葡萄糖-6-磷酸脱氢酶缺乏症研究现状

葡萄糖-6-磷酸脱氢酶（ glucose-6-phosphate dehydrogenase,G6PD）是磷酸戊糖途径的主要调节酶,对维持细胞内能量代谢和氧化还原反应的平衡起着重要作用。 G6PD缺乏症是最常见的遗传性红细胞酶缺陷病。目前尚无有效治疗方法,防治重点是尽早明确诊断,避免接触易导致发病的敏感性因素。目前应用于临床诊断的方法主要是G6PD酶活性的检测,该方法对女性杂合子检出率低。国内外研究表明, G6PD杂合子是新生儿高胆红素血症的危险因素。临床迫切需要可以同时检出G6PD缺乏症不同基因型的诊断方法。该文就G6PD缺乏症的研究现状作一综述。     

浙江地区新生儿葡萄糖-6-磷酸脱氢酶缺乏症的遗传学分析

目的　分析浙江地区新生儿葡萄糖-6-磷酸脱氢酶（glucose-6-phosphate dehydrogenase，G6PD）缺乏症的基因突变特点，探讨其遗传多样性。方法　以2015年3月至2017年9月在浙江地区出生、经浙江省新生儿遗传代谢筛查中心G6PD缺乏症筛查发现的2242例患儿为对象，收集其新生儿筛查的G6PD活性值与剩余干滤纸血斑，并提取其血斑的基因组DNA。采用MassARRAY技术检测35个G6PD突变位点。采用SPSS 22.0软件统计分析基因型与G6PD活性的关系，P＜0.05为差异有统计学意义。结果　2163例检出突变，总检出率为96.47%，其中男性为96.51%（1995/2067），女性为96%（168/175）。共检出21种突变位点，44种变异基因型，其中男性半合子19型，女性杂合子14型，女性纯合子3型，女性复合杂合8型。95.93%的G6PD突变位于12、9、2、5外显子，其中c.1376G＞T、c.1388G＞A、c.1024C＞T、c.95A＞G、c.871G＞A、c.392G＞T占92.96%。c.1376G＞T、c.1388G＞A、c.1024C＞T、c.95A＞G四种基因型的G6PD活性差异有统计学意义（P＜0.0001）。结论　浙江地区G6PD缺乏症存在基因突变热点，c.1024 C＞T的突变频率具有明显地域特征，MassARRAY技术检测特定G6PD突变位点可推荐为G6PD缺乏症的二级筛查方法之一。     

浙江地区新生儿葡萄糖-6-磷酸脱氢酶缺乏症的遗传学分析

目的　分析浙江地区新生儿葡萄糖-6-磷酸脱氢酶（glucose-6-phosphate dehydrogenase,G6PD）缺乏症的基因突变特点,探讨其遗传多样性。方法　以2015年3月至2017年9月在浙江地区出生、经浙江省新生儿遗传代谢筛查中心G6PD缺乏症筛查发现的2242例患儿为对象,收集其新生儿筛查的G6PD活性值与剩余干滤纸血斑,并提取其血斑的基因组DNA。采用MassARRAY技术检测35个G6PD突变位点。采用SPSS 22.0软件统计分析基因型与G6PD活性的关系,P＜0.05为差异有统计学意义。结果　2163例检出突变,总检出率为96.47%,其中男性为96.51%（1995/2067）,女性为96%（168/175）。共检出21种突变位点,44种变异基因型,其中男性半合子19型,女性杂合子14型,女性纯合子3型,女性复合杂合8型。95.93%的G6PD突变位于12、9、2、5外显子,其中c.1376G＞T、c.1388G＞A、c.1024C＞T、c.95A＞G、c.871G＞A、c.392G＞T占92.96%。c.1376G＞T、c.1388G＞A、c.1024C＞T、c.95A＞G四种基因型的G6PD活性差异有统计学意义（P＜0.0001）。结论　浙江地区G6PD缺乏症存在基因突变热点,c.1024 C＞T的突变频率具有明显地域特征,MassARRAY技术检测特定G6PD突变位点可推荐为G6PD缺乏症的二级筛查方法之一。     

