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

David Cheillan 1 Marie Joncquel-Chevalier Curt 2 Gilbert Briand 2, 3 Gajja Salomons 4 Karine Mention-Mulliez 5 Dries Dobbelaere 5 Jean-Marie Cuisset 6 Laurence Lion-François 7 Vincent Des Portes 5 Allel Chabli 8 Vassili Valayannopoulos 9 Jean-François Benoist 10 Jean-Marc Pinard 11 Gilles Simard 12 Olivier Douay 5 Kumaran Deiva 13 Alexandra Afenjar 14 Delphine Héron 15 François Rivier 16 Brigitte Chabrol 17 Fabienne Prieur 18 François Cartault 19 Gaëlle Pitelet 20 Alice Goldenberg 21 Soumeya Bekri 22 Marion Gerard 23 Richard Delorme 24 Marc Tardieu 5 Nicole Porchet 2 Christine Vianey-Saban 5 Joseph Vamecq 2, *
Abstract : 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.
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Orphanet Journal of Rare Diseases, BioMed Central, 2012, 7 (1), pp.96. 〈10.1186/1750-1172-7-96〉
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David Cheillan, Marie Joncquel-Chevalier Curt, Gilbert Briand, Gajja Salomons, Karine Mention-Mulliez, et al.. Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.. Orphanet Journal of Rare Diseases, BioMed Central, 2012, 7 (1), pp.96. 〈10.1186/1750-1172-7-96〉. 〈inserm-00780328〉

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