Mutations In ABCC8 Gene Research Articles

Neonatal Diabetes: Case Report of a 9-Week-Old Presenting Diabetic Ketoacidosis Due to an Activating ABCC8 Gene Mutation.

Context: Neonatal diabetes mellitus, a rare condition occurring in approximately 1 in 500 000 live births, is defined as insulin-requiring hyperglycemia presenting in the first months of life. Neonatal diabetes can be transient or permanent, with studies characterizing the condition as a monogenic disorder. Case Report: We describe a case of a 9-week-old infant with neonatal diabetes who presented in diabetic ketoacidosis due to a mutation affecting the ABCC8 gene that encodes the SUR1 subunit of the potassium ATP channel. Conclusion: This genetic diagnosis has therapeutic implications regarding the initiation of sulfonylurea administration as 85% of patients with neonatal diabetes due to ABCC8 gene mutations can be successfully treated with oral sulfonylurea treatment.

Assessment of Nifedipine Therapy in Hyperinsulinemic Hypoglycemia due to Mutations in the ABCC8 Gene.

Previous case reports have documented the effectiveness of l-type calcium channel blockers (such as nifedipine and verapamil) for treating different forms of hyperinsulinemic hypoglycemia (HH). To systematically assess the glycemic response to nifedipine therapy in 11 patients with HH due to mutations in the ABCC8 gene. Dose escalation of nifedipine therapy. Eleven children who were inpatients at a tertiary hospital and had diazoxide unresponsive HH due to mutations in the ABCC8 gene. Nifedipine was administered orally at an escalating dose up to a maximum of 2.5 mg/kg/d. Improvement in glycemic control, avoidance of hypoglycemic episodes, reduction of intravenous glucose infusion, and reduction in the requirements of other medical therapies. The median age of the patients was 0.44 years (range 0.14 to 3.77). The ABCC8 gene mutations were homozygous in 3 cases, paternally inherited heterozygous in 4, and compound heterozygous in 4. 18F-DOPA PET/CT scan demonstrated a focal lesion in 2 cases and the rest were diffuse HH disease. One subject had nifedipine as monotherapy, whereas the rest had it in combination with octreotide/glucagon/diazoxide or cornstarch. After a median of 6.5 (3 to 23) days of maximal (2.5 mg/kg/d) dose of nifedipine therapy, none of the patients showed any improvement in glycemic control and patients continued to have hypoglycemic episodes. HH due to mutations in the ABCC8 gene does not respond to nifedipine therapy. Mutations in the KATP channel genes might render the l-type calcium channel ineffective to therapy with nifedipine.

A Novel Approach to the Management of Neonatal Diabetes Using Sensor-Augmented Insulin Pump Therapy With Threshold Suspend Technology at Diagnosis.

Neonatal diabetes mellitus (NDM) is a rare genetic condition with an incidence of 1 in 100,000 (1) that presents before 1 year of age (2). There are two main clinical forms of NDM: permanent NDM (PNDM), which requires lifelong treatment with insulin, and transient NDM (TNDM), which may spontaneously remit and sometimes recurs in the second to third decade of life. In most cases, TNDM and PNDM cannot be distinguished clinically at the time of diagnosis, and genetic analysis needs to be performed. The genetic origin for >90% of TNDM cases has been established. In TNDM, 68% of the cases have abnormalities in an imprinted region on chromosome 6q24; 10% have KCNJ11 gene mutations; and 13% have an ABCC8 gene mutation (3). Multiple genes involved in pancreatic development, β-cell apoptosis, or dysfunction cause PNDM (4). The most common mutations are in the KATP channel genes KCNJ11 (30%) and ABCC8 (11%) or the insulin (INS) gene (13%) (3). Insulin is acutely required in most infants to establish metabolic control in NDM (5). Early initiation of sulfonylurea treatment is also recommended (6) as a treatment option in selected cases of NDM caused by ABCC8 and KCNJ11 mutations, and, in responsive cases, sulfonylurea therapy provides better long-term metabolic control (7,8) and could even improve neurodevelopmental outcomes (9). The MiniMed 530G (Medtronic, Inc., Northridge, CA) is a first-generation artificial pancreas system approved by the U.S. Food and Drug Administration (FDA) on 26 September 2013 for the management of diabetes in people ≥16 years of age. The system includes an external glucose sensor and insulin pump, transmitter, glucose meter, and therapy management software. Sensor signals are transmitted to the MiniMed 530G insulin pump and converted into glucose values every 5 minutes. Fingerstick blood glucose testing is still required for both …

