中链酰基辅酶A脱氢酶缺乏症1例肝脏病理分析及基因检测

目的探讨中链酰基辅酶A脱氢酶缺乏症(MCADD)的诊断和治疗。方法回顾性分析1例MCADD患儿的临床表现、实验室检查以及基因检测结果,并复习相关文献。结果 3岁男性患儿,有一过性低血糖、高氨血症、肝功能损伤;血串联质谱分析提示辛酰肉碱、多种酰基肉碱增高,尿气相色谱质谱分析正常;基因检查示酰基辅酶A脱氢酶基因(acyl-Coenzyme A dehydrogenase,ACADM)c.572GA p.(Trp191*)纯合突变;肝脏病理提示肝细胞轻度损害,炎症程度2级,纤维化程度1级。给予高碳水化合物、高蛋白、低脂肪饮食,积极护肝、降酶、补充肉碱等治疗后患儿肝功能恢复正常。结论血串联质谱分析及基因检测可确诊MCADD,确诊后应积极补充高能量营养物质、肉碱,以预防疾病发作和病情进展。     

极长链酰基辅酶A脱氢酶缺乏症研究进展

极长链酰基辅酶A脱氢酶缺乏症是一种较罕见的脂肪酸代谢障碍疾病,根据起病年龄和临床表现分为三型：心肌病型、肝型、肌病型。心肌病型病情重,病死率高。临床诊断可通过血串联质谱(MS/MS)检测血肉豆蔻烯酰基肉碱(C14:1)水平进行,进一步确诊可通过基因诊断、酶学分析及脂肪酸氧化流量分析。治疗上主要包括避免空腹,减少长链脂肪酸的摄入,补充中链甘油三酯等。     

上呼吸道感染患儿口服尼美舒利后发生瑞氏综合征及猝死样症状

患儿，男，6岁3个月，2个月前因上呼吸道感染、发热，父母参照说明书予以尼美舒利口服，半小时后抽搐，呼吸心跳骤停，急诊检查发现低酮性低血糖，代谢性酸中毒，血清转氨酶及肌酶显著升高，肾功能受损。经积极复苏治疗后患儿意识及生命体征恢复，但是智力、运动严重倒退。患儿血液游离肉碱降低，中长链酯酰肉碱增高，尿液戊二酸、3-羟基戊二酸、异戊酰甘氨酸、乙基丙二酸等增高，提示多种酯酰辅酶A脱氢酶缺乏症。经维生素B₂、左卡尼汀、苯扎贝特等治疗后患儿病情逐渐好转，3个月后复查生化指标恢复正常。患儿ETFDH基因存在复合杂合突变，c.341G > A（p.R114H）为已知突变（来自母亲），c.1484C > G（p.P495R）为未报道的新突变（来自父亲）。患儿最终确诊为多种酰基辅酶A脱氢酶缺乏症，因发热服用尼美舒利诱发急性代谢危象，导致瑞氏综合征、猝死样发作。遗传代谢病是导致瑞氏综合征、猝死的一组主要病因，生化及基因分析是识别潜在疾病的关键。     

多种酰基辅酶A脱氢酶缺乏症遗传学研究进展

<正>多种酰基辅酶A脱氢酶缺乏症(multiple acyl-CoA dehydrogenasedeficiency,MADD)是由于线粒体氧化呼吸链脱氢产生的电子传递障碍导致脂肪酸、氨基酸及胆碱代谢障碍的一组临床异质性遗传病^[1]。可通过串联质谱分析血酰基肉碱水平对MADD进行新生儿筛查,不同国家和地区新生儿发病率差异较大,美国发病率为1/378 272,德国发病率为1/195 000,     