广西崇左市葡萄糖-6-磷酸脱氢酶缺乏症基因突变型研究

目的 研究广西崇左市葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症的发生率及基因突变类型.方法 对广西崇左市510例病例采用四氮唑蓝定量法筛查G6PD活性.对诊断为G6PD缺乏的病例采用PCR/限制性内切酶消化试验检测出G1376T、G1388A、A95G、G871A和C1024T 5种常见G6PD基因突变类型,用DNA直接测序法检测未确定突变类型的标本.结果 在广西崇左市510名居民中筛查出52例G6PD缺乏症,其缺乏率为10.20％.在52例G6PD缺乏症标本中,检出G1376T突变14例、G1388A突变12例、A95G突变13例、G871A突变6例、C1024T突变1例,C1360T突变1例、C519T突变l例,未定型4例.结论 G6PD缺乏症在广西崇左市的发病率为10.20％.G1388A、G1376T、A95G也是广西崇左市G6PD缺乏症最常见的基因突变.发现G6PDUnion 1例,很可能属于零星分布.     

广西地区葡萄糖-6-磷酸脱氢酶缺乏症与病毒性肝炎的关系

目的了解病毒性肝炎并葡萄糖-6磷-酸脱氢酶(G6PD)缺乏症患儿的基因突变类型,探讨G6PD缺乏基因突变与病毒性肝炎的关系。方法采用自然或错配引物介导的聚合酶链反应(PCR)限/制性内切酶分析,对病毒性肝炎并G6PD缺乏症18例患儿进行G6PD基因3种常见突变类型的分析,并对其临床表现进行分析。结果18例检测出8例G1388A突变,4例G1376T突变,1例A95G突变,突变率为72.22%,与单纯的G6PD缺乏症的基因突变型比较无显著差异。肝炎并G6PD缺乏症患儿急性溶血及急性肾衰竭的发生较单纯肝炎明显增加。结论肝炎患儿G6PD缺乏可能是原发性改变,而肝炎并G6PD缺乏症患儿较单纯肝炎病情重、并发症多。     

贵州省17例葡萄糖-6-磷酸脱氢酶缺乏症患者临床特征和致病基因突变分析

目的 探讨中国贵州省17例葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症患者的临床特征及分子遗传特征.方法 分析患者的临床特征,收集患者及其部分母亲外周血,提取基因组DNA,针对C6PD基因所有编码外显子及外显子和内含子交界处进行PCR扩增测序.结果 患者的临床表型多样,如表现为蚕豆病、药物性溶血、新生儿高胆红素血症、感染性溶血及慢性非球形红细胞性溶血性贫血等.3例患者有伴发病,分别为α地中海贫血、急性髓系白血病M2型、新生儿肛门膜状狭窄.基因分析显示G1376T、G1388A及A95G是最常见的3种G6PD基因突变类型.G1376T、G1388A及A95G占总突变的发生率为82.4％.2例患者仅有c.1311C＞T,IVS11 nt93T＞C变异.世界范围内首次发现1例贵州省榕江县患者有一新的c.G1388A,IVS10-10 T＞G基因复合变异.1例贵州省贵阳市患者母亲为c.1376 G ＞T,1311C ＞T,IVS11 nt93 T＞C基因复合变异携带者.结论 G6PD缺乏症具有一个广泛的临床异质性.世界范围内首次发现G6PD缺乏症患者中存在一新的G6PD基因复合变异单倍型c.G1388A,IVS10-10 T＞G,丰富了G6PD基因多态谱.贵州省患者可能存在G6PD基因复合变异单倍型c.1376 G＞T,1311C＞T,IVS11 nt 93 T＞C.     

四川省儿童中三种常见的葡萄糖-6-磷酸脱氢酶基因突变型

遗传性红细胞葡萄糖 6 磷酸脱氢酶 (Ｇ6ＰＤ)缺乏症是一组溶血性疾病的遗传基础 ,我国南方为高发区 ,在儿童中最为常见。发病的分子基础是Ｇ6ＰＤ基因突变 ,目前全世界已报道的Ｇ6ＰＤ突变类型已超过 1 2 2种[1 ] ,中国人中Ｇ6ＰＤ突变型为 1 5种 ,均为点突变[2 ,3] 。其中最常见的有 3种 ,即Ｇ1 388Ａ、Ｇ1 376Ｔ和Ａ95Ｇ突变 ,占 50 %以上。我国广东、广西、海南、云南等省和地区已进行了Ｇ6ＰＤ基因突变型研究。我们自 2 0 0 0年 1 0月以来应用突变扩增系统 (ＡＲＭＳ)方法 ,在Ｇ6ＰＤ缺乏症高发区四川省 2 5例四川籍儿童中检测上述 3种…     

