Comment on: Khurana et al. The Diagnosis of Neonatal Diabetes in a Mother at 25 Years of Age. Diabetes Care 2012;35:e59

Background: A very rare disease, neonatal diabetes has historically been treated with subcutaneous insulin. A recent study showed efficacy of oral glyburide on a specific subset of newborns diagnosed with neonatal diabetes, and that it is safe to try even before genetic test results are available. Clinical Case: 1 day old male born at 41 weeks and 1 day was found to by hyperglycemic to the 300s. At that time, it was thought to be reactive hyperglycemia as he was in respiratory distress, had a pneumothorax, and his mother was GBS positive. He was started on an insulin drip, which was titrated to his blood glucose levels. At this time, serum insulin and C-peptide levels were found to be undetectable, confirming a diagnosis of neonatal diabetes (Insulin <1.0, n 2.0-19.6, C-peptide <0.10, n 0.8-3.85). Genetic testing was sent on genes commonly responsible for neonatal diabetes. On day of life 12 (DOL 12), he was started on diluted subcutaneous insulin Lispro. He was exquisitely sensitive to small amounts of insulin and was often hypoglycemic after even 0.1 units of diluted insulin (0.01u of commercial insulin Lispro). On DOL 14, as genetic testing results were still pending, he was started on oral glyburide. The drug was administered twice daily, but he remained hyperglycemic requiring advancement of the target dose to 0.5mg/kg/day. On DOL 22, Insulin and C-peptide levels were drawn after subcutaneous insulin had been discontinued for 48 hours. While not yet within normal limits, both values increased to detectable levels, demonstrating objective response the the glyburide therapy (Insulin 1.1, n 2.0-19.6, C-peptide 0.32, n 0.8-3.85). Ultimately, this dose of glyburide was too high for him, and he was discharged home on DOL 26 with 0.036mg/kg/day that will be titrated up as an outpatient as he continues to grow. Since discharge, his blood glucose levels have ranged between 100-200, with no values below 85. Interestingly, his first genetic testing results came back negative for all the mutations in the panel, including the most common mutations in neonatal diabetes that respond to sulfonylurea therapy, ABCC8 and KCNJ11. He is in the process of being enrolled in the a Neonatal Diabetes Registry where they will test for other genes implicated in neonatal diabetes. Conclusion: This is a case of neonatal diabetes with an unknown gene mutation showing efficacy of oral glyburide therapy.

BackgroundNeonatal diabetes along with congenital anomalies like duodenal atresia, tracheoesophageal fistula, intra uterine growth retardation, extrahepatic biliary obstruction and hypoplasia of pancreas is a very rare occurrence with evidence linking...

Neonatal diabetes mellitus (NDM) is defined as the occurrence of severe hyperglycemia in infants under 6 months old and may be permanent (PNDM) or transient (TNDM). When diabetes is diagnosed at 6-12months of age (early onset diabetes [EOD]), the etiology may be monogenic; however, most cases consist of type 1 diabetes mellitus (T1DM). Molecular diagnosis was determined in a cohort of 35 unrelated Brazilian patients with NDM or EOD based on targeted next-generation sequencing panel and/or chromosome 6q24 abnormalities. The impact of genetic testing on treatment and follow-up was evaluated. Overall, 24 patients had NDM: with 18 (75.0%) having PNDM, 5 TNDM (20.8%) and 1 case in which this information was unknown. Eleven patients had EOD. Genetic testing was positive in 20/24 patients with NDM (83.3%) and in 18.2% of cases of EOD. The commonest causes were ATP-sensitive potassium (KATP) channel genes, and GCK and IPEX mutations (37.1%, 11.4% and 5.7%, respectively). Patients with PNDM due to KCNJ11 and ABCC8 mutations transitioned successfully to sulfonylureas in almost 60% of cases, reinforcing the benefit of performing genetic testing in NDM as early as possible. This report refers to the largest series of cases of NDM (TNDM and PNDM) and EOD in Brazil in which patients were submitted to molecular investigation and in which the clinical impact of genetic diagnosis was also evaluated.

In this report, we present the first known case of intermediate developmental delay, epilepsy and permanent neonatal diabetes (DEND) syndrome caused by a Q52R mutation in the KCNJ11 gene who was successfully switched (at age 1.3 years) to sulphonylurea monotherapy, namely glibenclamide. The most recent evaluation, after 2 years, showed a glycated hemoglobin level of 6.0% (42 mmol/mol). This mutation is so severe that none of the previously reported four cases were able to switch from insulin to sulphonylurea monotherapy. The Q52R mutation seems to have a chance of positive response to glibenclamide administered every 3–6 h instead of the classical 8–12 h, in doses around or above 2.5 mg/kg/day.

