恶性高热实验室诊断方法的建立及临床应用
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摘要
第一部分恶性高热实验室诊断方法的建立
目的建立恶性高热(Malignant Hyperthermia,MH)的实验室诊断方法-咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracture test,CHCT)。
方法根据北美MH研究组的标准建立CHCT的试验装置后,通过10头实验小型猪和1头皮特兰猪检测CHCT设备的稳定性及结果的可靠性。1.MH诱发实验:应用氯胺酮和安定进行基础麻醉后,静脉给予硫喷妥钠和琥珀胆碱(2mg/kg)进行气管插管,成功后机控呼吸并持续吸入2～3%氟烷(氧气:空气=1:1)维持麻醉;观察所有实验动物是否出现MH的典型表现;2.基因检测:取猪的耳组织,采用常规酚氯仿方法,提取基因组DNA,设计特异性引物PCR扩增RYR1基因的突变热点区域,取PCR产物经HhalI限制性内切酶进行酶切分析;3.CHCT:取猪股四头肌近肌腱部位的肌纤维2～3cm,固定于37℃恒温Krebs液内并持续通入含5%二氧化碳的氧气,连接张力传感器和电刺激仪,给予一定电刺激,测定不同浓度氟烷(和/或咖啡因)下肌肉收缩张力的改变。
结果1.MH诱发实验:所有实验小型猪的MH诱发实验过程平稳,均未出现MH发作的表现;皮特兰猪在MH诱发实验后出现四肢僵直、PaCO_2及体温升高、CK升高、肌红蛋白尿等MH的临床表现。2.基因检测:实验小型猪均为氟烷抗性基因型HALNN,皮特兰猪为氟烷易感基因型HALnn。3.CHCT:所有实验小型猪的咖啡因试验和氟烷试验均为阴性,符合非MH易感猪的诊断;皮特兰猪的咖啡因试验和氟烷试验均为阳性,符合MH易感猪的诊断。
结论本研究中,实验小型猪和皮特兰猪的CHCT诊断结果与MH诱发实验的临床表现及基因检测结果均一致,初步验证本实验室CHCT设备的稳定性及结果的可靠性。
第二部分恶性高热实验室诊断方法的临床应用
目的应用咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracturetest,CHCT)明确恶性高热(Malignant hyperthermia,MH)的诊断。
方法总结和介绍4例临床诊断为MH病例的麻醉用药、麻醉方法、临床表现、化验检查、抢救措施及临床转归等临床资料。介绍1例NMS患者可疑同时发生MH,1例嗜铬细胞瘤患者可疑因为服用吗叮啉发生横纹肌溶解的临床表现、化验检查及临床转归等临床资料。进一步应用CHCT进行确诊和鉴别诊断:取患者股四头肌或腹直肌近肌腱部位的肌纤维2～3cm,固定于37℃恒温Krebs液内并持续通入含5%二氧化碳的氧气,连接张力传感器和电刺激仪,给予一定电刺激,测定不同浓度氟烷(和/或咖啡因)下肌肉收缩张力的改变。
结果4例临床诊断为MH的患者的咖啡因试验均为阳性,根据北美MH的诊断标准确诊为MH易感者;另2例患者的咖啡因试验和氟烷试验均为阴性,符合非MH易感者的诊断。
结论本实验室的CHCT可用于MH的确诊和鉴别诊断。
第三部分恶性高热家系的分子遗传学研究
目的在咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracturetest,CHCT)确诊恶性高热(Malignant hyperthermia,MH)的基础上,研究中国人MH家系分子遗传学特点。
方法在遵守知情同意原则的基础上,一共收集了4个MH家系。分别为家系A、家系B、家系C和家系D,每个家系的先证者均在麻醉中出现典型的MH表现,符合MH的临床诊断标准,并经确诊MH的金标准—CHCT确证为MH患者。分别提取明确诊断为MH的先证者及其他家系成员外周血白细胞的基因组DNA,通过PCR扩增先证者RYR1基因部分外显子并进行直接测序分析。根据基因测序结果,对发现有基因突变的患者,利用FokⅠ限制酶分析验证先证者及其他家系成员基因突变情况。
结果家系A中先证者PCR产物测序结果表明:RYR1基因第6724位碱基C突变为T(c.6724C＞T),所编码2206位氨基酸由苏氨酸变为甲硫氨酸(p.T2206M),此种突变在白种人已有报道。限制酶分析确认:先证者的4个子女中有2个为该错义突变携带者,为MH易感者。家系B、家系C和家系D中的先证者及其他家系成员的RYR1基因热点区外显子均未发现突变。
结论中国人中部分MH易感者携带在白种人MH中频发的RYR1基因突变,但中国人MH家系分子遗传学特点尚需要进一步研究。
Part 1 Establishment of the laboratory diagnostic test of malignant hyperthermia
Objective To establish laboratory diagnostic test of malignant hyperthermia (MH) -Caffeine and halothane contracture test (CHCT).
