Non classic presentations of a genetic mutation typically associated with transient neonatal diabetes

Abstract

Summary 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. Learning points: 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.

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

“…Approximately 38.5% of mutations in the KCNJ11 gene, which encodes Kir 6.2 and consists of a single exon containing 390 amino acids, have been identified, which is associated with clinical diseases including but not limited to neonatal diabetes mellitus, maturity-onset diabetes of the young, type 2 diabetes mellitus, and even persistent hyperinsulinemic hypoglycemia of infancy ( He et al, 2021 ). Patients with the E227K mutation in the KCNJ11 gene typically manifest with transient neonatal diabetes, which remits spontaneously, usually within 4–60 weeks of onset; however, more than half of these patients relapse into permanent diabetes in adolescence or early adulthood ( Devaraja et al, 2020 ). rs5215 G/G (nucleotide change; G-A, amino acid change; Val337Ile) of the KCNJ11 gene, located at 11p15.1 and encoding the Kir6.2 subunit, causes valine-isoleucine substitution in exon 1,009 (ATC-GTC), and it is associated with a gain of function of the K ATP channel, leading to vasodilation augmentation and shear stress reduction, which protects humans from lower coronary microvascular dysfunction, reducing the risk of ischemic heart disease in women ( Severino et al, 2020 ).…”

The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

“…K ATP is the only ion channel besides TALK-1 to be linked to MODY; this is due to mutations in genes encoding the K ATP channel complex ( KCNJ11 and ABCC8 ) or mutations in genes affecting ATP synthesis (e.g., glucokinase) (19, 20). Interestingly, MODY-associated mutations in KCNJ11 and ABCC8 have also been found to cause other diabetic phenotypes including permanent or transient neonatal diabetes, and late-onset diabetes (21, 22). Although the two families with Kcnk16 L114P exhibit a MODY phenotype, it remains to be determined if KCNK16 mutations are associated with other diabetic phenotypes besides MODY.…”

“…Interestingly, MODY-associated mutations in KCNJ11 and ABCC8 have also been found to cause other diabetic phenotypes including permanent or transient neonatal diabetes, and late-onset diabetes (21,22). Although the two families with TALK-1 L114P primarily exhibit a MODY phenotype, it remains to be determined if KCNK16 mutations are associated with other diabetic phenotypes besides MODY.…”

The role of intermittent continuous glucose monitoring in a successful outpatient transition from insulin to glibenclamide in a patient with transient neonatal diabetes

“…Approximately 30% of TNDM cases will have an activating mutation in the K ATP channel genes ABCC8 and KCNJ11, which code, respectively, for the SUR1 and Kir6.2 subunits of the channel (4). Pathogenic gain-of-function variants in the KCNJ11 gene cause the permanent opening of the K ATP channel, which maintains the resting state of the cell membrane of the beta-cell.…”