Service de Biochimie Hormonologie

Hôpital-Camfrout, France

Service de Biochimie Hormonologie

Hôpital-Camfrout, France
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Rachid M.,Service de Biochimie hormonologie | Dreux S.,Service de Biochimie hormonologie | De Ponfilly G.P.,Service de Biochimie hormonologie | Vargas-Poussou R.,Hopital Europeen Georges Pompidou | And 6 more authors.
Annales de Biologie Clinique | Year: 2017

Bartter syndrome is a severe inherited tubulopathy characterized at birth by salt wasting, severe polyuria, dehydration, growth retardation and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following onset of severe polyhydramnios. We studied amniotic fluid aldosterone concentration in cases of Bartter syndrome and in control groups. Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of postnatally diagnosed Bartter syndrome and 144 controls matched for gestational age. Two controls groups were defined: controls with polyhydramnios (n=72) and control without polyhydramnios (n=72). Amniotic fluid aldosterone was compared between the three groups. The median amniotic fluid aldosterone concentration in the Bartter syndrome group (90 pg/mL) did not differ significantly from that in the controls with polyhydramnios (90 pg/mL, p=0.33) or the controls without polyhydramnios (87 pg/mL, p=0.41). In conclusion, amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter syndrome.

Veyrat B.,LBM Medilys | Tosetti F.,LBM Oriade Noviale | Morin J.-F.,University of Monastir | Moineau M.-P.,Brest University Hospital Center | And 5 more authors.
Annales de Biologie Clinique | Year: 2017

Down syndrome maternal serum marker screening is based on a risk calculation including the free β - human chorionic gonadotropin (hCGβ) and pregnancy-associated placenta protein type A (PAPP-A). The aim of this study was to define the pre-analytical conditions of stability of these markers both in whole blood at 15-25 °C and, after centrifugation, in serum at 4-8 °C. 158 patients were included in the study. Two automated workstations were used for assays, Cobas 8000e602, Roche Diagnostics (58 patients tested) and DELFIAXpress, PerkinElmer (100 patients tested). The stability of markers was studied in whole blood (15-25 °C) 2, 4, 6 and 8 hours after sampling and in serum stored after centrifugation at 4-8 °C at 24, 72 and 120 hours. Variations were defined by (CT - C2)/C2, C2 being the marker concentration at 2 hours and CT the concentration at time T. In whole blood kept for 8 hours at 15-25 °C, hCGβ increased by a mean 2.4%, whereas the mean increase of PAPP-A was < 1%. In the serum kept for 5 days at 4-8°C, the mean increase of hCGβ was 4.2%, with no change in PAPP-A. The impact of these variations on risk calculation is low. In conclusion, maternal serum can be store 8 hours at 15-25°C in whole blood and 5 days at 4-8°C after centrifugation and serum separation for Down syndrome maternal serum screening.

Mochel F.,French Institute of Health and Medical Research | Duteil S.,Institute Of Myologie | Duteil S.,French Atomic Energy Commission | Duteil S.,University Pierre and Marie Curie | And 11 more authors.
European Journal of Human Genetics | Year: 2010

We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites-C5 ketone bodies-cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33±13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and 31P-NMR spectroscopy (NMRS) in muscle. At baseline, 31P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205±60 ng/ml versus 246±68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD. © 2010 Macmillan Publishers Limited All rights reserved.

Lemaitre C.,University Paris Diderot | Bidet P.,University Paris Diderot | Benoist J.-F.,Service de Biochimie Hormonologie | Benoist J.-F.,University Paris - Sud | And 4 more authors.
Journal of Bacteriology | Year: 2014

The ability to capture iron is a challenge for most bacteria. The neonatal meningitis Escherichia coli strain S88 possesses several iron uptake systems, notably including siderophores. Transcriptional analysis of the ColV plasmid pS88 has shown strong induction of a previously undescribed gene with low identity to three E. coli chromosomal genes encoding phospho-2-dehydro-3-deoxyheptonate aldolases involved in aromatic amino acid and catecholate/phenolate siderophore biosynthesis through the shikimate pathway. Here, we investigated the role of this gene, ssbLp (ssbL carried on the plasmid), in siderophore biosynthesis and, consequently, in S88 virulence. We constructed an S88 mutant designated S88 δssbLp, which exhibited reduced growth under low-iron conditions compared to the wild-type strain. Liquid chromatography-mass spectroscopy analysis of culture supernatants showed that the mutant secreted significantly smaller amounts of enterobactin, salmochelin SX, and yersiniabactin than the wild-type strain. The mutant was also less virulent in a neonatal rat sepsis model, with significantly lower bacteremia and mortality. Supplementation with chorismate, the final product of the shikimate pathway, restored the wild-type phenotype in vitro. In a collection of human extraintestinal E. coli isolates, we found that ssbL was present only in strains harboring the iro locus, encoding salmochelins, and was located either on the chromosome or on plasmids. Acquisition of the iro locus has been accompanied by acquisition of the auxiliary gene ssbL, which boosts the metabolic pathway essential for catecholate/phenolate siderophore biosynthesis and could represent potential therapeutic targets. © 2014, American Society for Microbiology.

