Mutations In ABCC8 Gene Research Articles

Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing & PET Imaging in Stratification & Management of Diazoxide Unresponsive CHI

Congenital Hyperinsulinism (CHI) may be transient or permanent and inherited either in autosomal recessive or dominant forms. Variants in ABCC8 and KCNJ11 genes coding for Sulphonyl Urea Receptor (SUR1) and potassium channel subunit (Kir6.2) respectively, account for 82% cases of diazoxide-unresponsive patients and 45% of all cases of CHI. The histology of CHI is classified into focal and diffuse. Approximately half of all cases can be classified as diffuse, 40 % as focal, and 10% of cases are considered atypical. We report a 1 month old male with recurrent hypoglycemia detected with focal congenital hyperinsulinism secondary to a paternally inherited heterozygous ABCC8 gene mutation. Focal disease results due to inheritance of a monoallelic recessive paternal ABCC8 or KCNJ11 variant together with somatic Loss of Heterozygosity (LOH) of the maternal allele at 11p15 within a pancreatic progenitor cell. Infants & children with focal disease may be cured by resection of their hyperplastic lesion and the risk for postoperative diabetes is significantly lower as compared to that following pancreatectomy for diffuse CHI. The report describes molecular mechanisms underlying CHI & emphasises the need of genetic testing and diagnostic functional imaging modalities in diazoxide unresponsive CHI to guide management and improve clinical outcomes.

Case report: Maturity-Onset Diabetes of the Young (MODY12) caused by ABCC8 gene mutations

Case report: Maturity-Onset Diabetes of the Young (MODY12) caused by ABCC8 gene mutations

A case of diazoxide unresponsive congenital hyperinsulinemic hypoglycemia with missense mutation in ABCC8 gene

Hypersecretion of insulin by pancreatic ß-cells causes hypoglycemia called congenital hyperinsulinism (CHI). It can inhibit brain development in infants. It is associated with mutations in the ABCC8 or KCNJ11 genes encoding for the SUR1 and KIR 6 (subunits of the ATP-sensitive potassium (KATP channel) a rare genetic disorder. It has an incidence rate of 1 in 50,000 in general populations and 1 in 2000 in areas with a higher rate of consanguinity. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a late preterm female infant who developed late-onset hypoglycemia. The infant developed hypoglycemic seizures on day 3 of life and her metabolic workup revealed hyperinsulinemia. A high glucose infusion rate and enteral feeding could not maintain the infant's serum glucose level. PET scan showed no abnormal somatostatin receptor avid lesion in pancreatic parenchyma. Hence genetic workup was done which showed a missense mutation in the ABCC8 gene which was c.4154C>G/p.Ser1385Cys. Over 9 months of follow-up, the infant is treated with octreotide and diazoxide, hasn't had any hypoglycemic events and has normal growth and psychomotor development for her age.

A case report of maturity-onset diabetes of the young (MODY12) in a Chinese Han patient with a novel ABCC8 gene mutation

Maturity onset diabetes of the young (MODY) is the most common type of monogenic diabetes, characterized by autosomal dominant inheritance, the age of onset is often <25 years old, and the clinical manifestations are atypical. MODY12 is caused by a rare missense mutation of adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene and more than 50 ABCC8 variants were associated with MODY12. The patient was a 30-year-old Chinese Han man. He was overweight with a poor control of blood glucose. The patient was diagnosed with MODY12. The patient was given glimepiride (4 mg/d) with diet and exercise therapy to reduce blood glucose and weight. The level of fasting blood glucose and C-peptide was improved after 1 year treatment as well as body weight. A Chinese Han adult with a heterozygous missense mutation c.3976G > A (p.Glu1326Lys) was diagnosed with MODY12, which was the new pathogenic mutation for the disease. This report expands the spectrum of variants causing MODY12 and reduces misdiagnosis.

Using low-dose octreotide with diazoxide-resistant congenital hyperinsulinism resulting from compound heterozygous mutations in the ABCC8 gene.

Congenital hyperinsulinism (CHI) is an over-secretion of insulin by pancreatic ß-cells, causing hypoglycemia which can inhibit brain development in infants. CHI is primarily associated with mutations in the ABCC8 or KCNJ11 genes, which encode the SUR1 and KIR 6.2 subunits of the ATP-sensitive potassium (KATP) channel. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a full term, female, Korean infant who developed early onset hypoglycemia but was not subject to either genetic or metabolic workup. This infant was later admitted to the ER because of a hypoglycemic seizure, but her metabolic work up revealed that both her fasting insulin and C-peptide levels were within the normal range. Despite this glucagon stimulation produced positive results and the genetic workup revealed c.[298G>T(;)4252C>T] mutations in the ABCC8 gene. This indicated diazoxide treatment, but following an unsuccessful course of treatment we switched to octreotide which helped stabilize her glucose. Over 5 years of follow-up, the patient treated with a low dose of octreotide has had no hypoglycemic event, and her growth and psychomotor development remained within normal ranges. However, she is severely obese (BMI over 97 %) despite using octreotide. Thus, we report a mild case of CHI with octreotide treatment, wherein the patient has normal insulin and C-peptide levels and normal development, but is severe obese.

