title: Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected].
abstract: BACKGROUND
  Neonatal diabetes mellitus is a rare genetic form of pancreatic β-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without β-cell autoimmunity and with normal pancreas morphology.
  
  
  METHODS
  We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for β-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities.
  
  
  RESULTS
  We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36).
  
  
  CONCLUSIONS
  Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus.
  
  
  BACKGROUND
  Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.
authors.affiliation: INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
authors.forename: Kanetee
authors.initials: K
authors.lastname: Busiah
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Drunat
authors.affiliation: Inserm UMR-S0669 Université Paris Sud, Paris Descartes, Sorbonne Paris Cité, Department of Paediatrics, Cochin Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Vaivre-Douret
authors.affiliation: CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: Department of Paediatrics, André Mignot Hospital, Le Chesnay, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Simon
authors.affiliation: Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Flechtner
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pouvreau
authors.affiliation: Clinical Research Unit, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Elie
authors.affiliation: The Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, The National Center for Childhood Diabetes, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
authors.forename: Revital
authors.initials: R
authors.lastname: Nimri
authors.affiliation: The Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, The National Center for Childhood Diabetes, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: De Vries
authors.affiliation: Department of Paediatric Endocrinology and Diabetology, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Tubiana-Rufi
authors.affiliation: Department of Paediatrics, Brest Teaching Hospital, Brest, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Metz
authors.affiliation: Department of Paediatrics, Besançon Hospital, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bertrand
authors.affiliation: Department of Paediatrics, Rennes Teaching Hospital, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Nivot-Adamiak
authors.affiliation: Department of Paediatrics, Rennes Teaching Hospital, Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: de Kerdanet
authors.affiliation: Department of Paediatrics, Jeanne de Flandre Teaching Hospital, Lille, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Stuckens
authors.affiliation: Department of Paediatric Endocrinology and Diabetology, A Harouchi Paediatric Teaching Hospital, Casablanca, Morocco.
authors.forename: Farida
authors.initials: F
authors.lastname: Jennane
authors.affiliation: Department of Paediatrics, American Memorial Hospital, Reims, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Souchon
authors.affiliation: Department of Paediatrics, Paediatric Teaching Hospital, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Le Tallec
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Désirée
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pereira
authors.affiliation: CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dechaume
authors.affiliation: Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Robert
authors.affiliation: The Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, The National Center for Childhood Diabetes, Schneider Children's Medical Centre of Israel, Petah Tikva, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Czernichow
authors.affiliation: CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France; Department of Genomics of Common Disease, School of Public Health, Hammersmith Hospital, Imperial College London, London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: CNRS-UMR-8199, Lille Pasteur Institute, Lille, France; EGID-FR3508, Lille, France; Lille 2 University, Lille, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.affiliation: INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE affiliate, Paris, France. Electronic address: michel.polak@nck.aphp.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: Department of Genetics, Robert-Debré Teaching Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
mesh_terms: D002648:Child; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D015331:Cohort Studies; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000235:genetics*; D005602:France / Q000453:epidemiology; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics; D053208:Kaplan-Meier Estimate; D009154:Mutation / Q000235:genetics; D010179:Pancreas / Q000000981:diagnostic imaging; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011446:Prospective Studies; D011498:Protein Precursors / Q000235:genetics; D011596:Psychomotor Disorders / Q000235:genetics* / Q000473:pathology; D064233:Sulfonylurea Receptors / Q000235:genetics; D014463:Ultrasonography; D000099161:Kcnj11 Channel
chemical_list: D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011498:Protein Precursors; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human; C013737:preproinsulin