Transient neonatal diabetes with two novel mutations in the KCNJ11 gene and response to sulfonylurea treatment in a preterm infant

Neonatal diabetes mellitus (NDM) is a rare condition that can be either transient or permanent. K(ATP) channel (Kir6.2 or SUR1) mutation, chromosome 6 abnormalities, insulin, or glucokinase gene mutations can lead to isolated NDM. Cases caused by Kir6.2 mutation usually result in permanent NDM (PNDM) rather than transient NDM (TNDM). The majority of patients with the Kir6.2 or SUR1 mutation can be successfully managed with a sulfonylurea agent, without the need for insulin. We report a preterm male with NDM having two novel missense mutations, E322A and D352H, in the KCNJ11 gene. At 2 months of age, successful transition from insulin to glibenclamide (glyburide) therapy of the patient was managed. At 5 months of age, his diabetes went in to remission.     

Permanent neonatal diabetes due to KCNJ11 gene mutation

Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of diabetes within the first six months of life and insulin dependence life long. It has been recently discovered that mutation in KCNJ11 gene encoding Kir6.2, the pore forming subunit of ATP sensitive potassium channel (K_ATP) is the most common cause and such patients may respond better to oral sulphonylurea drugs than insulin. Here is a rare case of permanent neonatal diabetes due to R201C mutation in KCNJ11 gene.     

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.     

Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15‐yr‐old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM

Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15‐yr‐old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP‐sensitive potassium channel, often result in neonatal diabetes. Patients with this mutation have been successfully transitioned from insulin to sulfonylurea (SU) therapy without compromise in their glycemic control. Among patients with neonatal diabetes due to KCNJ11 mutations, approximately 25% have neurological findings including developmental delay, motor dysfunction, and epilepsy, known as DEND syndrome. There have been rare cases of juvenile patients with intermediate DEND syndrome (iDEND) reporting variable improvement in neurological function following transition from insulin to SU treatment. We describe the response to glyburide in a 15‐yr‐old boy with severe global developmental delays resulting from the KCNJ11 mutation V59M. The patient was discovered to have diabetes mellitus at 11.5 months of age, making this the oldest age at diagnosis of a KCNJ11 mutation‐related case of neonatal diabetes. Because consensus has been to screen patients for this mutation only if younger than 6 months at the time of diagnosis, we suggest that all patients under the age of 12 months at diagnosis should receive genetic testing for monogenic causes of diabetes.     

Permanent neonatal diabetes with known genetic background: oral drugs in treatment of childhood diabetes

Diabetes, which is diagnosed before 6 months of age, is patogenetically different than type 1 diabetes. This kind of diabetes also known as a neonatal diabetes is genetically determined with monogenic mode of inheritance. Most of these patients are carriers of heterozygous mutation in the KCNJ11 or ABCC8 gene. These mutations may activate the Kir6.2/SUR1 potassium channel in the beta cells and disturb insulin secretion, which in consequence leads to diabetes. This patological phenomenon is reversible if sulfonylureas are used as a first line therapy. In the current paper a systematic review of clinical aspects of sulfonylurea treatment in neonatal diabetes has been performed. This gives the further evidence that knowlegde of the patogenesis of neonatal diabetes may be easily transferred to bedside and clinical practice.     

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

Abstract:  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.     

Transition from insulin to sulfonylurea in a child with diabetes due to a mutation in <Emphasis Type="Italic">KCNJ11</Emphasis> encoding Kir6.2—initial and long-term response to sulfonylurea therapy

Background  Mutations in the KCNJ11 gene encoding the adenosine triphosphate (ATP)-sensitive potassium channel (K_ATP) subunit Kir6.2 are the most frequent cause of diabetes in infancy. Sulfonylurea (SU) treatment restores insulin secretion in patients with KCNJ11 mutations. Materials and methods  We report a 9-year-old boy who presented at the age of three months with diabetic ketoacidosis. Results Sequencing of the KCNJ11 gene revealed an R201H mutation. Therefore, he was transferred from insulin to oral SU therapy. He required a high-threshold dose before insulin could be discontinued. After transition, a subsequent dose reduction was necessary to avoid hypoglycemia. Improved sustained metabolic control without complications was achieved on a low SU maintenance dose twice daily over 36 months. Conclusion  SU therapy is safe for patients with diabetes due to KCNJ11 mutations. The mechanism of a threshold dose and the twice-daily requirement needs further attention.     

Neonatal diabetes: a disease linked to multiple mechanisms]

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.     

