KCNJ11 Mutations Research Articles

Neonatal hyperglycaemia and abnormal development of the pancreas

Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions occurring in around 1 per 300,000 live births. In TNDM, growth-retarded infants develop diabetes in the first few weeks of life, only to go into remission after a few months with possible relapse to permanent diabetes usually around adolescence or in adulthood. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. The very recently elucidated mutations in KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunits of the pancreatic K(ATP) channel involved in regulation of insulin secretion, account for a third to a half of the PNDM cases. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provides a tool for distinguishing transient from permanent neonatal diabetes mellitus in the neonatal period. Some patients (those with mutations in KCNJ11 and ABCC8) may be transferred from insulin therapy to sulphonylureas.

Outpatient transition of an infant with permanent neonatal diabetes due to a KCNJ11 activating mutation from subcutaneous insulin to oral glyburide

Neonatal diabetes mellitus is rare, may either be transient or permanent, and may be caused by mutations in any of the several different genes. Until recently, most forms of permanent neonatal diabetes required lifelong subcutaneous insulin for management; however, permanent neonatal diabetes due to activating mutations in the KCNJ11 gene, which encodes the Kir6.2 protein subunit of the ATP-sensitive K+ (K(ATP)) channel, may be amenable to oral sulfonylurea therapy. We describe a case of an 18-month-old infant with permanent neonatal diabetes due to an activating KCNJ11 mutation successfully transitioned from subcutaneous insulin therapy to oral sulfonylurea therapy in the outpatient setting.

Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8, which encode the two subunits of the ATP-sensitive K(+) channel (K(ATP) channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a K(ATP) channel mutation. We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation. We identified three missense mutations in the INS gene in four probands. Two of four mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent approximately 10% of all permanent neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with K(ATP) channel mutations. CONCLUSIONS; Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable, since residual beta-cell function is still present in some patients.

PREVALENCE AND INCIDENCE OF A NEWLY DEFINED TYPE OF DIABETES IN CHILDREN, ADOLESCENTS, AND ADULTS IN THE LARGEST INTERNATIONAL SERIES TO DATE

INTRODUCTION: Recently, interest in “neonatal” diabetes has increased because patients could stop taking insulin and improve glycemic control and associated neurologic features. OBJECTIVE: Our objective was to determine the anticipated increase in prevalence and incidence of permanent neonatal diabetes in children, adolescents, and adults and investigate the impact of the new definition. METHODS: We studied 293 (53% male) referrals to the Exeter Laboratory (Devon, United Kingdom) as part of the largest international series to date. The referred patients were diagnosed with diabetes below 6 months of age irrespective of current age, and their conditions had not remitted at the time of study. Data on 27 countries were collected, and age of diagnosis, date of birth, and gender were obtained from standardized forms. All referred patients were tested for KCNJ11 mutations. RESULTS: The minimum observed prevalence of the 5 most representative countries was 1.17 (1.01–1.31) per million population, with the estimated true prevalence twice as high. Prevalence was higher for the pediatric versus adult age range (odds ratio: 0.78 [95% confidence interval: 0.54–1.31] vs 0.42 [95% confidence interval: 0–0.50], respectively; P = .009). Seventy-five percent of the patients were below 16 years of age with a median (interquartile range) of 5.7 (2.4–10.2) years, which implies underdiagnosis beyond 5 years of age. Age of diagnosis was skewed to a median (interquartile range) of 6 (1–13) weeks, with 62% in the first 8 weeks. During 2000–2004, the minimum observed incidence was 2.95 (0–49.1) per million live births. CONCLUSIONS: This is the first report to show 2 to 25 times higher prevalence than previous reports from 10 years ago. “Neonatal” should be changed to “diagnosed at <6 months of age irrespective of current age,” and awareness should be increased, especially for those who are older than 5 years and present with treatment implications.

Insulin Mutation Screening in 1,044 Patients With Diabetes

Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood. The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes. We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant. We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.

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.

Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11

A 12-week-old female presented with neonatal diabetes. Insulin therapy alleviated the diabetes, but the patient showed marked motor and mental developmental delay. The patient underwent genetic evaluation at the age of 6 years, prompted by reports that mutations in the KCNJ11 gene caused neonatal diabetes. Genomic sequencing of the ATP-sensitive potassium (K(ATP)) channel gene KCNJ11 and in vitro functional analysis of the channel defect, and single-photon emission CT imaging before and after glibenclamide therapy. Genetic evaluation revealed a missense mutation (His46Leu) in KCNJ11, which encodes the Kir6.2 subunit of the K(ATP) channel, conferring reduced ATP sensitivity. Functional studies demonstrated that the mutant channels were strongly inhibited by the sulfonylurea tolbutamide. Sulfonylurea (glibenclamide) treatment led to both improved glucose homeostasis and an increase in mental and motor function.

Sulfonylrea Treatment in Permanent Neonatal Diabetes Due to G53D Mutation in the KCNJ11 Gene

Previous studies have reported the successful switch from insulin to sulfonylrea therapy in some patients who have neonatal diabetes due to KCNJ11 mutations (1); however, data on adults are limited (2,3). Also, it has not yet been determined whether neurological symptoms can be improved by the action of sulfonylrea therapy. Here, we report the glycemic and neurological responses in an adult patient with the G53D mutation in the KCNJ11 gene who was transferred from insulin to sulfonylurea. A 26-year-old male patient was diagnosed with diabetes in the third month of …

Abstract 910: Catecholaminergic Polymorphic Ventricular Tachycardia: Genetics, Natural History and Response to Therapy

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmo-genic cardiac disease predisposing affected individuals to sudden cardiac death (SCD). Methods and Results: Here we provide data on the largest CPVT population thus far described. The study population consisted of 177 patients (64% female) of 93 families. All 93 probands (pbs) were screened for RYR2 mutations: 54 (58%) pbs carried a heterozygous RYR2 mutation, 1 pb a compound heterozygous RYR2 mutation and 3 pbs a homozygous (1), compound heterozygous (1) or heterozygous (1) CASQ2 mutation. One KCNJ2 mutation (T305I) was detected in a total of 15 pbs. In family members, another 40 RYR2 mutation carriers were identified. Only 29 of 95 gene carriers were phenotypically silent, therefore the penetrance of a RYR2 mutation was 69%. Of note, female sex was predominant among CPVT probands without a RYR2 mutation. Before the initiation of any treatment related to CPVT, 77 of 93 (83%) pbs experienced a cardiac e vent. Mean age of first event was 12±9 years. Neither sex nor the presence/absence of a RYR2 mutation was associated with a higher risk of developing events or with a younger age at onset of symptoms. Before therapy, 70% and 40% of 177 patients remained free of cardiac arrest and SCD before therapy by age 20 and 40 years, respectively. A history of juvenile SCD (&lt;40 yrs) was present in 36% of families: the mean age of the lethal event was 18±9 yrs. One-hundred CPVT patients were initiated on β-blockers. On top, 41 patients were implanted with an ICD. During a mean follow-up time of 4.5±3 years, 28% of patients experienced a syncope (n=11), cardiac arrest (n=5) or appropriate ICD shock (n=12). Neither sex nor genotype was associated with a worse response to therapy. Conclusions: In this largest CPVT population reported so far, the presence/absence of a RYR2 mutation wasn’t associated with different clinical characteristics or response to therapy as compared to non-mutation carriers. CPVT remains a highly malignant disease with only a moderate response to β-blockers.

Diabète néonatal : une maladie aux multiples mécanismes

Transient (TNDM) and Permanent (PNDM) Neonatal Diabetes Mellitus are rare conditions occurring in about 1: 300,000 live births. In TNDM growth retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with possible relapse to a permanent diabetes state usually around adolescence or as adults. We believe that pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular levels. Among those, the very recently elucidated mutations in KCNJ11 and ABCC8 gene, encoding the Kir6.2 and SUR1 subunit of the pancreatic K ATP channel involved in regulation of insulin secretion accounts for one third to a half of the PNDM cases. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances. Recurrent diabetes is common in patients with “transient” neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Molecular analysis of chromosome 6 anomalies, the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provide a tool to identify transient from permanent neonatal diabetes mellitus in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 from insulin therapy to sulfonylureas. Realizing how difficult it is to take care of a child of this age with diabetes mellitus should prompt clinicians to transfer these children to specialized centers. Insulin therapy and high caloric intake are the basis of the treatment. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.

