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.     

The genetic basis of neonatal diabetes mellitus

Neonatal diabetes mellitus is a rare condition occurring within the first few months of life that can either be permanent or transient. Various genetic defects responsible for both permanent and transient neonatal diabetes have been identified. ATP-sensitive potassium (KATP) channels are key regulators of nutrient-induced insulin secretion in pancreatic beta cells. Activating mutations of the KATP channel, which prevent closure of the channel and thus inhibit insulin secretion, are now known to be the predominant cause of permanent neonatal diabetes. Transient neonatal diabetes may also be associated with activating mutations of the KATP channel. However, the majority of cases of transient neonatal diabetes have a mutation that maps to a locus on the long arm of chromosome 6, and mutations in two overlapping genes, ZAC and HYMA1, have been identified as the predominant cause of transient neonatal diabetes. These findings provide important insights into the molecular and genetic basis in the broad spectrum of diabetes mellitus.     

Neonatal Diabetes Mellitus Due to a Novel ABCC8 Gene Mutation Mimicking an Organic Acidemia

Neonatal diabetes mellitus and organic acidemias, may present with similar features like hyperglycemia, ketoacidosis and failure to thrive. A four-mo-old girl presented with diabetic ketoacidosis following a febrile respiratory illness during which high anion gap metabolic acidosis and hyperglycemia were detected. She also had hyperammonemia, which led to diagnostic uncertainty. Euglycemia was achieved with insulin injections. Genotyping revealed a homozygous novel mutation of the ABCC8 gene coding for the SUR1 subunit of the pancreatic beta cell potassium channel. Subsequently, the child was successfully transitioned to oral glibenclamide therapy. Developmental delay was noted on follow-up which raised the possibility of intermediate DEND syndrome. A possible cause for hyperammonemia in neonatal diabetes mellitus has been postulated in the discussion.     

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.     

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).     

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.     

KCNJ11 activating mutations cause both transient and permanent neonatal diabetes mellitus in Cypriot patients

Heterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanent neonatal diabetes mellitus cases diagnosed before 6 months of age. The K(ATP) channel plays an essential role in the regulation of the electrical status of the membrane through which the secretion of insulin is activated. Transient neonatal diabetes mellitus due to KCNJ11 mutations is less frequent than abnormalities affecting the imprinted region of chromosome 6q24. We studied the genetic basis of two Cypriot patients who developed diabetes before 6 months of age. They both carried mutations of the KCNJ11 gene. The R201H mutation was identified in a patient who developed hyperglycemia and ketoacidosis at the age of 40 d and was successfully transferred to sulphonylureas which activate the channel through an ATP independent route. The R50Q mutation was identified in a child diagnosed at day 45 after birth with remission of his diabetes at 9 months of age. The same defect was identified both in his asymptomatic mother and the recently diagnosed 'type 2' diabetic maternal grandmother. The remission-relapse mechanism in cases of transient neonatal diabetes is not known. Nevertheless, it is possible that the residue of the mutation within the Kir6.2 molecule is associated with the sensitivity to ATP reflecting to the severity of the diabetic phenotype.     

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.     

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.     

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.     

Neonatal cholestatic jaundice as the first symptom of a mutation in the hepatocyte nuclear factor-1beta gene (HNF-1beta)

This report describes the phenotype of a novel de novo heterozygous frameshift mutation in the hepatocyte nuclear factor-1β gene (HNF-1β or TCF2) manifest as a neonatal paucity of intrahepatic bile ducts. HNF-1β mutations should be considered in neonates with cholestatic jaundice associated with renal malformation or diabetes mellitus.     

Microcephaly,epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease‐causing homozygous mutations were identified in the immediate early response‐3 interacting protein‐1 (IER3IP1) gene. We report here an affected male born to a non‐consanguineous couple who was noted to have insulin‐requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti‐epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next‐generation sequencing approaches—such as exome sequencing reported here—may be an efficient means of uncovering a diagnosis in future cases.     

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.     

Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation

ABCC8 gene mutations with different inheritance patterns have been well described to cause transient and permanent forms of neonatal diabetes with onset of hyperglycemia commonly before the age of 6 months, and rare cases between 6 and 12 months. However, recent analyses have also demonstrated ABCC8 gene mutations in patients with monogenic diabetes (maturity onset diabetes of the young, MODY), with milder clinical phenotypes and later onset of hyperglycemia. We report two siblings with diabetes mellitus due to a novel homozygous p.(Phe1068Ile) (c.3202T>A) missense mutation of the ABCC8 gene, but significantly different phenotypes. The index case was diagnosed with diabetes due to an incidental finding of hyperglycemia at the age of 3 years, while her younger sibling presented with severe hyperglycemia and hyperosmolar dehydration at the age of 10 weeks. The possibility of a significant discordance in the correlation between genotype and phenotype needs to be taken into account when ABCC8 mutation dependent diabetes occurs within the same family. Genetic screening in children with diabetes from consanguineous family needs consideration, especially in case of negative autoantibodies and early onset of hyperglycemia.     

Permanent neonatal diabetes in an Asian infant

We describe a novel homozygous missense glucokinase mutation (R397L) resulting in insulin-treated neonatal diabetes in an infant from a consanguineous Asian family. Both parents were heterozygous for R397L and had mild hyperglycemia. Glucokinase mutations should be considered in infants of all ethnic groups with neonatal diabetes and consanguinity.     

Neonatal diabetes mellitus: from understudy to center stage

PURPOSE OF REVIEW: Although neonatal diabetes mellitus is rare, its molecular basis has far-reaching implications for understanding the regulation of beta cell function, a prerequisite for understanding and treating type1 and type 2 diabetes mellitus especially by the manipulation of stem cells. The purpose of this review is to highlight the recent exciting discoveries concerning the genetic and molecular basis of the spectrum of disorders constituting neonatal diabetes mellitus. RECENT FINDINGS: Recent reports in the literature, all in the past year, have identified activating mutations in the KATP channel that prevent its closure and hence insulin secretion as the major cause of permanent neonatal diabetes mellitus. Concurrently, a transgenic mouse model of transient neonatal diabetes mellitus due to mutations in ZAC/HYMAI provides an exquisite tool to study its human counterpart. Already, mutations in KATP and ZAC/HYMAI have been shown to be associated with type 1 and type 2 diabetes mellitus in later life; some mutations in KATP are amenable to treatment with sulfonylureas. SUMMARY: The discoveries of the genes responsible for rarely occurring transient and permanent neonatal diabetes mellitus, and transgenic animal models to study them, are exciting milestones on the road to understanding and treating the common forms of type 1 and type 2 diabetes mellitus in children and adolescents.