广西南宁地区2033名新生儿葡萄糖6—磷酸脱氢酶缺乏症的筛查结果分析

广西是红细胞葡萄糖-6-磷酸脱氢酶(G-6-PD)缺乏症的高发区之一。目前广西百色地区报道该症的发生率为15.61％。G-6-PD缺乏症是引起新生儿高胆红素血症(简称高胆)的主要原因,约有40～50％的新生儿高胆是由G-6-PD缺乏引起的。新生儿G-6-PD缺乏引起的高胆所发生的核黄疸曾高达12.40～14.30％。因此,及时对新生儿G-6-     

新生儿Rh溶血病并葡萄糖-6-磷酸脱氢酶缺乏症1例

1 临床资料 患儿,女,15h.因皮肤、巩膜黄染进行性加重5h入院.患儿系第3胎(第1胎人工流产,第2胎出生约12h因黄疸未及时治疗至胆红素脑病死亡)足月顺产,体质量3100g.     

葡萄糖-6-磷酸脱氢酶缺乏症基因启动子甲基化研究

目的 了解葡萄糖-6-磷酸脱氢酶(G6PD)基因启动子区甲基化改变特点,探讨甲基化改变与G6PD缺乏症的关系。方法 将2013年8月至2014年7月期间195例贫血查因或体检儿童分为G6PD缺乏组(130例)和对照组(65例)。荧光定量PCR检测G6PDmRNA表达情况。甲基化敏感性高分辨率熔解曲线分析(MS-HRM)结合重亚硫酸盐PCR测序法(BSP)等方法分析G6PDmRNA表达偏低的G6PD缺乏症患者的基因启动子甲基化改变情况,另对G6PDmRNA表达正常的44例女性标本(G6PD缺乏组7例和正常对照组37例)的G6PD基因启动子甲基化情况进行分析。结果 22例(16.9%,22/130)G6PD缺乏症患者的G6PDmRNA表达偏低,其中的16例男性均无甲基化、6例女性均存在部分甲基化。44例G6PDmRNA表达正常的G6PD缺乏组及对照组女性中,40例检测到部分甲基化,4例无甲基化(G6PD缺乏组1例,对照组3例)。结论 基因启动子区甲基化与男性G6PD缺乏症没有关联。女性人群G6PD基因存在部分甲基化与无甲基化,提示甲基化改变对女性G6PD缺乏症可能有一定影响。     

RT-PCR测序法检测G6PD缺乏症基因突变

目的 葡萄糖-6-磷酸脱氢酶 （G6PD）缺乏症是最常见的遗传性溶血性红细胞酶缺陷病,绝大多数为编码区单碱基突变,现有的多种基因突变检测方法均存在漏检率。该研究拟探讨RT-PCR测序法检测G6PD缺乏症基因突变的可行性。方法 将2013年8月至2014年7月的195例贫血查因或体检儿童根据G6PD/6GPD比值 （结果 G6PD缺乏组的基因突变检出率为100%,共检出13种错义突变,包括1种新突变。对照组中28例男性均没有检出错义突变;37例女性中13例检出杂合型错义突变,1例国内外未见报道的纯合型同义突变C1191T,14例C1311T多态位点。对照组的女性标本存在较高的G6PD缺乏症 （携带者）漏检率 （35%,13/37）。结论 RT-PCR测序法对G6PD基因突变检出率高,具有较大临床诊断价值。     

Three mutations analysis of glucose-6-phosphate dehydrogenase deficiency in neonates in South-west China

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human enzymatic defects, is characterized by extreme molecular and biochemical heterogeneity. The underlying DNA changes associated with G6PD deficiency in Asian subjects have not been extensively investigated. METHODS: Three gene mutations (G1388A, G1376T, A95G, corresponding amino acid change: Arg463His, Arg459Leu, His32Arg, respectively) were examined in 240 G6PD-deficient subjects originating from South-west China using specific polymerase chain reaction. RESULTS: Of the 240 patients with G6PD deficiency, 190 were found to have the G1388A mutation, 48 had G1376T and two had A95G. There were no significant differences between the clinical manifestations caused by the former two gene mutations, which both cause acute hemolytic anemia and jaundice. Therefore the most common gene mutations of G6PD deficiency in neonates in South-west China are G1388A and G1376T mutations. CONCLUSION: It is suggested that G6PD deficiency screening be done in higher risk neonates with jaundice in qualified hospitals as soon as possible.     

