopt anesthesia precautions for surgery, and avoid infections (if possible). Additional treatment recommendations pertain to antipyretic (fever) therapy, intravenous hydration, and nutritional supplements during acute illnesses. Furthermore, because hypoxia can impair mitochondrial function, increasing oxygen delivery to dysfunctional mitochondria through hyperbaric oxygen therapy (HBOT) might aid in improving mitochondrial function.

中文翻译：
线粒体功能障碍的治疗还包括特定的预防措施：避免长时间禁食、实施饮食建议（确保足够的热量）、避免某些药物、采用手术麻醉预防措施、避免感染（如果可能）。其他治疗建议涉及退热治疗、静脉补液和急性疾病期间的营养补充。此外，由于缺氧可能损害线粒体功能，通过高压氧治疗(HBOT)增加对功能失调线粒体的氧气输送可能有助于改善线粒体功能。

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高压氧治疗(HBOT)

英文原文：
In one animal study, HBOT was reported to activate mitochondrial DNA transcription and replication, and increase the biogenesis of mitochondria in the brains of animals. Clinically, some patients treated by Dr. Rossignol who have ASD and mitochondrial disease have improved with the use of HBOT provided at low atmospheric pressure (1.3 to 1.5 atmospheres), including one child whose improvements in mitochondrial function were documented by repeat muscle biopsy. However, increasing oxygen delivery to mitochondria can increase oxidative stress; the HBOT pressure should therefore be carefully monitored under the guidance of an experienced physician, and generally low levels of pressure (1.3 to 1.5 atmospheres) and lower oxygen concentrations (~24%) should be used initially.

中文翻译：
在一项动物研究中，HBOT被报告能激活线粒体DNA转录和复制，并增加动物大脑中线粒体的生物发生。在临床上，一些由Rossignol医生治疗的ASD和线粒体疾病患者在使用低大气压（1.3至1.5个大气压）的HBOT后有所改善，包括一名儿童的线粒体功能改善通过重复肌肉活检记录证实。然而，增加线粒体的氧气输送可能增加氧化应激；因此，HBOT压力应在有经验的医生指导下仔细监测，通常应首先使用低压力水平（1.3至1.5个大气压）和较低的氧浓度（约24%）。

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未来展望

英文原文：
There is much still to be learned regarding the biology of mitochondrial disease and ASD. Evidence has rapidly accumulated that clearly supports an association between these two seemingly different disorders. Although some children with ASD have a genetic cause for mitochondrial dysfunction, many will have a secondary cause. It appears that at least a subpopulation of children with ASD has mitochondrial disease as the core biological lesion contributing to their ASD and associated comorbidities. Further studies in the field of mitochondrial medicine may one day help unlock the mysteries that define ASD.

中文翻译：
关于线粒体疾病和ASD的生物学还有很多需要了解。证据迅速积累，明确支持这两种看似不同的疾病之间的关联。虽然一些ASD儿童的线粒体功能障碍有遗传原因，但许多将有继发原因。似乎至少有一部分ASD儿童以线粒体疾病为核心生物病变，导致他们的ASD和相关共病。线粒体医学领域的进一步研究可能有一天有助于解开定义ASD的谜团。

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参考文献

1. Poling JS, Frye RE, Shoffner J, Zimmerman AW. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006;21(2):170-2.

2. Haas RH. Autism and mitochondrial disease. Dev Disabil Res Rev. 2010;16(2):144-53.

3. Frye RE, Rossignol DA. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res. 2011 May;69(5 Pt 2):41R-7R.

4. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2011 Jan 25.

5. Rossignol DA, Bradstreet JJ. Evidence of mitochondrial dysfunction in autism and implications for treatment. Am J Biochem Biotech. 2008;4(2):208-17.

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转载自 Autism Science Digest: The Journal of AutismOne