Genetics for the pediatric endocrinologists – 1

The advancement in genetic laboratory technology has helped immensely in the diagnosis of many genetic disorders which could not hitherto be diagnosed. Monogenic diabetes among children and adolescents is not uncommon and needs a high index of clinical suspicion to diagnose. With the availability of genetic diagnostic laboratories with the latest technology, more and more patients should benefit from early diagnosis, specific targeted treatment, and better outcomes. The pediatricians and pediatric endocrinologists managing children with diabetes need to clinically suspect and advise appropriate genetic tests to confirm the diagnosis of monogenic diabetes. Neonatal diabetes mellitus is one of the most rewarding diagnoses, if we pick up a specific genetic abnormality that could respond to sulfonylurea. The child with KCNJ11 or ABCC8 gene mutation responding to sulfonylurea could escape from the life-long insulin injections and complications of diabetes. It is equally important to identify other forms of monogenic diabetes as the specific diagnosis can have implications in the treatment, genetic counseling, and identifying other family members harboring the same gene mutation.

Correspondence to ‘Neonatal hypoglycaemia due to ABCC8 gene mutation’

Correspondence to ‘Neonatal hypoglycaemia due to ABCC8 gene mutation’

Persistent Hyperinsulinemic Hypoglycemia in Infancy-A Case Report

&#x0D; &#x0D; &#x0D; &#x0D; Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is one of the commonest reasons for severe, intractable hypoglycemia in neonates. Dysregulated insulin secretion is the major underlying pathogenesis which results in hyperinsulinemia, hypoketonemia and hypofatty acidemia. The management is extremely complicated. Early diagnosis and aggressive management of hyperinsulinemic hypoglycemia is essential for prevention of hypoglycemia induced neuronal injury. Here we describe a baby diagnosed as PHHI who was unresponsive to medical management with diazoxide and underwent near total pancreatectomy. Genetic work up revealed a homozygous termination mutation in ABCC8 gene at amino acid position 1452 with heterozygosity in both parents.&#x0D; &#x0D; &#x0D; &#x0D;

Clinical and genetic characteristics of patients with congenital hyperinsulinism in 21 non-consanguineous families from Serbia.

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates. What is Known: • Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI). • Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11. What is New: • Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations. • Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.

A rare ABCC8 gene mutation causing severe Maturity-Onset Diabetes of the Young (MODY-12): case report and mini review

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.

Clinical Efficacy Evaluation of Sirolimus in Congenital Hyperinsulinism.

Background Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with CHI who do not respond well to other treatments including diazoxide and octreotide. However, the safety and efficacy of this therapy are still unclear. This study aimed to evaluate the potential therapeutic effects of sirolimus in CHI patients with mutations in the ABCC8 and KCNJ11 genes. Methods During the period of this follow-up study, every child with a confirmed diagnosis of unresponsive CHI underwent genetic evaluation. Among those who had positive genetic testing, six families agreed to participate in this study. The participants were evaluated for ABCC8, KCNJ11, or HNF4α gene mutations by polymerase chain reaction (PCR) sequencing. The participants who were unresponsive to diazoxide and octreotide therapy received 0.5 mg/m2/d of sirolimus, and the dose was gradually increased until a serum concentration of 5–15 ng/ml was achieved. Then, the participants were followed up for any possible complications. Results Among the study participants, only one neonate was completely free of hypoglycemia after one year of follow-up, whereas three others experienced a partial reduction in hypoglycemic episodes over six months. One neonate underwent pancreatectomy despite receiving sirolimus. The oldest participant with a mutation in the ABCC8 gene responded well to sirolimus therapy after surgery and remained asymptomatic for 18 months. Conclusion This study suggested that sirolimus therapy needs further evaluation to determine which patients will benefit the most. The genetic basis of CHI may have possible implications for determining the patient's response.

Neonatal Hypoglycaemia due to ABCC8 Gene Mutation.

Neonatal Hypoglycaemia due to ABCC8 Gene Mutation.

Clinical Management and Gene Mutation Analysis of Children with Congenital Hyperinsulinism in South China