Childhood Onset of Sulfonylurea Responsive Neonatal Diabetes Due to a Novel Homozygous Autosomal Recessive Mutation in the ABCC8 Gene which was Presumed to be Type 1B Diabetes Before Genetic Analysis

ABSTRACT Objective: To describe an atypical childhood onset presentation of sulfonylurea-responsive neonatal diabetes mellitus (NDM) resulting from the unusually late expression of a homozygous, novel ABCC8 gene mutation. Onset was at 9 years of age and was initially misdiagnosed as being type 1B diabetes, with subsequent treatment as insulin-dependent diabetes before a genetic analysis was performed. Methods: Genetic screening of the individual and her family was conducted due to history of her youngest brother having classic NDM with onset at 2 months of age, later confirmed to be due to an identical homozygous mutation. Results: Both siblings were successfully shifted to treatment with an oral sulfonylurea following genetic diagnosis. Conclusion: We report the first case of a childhood onset, autosomal recessive ABCC8 mutation in a homozygous state presenting as type 1B diabetes. Current recommendations are to perform genetic screening for NDM only when the age of onset is less than 1 year. Our case hi...

Current Status of Childhood Hyperinsulinemic Hypoglycemia in Turkey.

Congenital hyperinsulinism (CHI) is a rare disease characterized by dysregulated insulin secretion from pancreatic β-cells. Recurrent hypoglycemia can lead to neurological insult and permanent brain injury. Recently, there are important advances in understanding the genetic mechanisms, histological characteristics, imaging, and surgical techniques of congenital hyperinsulinemic hypoglycemia that could reflect to improvement in the clinical care of infants with this disorder. In Turkey, there is a high rate of consanguinity, thus, the incidence of CHI is expected to be high. Until now, there are no nationwide data regarding the disorder, and some individual case reports or case series had been published. Determining the characteristics of Turkish patients with CHI can help develop a different perspective on this rare disease. In this review, we evaluated the clinical and molecular characteristics of Turkish patients with CHI based on reports published in the literature. The most frequently seen mutations were ABCC8 gene mutations (n=37), followed by HADH (n=11) and KCNJ11 gene (n=7) mutations. A total of 141 Turkish patients with CHI were reported until now. Among them, 115 patients had been genetically analyzed, and 56 of them had one of the mutation leading to hyperinsulinism.

A compound heterozygous mutation of ABCC8 gene causing a diazoxide-unresponsive congenital hyperinsulinism with an atypical form: Not a focal lesion in the pancreas reported by 18F-DOPA-PET/CT scan

Congenital hyperinsulinism (CHI) is a severe heterogeneous disorder due to dysregulation of insulin secretion from the pancreatic β-cells leading to severe hypoglycemia in infancy. 18-fluoro-l-3,4-dihydroxyphenylalanine positron emission tomography (18F‑DOPA‑PET)/CT is a useful tool in distinguishing between focal and diffuse disease preoperatively. But recent studies have suggested that the scanning may not be accurate as initially estimated. In this study we characterize a case of CHI with a compound heterozygous mutation of ABCC8 gene. The results of clinical investigation, gene mutation analysis, 18F‑DOPA‑PET/CT scan, and pathological examination showed some new characteristics that have never been reported. The patient was unresponsive to medical therapy with diazoxide and received pancreatectomy twice. Genetic analysis identified a compound heterozygous mutation in ABCC8 genes. Imaging with 18F‑DOPA‑PET/CT indicated a focal lesion in the head of the pancreas. The pathological diagnosis was an atypical form of CHI. The patient presented with a phenotype of atypical CHI unresponsive to diazoxide. It is considered that a relationship existed between the compound heterozygous mutation and the atypical form. 18F‑DOPA‑PET/CT is a useful tool in distinguishing between focal and diffuse forms preoperatively but the accuracy is not 100%. The scan result is best combined with genetic analysis and intra-operative biopsy to confirm the histological subtypes. The combination will provide the optimal strategy for the surgical treatment of patients with CHI.

