Devaraja Janani, Elder Charlotte, Scott Adrian
Sheffield Children's Hospital NHS Trust, Sheffield, UK.
Academic Directorate of Diabetes & Endocrinology at Sheffield Teaching Hospital NHS Trust, Sheffield, UK.
Endocrinol Diabetes Metab Case Rep. 2020 Feb 26;2020. doi: 10.1530/EDM-19-0125.
This case report describes a family pedigree of a mother and her children with an E227K mutation in the KCNJ11 gene. People with this particular gene mutation typically present with transient neonatal diabetes; with more than half the cohort relapsing into permanent diabetes in adolescence or early adulthood. However, the mother developed diabetes as an adolescent and thus was initially diagnosed as having Type 1 Diabetes. All her children have inherited the same genetic mutation but with differing presentations. Her second, third and fourth child presented with transient neonatal diabetes which remitted at varying times. Her first child is 16 years old but had not developed diabetes at the time of writing. The KCNJ11 gene codes for the KIR6.2 subunit of the KATP channels of the pancreatic beta cells. Mutations in this gene limit insulin release from beta cells despite high blood glucose concentrations. Most people with diabetes caused by this genetic mutation can be successfully managed with glibenclamide. Learning of the genetic mutation changed the therapeutic approach to the mother's diabetes and enabled rapid diagnosis for her children. Through this family, we identified that an identical genetic mutation does not necessarily lead to the same diabetic phenotype. We recommend clinicians to consider screening for this gene in their patients whom MODY is suspected; especially in those presenting before the age of 25 who remain C-peptide positive.
KATP channel closure in pancreatic beta cells is a critical step in stimulating insulin release. Mutations in the KIR6.2 subunit can result in the KATP channels remaining open, limiting insulin release. People with KCNJ11 mutations may not present with neonatal diabetes as the age of presentation of diabetes can be highly variable. Most affected individuals can be treated successfully with glibenclamide, which closes the KATP channels via an independent mechanism. All first degree relatives of the index case should be offered genetic testing, including asymptomatic individuals. Offspring of affected individuals should be monitored for neonatal diabetes from birth. Affected individuals will require long-term follow-up as there is a high risk of recurrence in later life.
本病例报告描述了一位母亲及其子女的家系，他们的KCNJ11基因存在E227K突变。携带这种特定基因突变的人通常会出现短暂性新生儿糖尿病；超过一半的患者在青春期或成年早期会复发为永久性糖尿病。然而，这位母亲在青少年时期就患上了糖尿病，因此最初被诊断为1型糖尿病。她所有的孩子都遗传了相同的基因突变，但表现各异。她的第二个、第三个和第四个孩子出现了短暂性新生儿糖尿病，并在不同时间缓解。她的第一个孩子16岁，但在撰写本文时尚未患糖尿病。KCNJ11基因编码胰腺β细胞KATP通道的KIR6.2亚基。该基因突变会限制β细胞在血糖浓度高时释放胰岛素。大多数由这种基因突变导致糖尿病的患者可以通过格列本脲成功治疗。了解到这种基因突变改变了对母亲糖尿病的治疗方法，并使她的孩子能够得到快速诊断。通过这个家系，我们发现相同的基因突变不一定会导致相同的糖尿病表型。我们建议临床医生对疑似青少年发病的成年型糖尿病（MODY）患者进行该基因筛查；尤其是那些在25岁之前发病且C肽仍为阳性的患者。
胰腺β细胞中KATP通道的关闭是刺激胰岛素释放的关键步骤。KIR6.2亚基的突变可导致KATP通道保持开放，限制胰岛素释放。携带KCNJ11突变的人可能不会表现为新生儿糖尿病，因为糖尿病的发病年龄差异很大。大多数受影响的个体可以通过格列本脲成功治疗，格列本脲通过独立机制关闭KATP通道。索引病例的所有一级亲属都应进行基因检测，包括无症状个体。受影响个体的后代应从出生起就监测是否患有新生儿糖尿病。受影响个体需要长期随访，因为后期复发风险很高。