Of mighty mice and diabetic men: animal models of islet dysfunction

Of mighty mice and diabetic men: animal models of islet dysfunction

Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period

Mutations in the ABCC8 gene encoding the SUR1 subunit of the pancreatic ATP-sensitive potassium channel cause permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We reviewed the existing literature, extended the number of cases and explored genotype-phenotype correlations. Mutations were identified by sequencing in patients diagnosed with diabetes before 6 months without a KCNJ11 mutation. We identified ABCC8 mutations in an additional nine probands (including five novel mutations L135P, R306H, R1314H, L438F and M1290V), bringing the total of reported families to 48. Both dominant and recessive mutations were observed with recessive inheritance more common in PNDM than TNDM (9 vs. 1; p < 0.01). The remainder of the PNDM probands (n = 12) had de novo mutations. Seventeen of twenty-five children with TNDM inherited their heterozygous mutation from a parent. Nine of these parents had permanent diabetes (median age at diagnosis: 27.5 years, range: 13-35 years). Recurrent mutations of residues R1183 and R1380 were found only in TNDM probands and dominant mutations causing PNDM clustered within exons 2-5. ABCC8 mutations cause PNDM, TNDM or permanent diabetes diagnosed outside the neonatal period. There is some evidence that the location of the mutation is correlated with the clinical phenotype.

Early Glibenclamide Treatment in a Clinical Newborn With KCNJ11 Gene Mutation

Activating mutations in the KCNJ11 gene, which code for the ATP-sensitive K+ channel subunit Kir6.2, are the most common cause of permanent neonatal diabetes. Recently, a switch from insulin treatment to oral sulfonylurea has been proposed if genetic testing reveals sulfonylurea-sensitive KCNJ11 mutations (1). Until now, hurdles for early treatment were 1 ) the time until the mutation analysis is finished and 2 ) the lack of knowledge about adverse effects of glibenclamide in …

Sulphonylurea treatment does not improve psychomotor development in children with KCNJ11 mutations causing permanent neonatal diabetes mellitus accompanied by developmental delay and epilepsy (DEND syndrome)

Diabetic MedicineVolume 24, Issue 10 p. 1176-1178 Sulphonylurea treatment does not improve psychomotor development in children with KCNJ11 mutations causing permanent neonatal diabetes mellitus accompanied by developmental delay and epilepsy (DEND syndrome) Z. Sumnik, Z. Sumnik Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorS. Kolouskova, S. Kolouskova Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorJ. K. H. Wales, J. K. H. Wales Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorV. Komarek, V. Komarek Department of Pediatric Neurology, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech RepublicSearch for more papers by this authorO. Cinek, O. Cinek Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this author Z. Sumnik, Z. Sumnik Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorS. Kolouskova, S. Kolouskova Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorJ. K. H. Wales, J. K. H. Wales Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this authorV. Komarek, V. Komarek Department of Pediatric Neurology, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech RepublicSearch for more papers by this authorO. Cinek, O. Cinek Department of Pediatrics, Second Faculty of Medicine, University Hospital Motol, Charles University in Prague, Prague, Czech Republic, Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK andSearch for more papers by this author First published: 24 September 2007 https://doi.org/10.1111/j.1464-5491.2007.02228.xCitations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume24, Issue10October 2007Pages 1176-1178 RelatedInformation

Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects

Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

Monogenic disorders of the pancreatic β-cell: personalizing treatment for rare forms of diabetes and hypoglycemia.

Over the past 10-20years, our understanding of the genetic etiology of monogenic disorders of the pancreatic β-cell has greatly improved. This has enabled clinicians to provide patients with more accurate information regarding prognosis and inheritance and has influenced treatment. Maturity-onset diabetes of the young and neonatal diabetes are two such examples. Patients with maturity-onset diabetes of the young due to glucokinase mutations can usually be managed by dietalone, while those affected by HNF-1α and HNF-4α mutations respond well to low doses of sulfonylureas. The identification of mutations in the ATP-dependent potassium channel genes KCNJ11 and ABCC8 as the most common cause of permanent neonatal diabetes has improved treatment regimes for affected children. In addition to enabling patients to stop insulin injections, their glycemic control has also improved. These advances show the importance of unravelling the genetics of a disease to achieve the best individualized treatment for the patients affected.

