Jacques Beltrand1, Caroline Elie2, Kanetee Busiah1, Emmanuel Fournier3, Nathalie Boddaert4, Nadia Bahi-Buisson5, Miriam Vera6, Emmanuel Bui-Quoc7, Isabelle Ingster-Moati8, Marianne Berdugo9, Albane Simon10, Claire Gozalo11, Zoubir Djerada11, Isabelle Flechtner6, Jean-Marc Treluyer2, Raphael Scharfmann12, Helene Cavé13, Laurence Vaivre-Douret14, Michel Polak15. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, Paris, France. 7. Service d'Ophtalmologie, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France. 8. 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. 9. 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. 10. 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. 11. Laboratoire de Pharmacologie-Toxicologie, Hôpital Maison Blanche, Centre Hospitalier et Universitaire de Reims, Reims, France. 12. Inserm U1016, Institut Cochin, Paris, France. 13. 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. 14. 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. 15. 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.
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. RESEARCH DESIGN AND 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.
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. RESEARCH DESIGN AND 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: Monica S Lanning; David Carmody; Łukasz Szczerbiński; Lisa R Letourneau; Rochelle N Naylor; Siri Atma W Greeley Journal: Pediatr Diabetes Date: 2017-12-05 Impact factor: 4.866
Authors: Pamela Bowman; Jacob Day; Lorna Torrens; Maggie H Shepherd; Bridget A Knight; Tamsin J Ford; Sarah E Flanagan; Ali Chakera; Andrew T Hattersley; Adam Zeman Journal: Diabetes Care Date: 2018-10-30 Impact factor: 19.112