Methods According to the North America MH Group protocol, the laboratory devices of CHCT were established. Ten Chinese experimental miniature pigs (CEMP) and one pietrain swine were selected for this study to validate the stability of laboratory devices of CHCT. 1.Experiment on the induction of MH in swine: After basal anesthesia with ketamine and diazepam, the pigs were anesthetized with thiopental sodium and tracheal intubation was facilitated with succinylcholine (2mg/kg) intravenously. Mechanical ventilation was applied and the anesthesia was maintained with 2～3% halothane inhalation in oxygen and air (O_2:air=1:1). All the pigs were observed whether the MH episodes were initiated or not. 2.Gene detection: The genome DNA were extracted by classic SDS-proteinase K-hydroxybenzene-chloroform methods from ear tissues of the swines. In order to detect mutations in the RYR1 gene, specific primers were designed and exons were amplified by polymerase chain reaction (PCR) and then subjected to HhalI restriction endonuclease analysis. 3. CHCT: 2～3cm femoral quadriceps' muscle fibers near tendon of the swines were collected and fixed in Krebs-Ringer solution at 37℃constant temperature with 95% oxygen and 5% carbon dioxide. The biopsies were connected to tension sensor and electrical stimulation instrument and then given certain electrical stimulations and the tension changes of the muscles under different concentrations of halothane and/or caffeine were determined.
Results 1.Experiment on the induction of MH in swine: The processes of experiments on the induction of MH were stationary and the life signs were stable and clinical manifestations of fulminant MH were not found in all the CEMPs. But the Pietrain swine presented clinical manifestations of MH after anerthesia, such as extremities rigor, increased PaCO_2 and body temperature, elevation of serum CK and serum and urinary myoglobin. 2.Gene detection: The RYR1 genotype of the CEMPs were HALNN and the Pietrain swine's was HALnn, therefore the phenotype of the CEMPs were MH negative and the Pietrain swine's was MH positive. 3. CHCT: All the CEMPs were diagnosed as MH negative (MHN) beaucase caffeine test and halothane test in CHCT were both negative in each animal. But the Pietrain swine were diagnosed as MH susceptibility (MHS) beaucase of both positive results of caffeine test and halothane test in CHCT.
Conclusion The results of CHCT were consistent with those of clinical manifestations and genetic screen, demonstrating that the devices of CHCT in present study were overall steady-going and reliable.
Part 2 Clinical application of the laboratory diagnostic test of malignant hyperthermia
Objective To apply caffeine and halothane contracture test (CHCT) for the confirmation of clinical diagnosis of malignant hyperthermia (MH).
Methods Four cases of MH were summerised. The characteristics of the four cases, including drugs and methods of anesthesia, clinical manifestations, results of lab examination,emergency treatment methods and prognosis were reported. Two cases were analyzed and reported, including clinical manifestations, results of lab examination and prognosis. One case was neuroleptic malignant syndrome(NMS) who was suspicious of MH episode imultaneously and the other case was pheochromocytoma whose symptoms of rhabdomyolysis were suspicious to be caused by domperidone. CHCT was applied for the confirmation of clinical diagnosis of MH by the steps as follow: 2～3cm muscle fibers of femoral quadriceps or rectus abdominis of the patients were collected and fixed in Krebs-Ringer solution at 37℃constant temperature with 95% oxygen and 5% carbon dioxide. The biopsies were connected to tension sensor and electrical stimulation instrument and then given certain electrical stimulations and the tension changes of the muscles under different concentrations of halothane and/or caffeine were determined.
Results All the results of caffeine test of the four cases who were clinically diagnosed as MH were positive and then the patients were all diagnosed as MH susceptibility (MHS) according to diagnostic criteria of the North America MH group. The other two cases were both diagnosed as MH negative (MHN) beaucase caffeine test and halothane test in CHCT were both negative in each patient.
Conclusion The CHCT in our laboratory can be used in diagnosis and differential diagnosis of MH.
Part 3 Molecular genetic study of malignant hyperthermia in Chinese Pedigrees
Objective To investigate genetically Chinese families who diagnosed as malignant hyperthermia (MH) by caffeine and halothane contracture test (CHCT).