Sabbagh A.,University of Paris Descartes | Pasmant E.,University of Paris Descartes | Imbard A.,Service de Biochimie Hormonologie | Luscan A.,University of Paris Descartes | And 10 more authors.
Human Mutation | Year: 2013

Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant-related patients. A genotype-phenotype study was performed in patients harboring a truncating (N = 368), in-frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity. © 2013 WILEY PERIODICALS, INC.

De Becdelievre A.,Groupe Hospitalier Henri Mondor Albert Chenevier | De Becdelievre A.,French Institute of Health and Medical Research | De Becdelievre A.,University Paris Est Creteil | Costa C.,Groupe Hospitalier Henri Mondor Albert Chenevier | And 20 more authors.
Human Genetics | Year: 2011

Fetal bowel anomalies may reveal cystic fibrosis (CF) and the search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the diagnostic investigations in such pregnancies, according to European recommendations. We report on our 18-year experience to document comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. CFTR gene analysis was performed in a multistep process, including search for frequent mutations in the parents and subsequent in-depth search for rare mutations, depending on the context. Ultrasound patterns were correlated with the genotypes. Cases were distinguished according to whether they had been referred directly to our laboratory or after an initial testing in another laboratory. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5/30 CF fetuses. 21.2% of fetuses carrying a frequent mutation had a second rare mutation, indicative of CF. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The results emphasize the need to search for rearrangements in the diagnosis strategy of fetal bowel anomalies. The diagnostic value of ultrasound patterns combining hyperechogenic bowel, loop dilatation and/or non-visualized gallbladder reveals a need to revise current strategies and to offer extensive CFTR gene testing when the triad is diagnosed, even when no frequent mutation is found in the first-step analysis. © 2010 Springer-Verlag.

Imbard A.,Service de Biochimie Hormonologie | Pasmant E.,University of Paris Descartes | Sabbagh A.,University of Paris Descartes | Luscan A.,University of Paris Descartes | And 11 more authors.
Journal of Human Genetics | Year: 2015

Neurofibromatosis type 1 (NF1) is caused by dominant loss-of-function mutations of the tumor suppressor NF1 containing 57 constitutive coding exons. A huge number of different pathogenic NF1 alterations has been reported. The aim of the present study was to evaluate the usefulness of a multiplex ligation-dependent probe amplification (MLPA) approach in NF1 patients to detect single and multi-exon NF1 gene copy number variations. A genotype-phenotype correlation was then performed in NF1 patients carrying these types of genetic alterations. Among 565 NF1 index cases from the French NF1 cohort, single and multi-exon deletions/duplications screening identified NF1 partial deletions/duplications in 22 patients (∼4%) using MLPA analysis. Eight single exon deletions, 11 multiple exons deletions, 1 complex rearrangement and 2 duplications were identified. All results were confirmed using a custom array-CGH. MLPA and custom array-CGH allowed the identification of rearrangements that were missed by cDNA/DNA sequencing or microsatellite analysis. We then performed a targeted next-generation sequencing of NF1 that allowed confirmation of all 22 rearrangements. No clear genotype-phenotype correlations were found for the most clinically significant disease features of NF1 in patients with single and multi-exons NF1 gene copy number changes. © 2015 The Japan Society of Human Genetics.

Chevenne D.,Service de biochimie hormonologie
Immuno-Analyse et Biologie Specialisee | Year: 2012

Produced by β-cells in pancreatic islets of Langerhans, the proinsulin is cleaved into insulin and C-peptide by a complex process of proteolytic conversion. However, a small amount of proinsulin escapes cleavage, partially or totally. Thus, secretion of insulin into the bloodstream is accompanied by the release of small amounts of proinsulins. The proinsulin immunoassays use various antibodies displaying different specificities. The measurement of proinsulinemia is useful for the diagnosis of insulinoma and family hyperproinsulinemia. Proinsulinemia is also associated with various β-cell disorders and insulinoresistance. © 2012 Elsevier Masson SAS.

Boizeau P.,French Institute of Health and Medical Research | Chevenne D.,Service de Biochimie Hormonologie | Crepon S.G.,French Institute of Health and Medical Research | Alberti C.,University Paris Diderot | And 5 more authors.
European Journal of Endocrinology | Year: 2015

Objective: To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children. Design: We conducted a university hospital-based observational study. Methods: All patients with GD followed for more than 1 year between 2003 and 2013 (nZ60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (≤8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD. Results: Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (nZ4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (nZ4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) I∪/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II. Conclusion: Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up. © 2015 European Society of Endocrinology. © 2015 European Society of Endocrinology.

van Kuilenburg A.B.P.,Metabolic | Dobritzsch D.,Karolinska Institutet | Meijer J.,Metabolic | Meinsma R.,Metabolic | And 17 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010

Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p.V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated. © 2010 Elsevier B.V.

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