Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms
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  • 作者：David Cheillan (1)
    Marie Joncquel-Chevalier Curt (2)
    Gilbert Briand (2) (3)
    Gajja S Salomons (4)
    Karine Mention-Mulliez (5)
    Dries Dobbelaere (5)
    Jean-Marie Cuisset (6)
    Laurence Lion-Fran?ois (7)
    Vincent Des Portes (7)
    Allel Chabli (8)
    Vassili Valayannopoulos (9)
    Jean-Fran?ois Benoist (10)
    Jean-Marc Pinard (11)
    Gilles Simard (12)
    Olivier Douay (12)
    Kumaran Deiva (13)
    Alexandra Afenjar (14)
    Delphine Héron (15)
    Fran?ois Rivier (16)
    Brigitte Chabrol (17)
    Fabienne Prieur (18)
    Fran?ois Cartault (19)
    Ga?lle Pitelet (20)
    Alice Goldenberg (21)
    Soumeya Bekri (22)
    Marion Gerard (23)
    Richard Delorme (24)
    Marc Tardieu (25)
    Nicole Porchet (2)
    Christine Vianey-Saban (1)
    Joseph Vamecq (2) (26)
  • 刊名：Orphanet Journal of Rare Diseases
  • 出版年：2012
  • 出版时间：December 2012
  • 年：2012
  • 卷：7
  • 期：1
  • 全文大小：228KB
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  • 作者单位：David Cheillan (1)
    Marie Joncquel-Chevalier Curt (2)
    Gilbert Briand (2) (3)
    Gajja S Salomons (4)
    Karine Mention-Mulliez (5)
    Dries Dobbelaere (5)
    Jean-Marie Cuisset (6)
    Laurence Lion-Fran?ois (7)
    Vincent Des Portes (7)
    Allel Chabli (8)
    Vassili Valayannopoulos (9)
    Jean-Fran?ois Benoist (10)
    Jean-Marc Pinard (11)
    Gilles Simard (12)
    Olivier Douay (12)
    Kumaran Deiva (13)
    Alexandra Afenjar (14)
    Delphine Héron (15)
    Fran?ois Rivier (16)
    Brigitte Chabrol (17)
    Fabienne Prieur (18)
    Fran?ois Cartault (19)
    Ga?lle Pitelet (20)
    Alice Goldenberg (21)
    Soumeya Bekri (22)
    Marion Gerard (23)
    Richard Delorme (24)
    Marc Tardieu (25)
    Nicole Porchet (2)
    Christine Vianey-Saban (1)
    Joseph Vamecq (2) (26)

    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, H?pital Jeanne de Flandres, CHRU Lille, Lille, 59037, France
    6. Service de Neurologie Infantile, H?pital Roger Salengro, CHRU Lille, Lille, 59037, France
    7. Service de neurologie pédiatrique, CHU de Lyon-GH Est - H?pital 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, H?pital Necker des Enfants Malades and Université Paris Descartes, 149 rue de Sèvres, Paris, 75015, France
    10. Département de Biochimie-Hormonologie, CHU H?pital Robert Debré, Paris, 75019, France
    11. Unité de Neurologie Pédiatrique, Département de Pédiatrie, H?pital 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, H?pital 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 H?pital de la Timone, Marseille Cedex 5, 13385, France
    18. Service de Génétique, CHU de Saint-étienne H?pital 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, H?pital 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 H?pital 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
文摘
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-gt;?T and c.289C-gt;?T] and 1 splicing [c.391--5G-gt;?T] mutations for the GAMT gene and, 2 missense [c.1208C-gt;?A and c.926C-gt;?A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G-gt;?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.

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