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

被引:31
作者
Cheillan, David [1 ]
Curt, Marie Joncquel-Chevalier [2 ]
Briand, Gilbert [2 ,3 ]
Salomons, Gajja S. [4 ]
Mention-Mulliez, Karine [5 ]
Dobbelaere, Dries [5 ]
Cuisset, Jean-Marie [6 ]
Lion-Francois, Laurence [7 ]
Portes, Vincent Des [7 ]
Chabli, Allel [8 ,9 ]
Valayannopoulos, Vassili [9 ,10 ]
Benoist, Jean-Francois [11 ]
Pinard, Jean-Marc [12 ]
Simard, Gilles [13 ]
Douay, Olivier [13 ]
Deiva, Kumaran [14 ]
Afenjar, Alexandra [15 ]
Heron, Delphine [16 ]
Rivier, Francois [17 ,18 ]
Chabrol, Brigitte [19 ]
Prieur, Fabienne [20 ]
Cartault, Francois [21 ]
Pitelet, Gaelle [22 ]
Goldenberg, Alice [23 ]
Bekri, Soumeya [24 ]
Gerard, Marion [25 ]
Delorme, Richard [26 ]
Tardieu, Marc [27 ]
Porchet, Nicole [2 ]
Vianey-Saban, Christine [1 ]
Vamecq, Joseph [2 ,28 ]
机构
[1] Groupement Hosp Est, Hosp Civils Lyon, Serv Malad Hereditaires Metab & Depistage Neontal, F-69677 Bron, France
[2] CHRU Lille, CBP Pierre Marie Degand, Lab Hormonol Metab Nutr & Oncol HMNO, Dept Biochim & Biol Mol, F-59037 Lille, France
[3] Univ Lille 2, Mass Spectrometry Applicat Lab, F-59045 Lille, France
[4] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Clin Chem, Metabol Unit, Amsterdam, Netherlands
[5] CHRU Lille, Hop Jeanne Flandres, Ctr Reference Malad Hereditaires Metab, F-59037 Lille, France
[6] CHRU Lille, Hop Roger Salengro, Serv Neurol Infantile, F-59037 Lille, France
[7] CHU Lyon GH Est Hop Femme Mere Enfant, Serv Neurol Pediat, F-69677 Bron, France
[8] Necker Enfants Malades Hosp, Lab Biochem, F-75015 Paris, France
[9] Univ Paris 05, F-75015 Paris, France
[10] Hop Necker Enfants Malad, Ctr Reference Malad Hereditaires Metab, F-75015 Paris, France
[11] CHU Hop Robert Debre, Dept Biochim Hormonol, F-75019 Paris, France
[12] Paris IdF Ouest Univ, Hop Raymond Poincare, Unite Neurol Pediat, Dept Pediat, Paris, France
[13] CHU Angers, Lab Biochim & Biol Mol, F-49033 Angers, France
[14] CHU Bicetre, Serv Neuropediat, F-94275 Le Kremlin Bicetre, France
[15] Groupement Hosp Univ Est, Hop Armand Trousseau, Serv Neuropediat, F-75012 Paris, France
[16] Grp Hosp Pitie Salpetriere, UMR S975, Ctr Reference Deficiences Intellectuelles Cause R, Unite Fonctionnelle Genet Med AP HP, F-75013 Paris, France
[17] Univ Montpellier 1 & 2, CHRU Montpellier, F-34295 Montpellier 5, France
[18] Univ Montpellier 1 & 2, Inserm U1046, F-34295 Montpellier 5, France
[19] AP Hop Timone, Serv Neuropediat, F-13385 Marseille, France
[20] CHU St Etienne Hop Nord, Serv Genet, F-42055 St Etienne 2, France
[21] Ctr Hosp Felix Guyon St Denis Bellep, Serv Genet, F-97405 St Denis, France
[22] Hop Archet 2, Serv Neuropediat, F-06202 Nice 3, France
[23] CHU Ch Nicolle, Serv Genet Med, F-76031 Rouen, France
[24] CHU Ch Nicolle, Inst Biol Clin, F-76031 Rouen, France
[25] CHU Clemenceau, Serv Genet, F-14033 Caen, France
[26] CHU Hop Robert Debre, Serv Pedopsychiat, F-75019 Paris, France
[27] CHU Bicetre, Serv Neuropediat, F-94275 Le Kremlin Bicetre, France
[28] CHRU Lille, CBP Pierre Marie Degand, HMNO, Inserm,Lab Externe,Dept Prof Nicole, F-59037 Lille, France
来源
ORPHANET JOURNAL OF RARE DISEASES | 2012年 / 7卷
关键词
GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY; ARGININE-GLYCINE AMIDINOTRANSFERASE; TRANSPORTER SLC6A8 MUTATIONS; LINKED MENTAL-RETARDATION; TANDEM MASS-SPECTROMETRY; CENTRAL-NERVOUS-SYSTEM; UREA CYCLE; PRESYMPTOMATIC TREATMENT; CLINICAL CHARACTERISTICS; MUSCLE-CONTRACTION;
D O I
10.1186/1750-1172-7-96
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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, H-1-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.
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