Genetics of congenital hyperinsulinism (original) (raw)
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Molecular Mechanisms of Neonatal Hyperinsulinism
Hormone Research in Paediatrics, 2006
Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K+ATP). The two subunits of the K+ATP channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or ...
Genotype and Phenotype Correlations in 417 Children With Congenital Hyperinsulinism
The Journal of Clinical Endocrinology & Metabolism, 2013
Context: Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Objective: Our objective was to correlate genotype with phenotype in 417 children with HI. Methods: Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1. Results: Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxideunresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity. Conclusions: Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI. (J Clin Endocrinol Metab 98: E355-E363, 2013) C ongenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. The disorder represents a heterogeneous group of diseases of pancreatic insulin regulation that differ with regard to responsiveness to medical treatment with diazoxide, requirement for surgery, histopathology, and molecular etiology (1). HI is most commonly associated with inactivating mutations in one of two adjacent genes located on chromosome 11p15.1: ABCC8 and KCNJ11, encoding the sulfonylurea receptor 1 and Kir6.2 proteins, which together form the ATP-sensitive plasma membrane potassium (KATP) channel in pancreatic -cells (2-5). The loss of KATP channel activity leads to persistent membrane depolarization and insulin release, regardless of
Journal of Clinical Investigation, 2008
Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K + (K ATP ) channel in the pancreatic β cell. Though most disease-causing mutations of the 2 genes encoding K ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K ATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited K ATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant K ATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited K ATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant K ATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy. Recently, a few cases have been reported with mutations of the K ATP channel associated with dominantly inherited hyperinsulinism (8-12). Three of these cases had ABCC8 mutations, and 1 had a KCNJ11 mutation. Children with these dominant K ATP hyperinsulinism mutations seemed to have a milder hypoglycemia phenotype than that seen in children with hyperinsulinism resulting from recessive K ATP mutations. Most cases appeared to be responsive to treatment Nonstandard abbreviations used: AIR, acute insulin response; KATP, ATP-sensitive K + ; MgADP, magnesium adenosine diphosphate.
A Novel Mutation in ABCC8 Gene in a Newborn with Congenital Hyperinsulinism –A Case Report
Fetal & Pediatric Pathology, 2013
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.
Congenital hyperinsulinism: current trends in diagnosis and therapy
Orphanet Journal of Rare Diseases, 2011
Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) muta...
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K IR 6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on -cells from six patients showed abnormal ATPsensitive K ؉ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes. (J Clin Endocrinol Metab 89: 6224 -6234, 2004)
Hormone Research in Paediatrics, 2010
Background: Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate-sensitive potassium (KATP) channels in β-cells) are the most common cause of medically unresponsive congenital hyperinsulinism (CHI) which requires a near-total pancreatectomy. Methods/Results: A patient born at term with marked macrosomia (5,900 g) presented at the age of 2 h with severe hyperinsulinaemic hypoglycaemia. He failed to respond to treatment with the KATP agonist, diazoxide. An 18FDOPA-PET scan showed intense diffuse uptake of 18FDOPA (consistent with diffuse disease) and genetic analysis of the ABCC8 gene confirmed a compound heterozygote missense ABCC8 mutation (R168C/S606T). However, unexpectedly in this patient the hyperinsulinaemic hypoglycaemia started to improve spontaneously at 7 weeks of age prior to planned pancreatic surgery. Conclusions: This is the first report of a patient with clinically severe autosomal-recessive diffuse CHI due t...
European Journal of Endocrinology, 2014
Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients. Design and methods: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. Results: Diazoxide unresponsiveness was observed in nearly half of the patients (nZ17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (nZ18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P!0.0001). Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydraterich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. Conclusions: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.
The genetic basis of congenital hyperinsulinism
Journal of Medical Genetics, 2009
Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic b-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period. Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from b-cells.
Orphanet journal of rare diseases, 2016
Patients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy. Twenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment. CHI p...