Methods Based on abiding strictly by the doctrine of informed consent of patients, this study was performed in four Chinese families(family A, family B, family C and familyD,respectively). Probands of all the family presented as typical clinical manifestations of MH during anesthesia and the diagnosis of MH were confirmed by CHCT. Total genome was extracted conventionally from peripheral leucocytes of the MH patients and other family members'. In order to detect mutations in the RYR1 gene, part exons were amplified by polymerase chain reaction (PCR) and then subjected to automatic DNA sequencing. According to the sequencing results, those who had gene mutation received Fok I restriction analysis to confirm the detected mutation in the index patient and other family members.
Results DNA sequencing of PCR-amplified fragments of the index patient in family A revealed c.6724C>T (p.T2206M), a recurrent missense mutation which had been detected in Caucasian MH cases. Restriction analysis of all available family members of family A showed that one daughter and one son of the index patient were heterozygous for the same mutation, indicating that they were MH-susceptible individuals. DNA sequencing of PCR-amplified fragments of all available family members in family B, family C and family D did not reveal mutation in the hot spots of mutation in RYR1 gene.
Conclusion Some of the Chinese MH susceptibles carries the similar gene mutation to the Caucasian one, but further studies should be conducted on molecular genetic characteristics of malignant hyperthermia in Chinese pedigrees.
目的建立恶性高热(Malignant Hyperthermia,MH)的实验室诊断方法-咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracture test,CHCT)。
方法根据北美MH研究组的标准建立CHCT的试验装置后,通过10头实验小型猪和1头皮特兰猪检测CHCT设备的稳定性及结果的可靠性。1.MH诱发实验:应用氯胺酮和安定进行基础麻醉后,静脉给予硫喷妥钠和琥珀胆碱(2mg/kg)进行气管插管,成功后机控呼吸并持续吸入2～3%氟烷(氧气:空气=1:1)维持麻醉;观察所有实验动物是否出现MH的典型表现;2.基因检测:取猪的耳组织,采用常规酚氯仿方法,提取基因组DNA,设计特异性引物PCR扩增RYR1基因的突变热点区域,取PCR产物经HhalI限制性内切酶进行酶切分析;3.CHCT:取猪股四头肌近肌腱部位的肌纤维2～3cm,固定于37℃恒温Krebs液内并持续通入含5%二氧化碳的氧气,连接张力传感器和电刺激仪,给予一定电刺激,测定不同浓度氟烷(和/或咖啡因)下肌肉收缩张力的改变。
结果1.MH诱发实验:所有实验小型猪的MH诱发实验过程平稳,均未出现MH发作的表现;皮特兰猪在MH诱发实验后出现四肢僵直、PaCO_2及体温升高、CK升高、肌红蛋白尿等MH的临床表现。2.基因检测:实验小型猪均为氟烷抗性基因型HALNN,皮特兰猪为氟烷易感基因型HALnn。3.CHCT:所有实验小型猪的咖啡因试验和氟烷试验均为阴性,符合非MH易感猪的诊断;皮特兰猪的咖啡因试验和氟烷试验均为阳性,符合MH易感猪的诊断。
结论本研究中,实验小型猪和皮特兰猪的CHCT诊断结果与MH诱发实验的临床表现及基因检测结果均一致,初步验证本实验室CHCT设备的稳定性及结果的可靠性。
第二部分恶性高热实验室诊断方法的临床应用
目的应用咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracturetest,CHCT)明确恶性高热(Malignant hyperthermia,MH)的诊断。
方法总结和介绍4例临床诊断为MH病例的麻醉用药、麻醉方法、临床表现、化验检查、抢救措施及临床转归等临床资料。介绍1例NMS患者可疑同时发生MH,1例嗜铬细胞瘤患者可疑因为服用吗叮啉发生横纹肌溶解的临床表现、化验检查及临床转归等临床资料。进一步应用CHCT进行确诊和鉴别诊断:取患者股四头肌或腹直肌近肌腱部位的肌纤维2～3cm,固定于37℃恒温Krebs液内并持续通入含5%二氧化碳的氧气,连接张力传感器和电刺激仪,给予一定电刺激,测定不同浓度氟烷(和/或咖啡因)下肌肉收缩张力的改变。
结果4例临床诊断为MH的患者的咖啡因试验均为阳性,根据北美MH的诊断标准确诊为MH易感者;另2例患者的咖啡因试验和氟烷试验均为阴性,符合非MH易感者的诊断。
结论本实验室的CHCT可用于MH的确诊和鉴别诊断。
第三部分恶性高热家系的分子遗传学研究
目的在咖啡因-氟烷骨骼肌收缩试验(Caffeine and halothane contracturetest,CHCT)确诊恶性高热(Malignant hyperthermia,MH)的基础上,研究中国人MH家系分子遗传学特点。
方法在遵守知情同意原则的基础上,一共收集了4个MH家系。分别为家系A、家系B、家系C和家系D,每个家系的先证者均在麻醉中出现典型的MH表现,符合MH的临床诊断标准,并经确诊MH的金标准—CHCT确证为MH患者。分别提取明确诊断为MH的先证者及其他家系成员外周血白细胞的基因组DNA,通过PCR扩增先证者RYR1基因部分外显子并进行直接测序分析。根据基因测序结果,对发现有基因突变的患者,利用FokⅠ限制酶分析验证先证者及其他家系成员基因突变情况。
