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      Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births

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          Abstract

          Until early 2000, permanent and transient neonatal diabetes mellitus (NDM), defined as diabetes with onset within 6 weeks from birth that requires insulin therapy for at least 2 weeks, were considered exceedingly rare conditions, with a global incidence of 1:500,000–1:400,000 live births. The new definition of NDM recently adopted, that includes patients with diabetes onset within 6 months of age, has prompted studies that have set the incidence of the permanent form alone between 1:210,000 and 1:260,000 live births. Aim of the present work was to ascertain the incidence of NDM (i.e. permanent + transient form) in Italy for years 2005–2010. Patients referred to the Italian reference laboratory for NDM between years 2005 and 2010 and screened for mutations in common NDM genes ( KCNJ11, ABCC8, and INS) and for uniparental isodisomy of chromosome 6 (UDP6) were reviewed. A questionnaire aimed at identifying NDM cases investigated in other laboratories was sent to 54 Italian reference centers for pediatric diabetes. Twenty-seven patients with NDM born between 2005 and 2010 were referred to the reference laboratory. In this group, a mutation of either KCNJ11, ABCC8 or INS was found in 18 patients, and a case with UDP6 was identified. Questionnaires revealed 4 additional cases with transient neonatal diabetes due to UDP6. Incidence of NDM was calculated at 1:90,000 (CI: 1:63,000–1:132,000) live births. Thus, with the definition currently in use, about 6 new cases with NDM are expected to be born in Italy each year.

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          Most cited references 14

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          Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

          Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society
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            Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism.

            The beta-cell ATP-sensitive potassium (K(ATP)) channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis it is therefore not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1 (SUR1). It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinism of infancy, while activating mutations in KCNJ11 and ABCC8 have recently been described that result in the opposite phenotype of diabetes. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment on diagnosing patients with mutations in these genes. (c) 2008 Wiley-Liss, Inc.
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              Neonatal diabetes mellitus.

              An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life. These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis. Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of beta-cell apoptosis and insulin processing, as well as the regulation of insulin release. For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes. For the clinician, these studies underscore the need to identify the genetic cause underlying each case. It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.
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                Author and article information

                Contributors
                +3906-2090-0672 , +3906-2090-0674 , Fabrizio.Barbetti@uniroma2.it
                Journal
                Acta Diabetol
                Acta Diabetol
                Acta Diabetologica
                Springer Milan (Milan )
                0940-5429
                1432-5233
                28 September 2011
                28 September 2011
                October 2012
                : 49
                : 5
                : 405-408
                Affiliations
                [1 ]Department of Pediatrics, Second University of Naples, Naples, Italy
                [2 ]Laboratory of Mendelian Diabetes, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
                [3 ]Department of Pediatrics, Regional Hospital, Bolzano, Italy
                [4 ]Department of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy
                [5 ]Endocrine Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
                [6 ]Medical Genetics Unit, Bianchi Melacrino Morelli Hospital, Reggio Calabria, Italy
                [7 ]Department of Pediatrics, University of Catania, Catania, Italy
                [8 ]Department of Pediatrics, Maurizio Bufalini Hospital, Cesena, Italy
                [20 ]Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA
                [9 ]Department of Laboratory Medicine, Tor Vergata University Hospital, Rome, Italy
                [10 ]Department of Pediatrics, H S Raffaele Hospital and Scientific Institute, Milan, Italy
                [11 ]Department of Epidemiology, Istituto Superiore di Sanità, Rome, Italy
                [12 ]Department of Internal Medicine, University of Tor Vergata, Via Montpellier 1, 00134 Rome, Italy
                Article
                331
                10.1007/s00592-011-0331-8
                3464369
                21953423
                © The Author(s) 2011
                Categories
                Short Communication
                Custom metadata
                © Springer-Verlag Italia 2012

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