title: Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.
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.
authors.affiliation: Hospices Civils de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Groupement Hospitalier, Bron, France.
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.forename: Marie
authors.initials: M
authors.lastname: Joncquel-Chevalier Curt
authors.forename: Gilbert
authors.initials: G
authors.lastname: Briand
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.forename: Karine
authors.initials: K
authors.lastname: Mention-Mulliez
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuisset
authors.forename: Laurence
authors.initials: L
authors.lastname: Lion-François
authors.forename: Vincent Des
authors.initials: VD
authors.lastname: Portes
authors.forename: Allel
authors.initials: A
authors.lastname: Chabli
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pinard
authors.forename: Gilles
authors.initials: G
authors.lastname: Simard
authors.forename: Olivier
authors.initials: O
authors.lastname: Douay
authors.forename: Kumaran
authors.initials: K
authors.lastname: Deiva
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.forename: Fabienne
authors.initials: F
authors.lastname: Prieur
authors.forename: François
authors.initials: F
authors.lastname: Cartault
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pitelet
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
authors.forename: Marion
authors.initials: M
authors.lastname: Gerard
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.forename: Joseph
authors.initials: J
authors.lastname: Vamecq
mesh_terms: D003401:Creatine / Q000172:deficiency* / Q000652:urine*; D003404:Creatinine / Q000652:urine; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000652:urine; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009422:Nervous System Diseases / Q000209:etiology* / Q000652:urine; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C094770:SLC6A8 protein, human; D003404:Creatinine; C004946:glycocyamine; D003401:Creatine; D005998:Glycine