PP07.9 – 2445: Epilepsy and neurological manifestations in children with congenital hyperinsulinism

Objective Hypoglycemia in congenital hyperinsulinism (CHI) in children increases the risk of brain damage, seizures and development delay. Aim was evaluate the frequency of epilepsy, development delay and neurological manifestations in children with CHI. Methods Clinical, EEG, MRI, genetic, psychological testing. Results 8 boys and 7 girls with CHI aged from 5 month to 7 years (on average 3 years 3 months) were examined. Hypoglycemia was found one the first week of life in 10 children, before 12 month – 5. It was manifested as seizures in 10 of 15 patients (66%). During the follow-up epilepsy developed in 3 patients (20%) and antiepileptic drugs were prescribed. On the neurological examination 6 children had only mild changes, 3 – cerebral palsy (60%). Brain MRI revealed abnormalities in 8 (53%) cases: 7 – atrophy of different localization. Epileptiform abnormalities on the EEG were registered in 4 cases, bifrontal slowdown – in other 5 cases. On psychological testing performed in 9 of 15 patients development delay was observed, which was mild in 2, moderate – in 3, severe – in 4. Before the CHI diagnosing 5 children received anticonvulsive therapy, which was ineffective in all cases before starting specific therapy. The genetic assessment was done in 13 children: in 2 cases the KCNJ11 gene mutation was found, in 4 – ABCC8 gene mutation. Children with ABCC8 gene mutation had more complicated course of CHI, 2 of them had epilepsy, 3 – severe development delay. Conclusion The seizures in CHI do not always require diagnosing “epilepsy” and prescription of antiepileptic drugs. EEG abnormalities in these children may be observed despite of the absence of epileptic seizures. Development delay was more often revealed in children with abnormalities on neurologic examination and MRI. Children with ABCC8 gene mutation have more complicated course of CHI and more prominent development delay.

Molecular genetics, correlation between genotype and phenotype of 65 Vietnames patients with congenital hyperinsulinism

Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic β-cells. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A and UCP2). Severe forms of congenital HH are caused by inactivating mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic β-cell ATP-sensitive potassium channel. Our aim is to identify mutations in the ABCC8 and KCNJ11, HNF4A and GLUD genes, and to describe genotype and phenotype correlations of Vietnamese children with congenital hyperinsulinism. A prospective study was conducted on 65 cases with congenital hyperinsulinism diagnosed and treated at the National Hospital of Pediatric from January 2007 to April 2014. Patients were selected by using inclusion criteria of Hussain K (2008). Mutations were identified in 32 cases (49.2%) including mutations of ABCC8 gene (28 cases; 43.1%), KCNJ11 (3 cases; 4.6%), HNF4A (1 case; 1.5%). 100% of cases with homozygous/compound heterozygous recessive mutations or one paternal dominant mutation of ABCC8 gene did not respond to diazoxide treatment and required 95% pancreatectomy. Molecular analysis using pancreas tissue after surgery from cases with one mutation of ABCC8 gene inherited from father confirmed focal lesion type. Other cases without identified mutations usually responded to diazoxide. In conclusions, children with congenital hyperinsulinism should be performed mutation analysis which helps in making diagnosis and treatment decision. Families of children with congenital hyperinsulinism should be given genetic counseling. Prenatal diagnosis should be performed as well as follow - up and treatment should be given to children with congenital hyperinsulinism immediately after birth.

