Gillies R L, Bjorksten A R, Davis M, Du Sart D
Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, Australia.
Anaesth Intensive Care. 2008 May;36(3):391-403. doi: 10.1177/0310057X0803600311.
Advances in analysis of the RYR1 gene (which encodes the skeletal muscle ryanodine receptor) show that genetic examination is a useful adjunct to the in vitro contracture test in the diagnosis of malignant hyperthermia, as defects in RYR1 have been shown to be responsible for malignant hyperthermia susceptibility. DNA from 34 malignant hyperthermia susceptible individuals and four malignant hyperthermia equivocal subjects was examined using direct sequencing of 'hot-spots' in the RYR1 gene to identify mutations associated with malignant hyperthermia. Seven different causative mutations (as defined by the European Malignant Hyperthermia Group) in nine malignant hyperthermia susceptible individuals were identified. In another six malignant hyperthermia susceptible individuals, five different published but as yet functionally uncharacterised mutations were identified. A further three as yet unpublished and functionally uncharacterised (novel) mutations were identified in three malignant hyperthermia susceptible samples. If the novel and previously published mutations prove to be functionally associated with calcium homeostasis, then this method of analysis achieved a mutation detection rate of 47%. Based on the number of relatives presenting to our unit in the study period, the muscle biopsy rate would have decreased by 25%. That we only identified a genetic defect in RYR1 in 47% of in vitro contracture test positive individuals suggests that there are other areas in RYR1 where pathogenic mutations may occur and that RYR1 may not be the sole gene associated with malignant hyperthermia. It may also reflect a less than 100% specificity of the in vitro contracture test.
对编码骨骼肌兰尼碱受体的RYR1基因的分析进展表明，基因检测作为体外挛缩试验的辅助手段，在恶性高热的诊断中很有用，因为已证明RYR1缺陷是恶性高热易感性的原因。使用RYR1基因“热点”的直接测序法对34名恶性高热易感个体和4名恶性高热疑似个体的DNA进行检测，以识别与恶性高热相关的突变。在9名恶性高热易感个体中鉴定出7种不同的致病突变（由欧洲恶性高热研究组定义）。在另外6名恶性高热易感个体中，鉴定出5种不同的已发表但尚未进行功能表征的突变。在3个恶性高热易感样本中鉴定出另外3种尚未发表且未进行功能表征的（新）突变。如果新的和先前发表的突变被证明与钙稳态功能相关，那么这种分析方法的突变检出率达到47%。根据研究期间到我们科室就诊的亲属数量，肌肉活检率将降低25%。我们仅在47%的体外挛缩试验阳性个体中鉴定出RYR1基因缺陷，这表明RYR1基因中可能存在其他致病突变区域，并且RYR1可能不是与恶性高热相关的唯一基因。这也可能反映出体外挛缩试验的特异性不足100%。