G-6-PD缺乏症和新生儿高胆红素血症

葡萄糖-6-磷酸脱氢酶缺乏症是一种常见的单基因遗传性疾病,在全球范围内分布非常广泛,而且人群中携带者频率很高。患者突然出现的急性溶血会导致血清总胆红素升高,引起高胆红素血症,甚至胆红素脑病。新生儿高胆红素血症是儿科医生经常遇到的问题,需要及时发现和处理。     

Glucose-6-phosphate dehydrogenase deficiency in neonates

Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited deficiency that may be the cause of neonatal hyperbilirubinemia, as has been found in several countries and among widely different ethnic groups, especially in Mediterranean region. Our aim was to study the prevalence of G6PD deficiency in relation to neonatal jaundice.Methods : From March 1998 to April 2001 we studied 705 clinically icteric neonates who were admitted to Al-Zahra and Beheshti hospitals, two teaching hospitals in Isfahan, Iran. Laboratory investigations included determination of direct and indirect serum bilirubin concentrations, blood group typing, direct coomb’s test, hemoglobin, blood smear, reticulocyte count and G6PD level.Results: In only 53(7.5%) of cases G6PD deficiency was diagnosed. In all G6PD deficient neonates no evidence of other factors known to cause hyperbilirubinemia were detected. The sex distribution was 13(24.5%)females and 40(75.5%)males in the G6PD deficient group. The mean bilirubin level in G6PD deficient and G6PD normal groups were 22.26 +/-8.36 and 18.14 +/-3.85 mg/dl, respectively (p=0.001). Phototherapy was required in G6PD deficient and other icteric neonates with duration of 3.76 +/-1.93 and 3.13 +/-2.14 days, respectively (p=0.045). Twenty-seven of the 53(50.9%) G6PD deficient infants required exchange transfusion. None of them developed kernicterus.Conclusions: Since the prevalence of severe hyperbilirubinemia among our neonates was relatively high and about half of them required exchange transfusion, early detection of this enzymopathy regardless of sex and close surveillance of the affected newborns may be important in reducing the risk of severe hyperbilirubinemia and exchange transfusion.     

逆转录-PCR-变性梯度凝胶电泳法检测葡萄糖-6-磷酸脱氢酶基因缺陷女性携带者

目的：探讨应用逆转录-PCR-变性梯度凝胶电泳法(RT-PCR-DGGE)对葡萄糖-6-磷酸脱氢酶(G6PD)基因缺陷女性携带者人群进行分子诊断的可行性。方法：对54例G6PD基因缺陷可疑携带女性的血液标本,应用外周血提取总RNA并逆转录成cDNA;针对已报道的中国人群17种突变位点,以cDNA为模版,分段设计6对DGGE引物,PCR扩增、DGGE筛查分型,必要时进行测序验证。结果：54例可疑标本共检出1例1024C/T、20例1376G/T、12例1388G/A ,共检出杂合突变标本33例,总检出率为61.1%。结论： RT-PCR-DGGE对G6PD基因缺陷女性携带者人群具有较高的检出率,具有临床诊断意义。［中国当代儿科杂志,2009,11（8）：613-616］     

Hyperbilirubinemia, glucose-6-phosphate-dehydrogenase deficiency and Gilbert's syndrome

The pathogenesis of neonatal hyperbilirubinemia has not yet been completely defined in normal and glucose-6-phosphate-dehydrogenase (G6PD)-deficient newborns. The recent identification of a variant promoter in the gene encoding for the bilirubin uridine-diphosphoglucuronosyl-transferase (UGT-1 A) associated with Gilbert's syndrome, allowed us to explore whether the presence of this variant promoter is a risk factor for the development of neonatal hyperbilirubinemia in normal newborns and in association with G6PD deficiency. We found that the variant (TA)7/(TA)7 promoter shows no statistically significant difference in normal or G6PD-deficient newborns developing severe hyperbilirubinemia and in control subjects from the same population. This finding indicates that the variant promoter of UGT-1 A does not contribute to the development of hyperbilirubinemia in the newborn. Received: 1 July 1998 / Accepted: 10 May 1999     

