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1
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The genetics of neonatal hyperinsulinism.
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Fournet JC; Junien C
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Horm Res 2003;59 Suppl 1:30-4.
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Congenital hyperinsulinism (CHI) is the most important cause of persistent hypoglycaemia in the neonate and infant. It is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe life-threatening disease to very mild clinical symptoms which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Two histopathological forms have been described: a diffuse form of CHI and a focal form of CHI. Recent discoveries have begun to clarify the molecular aetiology of the disease and therefore the mechanisms responsible for its clinical heterogeneity are becoming clearer. Mutations in four different genes have been identified in patients with CHI. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). In the diffuse form of CHI, the hyperinsulinism is due to a recessive mutation of both alleles of these genes (rare dominant mutations have been described). In the focal form of CHI, two events intervene: first, the inheritance of a paternal ABCC8/KCNJ11 mutation; second, the focal reduction to homozygosity of the mutation during pancreatic development by a localized loss of the maternal 11p15 region. Others cases of CHI are due to rare mutations in the beta-cell enzymes glucokinase (only one family described) and glutamate dehydrogenase in hyperammonaemia-associated hyperinsulinism. However, in as many as 50% of cases, no genetic aetiology has yet been identified.
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| AD |
INSERM Unite 383 'Genetique, Chromosome et Cancer', Hopital des Enfants Malades, Paris, France.
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| PMID |
12566718
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2
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Clinical and genetic heterogeneity in congenital hyperinsulinism.
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Meissner T; Mayatepek E
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Eur J Pediatr 2002 Jan;161(1):6-20.
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Congenital hyperinsulinism is one of the most common causes of recurrent hypoglycaemia in early infancy. It is characterised by dysregulation of insulin secretion. Over the last few years, substantial progress has been made in understanding the molecular mechanisms of normal and pathological insulin secretion. Mutations in different genes (those for the sulphonylurea receptor, inward-rectifying potassium channel, glutamate dehydrogenase and glucokinase) are associated with different modes of inheritance. The clinical heterogeneity of the various forms is explained by different pathogenic mechanisms resulting in inappropriate, partly unregulated secretion of insulin. Early recognition of hypoglycaemia, correct differentiation between histological types (focal or diffuse), and maintenance of adequate glucose levels are of critical importance for the outcome of these patients. Conclusion: the recent advances in the knowledge of the basis of congenital hyperinsulinism have resulted in new diagnostic and treatment strategies. Application of these aspects to general clinical practice will lead to an improvement of the management and long-term outcome of affected patients.
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Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany.
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| PMID |
11808881
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3
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Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases.
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de Lonlay P; Fournet JC; Touati G; Groos MS; Martin D; Sevin C; Delagne V; Mayaud C; Chigot V; Sempoux C; Brusset MC; Laborde K; Bellane-Chantelot C; Vassault A; Rahier J; Junien C; Brunelle F; Nihoul-Fekete C; Saudubray JM; Robert JJ
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Eur J Pediatr 2002 Jan;161(1):37-48.
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Hyperinsulinism is a heterogeneous disorder characterised by severe hypoglycaemia due to an inappropriate oversecretion of insulin. In a personal series of 175 patients investigated for hyperinsulinaemic hypoglycaemia over the last 20 years, we review clinical presentations, molecular studies and therapeutic management of hyperinsulinism. There were 98 neonatal-onset patients, including 86 permanent hyperinsulinism and 12 transient forms, 68 with infancy-onset and nine with childhood-onset. Hyperammonaemia was found in 12 out of 69 patients tested, 4 neonates and 8 infants. Neonates were clinically more severely affected than infants. Diagnosis of infancy-onset hyperinsulinism was often delayed because of less profound hypoglycaemia and better tolerance to hypoglycaemia. Neonates required higher rates of i.v. glucose than infants to maintain normal plasma glucose levels (16 mg/kg per min versus 12 mg/kg per min). Only 16% of neonates were diazoxide-sensitive compared to 66% of the infants. Neonates with hyperammonaemia or transient hyperinsulinism were diazoxide-sensitive. Most neonates were pancreatectomised whereas 65% of the infants were treated medically. Among surgically-treated patients, 47% had a focal adenomatous hyperplasia (31 neonates and 13 infants) and 53% a diffuse form of hyperinsulinism (39 neonates and 11 infants). Diazoxide-responsiveness in the focal and diffuse forms did not differ in both neonates and infants; it depended onlyupon the age of onset of hypoglycaemia. One or two mutations, SUR1 or KIR6.2, were found in 41 of 73 neonates who were investigated and in 13/38 infants using polymerase chain reaction-single strand conformational polymorphism analysis of both genes. Almost all patients with SUR1 (38/41) or KIR6.2 (5/7) mutations were resistant to diazoxide. Ten patients with hyperinsulinism-hyperammonaemia syndrome had a mutation in the glutamate dehydrogenase gene (three neonates and seven infants) after reverse transcriptase-polymerase chain reaction and sequence analysis of cDNA. No mutation was found by polymerase chain reaction-single strand conformational polymorphism in the glucokinase gene. Eight of nine patients with childhood onset hyperinsulinism were treated surgically and histological examination confirmed an adenoma in each case. Conclusion: the clinical severity of hyperinsulinism varies mainly with age at onset of hypoglycaemia. The heterogeneity of hyperinsulinism has major consequences in terms of therapeutic outcome and genetic counselling.
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Federation de Pediatrie, Hopital Necker-Enfants-Malades, Paris, France. pascale.de-lonlay@necker.fr
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| PMID |
11808879
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4
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Genetic heterogeneity in familial hyperinsulinism.
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Nestorowicz A; Glaser B; Wilson BA; Shyng SL; Nichols CG; Stanley CA; Thornton PS; Permutt MA
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Hum Mol Genet 1998 Jul;7(7):1119-28.
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Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.
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Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St Louis, MO 63110, USA.
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| PMID |
9618169
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