Background: Neonatal diabetes mellitus (NDM) is a severe type of glucose metabolism disorder that appears in the first months of life and mostly presents with symptoms such as dehydration, inability to gain weight, and in extreme cases, ketoacidosis and coma. Strong evidence shows the benefits of early molecular tests that investigate variability in kATP channels such as KCNJ11, ABCC8, INS gene mutations, and 6q24 abnormalities. In the presence of these genomics changes, switching from Insulin treatment toward high-dose oral sulfonylurea can enhance the course of treatment, prognosis, and quality of life. Case Report: In this study, we report four cases of neonatal diabetes with different symptoms who were referred to Shahid Sadoughi Medical Center in Yazd, Iran. Conclusion: The diagnosis and treatment of NDM is a good model for implementing patient-centered and personalized medicine. For all patients with diabetes diagnosed before the 6th month of their age (even the 12th month), genetic testing should be considered.

Introduction: To date Neonatal Diabetes Mellitus (NDM) has not been reported in Singapore. Neonatal diabetes is a rare (1 in 100,00–300,000 live births) insulin-requiring form of diabetes with well defined subgroups, permanent neonatal diabetes (PND) and transient neonatal diabetes (TND), each accounting for approximately 50% of patients. Genotyping NDM identifies the exact unique molecular aetiology of very early onset insulin requiring diabetes and has the potential to dramatically alter the management of the patient, who would otherwise be insulin dependent for life. Method: We identified a child who presented at 3 and half months of age with diabetic ketoacidosis and determined the phenotypic and genotypic characteristics. Blood samples for molecular genetic analysis were sent to Royal Devon and Exeter Foundation Trust, UK. We determined her Continuous Glucose Monitoring profiles after initiation of sulphonylurea therapy. Results: The patient was diagnosed as a heterozygous for a missense mutation R201H, in the KCNJ11 gene. Results confirmed a diagnosis of permanent neonatal diabetes due to a mutation in the Kir6.2 subunit of the KATP channel. We initiated sulphonylurea therapy and subsequently ceased insulin treatment successfully. Currently 2 years old, this patient is no longer insulin dependent. Conclusion: This is the first case report of neonatal diabetes in Singapore. It describes the importance of correct identification of the case, and successful conversion of therapy from insulin to sulphonylureas with optimal blood glucose control. We emphasise the need for medical practitioners to consider molecular testing for all patients who present with diabetes below 6 months of age as this will facilitate accurate diagnosis and appropriate therapy.

BackgroundChildren with neonatal diabetes often present with diabetic ketoacidosis and hence are at risk of cerebral oedema and subsequent long‐term neurological deficits. These complications are difficult to identify because neurological features can also occur as a result of the specific genetic aetiology causing neonatal diabetes.Case reportsWe report two cases of neonatal diabetes where ketoacidosis‐related cerebral oedema was the major cause of their permanent neurological disability. Case 1 (male, 18 years, compound heterozygous ABCC8 mutation) and case 2 (female, 29 years, heterozygous KCNJ11 mutation) presented with severe diabetic ketoacidosis at 6 and 16 weeks of age. Both had reduced consciousness, seizures and required intensive care for cerebral oedema. They subsequently developed spastic tetraplegia. Neurological examination in adulthood confirmed spastic tetraplegia and severe disability. Case 1 is wheelchair‐bound and needs assistance for transfers, washing and dressing, whereas case 2 requires institutional care for all activities of daily living. Both cases have first‐degree relatives with the same mutation with diabetes, who did not have ketoacidosis at diagnosis and do not have neurological disability.DiscussionKetoacidosis‐related cerebral oedema at diagnosis in neonatal diabetes can cause long‐term severe neurological disability. This will give additional neurological features to those directly caused by the genetic aetiology of the neonatal diabetes. Our cases highlight the need for increased awareness of neonatal diabetes and earlier and better initial treatment of the severe hyperglycaemia and ketoacidosis often seen at diagnosis of these children.

Genetics in the Real World: Resources for Pediatric Nurses Using Monogenic Diabetes as an Exemplar

Introduction : we present 2 cases of neonatal diabetes. Mutations in ABCC8 and KCNJ11 genes encoding for the pancreatic KATP channel can lead to transient neonatal diabetes (TNDM) as well as permanent neonatal diabetes (PNDM). KATP channel mutations causing TNDM typically result in diabetes being diagnosed before 6 months of age. Majority of neonatal diabetes patients with KATP channel mutations can be managed with sulphonylureas. Methods : sequence analysis of the ABCC8, KCNJ11, INS and EIF2AK3 genes. Results : case 1: a 9-day old male who presented with jaundice for 3 days and fever for a day. On presentation, baby was febrile, lethargic, with no primitive reflexes. A diagnosis of bilirubin encephalopathy and sepsis was made. On presentation, serum bilirubin was 902 micromil/dl and dropped to 70micromil/dl after 48hours of intensive phototherapy and IV rehydration. On day 3 of admission, infant was noticed to be severely dehydrated although his diapers were soaked with urine. Investigations showed: Random blood sugar 33.1, glucosuria 3+, ketonuria 2+, and enterobacter sepsis. He was managed with insulin infusions and IV antibiotics. By 4th week, baby no longer required insulin, was tolerating full feeds and temperature had settled. Blood sugars have remained within normal range. Sequence analysis of the ABCC8, KCNJ11, INS and EIF2AK3 genes did not identify a pathogenic mutation. Case 2: a 16 week old baby bought to the ER on account of severe weight loss despite good appetite. Random blood sugar on presentation was 33.3mmol/l . Baby was was managed for DKA and discharged home on human premix insulin 30/70 after 2 months of hospital stay. Genetic testing revealed a mutation in the KCNJ11 gene. Baby was switched to glibenclamide, and blood sugars have remained stable. Conclusion : a diagnosis of diabetes before 6 months of age warrants genetic testing to guide treatment decisions.