广西南宁地区G6PD基因突变与新生儿黄疸的关系

目的：分析本地区最常见的三种基因突变型G1388A、G1376T和A95G与葡萄糖-6-磷酸脱氢酶（G-6-PD）活性之间的相关性,并探讨G-6-PD基因突变对新生儿黄疸的影响。方法：124例广西南宁的高胆红素血症新生儿为研究对象。应用突变特异性扩增系统法检测G-6-PD基因突变,应用硝基四氮唑蓝（NBT）定量法检测G-6-PD活性。比较G-6-PD不同基因突变型之间以及与正常组之间胆红素脑病发生率、出生72 h后血清胆红素峰值组间的差异。采用非条件logistic回归分析血清胆红素值>340 μmol/L的危险度。结果：124例中有37例G-6-PD 基因突变（G1388A 20例,G1376T 14例,A95G 4例,1例同时存在G1388A与A95G突变）。20例G1388A突变者中5例（25%）G-6-PD酶活性正常,14例G1376T突变者中4例（29%）G-6-PD酶活性正常,4例A95G突变者G-6-PD 酶活性均缺乏。G1388A与G1376T组胆红素脑病发生率及出生72 h后血清胆红素峰值差异无显著性。G-6-PD 突变组出生72 h后血清胆红素峰值、胆红素脑病发生率及血清胆红素>340 μmol/L的危险度与G-6-PD正常组相比,差异无显著性。结论：广西南宁地区G-6-PD突变仍常见G1388A、G1376T和A95G基因型。NBT法诊断G-6-PD缺乏存在假阴性。不同基因型对出生72 h后血清胆红素峰值、胆红素脑病发生率的影响无差异。单独的G-6-PD基因突变对生后72 h血清胆红素峰值、急性胆红素脑病发生率及血清胆红素大于340 μmol/L危险性均无影响。［中国当代儿科杂志,2009,11（12）：970-972］     

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目的探讨葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变、葡萄糖-6-磷酸脱氢酶(G6PD)缺陷对新生儿生后前3d胆红素浓度的影响.方法测定81例新生儿脐血的G6PD活性及G71R基因型,分组比较生后前3d光疗前胆红素值的组间差异.用等位基因特异性寡核苷酸探针点杂交法(ASO)确定G71R基因型.结果在G71R野生型新生儿中,G6PD缺乏组与G6PD正常组相比,生后前3d胆红素值间无统计学差异.G6PD正常新生儿中,G71R突变纯合子或杂合子的新生儿生后前3d胆红素浓度与G71R正常野生型新生儿相比无统计学差异.G6PD缺陷新生儿中,同时合并有G71R突变纯合子或杂合子的新生儿组生后第2天、第3天胆红素浓度高于G71R正常野生型新生儿组.结论G6PD缺乏与G71R基因突变并存加重新生儿黄疸程度.     

Screening for glucose-6-phosphate dehydrogenase deficiency using a modified formazan method: A pilot study on Filipino male newborns

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency has increased prevalence rates in tropical Africa, tropical and subtropical Asia and some parts of the Mediterranean. Earlier studies on G6PD deficiency in the Philippines have shown prevalence rates of 4.5% to 25.7%. METHODS: In the present study, 3278 male newborns were screened for G6PD deficiency using the modified formazan method, a simple screening procedure affordable in the setting of a developing country. Subjects with positive screening results were recalled for confirmatory testing using a commercial assay kit for quantitative enzyme determination. RESULTS: Of the 3278 boys studied, 186 revealed positive screening results. Of the 186, 65 boys had confirmatory testing. Of these 65 boys, 45 were confirmed to have G6PD deficiency and 20 had normal results. This study reveals an incidence of G6PD deficiency of 3.9% among male Filipinos. CONCLUSIONS: This study recommends the inclusion of G6PD deficiency in the panel of disorders for newborn screening among Filipino newborns.