AV59M KCNJ11 gene mutation leading to intermediate DEND syndrome in a Chinese child

Heterozygous activating mutations in the KCNJ11 gene can cause permanent and transient neonatal diabetes. In the present study, we sequenced the KCNJ11 gene in a Chinese boy diagnosed with permanent neonatal diabetes mellitus (PNDM) and also in his parents. A heterozygous 175G > A (V59M) mutation was identified in the patient, while no KCNJ11 gene mutations were found in his parents, indicating that this mutation is de novo. The patient with the V59M mutation successfully switched from insulin injections to oral glibenclamide; 2 years of follow-up revealed that the patient had intermediate developmental delay, epilepsy and neonatal diabetes (DEND) syndrome. This is the first patient who is reported to have iDEND syndrome due to KCNJ11 V59M mutation in China.     

Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/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 Caused by a Novel Mutation

Most cases of permanent form of neonatal diabetes mellitus (PNDM) are due to dominant heterozygous gain of function (activating) mutations in either KCNJ11 or ABCC8 genes, that code for Kir 6.2 and SUR1 subunits, respectively of the pancreatic β-cell KATP channel. We describe the interesting case of an infant with PNDM, in whom a compound heterozygous activating/ inactivating mutation was found with clinically unaffected parents, each carrying a heterozygous mutation in ABCC8, one predicting gain of function (neonatal diabetes) and the other a loss of function (hyperinsulinemia).     

Diagnosis and treatment of neonatal diabetes: a United States experience

Background/objective: Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50% of patients diagnosed with diabetes before 6 months of age and in a small fraction of those diagnosed between 6 and 12 months. The aim of this study was to identify the genetic cause of diabetes in 77 consecutive patients referred to the University of Chicago with diabetes diagnosed before 1 yr of age. Methods: We used Oragene? DNA Self‐Collection kit to obtain a saliva sample for DNA. We sequenced the protein‐coding regions of KCNJ11, ABCC8, and INS using standard methods. Results: We enrolled 32 patients diagnosed with diabetes before 6 months of age and 45 patients diagnosed between 6 and 12 months. We identified a mutation in KCNJ11 in 14 patients from 12 families and in INS in 7 patients from 4 families. Three of the patients with an INS mutation were diagnosed with diabetes between 6 and 12 months of age. Finally, we found that two patients had an abnormality of chromosome 6q24 associated with transient neonatal diabetes mellitus. Conclusions: We were able to establish a genetic cause of diabetes in 63% of patients diagnosed with diabetes before 6 months of age and in 7% of patients diagnosed between 6 and 12 months. Genetic testing, which is critical for guiding appropriate management, should be considered in patients diagnosed with diabetes before 1 yr of age, especially if they are autoantibody negative, although the presence of autoantibodies does not rule out a monogenic cause.     

KATP channel mutations in congenital hyperinsulinism

Adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP) channels) have a central role in the regulation of insulin secretion in pancreatic β cells. They are octameric complexes organized around the central core constituted by the Kir6.2 subunits. The regulation of the channel itself takes place on the sulfonylurea receptor-1 subunit. The channel opens and closes according to the balance between adenine nucleotide ATP and adenosine diphosphate. Hyperinsulinemic hypoglycemia (also named congenital hyperinsulinism, or CHI) is associated with loss-of-function K(ATP) channel mutations. Their frequency depends on the histopathological form and the responsiveness of CHI patients to diazoxide. ABCC8/KCNJ11 defects are identified in approximately 80% of patients with CHI refractory to diazoxide. Within this group, focal forms are related to a paternally inherited KCNJ11 or ABCC8 mutation and the loss of the corresponding maternal allele in some pancreatic β cells leading to a focal lesion. Diffuse forms are mostly associated with recessively inherited mutations. Some patients with diffuse forms also carried a single K(ATP) channel mutation. In contrast, K(ATP) mutations are involved in 15% of diazoxide-responsive CHI cases that are either sporadic or dominantly inherited.     

Permanent neonatal diabetes with arthrogryposis multiplex congenita and neurogenic bladder – a new syndrome?

Abstract: Neonatal diabetes mellitus is a rare (1/400 000 newborns) but potentially devastating condition, which may be transient or permanent; typical symptoms occur within the first 4 wk of life. The transient form is a developmental insulin production disorder that resolves postnatally. Fifty to 60% of cases can be seen as transient form. Cases that require lifelong insulin therapy can be described as permanent condition. This fraction of cases is less common than the transient form. There are no clinical features that can predict whether a neonate with diabetes mellitus but no other dysmorphology will eventually have permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus. Some metabolic or genetic defects such as complete deficiency of glucokinase or heterozygous activating mutations of KCNJ11, encoding Kir6.2, were found in patients with PNDM. A preterm female infant with a gestational age of 36 wk was admitted to the neonatal intensive care unit in the first hours of life due to prematurity and intra‐uterine growth retardation. She was diagnosed as having arthrogryposis multiplex congenita on the first day. Hyperglycemia was detected on the third day of life, and she required insulin treatment. The patient is now 6 yr old with PNDM, arthrogryposis multiplex, neurogenic bladder, immune deficiency, constipation, and ichthyosis. Is this a new form of neonatal diabetes mellitus?     

Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections

Abstract:  Pancreatic agenesis is a rare cause of neonatal diabetes mellitus (NDM). It can be associated with malformations of the heart, the biliary tract, and the cerebellum. We report an infant with NDM because of pancreatic agenesis, intra-uterine growth retardation, dysmorphic features, and recurrent bacterial infections. He was born to healthy consanguineous parents. With adequate replacement of insulin and pancreatic enzymes, his blood glucose levels were controlled and his weight slowly increased. However, he continued to develop recurrent serious bacterial infections and died at the age of 11 months with sepsis and respiratory failure. Analysis of the PTF1A and PDX1 genes, which have been associated with congenital agenesis of the pancreas, did not reveal any mutation. Genetic abnormalities of chromosome 6 associated with transient neonatal diabetes as well as mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic potassium channel were also excluded as a cause of the NDM in this patient. The association of permanent neonatal diabetes because of pancreatic agenesis, dysmorphism, and non-specific immunodeficiency is previously undescribed and may represent a new possibly autosomal recessive syndrome.     

From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels

Pancreatic beta-cell adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. K(ATP) channels are hetero-octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the K(ATP) channels. Loss-of-function mutations in the genes encoding the two subunits of K(ATP) channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of K(ATP) channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic beta-cell K(ATP) channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other.     

Familial permanent neonatal diabetes with KCNJ11 mutation and the response to glyburide therapy--a three-year follow-up

We describe 3 years follow-up of glyburide therapy in a child with permanent neonatal diabetes mellitus (PND) born to a 19 year-old mother with congenital diabetes mellitus. Genetic analysis identified a KCNJ11 mutation (R201H) in both the child and her mother. After 2 years of insulin therapy, the patient was switched to oral glyburide. After initial stabilization, glyburide therapy resulted in a marked decrease in glucose excursions in comparison to insulin. The patient had 3-10 episodes of hypoglycemia per week, including a total of eight episodes resulting in seizures, while on insulin. In contrast, no severe hypoglycemia was reported on glyburide. The patient's basal C-peptide was undetectable on insulin therapy (< 166 pmol/l) but was easily detectable on glyburide (189-761 pmol/l). The range of HbA1c improved significantly from 8-12% on insulin to 4.7-6% on glyburide. The frequency of glucose monitoring was gradually decreased from 4-8 times to 2-3 times a day on oral glyburide. This report confirms the superiority of sulfonylurea therapy in the treatment of PND with Kir6.2 mutations and shows sustained improved glycemic control over a 3-year follow-up period. Genetic exploration in other family members with diabetes might provide further insight into the nature of familial neonatal diabetes.     

A new variant of a known mutation in two siblings with permanent neonatal diabetes mellitus

Permanent neonatal diabetes mellitus is a rare disorder usually presenting within the first few weeks or months of life. This disorder is genetically heterogeneous and has been associated with mutations in various genes. The genetic cause remains mostly unknown although several genes have been linked to this disorder. Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50%-60% of the patients. With genetic studies, we hope to increase our knowledge of neonatal diabetes, whereby new treatment models can become possible. Here, we defined a new variant of a known mutation, INS Exon 1-3 homozygous deletion, in two siblings diagnosed with permanent neonatal diabetes mellitus.     

Transient neonatal diabetes due to activating mutation in the ABCC8 gene encoding SUR1

We report a 2 month male child presenting with diabetic ketoacidosis (DKA) and seizures treated with intravenous fluids and intravenous insulin infusion till the ketoacidosis was reversed, thereafter responding well to sulphonylureas and at age of 13 months going into complete remission. At age of 11 months developmental delay in the form of negative neck holding and inability to sit without support was seen. The child is 3 years of age now, euglycemic without any insulin or oral hypoglycemic agents but has severe developmental delay. Genetic analysis was negative for mutations of KCNJ11, 6q24, Glucokinase and IPF-1 genes. A mutation R1183W was found in the ABCC8 gene encoding SUR1, which was the cause of neonatal diabetes in this case.     

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.