A Recessive Mutation in the Insulin Gene in Neonatal Diabetes

Neonatal diabetes (ND) is a form of monogenic diabetes that occurs during the first 6 months of life. A recent study estimated its minimum incidence as 1 in 90 000 population (1). ND is clinically divided in two forms: transient ND (TND) and permanent ND (PND) which is caused by several genetic defects (2). Mutations in KCNJ11, ABCC8, and insulin gene (INS) are the main causes of PND (2). KCNJ11 and ABCC8 encode the subunits of the ATP-sensitive potassium channel (K(ATP)) of the pancreatic β-cells. Loss of insulin secretion occurs due to activating mutations of these subunits (3). INS mutations are associated with PND and other clinical conditions such as type 1b diabetes, maturity onset diabetes of the youth (MODY), type 2 diabetes, and TND (4). Here, we report a case of PND due to recessive inheritance INS mutation accompanied by diabetic ketoacidosis (DKA). Case Report

НЕВРОЛОГИЧЕСКИЕ ПАРОКСИЗМАЛЬНЫЕ НАРУШЕНИЯ У ДЕТЕЙ С ГИПОГЛИКЕМИЕЙ НА ФОНЕ ВРОЖДЕННОГО ГИПЕРИНСУЛИНИЗМА: ПОЛИМОРФИЗМ КЛИНИЧЕСКИХ ПРОЯВЛЕНИЙ

Hypoglycemia in congenital hyperinsulinism (WGI) in children increases the risk of brain damage, seizures and development delay. The aim of our study was to evaluate the clinical manifestations in children with CHI. Hypoglycemia is often manifests with seizures, which are sometimes in the future may lead to the development of epilepsy. Seizures in CHI do not always require a diagnosis of epilepsy and prescription of anticonvulsants. EEG changes in these children may be observed in the absence of epileptic seizures. Developmental delay was more common in children with neurological abnormalities and MRI changes. Children with ABCC8 gene mutations have more complicated for CHI and more prominent developmental delay.

A case of a Japanese patient with neonatal diabetes mellitus caused by a novel mutation in the ABCC8 gene and successfully controlled with oral glibenclamide.

Permanent neonatal diabetes mellitus (PNDM) is a rare form of insulin-dependent diabetes mellitus that presents within the first 6 months after birth and may require lifelong insulin treatment. Approximately 40% of all PNDM cases are caused by activating mutations in either the KCNJ11 gene or ABCC8 gene, which encode the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the ATP-sensitive potassium channel (KATP channel), respectively (1,2,3). The KATP channel is expressed on the surface of pancreatic beta cells. In this context, a heterozygous gain-of-function mutation in ABCC8 or KCNJ11 causes PNDM. High-dose oral sulfonylurea has been reported to be an effective treatment agent for PNDM with ABCC8 and KCNJ11 gene mutations compared with insulin injection (4). Here we report a patient with PNDM caused by a novel heterozygous missense mutation in ABCC8 and controlled with oral glibenclamide for more than 3 yr.

Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia.

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the β-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.

A Novel Mutation in ABCC8 Gene in a Newborn with Congenital Hyperinsulinism –A Case Report

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. The genetic basis of CHI includes a variety of defects in key genes regulating insulin secretion. Mutations in at least seven genes are found in 50% of cases. The most common forms of medically unresponsive CHI, which requires a near-total pancreatectomy are associated with autosomal recessive mutations in the ABCC8 and KCNJ11 genes encoding the two subunits of the pancreatic β-cell ATP-sensitive potassium channel. We report a neonate with CHI and have a novel homozygous splicing mutation in the ABCC8 gene.