Sulfonylurea therapy can improve glycemic control and ameliorate neurodevelopmental outcomes in patients suffering from neonatal diabetes mellitus (NDM) with KCNJ11 or ABCC8 mutations. As genetic testing results are often delayed, it remains controversial whether sulfonylurea treatment should be attempted immediately at diagnosis or doctors should await genetic confirmation. This study aimed to investigate the effectiveness and safety of sulfonylurea therapy in Chinese NDM patients during infancy before genetic testing results were available. The medical records of NDM patients with their follow-up details were reviewed and molecular genetic analysis was performed. Sulfonylurea transfer regimens were applied in patients diagnosed after May 2010, and glycemic status and side effects were evaluated in each patient. There were 23 NDM patients from 22 unrelated families, 10 had KCNJ11 mutations, 3 harbored ABCC8 mutations, 1 had INS mutations, 4 had chromosome 6q24 abnormalities, 1 had a deletion at chromosome 1p36.23p36.12, and 4 had no genetic abnormality identified. Sixteen NDM infants were treated with glyburide at an average age of 49 days (range 14-120 days) before genetic confirmation. A total of 11 of 16 (69%) were able to successfully switch to glyburide with a more stable glucose profile. The responsive glyburide dose was 0.51 ± 0.16 mg/kg/d (0.3-0.8 mg/kg/d), while the maintenance dose was 0.30 ± 0.07 mg/kg/d (0.2-0.4 mg/kg/d). No serious adverse events were reported. Molecular genetic diagnosis is recommended in all patients with NDM. However, if genetic testing results are delayed, sulfonylurea therapy should be considered before such results are received, even in infants with newly diagnosed NDM.

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely. We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment. Insulin pump requirement for the 4 neonatal diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea. During the neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent neonatal diabetes mellitus.

Introduction. Neonatal diabetes is a rare disease and it is frequently caused by a mutation in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium channel. If the neonatal diabetes is associated with epilepsy and developmental delay, then the diagnosis is of DEND syndrome (developmental delay, epilepsy and neonatal diabetes).Aim. To determine which are the best methods of diagnosis and treatment for a child with neonatal diabetes.Methods and results. We present the case of a 9 years old girl, diagnosed with neonatal diabetes at age 3 months, who was first admitted to our clinic in December 2015 for frequent episodes of hyperglycemia at home and absence seizure lasting 2-4 minutes, suggesting minor epilepsy. The patient was treated with insulin from the moment of diagnosis until age 9 months, then with oral antidiabetic agents until January 2015, when she started again the insulin therapy in the context of persistent hyperglycemia and a level of glycated hemoglobin (HbA1c) of 10.6%. Her physical examination revealed height and weight according to age, with stable vital signs. The laboratory findings were all unremarkable, except for blood glucose values of 200-300 mg/dl and HbA1c level of 10.3%. The patient also had moderate mental delay, with an IQ of 66. The genetic testing for neonatal diabetes revealed a heterozygous mutation in KCNJ11 gene, so the diagnosis was of DEND syndrome. We initiated the treatment with glibenclamide 3.5 mg, 8 tablets/day and we recommended cognitive functions’ stimulation with exercises and reading 4-5 hours/day.Conclusions. The genetic testing for the identification of a mutation in KCNJ11 gene has an important impact on the therapeutic approach in children with neonatal diabetes, as there is the possibility to replace the insulin therapy with antidiabetic oral agents, therefore improving the quality of life and possibly the epilepsy seizures.

Neonatal diabetes mellitus (NDM) is defined as a heterogeneous group of genetic disorders with onset before 6 months of age. Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of NDM. Accurate molecular diagnosis of NDM has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members .&#x0D; In this report we present the results of a genetic examination of 70 patients with NDM, generalized the experience of using sulfonylurea in patients with KCNJ11 and ABCC8 genes mutations for the period from 2009 to 2016. A correlation is shown between the type of mutation, the course of the disease, and the sensitivity of patients to glibenclamide.

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.

The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.