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Port-Saint-Louis-du-Rhône, France

Crouzet-Ozenda Luci L.,Pole de pediatrie | De Smet S.,Pole de pediatrie | Monpoux F.,Pole de pediatrie | Ferrero-Vacher C.,Laboratoire Central dHematologie | And 2 more authors.
Archives de Pediatrie | Year: 2011

Galactosemia and congenital Rogers syndrome or thiamine-responsive megaloblastic anemia are 2 rare inherited metabolic diseases. The combination of the 2 diseases has never been reported in the literature. We describe the case of an infant followed for congenital galactosemia since the age of 8 days, with thiamine-responsive megaloblastic anemia diagnosed at the age of 10 months. Galactosemia's symptoms occur in the first 2 weeks of life with severe liver disease. Total eviction of the galactose allows complete regression and prevention of early symptoms but does not prevent late complications. Rogers syndrome associates megaloblastic anemia, deafness, and diabetes mellitus that begin in childhood. Supplementation with thiamine allows regression of anemia and prevents the onset of diabetes at least until adolescence. © 2010 Elsevier Masson SAS.

Reimann C.,University of Paris Descartes | Reimann C.,Albert Ludwigs University of Freiburg | Six E.,University of Paris Descartes | Dal-Cortivo L.,AP HP | And 11 more authors.
Stem Cells | Year: 2012

Slow T-cell reconstitution is a major clinical concern after transplantation of cord blood (CB)-derived hematopoietic stem cells. Adoptive transfer of in vitro-generated T-cell progenitors has emerged as a promising strategy for promoting de novo thymopoiesis and thus accelerating T-cell reconstitution. Here, we describe the development of a new culture system based on the immobilized Notch ligand Delta-like-4 (DL-4). Culture of human CD34 + CB cells in this new DL-4 system enabled the in vitro generation of large amounts of T-cell progenitor cells that (a) displayed the phenotypic and molecular signatures of early thymic progenitors and (b) had high T lymphopoietic potential. When transferred into NOD/SCID/γc-/- (NSG) mice, DL-4 primed T-cell progenitors migrated to the thymus and developed into functional, mature, polyclonal αβ T cells that subsequently left the thymus and accelerated T-cell reconstitution. T-cell reconstitution was even faster and more robust when ex vivo-manipulated and nonmanipulated CB samples were simultaneously injected into NSG mice (i.e., a situation reminiscent of the double CB transplant setting). This work provides further evidence of the ability of in vitro-generated human T-cell progenitors to accelerate T-cell reconstitution and also introduces a feeder-cell-free culture technique with the potential for rapid, safe transfer to a clinical setting. © AlphaMed Press.

Moreau C.,University of Paris Descartes | Bajolle F.,University of Paris Descartes | Siguret V.,AP HP | Siguret V.,University of Paris Descartes | And 8 more authors.
Blood | Year: 2012

Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/ CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/ below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated. © 2012 by The American Society of Hematology.

Bruzzoni-Giovanelli H.,University Paris Diderot | Bruzzoni-Giovanelli H.,French Institute of Health and Medical Research | Gonzalez J.R.,Institute Municipal dInvestigacio Medica IMIM | Gonzalez J.R.,CIBER ISCIII | And 9 more authors.
Oncotarget | Year: 2015

Little is known about inherited factors associated with the risk of developing chronic myelogenous leukemia (CML). We used a dedicated DNA chip containing 16 561 single nucleotide polymorphisms (SNPs) covering 1 916 candidate genes to analyze 437 CML patients and 1 144 healthy control individuals. Single SNP association analysis identified 139 SNPs that passed multiple comparisons (1% false discovery rate). The HDAC9, AVEN, SEMA3C, IKBKB, GSTA3, RIPK1 and FGF2 genes were each represented by three SNPs, the PSM family by four SNPs and the SLC15A1 gene by six. Haplotype analysis showed that certain combinations of rare alleles of these genes increased the risk of developing CML by more than two or three-fold. A classification tree model identified five SNPs belonging to the genes PSMB10, TNFRSF10D, PSMB2, PPARD and CYP26B1, which were associated with CML predisposition. A CML-risk-allele score was created using these five SNPs. This score was accurate for discriminating CML status (AUC: 0.61, 95%CI: 0.58-0.64). Interestingly, the score was associated with age at diagnosis and the average number of risk alleles was significantly higher in younger patients. The risk-allele score showed the same distribution in the general population (HapMap CEU samples) as in our control individuals and was associated with differential gene expression patterns of two genes (VAPA and TDRKH). In conclusion, we describe haplotypes and a genetic score that are significantly associated with a predisposition to develop CML. The SNPs identified will also serve to drive fundamental research on the putative role of these genes in CML development.

Damaj G.,Center Hospitalier University | Damaj G.,French National Center for Scientific Research | Joris M.,Center Hospitalier University | Chandesris O.,University of Paris Descartes | And 21 more authors.
PLoS ONE | Year: 2014

Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS. © 2014 Damaj et al.

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