中链酰基辅酶A脱氢酶缺乏症新生儿筛查及随访研究

目的 探讨中链酰基辅酶A脱氢酶缺乏症（MCADD）中国人群流行病学特征、表型、基因型及预后。方法 回顾性分析2009年1月至2018年6月期间经高效液相色谱串联质谱（HPLC-MS/MS）筛查并结合基因检测诊断为MCADD的新生儿资料。结果 2 674 835例接受筛查的新生儿中诊断MCADD的12例（1/222 902）。其中10例接受基因检测,发现ACADM基因16个突变位点的13种突变类型：7种为已报道突变（p.T150Rfs^*4、p.M1V、p.R206C、p.R294T、p.G310R、p.M328V、p.G362E）;5种新突变（p.N194D、p.A324P、p.N366S、c.118+3A > G、c.387+1del G）和1例11号外显子缺失,以p.T150Rfs^*4最常见（4/16）。ACADM基因突变位点检出率80%。未见表型-基因型相关性。确诊后给予饮食指导及对症治疗,随访4~82个月期间未见急性代谢失衡发作,除1例合并脑发育不良外均预后良好。结论 MCADD在中国南方人群相对罕见;p.T150Rfs^*4为中国人群热点突变;筛查阳性的病例建议联合辛酰基肉碱检测及基因判断。     

中链酰基辅酶A脱氢酶缺乏症研究进展

中链酰基辅酶A脱氢酶缺乏症(MCADD)是脂肪酸氧化缺陷病中最常见的一种，其发病率与苯丙酮尿症相当，临床表现主要为低酮性低血糖、呕吐和肌无力。串联质谱方法能检测出无症状的MCADD新生儿血浆中升高的酰基肉碱，兼有敏感度高、特异性高、自动化程度高、高通量等特点。约24％病人第一次发作即导致死亡，32％存活者有心理行为问题或神经功能障碍。若经新生儿疾病筛查得到诊断，现有的预防和治疗效果均较满意。MCADD符合新生儿筛查病种入选标准，部分发达国家已将此病列入新生儿疾病常规筛查项目。     

多种酰基辅酶A脱氢酶缺乏症的诊治进展

多种酰基辅酶A脱氢酶缺乏症是一种较为常见的脂肪酸代谢紊乱,临床表现高度异质,常有呕吐、酸中毒以及脂质沉积性肌病表现,根据血多种酰基肉碱升高及尿中戊二酸等有机酸升高可明确诊断.新生儿发作型临床表现重,预后较差;核黄素治疗反应性患者给予核黄素治疗可完全纠正其临床症状及生化紊乱;核黄素无反应者应同时给予低脂、低蛋白、高碳水化合物饮食,并预防急性代谢紊乱的发作.     

多种酰基辅酶A脱氢酶缺乏症儿童与成人患者临床特点比较

目的比较儿童和成人多种酰基辅酶A脱氢酶缺乏症(MADD)患者的临床和实验室检查特点。方法对12例儿童和19例成人MADD患者进行常规实验室检查、血酰基肉碱谱及尿有机酸分析。对中国人电子转运黄素蛋白脱氢酶(ETFDH)基因常见突变A84T通过DNA测序方法进行筛检。结果儿童MADD患者临床表现高度异质,可表现为肌无力、肝大、低酮性低血糖、肥厚性心肌病或脑发育不良及脱髓鞘病变;而成人患者均以肌无力起病。成人和儿童MADD有肝酶和CK升高,血多种酰基肉碱升高,多数伴有二羧酸尿。儿童组3例死亡,成人组全部存活。存活患者的症状和生化指标治疗后好转或正常。A84T突变在儿童和成人患者的发生率分别为20.8%(5/24)和21%(8/38)。结论儿童与成人MADD患者的临床表现和预后存在差异,成人患者预后好;A84T突变可能与轻型相关。[临床儿科杂志,2012,30(5):446-449]     

新生儿全血细胞减少伴代谢异常

患儿,男,9d,急性起病,表现为咳嗽、气促、喂养困难、嗜睡、昏迷。辅助检查提示肺部感染、严重代谢性酸中毒、高血糖、高血氨、血象三系减少。为查明病因,进行了血液酯酰肉碱谱及尿液有机酸分析及基因诊断。结果发现：血异戊酰肉碱及尿异戊酰甘氨酸和3-羟基异戊酸显著升高,游离肉碱降低,提示异戊酸血症 （IVA）;基因检测提示第12号外显子纯合突变c.1208A > G （p.Tyr403Cys）,父母为杂合突变携带者。经低亮氨酸饮食、左卡尼汀等治疗后症状稍改善,但1周后患儿死亡。新生儿肺炎是新生儿常见感染,但可能是遗传代谢病患儿的诱发因素,因此对于肺炎起病的伴有难以解释的代谢异常患儿,应进行遗传代谢性疾病筛查。     