结果家系A中先证者PCR产物测序结果表明:RYR1基因第6724位碱基C突变为T(c.6724C＞T),所编码2206位氨基酸由苏氨酸变为甲硫氨酸(p.T2206M),此种突变在白种人已有报道。限制酶分析确认:先证者的4个子女中有2个为该错义突变携带者,为MH易感者。家系B、家系C和家系D中的先证者及其他家系成员的RYR1基因热点区外显子均未发现突变。
结论中国人中部分MH易感者携带在白种人MH中频发的RYR1基因突变,但中国人MH家系分子遗传学特点尚需要进一步研究。
Part 1 Establishment of the laboratory diagnostic test of malignant hyperthermia
Objective To establish laboratory diagnostic test of malignant hyperthermia (MH) -Caffeine and halothane contracture test (CHCT).
Methods According to the North America MH Group protocol, the laboratory devices of CHCT were established. Ten Chinese experimental miniature pigs (CEMP) and one pietrain swine were selected for this study to validate the stability of laboratory devices of CHCT. 1.Experiment on the induction of MH in swine: After basal anesthesia with ketamine and diazepam, the pigs were anesthetized with thiopental sodium and tracheal intubation was facilitated with succinylcholine (2mg/kg) intravenously. Mechanical ventilation was applied and the anesthesia was maintained with 2～3% halothane inhalation in oxygen and air (O_2:air=1:1). All the pigs were observed whether the MH episodes were initiated or not. 2.Gene detection: The genome DNA were extracted by classic SDS-proteinase K-hydroxybenzene-chloroform methods from ear tissues of the swines. In order to detect mutations in the RYR1 gene, specific primers were designed and exons were amplified by polymerase chain reaction (PCR) and then subjected to HhalI restriction endonuclease analysis. 3. CHCT: 2～3cm femoral quadriceps' muscle fibers near tendon of the swines were collected and fixed in Krebs-Ringer solution at 37℃constant temperature with 95% oxygen and 5% carbon dioxide. The biopsies were connected to tension sensor and electrical stimulation instrument and then given certain electrical stimulations and the tension changes of the muscles under different concentrations of halothane and/or caffeine were determined.
Results 1.Experiment on the induction of MH in swine: The processes of experiments on the induction of MH were stationary and the life signs were stable and clinical manifestations of fulminant MH were not found in all the CEMPs. But the Pietrain swine presented clinical manifestations of MH after anerthesia, such as extremities rigor, increased PaCO_2 and body temperature, elevation of serum CK and serum and urinary myoglobin. 2.Gene detection: The RYR1 genotype of the CEMPs were HALNN and the Pietrain swine's was HALnn, therefore the phenotype of the CEMPs were MH negative and the Pietrain swine's was MH positive. 3. CHCT: All the CEMPs were diagnosed as MH negative (MHN) beaucase caffeine test and halothane test in CHCT were both negative in each animal. But the Pietrain swine were diagnosed as MH susceptibility (MHS) beaucase of both positive results of caffeine test and halothane test in CHCT.
Conclusion The results of CHCT were consistent with those of clinical manifestations and genetic screen, demonstrating that the devices of CHCT in present study were overall steady-going and reliable.
Part 2 Clinical application of the laboratory diagnostic test of malignant hyperthermia
Objective To apply caffeine and halothane contracture test (CHCT) for the confirmation of clinical diagnosis of malignant hyperthermia (MH).
