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      Molecular Mechanisms of Neonatal Hyperinsulinism

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          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<sup>+</sup><sub>ATP</sub>). The two subunits of the K<sup>+</sup><sub>ATP</sub> 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 KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.

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          Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene.

          A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts. The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.
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            Familial hyperinsulinism caused by an activating glucokinase mutation.

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              Practical management of hyperinsulinism in infancy.

              Hyperinsulinism in infancy is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without difficulty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It offers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                November 2006
                30 November 2006
                : 66
                : 6
                : 289-296
                aINSERM U654 and Department of Genetics, Hôpital Henri Mondor, Créteil; bDepartment of Biology, Hôpital Saint-Antoine, Paris; cERM 0205 INSERM-CEA, Service Hospitalier Frédéric Joliot, DSV, DRM, Orsay; dDepartments of Pediatrics, Radiology, Surgery and Pathology, Hôpital Necker-Enfants Malades, Paris, France; eDepartment of Pathology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; fDepartments of Pediatrics, Humboldt-Universität zu Berlin, and Charité CVK OHC Kinderklinik, Berlin, Germany; and gDepartments of Pediatrics, Great Ormond Street Children’s Hospital NHS Trust and Institute of Child Health, London, UK
                95938 Horm Res 2006;66:289–296
                © 2006 S. Karger AG, Basel

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                Figures: 2, Tables: 1, References: 55, Pages: 8
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