title: Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations.
abstract: OBJECTIVE
  Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin.
  
  
  METHODS
  We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing.
  
  
  RESULTS
  At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin.
  
  
  CONCLUSIONS
  SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm U1016, Institut Cochin, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Beltrand
authors.affiliation: Unité de Recherche Clinique et Centre d'Investigation Clinique 1419, Unité de Pharmacologie EA 7323, Paris Descartes-Université Sorbonne Paris Cité, Hôpital Universitaire Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Elie
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm U1016, Institut Cochin, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France.
authors.forename: Kanetee
authors.initials: K
authors.lastname: Busiah
authors.affiliation: Département de Neurophysiologie Clinique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France UMR S 1127, Centre de Référence des Canalopathies Musculaires, Université Pierre et Marie Curie, Université Paris 06, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fournier
authors.affiliation: Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Service d'Imagerie Médicale, Inserm U1000, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Service de Neurologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Miriam
authors.initials: M
authors.lastname: Vera
authors.affiliation: Service d'Ophtalmologie, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bui-Quoc
authors.affiliation: Service d'Ophtalmologie, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine Paris-Diderot, Université Sorbonne-Paris-Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ingster-Moati
authors.affiliation: Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm U1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Berdugo
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Service de Pédiatrie, Centre Hospitalier de Versailles, Le Chesnay, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Simon
authors.affiliation: Laboratoire de Pharmacologie-Toxicologie, Hôpital Maison Blanche, Centre Hospitalier et Universitaire de Reims, Reims, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gozalo
authors.affiliation: Laboratoire de Pharmacologie-Toxicologie, Hôpital Maison Blanche, Centre Hospitalier et Universitaire de Reims, Reims, France.
authors.forename: Zoubir
authors.initials: Z
authors.lastname: Djerada
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Flechtner
authors.affiliation: Unité de Recherche Clinique et Centre d'Investigation Clinique 1419, Unité de Pharmacologie EA 7323, Paris Descartes-Université Sorbonne Paris Cité, Hôpital Universitaire Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: Inserm U1016, Institut Cochin, Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: Faculté de Médecine Paris-Diderot, Université Sorbonne-Paris-Cité, Paris, France Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Service d'Obstétrique et de Gynécologie, Hôpitaux Universitaires Paris Centre, Cochin Port Royal, Assistance Publique-Hôpitaux de Paris, Paris, France Inserm UMR 1178, Service de Pédopsychiatrie, Hôpital Universitaire Necker Enfants Malades Paris, Universités Paris Sud et Paris Descartes, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Vaivre-Douret
authors.affiliation: Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France Faculté de Médecine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France Inserm U1016, Institut Cochin, Paris, France Inserm UMR 1163, Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France michel.polak@nck.aphp.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D057915:Drug Substitution; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009461:Neurologic Manifestations; D009483:Neuropsychological Tests; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011597:Psychomotor Performance; D064233:Sulfonylurea Receptors / Q000235:genetics; D000099161:Kcnj11 Channel
chemical_list: D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human