Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, caused by de novo mutations in ABCC8 / KCNJ11 genes encoding Adenosine Triphosphate (ATP)-sensitive potassium channels, is an unusual cause of infantile-onset developmental/epileptic encephalopathy. Here, we report the long-term seizure and neurodevelopmental outcomes of three children with pathogenic variants in ABCC8 / KCNJ11 genes and the phenotypic spectrum of DEND syndrome. Genetic confirmation was followed by an immediate therapeutic switch from insulin to sulfonylurea in all three children. At the last visit, all these children had good seizure control. However, all of them had residual neurodevelopmental impairments of varying clinical severity. Further large-scale, prospective, multicenter cohorts might be needed to clearly estimate the effect of early initiation of sulphonylurea on long-term seizure and neurodevelopmental outcomes of this rare syndrome. Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to age 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and history of intrauterine growth deficiency. Therapy with insulin and/or oral hypoglycemic medications (in some molecular causes of PNDM) can correct the hyperglycemia and result in dramatic catch-up growth. The course of PNDM varies by genotype. The diagnosis of PNDM is established in an infant with diabetes mellitus diagnosed in the first six months of life that does not resolve over time. Molecular genetic testing is recommended, as identification of a specific molecular cause of PNMD can guide treatment. Targeted therapy: Oral sulfonylureas after initial management with insulin in those with ABCC8- or KCNJ11-related PNDM. Supportive care: Rehydration and intravenous insulin infusion promptly after diagnosis; subcutaneous insulin therapy when the infant is stable and tolerating oral feedings; high caloric diet to achieve weight gain; developmental and educational support in those with KCNJ11-, MNX1-, NEUROD1-, or NKX2-2-related PNDM; anti-seizure medication as needed in those with DEND syndrome (developmental delay, epilepsy, and neonatal diabetes mellitus); pancreatic enzyme replacement therapy in those with exocrine pancreatic insufficiency. Surveillance: Frequent blood glucose monitoring; urinalysis for microalbuminuria and cystatin C measurement annually beginning at age ten years to screen for kidney manifestations of persistent hyperglycemia; ophthalmologic examination for retinopathy annually beginning at age ten years; developmental evaluation annually or as needed in those with KCNJ11-, MNX1-, NEUROD1-, or NKX2-2-related PNDM; neurology evaluation and EEG in those with KCNJ11-related DEND syndrome; evaluation of pancreatic exocrine function in those with symptoms of malabsorption; serum concentrations of fat-soluble vitamins every six months in those with known exocrine pancreatic insufficiency. Agents/circumstances to avoid: In general, avoid rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations (except as a continuous intravenous or subcutaneous infusion), as they may cause severe hypoglycemia in young children. Evaluation of relatives at risk: Evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia. Pregnancy management: Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist; high-resolution ultrasonography and fetal echocardiography should be offered during pregnancy to screen for congenital anomalies in the fetus. The mode of inheritance of PNDM varies by gene: ABCC8- and INS-related PNDM are inherited in an autosomal dominant or an autosomal recessive manner; GATA6-, HNF1B-, and KCNJ11-related PNDM are inherited in an autosomal dominant manner; EIF2AK3-, GCK-, GLIS3-, MNX1-, NEUROD1-, NKX2-2-, PDX1-, PTF1A-, RFX6-, SLC2A2-, and SLC19A2-related PNDM are inherited in an autosomal recessive manner. Autosomal dominant inheritance: The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in ABCC8, INS, or KCNJ11 have the disorder as the result of a de novo pathogenic variant. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the PNDM-related pathogenic variant. Autosomal recessive inheritance: The parents of an individual with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus. If both parents are known to be heterozygous for a PNDM-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. Heterozygote testing for at-risk relatives requires prior identification of the PNDM-related pathogenic variants in the family. Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PNDM are possible.

Neonatal diabetes mellitus (NDM) is a rare cause of diabetes characterized by the presence of severe hyperglycemia typically diagnosed within the first six months of life. Among the main causes are activating variants in heterozygosity in the KCNJ11 gene. Variants in this gene can lead to a spectrum of clinical manifestations, from transitory neonatal diabetes mellitus to DEND syndrome, the most severe form, characterized by developmental delay, epilepsy, neonatal diabetes, and muscle hypotonia. The disease may be present in a milder intermediate form named iDEND syndrome. Patients with KCNJ11 variants may present with attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), developmental coordination disorder (DCD), and learning difficulties due to diminished intelligence quotient (IQ) and dyslexia. These patients can benefit from genetic counseling as most of them can switch from insulin to sulfonylurea treatment with good glycemic control and no severe side effects; besides, some studies report a neurological improvement after the treatment switch. In the present work, we reported a follow-up of a 24-year-old Brazilian male with DEND syndrome due to the KCNJ11 c.754G>A; p.(Val252Met) variant. He was diagnosed with diabetes at 25 days of age and presented with bilateral hypoacusis in the first years of life. He started insulin at the diagnosis. However, the genetic diagnosis was made only at the age of 15 years, and he was switched from insulin to sulfonylurea. At 24 years of age, he presents with good glycemic control and reports no severe episodes of hypoglycemia or hyperglycemia. However, no neurological improvement was observed. This report highlights the potential benefits of switching to sulfonylurea treatment, even in patients with long-standing diagnoses of DEND syndrome, and underscores the importance of genetic diagnosis, as early initiation of sulfonylurea therapy may improve metabolic control and, in some cases, neurological outcomes.

ATP-sensitive potassium (KATP) channel in pancreatic β-cells is composed of four pore-forming inward rectifier potassium (Kir) 6.2 subunits and four regulatory sulfonylurea receptor (SUR) 1 subunits and regulate insulin secretion. Kir6.2 consists of a N-terminal region, an outer transmembrane helix (TM1), an intramembrane region that functions as a potassium selectivity filter, an inner transmembrane helix (TM2) that forms a bundle-crossing gate, and a C-terminal cytoplasmic domain. Mutations in the Kir6.2 subunit can cause neonatal diabetes with severe neurological features (DEND syndrome). The DEND syndrome-inducing I167L mutation of Kir6.2 increases the open probability (Po) of the KATP channel. To investigate the gating mechanism impacted by this mutation in Kir6.2 alone, we used C-terminus-truncated Kir6.2 channels to ascertain the impact of I167 mutations on Po in Kir6.2 channels in the absence of SUR1. We found that I167L and I167F mutations showed an increased Po while the Po of other mutations (I167A, I167V) were unchanged when compared to wild-type channels. By mutating residues in TM1 (W68, L72, F75) that may interact with I167, we found that a double mutation of I167L and F75A normalized the Po. These results would suggest that I167 may play an important role in stabilizing the open state of Kir6.2 channels.

Bupropion, a norepinephrine-dopamine reuptake inhibitor, is widely used as an antidepressant and smoking cessation aid. At high doses, it also inhibits pancreatic β-cell ATP-sensitive potassium (KATP) channels, inducing insulin secretion. KATP channels are also expressed in the brain, and their gain-of-function mutations cause neurological disorders such as developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). This study investigates bupropion's effects on KATP channels in mouse hippocampal CA1 pyramidal neurons. The effects of bupropion on neuronal activity were examined in mouse hippocampal CA1 neurons using electrophysiological techniques. Specifically, whole-cell patch-clamp recordings were performed to measure changes in action potential firing frequency and membrane potential in response to bupropion application. To investigate the potential binding mechanism of bupropion to the KATP channel complex, AlphaFold3, an artificial intelligence-based protein structure prediction tool, was utilized. Electrophysiology revealed that bupropion significantly increased action potential firing frequency and altered membrane potential. AlphaFold3-predicted bupropion binding poses within sulfonylurea receptor 1 's transmembrane domain 0 highlighted key interactions. These structural predictions provide a plausible molecular basis for bupropion's observed electrophysiological effects. These findings suggest bupropion's potential as a therapeutic strategy for DEND syndrome's neurological manifestations. Further investigation into the precise mechanisms and clinical applicability of these findings is warranted.

Neonatal diabetes (NDM) is a rare genetic disorder diagnosed in infants under six months of age, characterized by persistent hyperglycemia resulting from insufficient or absent insulin production. Unlike the more common forms of diabetes, such as type 1 diabetes (T1D) and type 2 diabetes (T2D), NDM is predominantly caused by monogenic mutations affecting ATP-sensitive potassium (K-ATP) channels in pancreatic beta cells. The most common mutations involved in NDM are found in the KCNJ11 and ABCC8 genes, which encode the Kir6.2 and SUR1 subunits of the K-ATP channel, respectively. These mutations prevent normal insulin secretion by disrupting the function of the K-ATP channel. While genetic advances have identified about 40 genes implicated in NDM, the KCNJ11 and ABCC8 mutations are most commonly seen. This review provides a comprehensive exploration of the genetic basis, clinical presentation, and treatment strategies for NDM including the role of sulfonylureas, which have revolutionized the management of this condition. Furthermore, it presents a detailed case study of an infant diagnosed with an ABCC8 mutation, illustrating the pivotal role of genetic testing in guiding clinical decisions. Finally, the article discusses challenges in management, such as the persistence of neurological impairments, and outlines potential directions for future research including genetic therapies and prenatal diagnosis.