Open Access Research

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms

David Cheillan1, Marie Joncquel-Chevalier Curt2, Gilbert Briand23, Gajja S Salomons4, Karine Mention-Mulliez5, Dries Dobbelaere5, Jean-Marie Cuisset6, Laurence Lion-François7, Vincent Des Portes7, Allel Chabli8, Vassili Valayannopoulos9, Jean-François Benoist10, Jean-Marc Pinard11, Gilles Simard12, Olivier Douay12, Kumaran Deiva13, Alexandra Afenjar14, Delphine Héron15, François Rivier16, Brigitte Chabrol17, Fabienne Prieur18, François Cartault19, Gaëlle Pitelet20, Alice Goldenberg21, Soumeya Bekri22, Marion Gerard23, Richard Delorme24, Marc Tardieu25, Nicole Porchet2, Christine Vianey-Saban1 and Joseph Vamecq226*

Author Affiliations

1 Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Groupement Hospitalier Est, Bron, 69677, France

2 Département de Biochimie et Biologie Moléculaire, Laboratoire d’Hormonologie, Métabolisme-Nutrition & Oncologie (HMNO)–Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand, CHRU Lille, Lille, 59037, France

3 Mass Spectrometry Application Laboratory, University of Lille 2, Lille, 59045, France

4 Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

5 Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Jeanne de Flandres, CHRU Lille, Lille, 59037, France

6 Service de Neurologie Infantile, Hôpital Roger Salengro, CHRU Lille, Lille, 59037, France

7 Service de neurologie pédiatrique, CHU de Lyon-GH Est - Hôpital Femme Mère Enfant, Bron Cedex, 69677, France

8 Laboratory of Biochemistry, Necker – Enfants Malades Hospital and Université Paris Descartes, Paris, 75015, France

9 Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker des Enfants Malades and Université Paris Descartes, 149 rue de Sèvres, Paris, 75015, France

10 Département de Biochimie-Hormonologie, CHU Hôpital Robert Debré, Paris, 75019, France

11 Unité de Neurologie Pédiatrique, Département de Pédiatrie, Hôpital Raymond Poincare, Paris-IdF-Ouest University, Paris, France

12 Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, Angers, 49033, France

13 Service de Neuropédiatrie - CHU de Bicêtre, Le Kremlin Bicêtre Cedex, 94275, France

14 Service de Neuropédiatrie, Hôpital Armand Trousseau, Groupement hospitalier universitaire Est, Paris, 75012, France

15 Unité Fonctionnelle de Génétique Médicale AP-HP, Département de Génétique et Cytogénétique, Centre de Référence «Déficiences intellectuelles de causes rares », CRicm, UMR-S975, Groupe Hospitalier Pitié-Salpêtrière, Paris, F-75013, France

16 Neuropédiatrie, CHRU Montpellier, & Inserm U1046, Université Montpellier 1 & 2, Montpellier Cedex 5, 34295, France

17 Service Neuropédiatrie, AP-HM Hôpital de la Timone, Marseille Cedex 5, 13385, France

18 Service de Génétique, CHU de Saint-Étienne Hôpital Nord, Saint-Etienne Cédex 2, 42055, France

19 Service de génétique Centre hospitalier Felix Guyon (Saint-Denis) Bellepierre, Saint-Denis cedex, 97405, France

20 Service de Neuropédiatrie, Hôpital de l’Archet 2, Nice Cedex 3, 06202, France

21 Service de Génétique Médicale, CHU Ch. Nicolle, Rouen Cedex, 76031, France

22 Institut de Biologie Clinique, CHU Ch. Nicolle, Rouen Cedex, 76031, France

23 Service de Génétique, CHU Clémenceau, Caen, 14033, France

24 Service de Pédopsychiatrie CHU Hôpital Robert Debré, Paris, 75019, France

25 Service de Neuropédiatrie - CHU de Bicêtre, Le Kremlin Bicêtre Cedex, 94275, France

26 Inserm, Laboratoire Externe, Département du Prof. Nicole Porchet, HMNO, Centre de Biologie et Pathologie (CBP) Pierre-Marie Degand, CHRU Lille, Lille, 59037, France

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Orphanet Journal of Rare Diseases 2012, 7:96  doi:10.1186/1750-1172-7-96

Published: 13 December 2012

Abstract

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.