极长链酰基辅酶A脱氢酶缺乏症一例并文献复习

目的探讨中国人群极长链酰基辅酶A脱氢酶缺乏症(VLCADD)的临床特点及基因突变位点情况。方法回顾性分析郑州大学第三附属医院诊治的1例VLCADD患儿的临床诊治经过及基因位点;以"极长链酰基辅酶A脱氢酶缺乏症"为检索词, 检索万方数据库及中国知网数据库, 以"very long chain acyl-coenzyme A dehydrogenase deficiency"和"China"或"Chinese"为检索词, 检索PubMed数据库, 检索以中国人群为研究对象的相关文献, 总结分析VLCADD患者的临床特点, 探讨基因型与表型之间的关系, 以及新生儿筛查对于VLCADD患者预后的影响。结果根据患儿低血糖、肝脏肿大、肝酶升高、血串联质谱C14:1明显升高, 考虑VLCADD, 给予口服左卡尼汀及富含中链脂肪酸配方奶喂养, 患儿病情好转出院, 随访3年10个月, 生长发育正常, 监测血生化指标基本正常。基因检测发现ACADVL基因复合杂合突变, c.692-2₆92-1delAG (splicing)/c.1276G>A (p.A426T)。通过文献检索...     

Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Delayed diagnosis of fatal medium-chain acyl-CoA dehydrogenase deficiency in a child

A 5-year-old white female presented with coma and died unexpectedly. She had a history of recurrent episodes of febrile illnesses associated with lethargy and coma. Postmortem investigation revealed a fatty liver, leading to a suspicion of inborn error of fatty acid oxidation. The diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was suggested by abnormal acylcarnitine profile with increased octanoylcarnitine in the blood, and confirmed by fatty acid oxidation studies and mutation analysis in skin fibroblast cultures. This case emphasizes the need to consider fatty acid oxidation disorders in all children who present with hypoglycemia with absent or mild ketones in the urine and high anion gap metabolic acidosis.     

新生儿期至青春期血中肉碱和酰基肉碱的变化

目的 用串联质谱测定不同年龄儿童血中游离肉碱和各种酰基肉碱浓度,为诊断肉碱缺乏和各种有机酸和脂肪酸代谢病奠定基础.方法 研究对象是围产期新生儿1376例,大于1周的新生儿49例,小于1岁的婴幼儿64例,1～15岁儿童401例.围产期新生儿是无选择的产院出生儿,包括了少量早产儿和低出生体重儿.其余主要是排除了发热、腹泻、肝病、严重疾病等影响脂肪代谢的门诊小手术的体检儿童.用非衍生法前处理滤纸血片,串联质谱测定其中游离肉碱和30种酰基肉碱浓度.结果 游离肉碱(C0)、短链酰基肉碱(C2、C3、C4、C5)、中链酰基肉碱(C6、C8、C 10)及其烯酰基、羟基、二酰基肉碱和总肉碱水平新生儿阶段较低,1～3个月时最高,之后降低,2～15岁在相同水平维持.长链酰基肉碱(C12、C14、C16、C18)及其烯酰基肉碱、羟基酰基肉碱及其总和新生儿阶段最高,逐渐降低,2～15岁在相同水平维持.游离肉碱浓度(23.387±7.702)μmol/L,(30.064±8.252)μmol/L,(25.021±6.630)μmol/L,总长链酰基肉碱浓度(4.998±1.557)μmol/L,(2.854±0.821)μmol/L,(2.459±0.553)μmol/L,肉碱酰基肉碱总浓度(43.497±12.632)μmol/L,(49.013±12.497)μmol/L,(39.656±9.257)μmol/L在新生儿组、小于1岁组和大于1岁组差异有统计学意义(P＜0.01).围产期新生儿男婴组肉碱(24.115±7.715)μmol/L和肉碱和酰基肉碱总和(43.65±5.252)μmol/L分别高于女婴(22.696±7.246)μmol/L和(41.90±5.038)μmol/L(P＜0.05).新生儿组游离肉碱占总肉碱比值(54.0%±7.1%)明显小于非新生儿组(62.1%±6.1%,P＜0.05),而长链(33.5%±6.0%)、中链(1.3%±0.3%)和短链脂酰基肉碱(11.6%±2.5%)与总肉碱比值分别高于非新生儿组(30.1%±4.9%;0.9%±0.6%;6.5%±2.3%,P＜0.05).结论 1岁以内血中肉碱和酰基肉碱水平和构成变化较大,在评价肉碱营养状态和诊断有机酸和脂肪酸代谢病时要考虑年龄因素.围产期新生儿男婴肉碱和酰基肉碱略高于女婴.     