Methods Four cases of MH were summerised. The characteristics of the four cases, including drugs and methods of anesthesia, clinical manifestations, results of lab examination,emergency treatment methods and prognosis were reported. Two cases were analyzed and reported, including clinical manifestations, results of lab examination and prognosis. One case was neuroleptic malignant syndrome(NMS) who was suspicious of MH episode imultaneously and the other case was pheochromocytoma whose symptoms of rhabdomyolysis were suspicious to be caused by domperidone. CHCT was applied for the confirmation of clinical diagnosis of MH by the steps as follow: 2～3cm muscle fibers of femoral quadriceps or rectus abdominis of the patients were collected and fixed in Krebs-Ringer solution at 37℃constant temperature with 95% oxygen and 5% carbon dioxide. The biopsies were connected to tension sensor and electrical stimulation instrument and then given certain electrical stimulations and the tension changes of the muscles under different concentrations of halothane and/or caffeine were determined.
Results All the results of caffeine test of the four cases who were clinically diagnosed as MH were positive and then the patients were all diagnosed as MH susceptibility (MHS) according to diagnostic criteria of the North America MH group. The other two cases were both diagnosed as MH negative (MHN) beaucase caffeine test and halothane test in CHCT were both negative in each patient.
Conclusion The CHCT in our laboratory can be used in diagnosis and differential diagnosis of MH.
Part 3 Molecular genetic study of malignant hyperthermia in Chinese Pedigrees
Objective To investigate genetically Chinese families who diagnosed as malignant hyperthermia (MH) by caffeine and halothane contracture test (CHCT).
Methods Based on abiding strictly by the doctrine of informed consent of patients, this study was performed in four Chinese families(family A, family B, family C and familyD,respectively). Probands of all the family presented as typical clinical manifestations of MH during anesthesia and the diagnosis of MH were confirmed by CHCT. Total genome was extracted conventionally from peripheral leucocytes of the MH patients and other family members'. In order to detect mutations in the RYR1 gene, part exons were amplified by polymerase chain reaction (PCR) and then subjected to automatic DNA sequencing. According to the sequencing results, those who had gene mutation received Fok I restriction analysis to confirm the detected mutation in the index patient and other family members.
Results DNA sequencing of PCR-amplified fragments of the index patient in family A revealed c.6724C>T (p.T2206M), a recurrent missense mutation which had been detected in Caucasian MH cases. Restriction analysis of all available family members of family A showed that one daughter and one son of the index patient were heterozygous for the same mutation, indicating that they were MH-susceptible individuals. DNA sequencing of PCR-amplified fragments of all available family members in family B, family C and family D did not reveal mutation in the hot spots of mutation in RYR1 gene.
Conclusion Some of the Chinese MH susceptibles carries the similar gene mutation to the Caucasian one, but further studies should be conducted on molecular genetic characteristics of malignant hyperthermia in Chinese pedigrees.
引文
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1.王颖林,郭向阳,罗爱伦.我国大陆恶性高热病例的分析.中华麻醉学杂志,2006,26:107-109.
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1.王颖林,郭向阳,罗爱伦.我国大陆恶性高热病例的分析.中华麻醉学杂志,2006,26:107-109.
2.Hopkins PM.Malignant hyperthermia:advances in clinical management and diagnosis.Br J Anaesth,2000,85:118-128.
3.Litman RS,Rosenberg H.Malignant hyperthermia:update on susceptibility testing.JAMA,2005,293(23):2918-2924.
4.Rosenberg H,Antognini JF,Muldoon S.Testing for malignant hyperthermia.Anesthesiology,2002,96:232-237.
5.Larach MG.Standardization of the caffeine halothane muscle contracture test,North American Malignant Hyperthermia Group.Anesth Analg,1989,69:511-515.
6.Gunilla I,Eva RT.Comparison Between the European and North American Protocols for Diagnosis of Malignant Hyperthermia Susceptibility in Humans.Anesth Analg,1999,88:1155-1160.
7.柴栋,方翼,裴斐,等.单剂口服多潘立酮片在健康人体的生物等效性.中国临床药理学杂志,2005,21(3):190-193.
8.Mauritz W,Hackl W,Winkler M.Malignant hyperthermia:state of art.Intraoperative complications.Acta Anaesthesiol Scand,1997,111(suppl):310-312.
9.王颖林,郭向阳,罗爱伦.恶性高热诊断和治疗的研究进展.中华麻醉学杂志,2006,26:92-94.
10.Larach MG,Localio AR,Allen GC,et al.A clinical grading scale to predict malignant hyperthermia susceptibility.Anesthesiology,1994,80:771-779.
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