A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome

Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and life-threatening polymorphic ventricular tachyarrhythmias. LQT1 caused by KCNQ1 mutations is the most common form of LQTS. Patients diagnosed with LQTS were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and SCN5A. A novel mutation was identified in KCNQ1 caused by a three-base deletion at the position 824-826, predicting a deletion of phenylalanine at codon 275 in segment 5 of KCNQ1 (DeltaF275). Wild-type (WT) and DeltaF275-KCNQ1 constructs were generated and transiently transfected together with a KCNE1 construct in CHO-K1 cells to characterize the properties of the slowly activating delayed rectifier current (IKs) using conventional whole-cell patch-clamp techniques. Cells transfected with WT-KCNQ1 and KCNE1 (1:1.3 molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail current density measured at -40 mV following a two-second step to +60 mV was 381.3 +/- 62.6 pA/pF (n = 11). Cells transfected with DeltaF275-KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8 +/- 2.1 pA/pF, n = 11, P = 0.00001 vs WT). Cotransfection of WT- and DeltaF275- KCNQ1 (50/50), along with KCNE1, produced little to no current (tail current density: 10.3 +/- 3.5 pA/pF, n = 11, P = 0.00001 vs WT alone), suggesting a potent dominant negative effect. Immunohistochemistry showed normal membrane trafficking of DeltaF275-KCNQ1. Our data suggest that a DeltaF275 mutation in KCNQ1 is associated with a very potent dominant negative effect leading to an almost complete loss of function of IKs and that this defect underlies a LQT1 form of LQTS.

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.

Transition from insulin to glyburide in a 4-month-old girl with neonatal diabetes mellitus caused by a mutation in KCNJ11

Initial management of neonatal diabetes mellitus consists of insulin and adequate calories for growth. Once a genetic diagnosis is made, most patients with neonatal diabetes caused by mutations in the KCNJ11 gene can be successfully managed with a sulfonylurea agent without the need for insulin. We report on the transition from insulin to glyburide (glibenclamide) therapy in a 4-month-old girl with neonatal diabetes mellitus caused by a mutation in KCNJ11. Dosing of glyburide three times daily was critical for her successful transition.

Molecular Basis of Neonatal Diabetes in Japanese Patients

Neonatal diabetes mellitus (NDM) is classified clinically into a transient form (TNDM), in which insulin secretion recovers within several months, and a permanent form (PNDM), requiring lifelong medication. However, these conditions are genetically heterogeneous. Our objective was to evaluate the contribution of the responsible gene and delineate their clinical characteristics. The chromosome 6q24 abnormality and KCNJ11 and ABCC8 mutations were analyzed in 31 Japanese patients (16 with TNDM and 15 with PNDM). Moreover, FOXP3 and IPF1 mutations were analyzed in a patient with immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome and with pancreatic agenesis, respectively. A molecular basis for NDM was found in 23 patients: 6q24 in eleven, KCNJ11 in nine, ABCC8 in two, and FOXP3 in one. All the patients with the 6q24 abnormality and two patients with the KCNJ11 mutation proved to be TNDM. Five mutations were novel: two (p.A174G and p.R50G) [corrected] in KCNJ11, two (p.A90V and p.N1122D) in ABCC8, and one (p.P367L) in FOXP3. Comparing the 6q24 abnormality and KCNJ11 mutation, there were some significant clinical differences: the earlier onset of diabetes, the lower frequency of diabetic ketoacidosis at onset, and the higher proportion of the patients with macroglossia at initial presentation in the patients with 6q24 abnormality. In contrast, two patients with the KCNJ11 mutations manifested epilepsy and developmental delay. Both the 6q24 abnormality and KCNJ11 mutation are major causes of NDM in Japanese patients. Clinical differences between them could provide important insight into the decision of which gene to analyze in affected patients first.