Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism

Background. Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, ABCC8, KCNJ11, and HADH genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in ABCC8, KCNJ11, and HADH genes as causative genes for CHI in the Iranian population. Methods. The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in ABCC8, KCNJ11, and HADH genes were analyzed by the polymerase chain reaction and sequencing in our patients. Results. Among 20 pediatric patients, 16 of them had variants in ABCC8, KCNJ11, and HADH genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > A) mutation in the ABCC8 gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the ABCC8 gene and a missense variant (c.287-288delinsTG) in the KCNJ11 gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present. Conclusion. Most variants were located in the ABCC8 gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted.

Novel Perspectives of Super-High Dose Glybenclamide in an Infant With DEND Syndrome

Mutations in KCNJ11 gene cause a variety of persistent neonatal diabetes mellitus syndromes (PNDM), with and without developmental delay and epilepsy presentations (developmental delay, epilepsy, and neonatal diabetes - DEND Syndrome). We report a heterozygous mutation for pathogenic KCNJ11 missense variant: c.190G>A, p. (Val64Met), reported once so far, associated with severe epilepsy and neurological deterioration phenotype, responsive to a combination of super high doses of Glibenclamide (Sulfonylurea) and oral steroids. We had the patient attached to continuous glucose monitoring, performed electroencephalogramic tracings, magnetic resonance imaging and whole exome sequencing on parents and patient DNA and Sanger sequencing (SS) on candidate gene mutations. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. In conclusion, we have identified a de novo heterozygous missense mutation as the etiology for severe DEND syndrome in a one day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.

Association of ABCC8 and KCNJ11 gene variants with type 1 diabetes in south Indians

Background Type 1 diabetes mellitus (TIDM) is a polygenic disorder with the involvement of several genetic and environmental risk factors. Mutation in genes namely ABCC8 and KCNJ11 disrupt the potentiality of KATP channel and regulates the secretion of insulin by detecting a change in the blood glucose level and consequently maintains glucose homeostasis. The present study was designed to investigate the association of ABCC8 and KCNJ11gene polymorphisms with type 1 diabetes. A case-control study was conducted enrolling 60 cases suffering from T1DM and 60 healthy controls of comparable age and sex. Gene variations were determined by PCR-RFLP and ARMS-PCR method. Results The ABCC8-3C > T (rs1799854) variation was found to be significantly associated with T1DM (p<0.01) and “CT” genotype was found to be predominant in T1DM with a threefold increased risk to diabetes and the association was statistically significant. However, we did not find any significant association of C>T (rs1801261) polymorphism of ABCC8 with T1DM. A significant association was observed for genetic variation at rs5219 C>T polymorphism and the frequency of TT genotype was found to be significantly higher in patients (46.7%) than in controls (21.7%), indicating the significant role of the KCNJ11 rs5219 variant in T1DM susceptibility (p<0.001), but we did not observe any significant association of G>A (rs5215) polymorphism of KCNJ11 with T1DM. In addition, haplotype analysis of the two genes revealed four haplotypes such as T-C-G-T, T-C-A-T, C-C-G-T, and T-T-G-T as risk haplotypes for type 1 diabetes (p<0.02) potentially making individual effects of these variants on the disease susceptibility, thereby indicating the synergistic role of these genes in the regulation of glucose homeostasis. Conclusions The present study highlights the importance of personalized medicine based on individual genetic profile.

Successful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation

Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.

Focal congenital hyperinsulinism resulting from biallelic loss of function of KCNJ11 gene

Congenital hyperinsulinism (CHI) characterised by inappropriate secretion of insulin despite low blood glucose can result in irreversible brain damage if not promptly treated. The most common genetic cause of hyperinsulinism is the pathogenic variants in ABCC8 and KCNJ11, causing dysregulated insulin secretion. Rapid testing is crucial for all patients because finding a mutation significantly impacts this condition’s clinical management. We report a rare case of focal CHI after a homozygous KCNJ11 mutation who underwent a selective lesionectomy and required octreotide for euglycaemia.

Seizure as a Presentation of Permanent Neonatal Diabetes Mellitus due to Mutation in KCNJ11 Gene: A Case Report

Diabetes Mellitus in first six months of life is usually monogenic and is referred to as neonatal diabetes mellitus. The incidence of neonatal diabetes is extremely rare and varies from 1:89000 to 1:400000 live births. We report a two months old baby presenting with repeated seizures; on evaluation found to have diabetic ketoacidosis and initially managed with IV insulin infusion. Genetic study revealed heterozygous mutation, p. Valin 252 Leu in KCNJ 11 gene. This mutation suggests responsiveness to oral glibenclamide. The baby has responded to therapy. Seizure as a presenting feature for hyperglycemia is a rare entity