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??Multiple acyl-CoA dehydrogenase deficiency??also known as glutaric aciduria type??is an autosomal recessive inherited metabolic disease. It is a mitochondrial electron transport chain and fatty acid metabolism disorder caused by a defect of electron transfer flavoprotein??ETF?? or ETF dehydrogenase??ETFDH????resulting in the damage to multiple organs such as myocardia??liver??brain and skeletal muscle. The clinical diagnosis of multiple acyl-CoA dehydrogenase deficiency is difficult due to the lack of specific symptoms and signs of the patients. To make a definitive diagnosis??blood aminoacids and acylcarnitine profiles??urinary organic acids profiles and gene analysis are necessary. According to the response to riboflavin??or vitamin B2????multiple acyl-CoA dehydrogenase deficiency could be divided into riboflavin-responsive form and riboflavin-unresponsive form. The riboflavin-responsive form is usually observed in the late-onset cases with good outcome. The patients of riboflavin-unresponsive form usually have early-onset with severe diseases. Bezafibrate, L-carnitine??coenzyme Q10??sodium-D??L-3-hydroxybutyrate and low-fat die should be considered for the treatment. Some patients with riboflavin-unresponsive form show poor outcome.     

Influence of valproic acid on the expression of various acyl-CoA dehydrogenases in rats

BACKGROUND: Valproic acid (2-propyl-N-pentanoic acid, VPA) causes severe hepatic dysfunction, similar to Reye's syndrome, in a small number of patients. An enhanced excretion of dicarboxylic acids by patients indicates an interference with mitochondrial beta-oxidation. We investigated the expression of various acyl-coenzyme A (acyl-CoA) dehydrogenases (ACD), which catalyze the first step of beta-oxidation in VPA-treated rats. METHODS: The control group received normal saline and the experimental group received VPA (500 mg/kg per day) by intraperitoneal injections for 7 days. Various clinical chemistry parameters in rat blood and free and total carnitine levels in plasma and tissue were determined. Mitochondria were isolated from rat liver and heart and the relative amount of each ACD protein was determined by immunoblot analysis. Total RNA was prepared from various tissues and the mRNA levels for various ACD were measured by slot-blot hybridization analysis using respective cDNA probes. RESULTS: Administration of VPA to rats caused various metabolic effects including hypoglycemia, hyperammonemia and decreased beta-hydroxybutyrate concentration. Free carnitine levels in plasma and heart were also decreased. Enzyme activities of various acyl-CoA dehydrogenases, which are involved in fatty acid oxidation, decreased moderately in heart (57-79%), and slightly in liver (78-95%). The most prominent effects were observed in mRNA levels involved in fatty acid oxidation (short-, medium- and long-chain acyl-CoA dehydrogenase). Each mRNA increased in the liver, kidney, skeletal muscle and heart to varying degrees when rats were fed ad libitum. The increase of short- and medium- chain acyl-CoA dehydrogenase mRNA in the heart were particularly large. However, 3 day starvation strongly inhibited expression of ACD in VPA-treated rats. There was an apparent decrease in the amount of ACD mRNA and proteins in VPA-treated liver. CONCLUSIONS: Valproic acid causes enhanced expression of fatty ACD mRNA, especially in the heart, by a feedback mechanism related to inhibition of beta-oxidation in rats fed ad libitum. However, it impairs the expression of ACD in the liver when there is a drastic change in nutritional state.     

Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood

A child presented in early childhood with episodes of coma and hypoglycemia and a rapidly evolutive myopathy and cardiomyopathy leading to death at 9 mo of age. Ketosis was decreased (blood beta-hydroxybutyrate: 0.07 mmol/L) despite normal plasma levels of fatty acids (0.81 mmol/L). The patient's urine contained excessive amounts of the C6 to C10 dicarboxylic acids present in almost all defects of fatty acid mitochondrial oxidation. More specifically, gas chromatography-mass spectrometry identified an accumulation of medium- and long-chain (C8 to C14) 3-hydroxy-dicarboxylic acids, suggesting a defect of the mitochondrial enzyme that normally dehydrogenates these 3-hydroxyacyl-CoA esters. Biochemical studies in the patient's cultured fibroblasts confirmed the impairment of medium- and long-chain fatty acid oxidation, and allowed the recognition of the deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. The activities of long-, medium-, and short-chain acyl-CoA dehydrogenases and 3-ketoacyl-CoA thiolase were normal. These results describe a disorder of fatty acid metabolism that affects the liver, skeletal muscles, and myocardium. It is important to point out that long-chain 3-hydroxyacyl-CoA deficiency shares many clinical similarities with systemic carnitine deficiency, as well as with carnitine-palmityl-CoA transferase and long-chain acyl-CoA dehydrogenase deficiencies. The differential diagnosis of this disease relies on the demonstration of long-chain urinary dicarboxylic acids with a hydroxyl group in 3-position and the study of the enzyme activity in cultured fibroblasts.     

多种酰基辅酶A脱氢酶缺乏症的诊疗进展

多种酰基辅酶A脱氢酶缺乏症又称戊二酸尿症2型,是一种常染色体隐性遗传代谢病。由于编码线粒体电子转运黄素蛋白或电子转运黄素蛋白脱氢酶的基因缺陷导致线粒体电子传递链和脂肪酸代谢障碍,引起心肌、肝脏、脑、骨骼肌等多器官损伤。多种酰基辅酶A脱氢酶缺乏症患者缺乏特异性症状与体征,临床诊断困难,需要通过血液氨基酸肉碱谱、尿有机酸谱及基因分析明确诊断。根据患者对核黄素（或维生素B2）的反应,分为核黄素反应型与无反应型。核黄素反应型常为晚发型,治疗以核黄素为主,疗效良好。核黄素无反应型发病早,病情危重,治疗以苯扎贝特、左卡尼汀、辅酶Q10、3-羟基丁酸钠及低脂饮食等为主,一些患者预后不良。     

Medium-Chain Acyl-Coa Dehydrogenase Deficiency: Postmortem Diagnosis in a Case of Sudden Infant Death and Neonatal Diagnosis of an Affected Sibling

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an inherited disorder of fatty acid oxidation associated with sudden death in infants and, in its fulminant form(s), a Reye-like syndrome. In an 18-month-old female who died suddenly and unexpectedly, the postmortem diagnosis of MCAD deficiency was made by analysis of organic acids, acylglycines, and acylcarnitines and by analysis of the most common mutation causing MCAD deficiency (A985G) in a sample of heart blood obtained at autopsy and frozen at—20° C for 8 months. The patient was homozygous for A985G and metabolites characteristic of MCAD deficiency were identified. Parents and an older sibling were heterozygous for A985G. The mother was 6 months pregnant when the results were known. At the birth of her male infant, blood spot cards and urine were obtained. The infant was homozygous for A985G by analysis of DNA extracted from blood spots and he excreted metabolites characteristic of MCAD deficiency. These results demonstrate the use of novel molecular and metabolite analysis in making the postmortem diagnosis of MCAD deficiency. The neonatal diagnosis of an affected sib permits the institution of appropriate dietary measures to prevent potentially fatal episodes of illness.     

Mild or absent clinical signs in twin sisters with short-chain acyl-CoA dehydrogenase deficiency

Two HLA-identical twin sisters are reported, of whom one has remained essentially asymptomatic, and an episode of hypotonia and decreased level of conciousness being the only relevant clinical finding in the other. Organic acid analysis revealed that ethylmalonate was constantly, although sometimes only slightly, increased. No abnormal acylglycines or acylcarnitines could be detected. Enzyme assay in cultured skin fibroblasts confirmed short-chain acyl-CoA dehydrogenase deficiency. Conclusion The lack of appropriate biochemical markers for this deficiency makes the diagnosis difficult and consequently, the low number of patients described may be the result of underdiagnosis. Received: 11 June 1997 and in revised form 4 November 1997 / Accepted: 10 November 1997