KCNJ2基因新突变致Andersen-Tawil综合征一家系报道及既往病例回顾

A family with Andersen.Tawil syndrome induced by a new mutation Q164R in the KCNJ2 gene and previous literature review

目的报道一个Andersen－Tawil综合征家系的临床特点，检测并分析其致病基因突变情况。通过检索国内外所有已报道的Andersen－Tawil综合征患者资料，探索基因型与表型的相关性。方法对2016年12月2日就诊于山西医科大学第一医院神经内科的一个Andersen－Tawil综合征家系中2例患者进行病史资料收集和相关辅助检查，应用PCR和DNA扩增技术对SCN4A、CACNA1S、KCNJ2、KCNE3、KCNE4、KCNJ18、KCNJ5等离子通道疾病相关基因进行检测。随机抽取山西医科大学200名健康志愿者作为对照。检索国内外已报道的Andersen－Tawil综合征患者，收集所有符合统计标准的病例，对其基因型与表型进行分析总结。结果先证者与其父临床表现均符合Andersen－Tawil综合征的诊断标准，其突出特点为：室性心律失常、周期性瘫痪及身体发育畸形。2例患者均存在肾小管酸中毒，其中1例患者存在肾素－血管紧张素－醛固酮水平增高。经基因检测，这2例患者均存在KCNJ2基因新突变Q164R，该突变目前尚未见文献报道及数据库收录。家系其他成员及200名健康对照中未发现此突变。经复习文献，共纳入55例Andersen－Tawil综合征患者，其中54例为KCNJ2基因突变，1例为KCNJ5基因突变。对54例KCNJ2基因突变者进行统计分析，其结果为：患者周期性瘫痪的发病年龄与心脏症状发病年龄之间存在负相关（rs＝－0.698 1，P＝0.005 5）；出现周期性瘫痪的Andersen－Tawil综合征患者，其心脏症状的发生率较未出现周期性瘫痪者减低[33.33%（14/42）和9/11, χ2＝6.485，P＝0.011]；男性患者[96.00%（24/25）]比女性患者[65.52%（19/29）]更容易出现周期性瘫痪（χ2＝7.691，P＝0.006）；女性患者[64.29%（18/28）]比男性患者[20.00%（5/25）]更容易出现心脏症状（χ2＝10.545，P＝0.001）。结论KCNJ2基因新突变Q164R是Andersen－Tawil综合征的致病突变，可引起肾小管酸中毒，可能在钾离子调节醛固酮的生成通道中发挥作用。对KCNJ2基因突变的女性及周期性瘫痪发病年龄较晚的Andersen－Tawil综合征患者，要尽早行药物或人工干预，预防心源性不良事件发生。

ObjectiveTo discuss clinical characteristics of a family with Andersen-Tawil syndrome, test and analyze the mutation of their pathogenic gene, and to discover the dependency of genotype and phenotype by searching every reported Andersen-Tawil syndrome patient in all accessible literature worldwide.MethodsIn December 2nd, 2016, two patients in the Department of Neurology, the First Hospital of Shanxi Medical University, received medical history data collection and relevant examinations. PCR and DNA sequencing were applied to detect ion channel diseases related genes such as SCN4A, CACNA1S, KCNJ2, KCNE3, KCNE4, KCNJ18, KCNJ5. Random selection of 200 healthy volunteers from Shanxi Medical University served as normal controls. Andersen-Tawil syndrome cases, which are accorded with statistical criteria in published literature, were collected. Their genotype and phenotype were analyzed and summarized.ResultsClinical manifestation of the pre-confirmed patient and his father was accorded with diagnostic criteria of Andersen-Tawil syndrome. Prominent characteristics included ventricular arrhythmia, periodic paralysis, and dysmorphic features. The two patients had renal tubular acidosis. One of these two patients also had increased level of renin-angiotensin-aldosterone. New mutation Q164R in the KCNJ2 gene was found in these two patients. There was no report in any literature or any database that we could find about this gene mutation at present. The mutation was not found among other healthy family members and 200 healthy controls. In this study, we referenced 55 samples of Andersen-Tawil syndrome in 12 articles, in which 54 samples are KCNJ2 gene mutation, one is KCNJ5 gene mutation. We concluded a negative correlation between the onset age of periodic paralysis and the onset age of cardiac symptoms after a statistical analysis of these 54 patients with KCNJ2 gene mutation （rs=-0.698 1, P=0.005 5）. The incidence of cardiac symptoms in patients of Andersen-Tawil syndrome with periodic paralysis was reduced （33.33%（14/42） vs 9/11, χ2=6.485, P=0.011）. Men （96.00%（24/25）） were found more likely to have periodic paralysis than women （65.52%（19/29）; χ2=7.691, P=0.006）. Women （64.29%（18/28）） were found more likely to have cardiac symptoms than men （20.00%（5/25）; χ2=10.545, P=0.001）.ConclusionsNew mutation Q164R in the KCNJ2 gene is the cause of Andersen-Tawil syndrome, which could cause renal tubular acidosis. We speculate that the gene may play a role in the way of potassium regulating aldosterone. For women with the KCNJ2 gene mutation and the late-onset of periodic paralysis, it is important to take drug or manual intervention as early as possible to prevent the occurrence of cardiogenic adverse events.