摘要目的 研究中国人群中由编码ATP敏感性钾通道(KATP)基因突变导致的新生儿糖尿病(NDM)患者的临床特点以及基因型-临床表型关系.方法 纳入2007年8月至2016年8月就诊于北京协和医院的可疑NDM患者23例,详细收集临床资料,运用Sanger测序技术对分别编码KATP通道Kir6.2亚单位和SUR1亚单位的KCNJ11和ABCC8基因进行测序,明确分子遗传学诊断;对明确由KCNJ11或ABCC8基因突变导致的NDM患者,尝试行口服格列本脲替代胰岛素转换治疗.结果 共遗传学确诊KATP-NDM患者13例:KCNJ11突变(KCNJ11-NDM)9例,ABCC8突变(ABCC8-NDM)4例.发现4个新的KATP基因致病位点,分别为KCNJ11 p.I182M和ABCC8 p.Q211R、p.I585F、p.R653W.在9例KCNJ11-NDM中,2例为暂时性NDM(TNDM),7例为永久性NDM(PNDM),其中3例合并神经、肌肉发育迟缓(iDEND综合征).4例ABCC8-NDM均为PNDM,其中2例合并iDEND综合征.共9例(69.2%)患者成功停用胰岛素,转换为格列本脲单药降糖治疗.即使在KATP基因同一位点、发生相同或不同氨基酸类型突变,所导致的NDM在临床轻重程度、对磺脲类药物的反应均存在较大差异.结论 深入研究NDM的基因型-临床表型关系有助于更好地理解糖尿病(特别是NDM)的发病机制与临床转归.尽早确诊KATP-NDM并起始磺脲类药物治疗对预防iDEND综合征患者的神经肌肉系统发育异常具有重要意义.

abstractsObjective To elucidate the clinical characteristics and genotype-phenotype relationships of Chinese patients with neonatal diabetes mellitus (NDM) caused by ATP-sensitive potassium channel (KATP ) gene mutations (KATP-NDM). Methods Total of 23 suspected patients with NDM were recruited from Peking Union Medical College Hospital. Amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 gene were done for molecular genetic diagnosis. Patients with a definite diagnosis of KATP-NDM were switched from insulin injection to oral glibenclamide. Results Thirteen patients with KATP-NDM were identified, including 9 cases of KCNJ11-NDM and 4 cases of ABCC8-NDM. Four novel mutations of KATP were identified: 1 in KCNJ11 (I182M) and 3 in ABCC8 (Q211R, I585F, R653W). Among 9 patients with KCNJ11-NDM, 2 were transient NDM (TNDM) and 7 were permanent NDM (PNDM), and 3 of which had intermediate developmental delay, neonatal diabetes (iDEND syndrome). Four patients with ABCC8-NDM were all PNDM, 2 of them had iDEND syndrome. Switching from insulin to glibenclamide monotherapy was successful in 9 patients (69.2%). Conclusions Different clinical severities and treatment responses to sulfonylureas exist even among patients with the same mutation or with different amino acids at the same mutation site. Early diagnosis of KATP-NDM and initiation of sulfonylureas are of great importance in the prevention of neurological abnormalities in patients with iDEND syndrome.