Objective:To explore the clinical presentation and molecular genetic characteristics of a cohort of congenital hyperinsulinism (CHI) patients from southern China and also to explore the most appropriate therapeutic approaches.Methods:We retrospectively reviewed a cohort of 65 children with CHI. Mutational analysis was performed for KCNJ11 and ABCC8 genes. The GLUD1 gene was sequenced in patients with hyperammonaemia. GCK gene sequencing was performed in those patients with no mutation identified in the ABCC8, KCNJ11 or GLUD1 genes.Results:ABCC8 mutations were identified in 16 (25%) of the cohort, GLUD1 mutations were identified in five children, and no KCNJ11 or GCK mutations were identified. Moreover, some unique features of ABCC8 gene mutations in southern Chinese CHI patients were found in this study. The most common mutation was a deletion/insertion mutation p.Thr1042GlnfsX75 was found in five unrelated patients, which possibly represents a relatively common mutation in southern China. Five novel ABCC8 mutations were detected. The mutations were p.Phe5SerfsX72, p.Gln273ArgfsX85, p.Leu724del, p.Asp1447Gly and IVS 25-1G>T. Five compound heterozygous mutations of ABCC8 gene were identified in this study, and three of these patients were diazoxide-responsive. Forty patients were diazoxide-responsive, 13 patients were diazoxide-unresponsive and 12 patients received dietary treatment only. A pancreatectomy was performed in 10 patients who were unresponsive to medical treatment.Conclusion:To the best of our knowledge, this is the first study of CHI in south China. Mutations in ABCC8 are the most common causes of CHI in this cohort. Diazoxide and dietary treatment were effective in most patients. Multicentre studies are necessary to obtain the long-term follow-up characteristics of such patients at a national level.

A family in which people with a heterozygous ABCC8 gene mutation (p.Lys1385Gln) have progressed from hyperinsulinemic hypoglycemia to hyperglycemia.

Highlights Inactivating mutations of the ABCC8 gene usually cause hyperinsulinemic hypoglycemia. We report a family in which people with the inactivating mutation have progressed hyperinsulinemic hypoglycemia to hyperglycemia. Treatment with incretin‐related drugs might be a useful therapeutic approach to hyperglycemia in people with the inactivating mutation.

Identification of a compound heterozygous inactivating ABCC8 gene mutation responsible for young-onset diabetes with exome sequencing.

Activating mutations in the ABCC8 gene cause diabetes and inactivating mutations usually cause hyperinsulinemic hypoglycemia in infancy. Patients with hypoglycemia in infancy due to a heterozygous inactivating mutation have been reported to occasionally progress to diabetes later in life. We explored the gene responsible for diabetes in two brothers, who were suspected to have diabetes at 15 and 18 years‐of‐age, respectively, with whole exome sequencing, and identified a compound heterozygous ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). Although their father and mother were heterozygous carriers of the p.Arg168Cys and the p.Arg1421Cys mutation, respectively, neither parent had diabetes. These mutations have been reported to be responsible for hypoglycemia in infancy and function as an inactivating mutation. Our results suggest that the inactivating ABCC8 gene mutation is also important in the etiology of diabetes.

Large phenotypic variability of diabetes due to ABCC8 gene mutation illustrated by the paradigm of a family

Large phenotypic variability of diabetes due to ABCC8 gene mutation illustrated by the paradigm of a family

SUN-280 Sulfonylurea-Responsive Neonatal Diabetes: A Low Hanging Fruit That Has yet to Be Picked?

INTRODUCTION We present 2 contrasting cases of Neonatal Diabetes (NDM) switched from insulin to sulfonylurea in infancy vs adolescence. Importance of having high index of suspicion, making prompt diagnosis, choosing the right therapy is highlighted. METHODOLOGY Case1 13 mo/Female born premature 34 weeks presented with hyperglycemia after birth requiring insulin. Mother herself reported "Type1 Diabetes" (T1DM) diagnosed at 3 weeks. Patient was started on Glyburide 0.1mg/kgBID at 2 weeks, titrated with insulin wean. Blood sugars improved, stable at Glyburide dose 0.2mg/kg/day. HbA1c 6.4%, no hypoglycemia. Genetic testing showed KCNJ11 mutation (c.602G>A). Mother's testing showed same mutation, switched to glyburide, doing well. Case2 13 yo/Male transferred care for "T1DM" on insulin pump, diagnosed at 6 days old. Mother herself reported "T1DM" diagnosed at 2 weeks, on insulin pump. Maternal cousin diagnosed at 1 week, reported to have ABCC8 mutation. Patient's A1c >14%, feeling burnt out. DNA sequencing showed ABCC8 gene mutation (c.4136G>A;p.arg1379His). Glyburide 0.1 mg/kgBID started, titrated weekly with insulin wean. He is currently insulin-free, blood sugars range 72-118 at glyburide dose 0.7 mg/kg/day. Mother's genetic testing pending. DISCUSSION/CONCLUSION Most diabetes in infancy are monogenic. Technology for NDM diagnosis has been available for at least a decade. Oral sulfonylureas may be used in patients with KCNJ11 or ABCC8 mutation. Prompt diagnosis can make dramatic impact on quality of life, as illustrated by Case 1 (likely to be insulin-free for life) vs Case 2 who was burnt out. More education for diabetes providers is paramount regarding NDM and its proper management.

The Growth History of a Girl carrying ABCC8 Gene Mutation resulting in Congenital Hyperinsulinism

The Growth History of a Girl carrying ABCC8 Gene Mutation resulting in Congenital Hyperinsulinism

Analysis on the pathogenic genes of 60 Chinese children with congenital hyperinsulinemia.

This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children’s Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, eight patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. In conclusion, ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children’s families has an important guiding significance for treatment planning and prognosis assessment.