ABCC8, KCNJ11 and GLUD1 gene mutation analysis in congenital hyperinsulinism pedigree

To explore the ABCC8, KCNJ11, and GLUD1 gene mutations of the 11 patients diagnosed as congenital hyperinsulinism (CHI). A total of 11 CHI children hospitalized in Beijing Children's Hospital from November 2008 to February 2012 and their parents were chosen as the study subjects. Direct sequencing of PCR-DNA was used to analyze the 39 exons of ABCC8 gene, non-translational region and exon of KCNJ11 gene and 6, 7, 10, 11 and 12 exons of GLUD1 gene. An P629PfsX17 heterozygous mutation of ABCC8 gene was detected in case 1 and his father, an W288X heterozygous mutation of ABCC8 gene was detected in case 4 and his father, A640V and Q1196X mutations in ABCC8 gene in case 5 whose father only carried the Q1196X mutation. In case 6 and his father, an R269H mutation was found in GLUD1 gene. The genotype of 4 children's mothers was normal. No mutations were found in other 7 patients and their parents. The ABCC8 gene mutations are the main pathogenic mechanisms of Chinese children with CHI. In Chinese, P629PfsX17, W288X, A640V and Q1196X heterozygous mutation of ABCC8 gene and R269H heterozygous mutation of GLUD1 gene may lead to CHI. The inheritance mode of the mutations may be paternally or de novo.

Novel mutation c.597_598dup in exon 5 of ABCC8 gene causing congenital hyperinsulinism

Congenital hyperinsulinism (CHI), a clinically and genetically heterogeneous disease, characterized by the unregulated secretion of insulin from pancreatic β-cells, is the most common cause of persistent hypoglycemia in infancy. Early diagnosis and maintenance of normoglycaemia are essential to prevent adverse neurodevelopmental outcomes. The most common and severe forms of CHI are caused by inactivating mutations in ABCC8 and KCNJ11 genes, encoding the two subunits of the pancreatic β-cell ATP sensitive potassium channel (KATP). We report a case of neonatal CHI due to a novel homozygous recessive mutation in the ABCC8 gene.

Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.

The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic β-cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM). The coding regions and conserved splice sites of KCNJ11,ABCC8 and INS were screened for mutations in a 12-year-old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch-clamp experiments in COS-1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas invitro and in the patient. We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch-clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas invitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide. We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.

Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype

Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype

Permanent Neonatal Diabetes Mellitus: Same Mutation, Different Glycemic Control with Sulfonylurea Therapy on Long-Term Follow-up

Permanent neonatal diabetes mellitus (PNDM) is a rare condition presenting before six months of age. Mutations in the genes encoding the ATP-sensitive potassium (KATP) channel are the most common causes. Sulfonylurea (SU) therapy leads to dramatic improvement in diabetes control and quality of life in most patients who carry these mutations. Here, we report the long-term follow-up results of two siblings with PNDM who were treated with insulin until ABCC8 gene mutation was identified, and were successfully transferred to oral SU therapy. After 3.5 years of follow-up on SU, one patient had a very good response, while the other one had a poor response. Bad compliance to diet was thought to be the most probable reason for poor glycemic control in this patient. In conclusion, molecular genetic diagnosis in all patients with PNDM is recommended. Compliance to treatment should be an important aspect of the follow-up of these patients. Conflict of interest:None declared.

An ABCC8 gene mutation leading to the onset of KATP-congenital hyperinsulinism in a Chinese boy and his pedigree analysis

ABCC8,KCNJ11,and GLUD1 gene mutations were investigated in a male patient with congenital hyperinsulinism and his parents were also investigated.A 1484 G＞A mutation was found in the 10th exon of ABCC8 gene in the patient,which leads to amino acid substitution at the 495 residue of the sulphonylurea receptor SUR1 protein.The patient's father also carried the same heterozygous inactive mutation,while the genotype of the mother was normal,indicating that the gene mutation of the patient was paternally inherited.According to that mutation,it is deduced that the patient may suffer from the focal type of congenital hyperinsulinism. Key words: Congenital hyperinsulinism; ABCC8 gene; KATP channel

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism