Developmental Delay, Epilepsy, And Neonatal Diabetes Research Articles

SAT083 Comparing Grit, Anxiety, And Social Responsiveness In KCNJ11-NDM And Their Sibling Controls

Abstract Disclosure: J. Desai: None. L. Letourneau-Freiberg: None. M. Msall: None. M. Scott: None. R.N. Naylor: None. L. Philipson: None. S.W. Greeley: None. Background: Neonatal diabetes mellitus (NDM), diabetes with onset before 6-12 months of age, is most commonly caused from mutations in the ATP-dependent Potassium (KATP) channel genes: KCNJ11 (KCNJ11-NDM) or ABCC8. Because of brain expression of mutant KATP channels, a spectrum of neurodevelopmental difficulties have been described, such as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, learning disorders, and Attention-deficit/hyperactivity disorder (ADHD). In order to understand more about specific challenges, we compared self- and parent/caregiver-reported grit, anxiety, and social responsiveness among participants with KCNJ11 mutations and their sibling controls. Methods: We recruited 12 families (12 KCNJ11-NDM participants and 10 sibling controls) through the University of Chicago Monogenic Diabetes Registry (www.monogenicdiabetes.org). Affected participants and sibling controls, and in some cases their parent/caregiver, completed the SCARED/SCAARED (anxiety), SRS-2 (social responsiveness) and Grit Scale (grit) surveys. Nonparametric analyses were performed using the Mann-Whitney U-test for group comparisons. Results: Individuals with KCNJ11-NDM had significantly worse social responsiveness scores compared to sibling controls in both Total Social Responsiveness and 4/5 subscales including Social Awareness, Cognition, Communication, and Restricted Interests and Repetitive Behavior (p<0.05), but no difference for Motivation. In terms of deficits in social interaction, 20% of KCNJ11-NDM participants had total SRS-2 T-scores in the mild range, 30% with scores in the moderate range, and 40% with scores in the severe range. 80% of control participants had total SRS-2 T-scores in normal range. Grit results were not significantly different between groups. Total anxiety scores and anxiety subscale scores were not significantly different between groups. Nevertheless, both participants with KCNJ11-NDM and sibling controls revealed greater levels of anxiety as a whole; 50% of KCNJ11-NDM participants (n=6) and 40% of unaffected controls (n=4) had mean total anxiety scores ≥ 25, indicating the possible presence of a clinical anxiety disorder. Conclusion: The prevalence of social interaction challenges was high among KCNJ11-NDM participants, highlighting the importance of early clinical assessment and support for such problems. Results of the SRS-2 Motivation subscale and Grit, which measure more intrinsic levels of personality, may suggest that individuals with KCNJ11-NDM exhibit intrinsic motivation and grit. Elevated overall anxiety levels in both KCNJ11-NDM participants and sibling controls suggest the need for early assessment and supportive interventions for families affected by KCNJ11-NDM. Presentation: Saturday, June 17, 2023

Cognitive deficits and impaired hippocampal long-term potentiation in KATP-induced DEND syndrome

ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF.

Structure based analysis of KATP channel with a DEND syndrome mutation in murine skeletal muscle

Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated KATP channels in skeletal muscle remain elusive. Here, we describe the local effects of the KATP channel on muscle by expressing the mutation present in the KATP channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation. The present study revealed that the DEND mutation can lead to a hyperpolarized state of the muscle cell membrane, and molecular dynamics simulations based on a recently reported high-resolution structure provide an explanation as to why the mutation reduces ATP sensitivity and reveal the changes in the local interactions between ATP molecules and the channel.

Etiologic distribution and clinical characteristics of pediatric diabetes in 276 children and adolescents with diabetes at a single academic center

BackgroundThe prevalence of monogenic diabetes is estimated to be 1.1–6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years.MethodsThis study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively.ResultsOf the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness.ConclusionsGenetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling.

Severe Developmental Delay, Epilepsy and Neonatal Diabetes (DEND) Syndrome: A Case Report

Developmental delay, Epilepsy and Neonatal Diabetes (DEND) syndrome is the most severe form of Permanent Neonatal Diabetes with KCNJ11 gene mutation which accounts for most of the cases. We report the first DEND syndrome in Malaysia with heterozygous missense mutation Q52R at KCNJ11 (Kir6.2) gene with delayed presentation beyond 6 months of age and failure to transition to glibenclamide. This report signifies the phenotypical variability among patients with the same genetic mutation and the different response to treatment.

SUN-278 Neonatal Diabetes in an Infant with Heterozygous Mutation in KCNJ11 Gene

Background: Neonatal Diabetes is a rare form of monogenic diabetes that usually presents with hyperglycemia within the first 6 months of life. These infants usually are small for gestational age at birth. Unlike autoimmune diabetes, development of diabetic ketoacidosis (DKA) is extremely rare in this age group. We present a case of neonatal diabetes in a 3 month old, who presented in DKA. Genetic testing confirmed Kir6.2 subunit mutation. Clinical Case: A 3 month old African American male born to non-consanguineous parents presented with respiratory distress and poor weight gain. Initial blood testing showed serum glucose of 810 mg/dl and pH of 6.9 on an arterial blood gas analysis. Septic workup excluded infectious etiology. Antenatal history was significant for oligohydramnios. Birth history was unremarkable. He was born full term with birth weight of 2,579 grams. Physical examination was normal except for signs of severe dehydration. Both height and weight were below the 3rd percentile. Patient was started on DKA protocol. At the time of discharge, good glycemic control was obtained with a combination of short acting and long acting insulin. Genetic testing on our patient showed missense mutation c.601C>T on KCNJ11 gene on the Kir6.2 subunit encoding for beta cell ATP-sensitive potassium channel. Tight glycemic control was maintained with Lantus and Humalog for few months. He was then transitioned to oral Glyburide (0.2 mg/kg/day). He maintained good glycemic control and continued to develop age appropriate milestones. Conclusion: Neonatal diabetes is rare condition that usually presents with poor weight gain with in first few months of life. If remain undetected, these babies can present with DKA. Autoimmune markers are negative and genetic testing can help differentiate between temporary and permanent types. This particular mutation in our patient usually causes permanent diabetes and has a higher incidence of DEND (Developmental Delay, Epilepsy, and neonatal Diabetes). Unlike Type 1 DM, patients with KCNJ11 mutation are responsive to sulphonylureas and can be weaned off insulin. These infants need close neurological monitoring as well.

Functional Characterization of a Novel KCNJ11 in Frame Mutation-Deletion Associated with Infancy-Onset Diabetes and a Mild Form of Intermediate DEND: A Battle between KATP Gain of Channel Activity and Loss of Channel Expression

ATP-sensitive potassium (KATP) channels are widely distributed in various tissues and cell types where they couple cell metabolism to cell excitability. Gain of channel function (GOF) mutations in the genes encoding Kir6.2 (KCNJ11) or the associated regulatory ssulfonylurea receptor 1 subunit (ABCC8), cause developmental delay, epilepsy and neonatal diabetes (DEND) due to suppressed cell excitability in pancreatic β-cells and neurons. The objective of this study was to determine the molecular basis of infancy-onset diabetes and a mild form of intermediate DEND, resulting from a novel KCNJ11 in frame mutation plus deletion. The naturally occurring Kir6.2 mutation plus deletion (Ser225Thr, Pro226_Pro232del) as well as the isolated S225T mutation or isolated del226–232 deletion were coexpressed with SUR1 in COS cells in homozygous or heterozygous states. The protein expression and gating effects of the resulting channels were assessed biochemically and electrophysiologically. For both the deletion and point mutations, simulated heterozygous expression resulted in overall increased conductance in intact cells in basal conditions and rightward shifted ATP dose-response curves in excised patches, due to increased intrinsic open probability. Interestingly, homomeric channels for the combined deletion/mutation, or for the deletion alone, showed dramatically reduced channel expression at the cell membrane, which would underlie a reduced function in vivo. These results demonstrate that both the mis-sense mutation and the deleted region in the Kir6.2 subunit are important for control of the intrinsic channel gating and suggest that the clinical presentation could be affected by the competition between loss-of-function by reduced trafficking and enhanced channel gating.

Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with theKCNJ11/S225T, del226-232 mutation

Gain-of-function mutations of KCNJ11 can cause permanent neonatal diabetes mellitus, but only rarely after 6 months of age. Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or - more frequently - to a milder sub-type lacking epilepsy, denoted as intermediate-DEND (iDEND). Our aim was to consider a possible monogenic etiology in a 12-yr-old boy with early onset diabetes and mild neurological features. We studied a subject diagnosed with diabetes at 21 months of age, and negative to type 1 diabetes autoantibodies testing. He had learning difficulties during primary school, and a single episode of seizures at the age of 10 yr. We performed direct DNA sequencing of the KCNJ11 gene with subsequent functional study of mutated channels in COSm6 cells. The patient's clinical response to oral glyburide (Glyb) was assessed. Motor coordination was evaluated before and after 6 and 12 months of Glyb therapy. Sequencing of the KCNJ11 gene detected the novel, spontaneous mutation S225T, combined with deletion of amino acids 226-232. In vitro studies revealed that the mutation results in a K(ATP) channel with reduced sensitivity to the inhibitory action of ATP. Glyb improved diabetes control (hemoglobin A1c on insulin: 52 mmol/mol/6.9%; on Glyb: 36 mmol/mol/5.4%) and also performance on motor coordination tests that were impaired before the switch of therapy. We conclude that KCNJ11/S225T, del226-232 mutation caused a mild iDEND form in our patient. KCNJ11 should be considered as the etiology of diabetes even beyond the neonatal period if present in combination with negative autoantibody testing and even mild neurological symptoms.

Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM. The majority of the patients represent isolated cases resulting from de novo mutations. Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. Individuals with KCNJ11 mutations have been successfully transitioned from insulin to sulfonylurea (SU) therapy. Furthermore, there have been cases reported with variable improvement in neurological function following a successful switching. We describe a 12-year-old Portuguese girl with PNDM due to the previously reported R201C mutation in the KCNJ11 gene. Her medical history includes prematurity and moderate developmental delay. The mutation was inherited from her mother who has isolated PNDM. The patient was successfully transferred from insulin to SU, whereas her mother showed SU resistance. Despite good glycemic control, no improvements in the cognitive performance were verified. We present our experience in switching treatment from insulin to oral SUs in this family, and also discuss whether or not the girl's developmental delay is related with the Kir6.2 mutation. To our knowledge, this is the first Portuguese patient reported with successful transition to SU treatment.

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

What does the membrane KATP channel really do in skeletal muscle?

In this issue of The Journal of Physiology, Boudreault et al. (2010) present an interesting phenomenon resulting from inactivation or absence of the skeletal muscle surface membrane KATP channel. Muscles with non-functional KATP channels were subjected to two fatigue protocols separated by at least 15 min. During the second fatigue protocol compared to the first, tetanic force was maintained at a higher level, and the concentration of free myoplasmic Ca2+ ([Ca2+]i) and force during the inter-tetanic intervals showed only modest increases. The reason for the improved performance in the second fatigue protocol remains unclear. The KATP channel is abundant in the sarcolemma of striated muscle. It consists of four Kir6.x subunits that form the pore and four SURx ATP binding subunits (for recent review see Flagg et al. 2010). As the name suggests, ATP is the controller of the channel keeping it closed when [ATP] is above 1 mm (Spruce et al. 1985). Other modulators of the KATP channel, e.g. H+, PIP2, and phosphorylation, have also been described but at normal [ATP]i, their effect is modest. Interestingly, electrophysiological, pharmacological and gene analysis data indicate that while the predominant form of the striated muscle KATP channel is composed of Kir6.2 and SUR2A complexes, there can also be significant levels of Kir6.1, SUR2B and SUR1 in some muscles. The Kir6.1 and Kir6.2 pores have widely different conductances (35 and 80 pS, repectively) and this together with the heterogeneity of the SUR subunits underlies the maximal KATP current density seen in different mouse muscles, ranging from 10 pA μm−2 in the slow soleus to 80 pA μm−2 in the fast tibialis anterior (Tricario et al. 2006). The striking behaviour of the channel in opening at low levels of ATP led to its examination as a factor in muscle fatigue. A decline in muscle force or power output (commonly called fatigue) occurs when muscles are repeatedly contracted. Exercise involves a huge increase in ATP consumption and an attractive hypothesis advanced was that as [ATP]i declines, muscle KATP channels would open, partially depolarise the membrane and impair action potential activated release of Ca2+ from the sarcoplasmic reticulum. Thus, there would be a beneficial effect in that muscle energy consumption would be reduced. Despite the fact that [ATP]i rarely falls by more than 25% even during intensive exercise, the concept of ATP compartmentalisation and possibility of far greater declines in [ATP] close to the surface membrane KATP channel allowed this hypothesis to thrive. Pharmacological manipulations of the membrane KATP channel have yielded equivocal results. Opening the channel accelerated the loss of force but so too, in many but not all experiments, did blockers of the membrane KATP channel. When Kir6.2 knockout mice were tested, it was obvious that tetanic force production was markedly less than in wild-type mice. Fatigue developed more rapidly in muscles from Kir6.2 knockout mice than in those from wild-type mice (Cifelli et al. 2007). Boudreault et al. show in the present study that this rapid development of fatigue could be largely prevented by an earlier fatigue run. Thus, the role of KATP channels in fatigue is dubious. If the membrane KATP channel is not important in fatigue, then what is its role? One clue comes from the finding in the present paper of Boudreault et al. that muscles with non-functional membrane KATP channels have a slower recovery of force after the end of the fatiguing exercise. This slower recovery of force after exercise was preceded by a marked elevation in inter-tetanic concentration of internal Ca2+, which entered the muscle cells through verapamil sensitive channels, presumably L-type channels. It is well known that prolonged elevated [Ca2+]i leads to impaired force production and locally activates Ca2+-dependent proteases (Murphy & Lamb, 2009). Thus, the presence of functional membrane KATP channels may assist in limiting the influx of Ca2+ during sustained contractile activity. But for the fortunate individual without a mutation of Kir6.2 or the SUR subunits of the KATP channel, this is not a factor that will limit exercise capacity. Mutations of the subunits in the membrane KATP channel that lead to clinical manifestations are fortunately rare. One of the better known is the developmental delay, epilepsy and neonatal diabetes (DEND) syndrome which is accompanied by muscle flaccidity and motor impairment. Recently, a mouse model carrying a human mutation known to produce the DEND syndrome was developed. When expressed only in the muscles, no muscle or motor deficit was observed. However, when expressed in neurons, clear muscle and motor impairments were found (Clark et al. 2010). These results again reiterate the point that under normal daily activities, non-functional KATP channels in the membrane of skeletal muscle have little consequence but when the isolated muscle is fatigued to the extreme in vitro, some impairment may be seen.

The G53D Mutation in Kir6.2 (KCNJ11) Is Associated with Neonatal Diabetes and Motor Dysfunction in Adulthood that Is Improved with Sulfonylurea Therapy

Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (KATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of KATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood. The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient's response to SU therapy. The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on KATP activity. The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A. The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle KATP.

A novel mutation causing DEND syndrome

Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes. We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.

KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features

Heterozygous activating mutations in the gene encoding for the ATP-sensitive potassium channel subunit Kir6.2 (KCNJ11) have recently been shown to be a common cause of permanent neonatal diabetes. Kir6.2 is expressed in muscle, neuron and brain as well as the pancreatic beta-cell, so patients with KCNJ11 mutations could have a neurological phenotype in addition to their diabetes. It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes. We identified KCNJ11 mutations in four of 10 probands with permanent neonatal diabetes and one affected parent; this included the novel C166F mutation and the previously described V59M and R201H. Four of the five patients with mutations had neurological features: the patient with the C166F mutation had marked developmental delay, severe generalised epilepsy, hypotonia and muscle weakness; mild developmental delay was present in the patient with the V59M mutation; one patient with the R201H mutation had acute and chronic neurological consequences of cerebral oedema and another had diabetic neuropathy from chronic hyperglycaemia. In conclusion, the clinical features in these patients support the existence of a discrete neurological syndrome with KCNJ11 mutations. The severe DEND syndrome was seen with the novel C166F mutation and mild developmental delay with the V59M mutation. These features differ markedly from the neurological consequences of acute or chronic diabetes.

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. A minority of patients also have neurological features. The identification of a KCNJ11 mutation has important therapeutic implications, as many patients can replace insulin injections with sulfonylurea tablets. We aimed to determine the age of presentation of patients with KCNJ11 mutations and to examine if there was a relationship between genotype and phenotype. KCNJ11 was sequenced in 239 unrelated patients from 21 countries, who were diagnosed with permanent diabetes before 2 years of age. Thirty-one of the 120 patients (26%) diagnosed in the first 26 weeks of life had a KCNJ11 mutation; no mutations were found in the 119 cases (0%) diagnosed after this age. Fourteen different heterozygous mutations were identified, with the majority resulting from de novo mutations. These include seven novel mutations: H46Y, R50Q, G53D C166Y, K170T, L164P and Y330S. All 11 probands with the most common mutation, R201H, had isolated diabetes. In contrast, developmental delay in addition to diabetes was seen in four of five probands with the V59M mutation and two of four with the R201C mutation. Five patients with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome had unique mutations not associated with other phenotypes. KCNJ11 mutations are a common cause of permanent diabetes diagnosed in the first 6 months and all patients diagnosed in this age group should be tested. There is a strong genotype-phenotype relationship with the mutation being an important determinant of associated neurological features.

Activating Mutations in Kir6.2 and Neonatal Diabetes

Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at <6 months of age. There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause neonatal diabetes by reducing K(ATP) channel ATP sensitivity and increasing the K(ATP) current, which inhibits beta-cell electrical activity and insulin secretion. The severity of the clinical symptoms is reflected in the ATP sensitivity of heterozygous channels in vitro with wild type > transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.