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Georges Deschênes - One of the best experts on this subject based on the ideXlab platform.
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prevalence of novel maged2 mutations in antenatal Bartter Syndrome
Clinical Journal of The American Society of Nephrology, 2017Co-Authors: Anne Legrand, Georges Deschênes, Sophie Dreux, Cyrielle Treard, Isabelle Roncelin, Aurelia Bertholetthomas, Francoise Broux, Daniele Bruno, Stephane Decramer, Djamal DjeddiAbstract:Background and objectives Mutations in the MAGED2 gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter Syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter Syndrome. Design, setting, participants, & measurements The French cohort of patients with antenatal Bartter Syndrome encompasses 171 families. Mutations in genes responsible for types 1–4 have been detected in 75% of cases. In patients without identified genetic cause ( n =42), transient antenatal Bartter Syndrome was reported in 12 cases. We analyzed the MAGED2 gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases. Results We detected mutations in MAGED2 in 17 patients, including the 12 with transient antenatal Bartter Syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases. Conclusions MAGED2 mutations explained 9% of cases of antenatal Bartter Syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter Syndrome.
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Annales De Biologie Clinique, 2017Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract: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.
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fetal urine biochemistry in antenatal Bartter Syndrome a case report
Clinical Case Reports, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Jeanfrancois Oury, Isabelle Czerkiewicz, Dominique Mahieucaputo, Francoise MullerAbstract:Bartter Syndrome is a severe inherited tubulopathy responsible for renal salt wasting. It is caused by alterations in ion channels located in the thick ascending limb of Henle's loop. Five mutations in four genes – SLC12A1, KCNJ1, CLCNKB, and BSND – coding for transporters and one specific mutation (L125Q) in the CASR gene, which encodes the calcium‐sensing receptor, have been identified 1, 2. First described in 1962 3, two presentations are currently recognized. The classic form develops in childhood and is characterized by severe polyuria, dehydration, hypokalemic metabolic alkalosis, secondary hyper‐aldosteronism, and hypercalciuria sometimes leading to nephrocalcinosis. The second presentation is antenatal, more severe 4, 5 and is revealed by refractory polyhydramnios (caused by fetal polyuria) during the second trimester of pregnancy, without morphological anomalies. The major consequences are preterm birth, growth retardation, and severe dehydration at birth due to salt loss. In children with Bartter Syndrome, urinalysis highlights increased sodium, potassium, chloride and calcium excretion, and as a consequence hyponatremia, hypochloremia, and hypokalemia 4, 6. However, until now, no studies have been published about fetal urinalysis in antenatal Bartter Syndrome. A 28‐year‐old woman in a consanguineous marriage (first cousins), gravida 1, para 0, presented severe polyhydramnios at routine ultrasound examination at 22.6 weeks of amenorrhea. Megacystis was observed in a female fetus, without any other malformation. After genetic counseling, invasive procedures were offered to the parents and accepted: amniotic fluid sampling for karyotyping and biochemistry and fetal urine sampling for renal function evaluation. The karyotype was normal, 46,XX. A second amniocentesis was secondarily performed at 26.3 weeks for amniodrainage. Amniotic fluid alpha‐fetoprotein and total protein were decreased at both 22.6 and 26.3 weeks (Table 1), giving a Bartter index (total protein expressed in g/L x alpha‐fetoprotein in MoM) of 0.85 and 0.71, respectively 7. These values were strongly suggestive of Bartter Syndrome. In fetal urine we assayed electrolytes, beta‐2 microglobulin, and total protein. Results are presented in Table 1 in comparison with two fetal urine controls (one with renal failure and one with normal renal function, both performed because of megacystis). Electrolytes were significantly increased in Bartter Syndrome compared with controls (P < 0.001). A weekly check‐up was planned. The patient delivered a girl at 33.6 weeks of gestation. The baby presented clinical and laboratory signs of Bartter Syndrome. Postnatal screening for Bartter Syndrome mutations detected a homozygous mutation in the SLC12A1 gene. Table 1 Fetal urine and amniotic fluid electrolytes (mmol/L), β2‐microglobulin (β2 m), and total protein in Bartter Syndrome and controls
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Prenatal Diagnosis, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract:Objective Bartter Syndrome is a severe inherited tubulopathy characterized by postnatal salt wasting, severe polyuria, dehydration, failure to thrive and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following the onset of severe polyhydramnios in the second trimester. We studied amniotic fluid aldosterone concentration in Bartter Syndrome and in controls. Methods Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of prenatally suspected and postnatally confirmed Bartter Syndrome (22 with identified mutations): and 72 gestational age matched controls presenting with polyhydramnios and 72 without polyhydramnios. Amniotic fluid aldosterone was compared between the three groups. Results The median amniotic fluid aldosterone concentration in the Bartter Syndrome group (90 pg/mL) was not different from that in the controls with polyhydramnios (90 pg/mL, P = 0.33) or without polyhydramnios (87 pg/mL, P = 0.41). Conclusion Amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter Syndrome. © 2015 John Wiley & Sons, Ltd.
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primary molecular disorders and secondary biological adaptations in Bartter Syndrome
International Journal of Nephrology, 2011Co-Authors: Georges Deschênes, Marc FilaAbstract:Bartter Syndrome is a hereditary disorder that has been characterized by the association of hypokalemia, alkalosis, and the hypertrophy of the juxtaglomerular complex with secondary hyperaldosteronism and normal blood pressure. By contrast, the genetic causes of Bartter Syndrome primarily affect molecular structures directly involved in the sodium reabsorption at the level of the Henle loop. The ensuing urinary sodium wasting and chronic sodium depletion are responsible for the contraction of the extracellular volume, the activation of the renin-aldosterone axis, the secretion of prostaglandins, and the biological adaptations of downstream tubular segments, meaning the distal convoluted tubule and the collecting duct. These secondary biological adaptations lead to hypokalemia and alkalosis, illustrating a close integration of the solutes regulation in the tubular structures.
Francoise Muller - One of the best experts on this subject based on the ideXlab platform.
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Annales De Biologie Clinique, 2017Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract: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.
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fetal urine biochemistry in antenatal Bartter Syndrome a case report
Clinical Case Reports, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Jeanfrancois Oury, Isabelle Czerkiewicz, Dominique Mahieucaputo, Francoise MullerAbstract:Bartter Syndrome is a severe inherited tubulopathy responsible for renal salt wasting. It is caused by alterations in ion channels located in the thick ascending limb of Henle's loop. Five mutations in four genes – SLC12A1, KCNJ1, CLCNKB, and BSND – coding for transporters and one specific mutation (L125Q) in the CASR gene, which encodes the calcium‐sensing receptor, have been identified 1, 2. First described in 1962 3, two presentations are currently recognized. The classic form develops in childhood and is characterized by severe polyuria, dehydration, hypokalemic metabolic alkalosis, secondary hyper‐aldosteronism, and hypercalciuria sometimes leading to nephrocalcinosis. The second presentation is antenatal, more severe 4, 5 and is revealed by refractory polyhydramnios (caused by fetal polyuria) during the second trimester of pregnancy, without morphological anomalies. The major consequences are preterm birth, growth retardation, and severe dehydration at birth due to salt loss. In children with Bartter Syndrome, urinalysis highlights increased sodium, potassium, chloride and calcium excretion, and as a consequence hyponatremia, hypochloremia, and hypokalemia 4, 6. However, until now, no studies have been published about fetal urinalysis in antenatal Bartter Syndrome. A 28‐year‐old woman in a consanguineous marriage (first cousins), gravida 1, para 0, presented severe polyhydramnios at routine ultrasound examination at 22.6 weeks of amenorrhea. Megacystis was observed in a female fetus, without any other malformation. After genetic counseling, invasive procedures were offered to the parents and accepted: amniotic fluid sampling for karyotyping and biochemistry and fetal urine sampling for renal function evaluation. The karyotype was normal, 46,XX. A second amniocentesis was secondarily performed at 26.3 weeks for amniodrainage. Amniotic fluid alpha‐fetoprotein and total protein were decreased at both 22.6 and 26.3 weeks (Table 1), giving a Bartter index (total protein expressed in g/L x alpha‐fetoprotein in MoM) of 0.85 and 0.71, respectively 7. These values were strongly suggestive of Bartter Syndrome. In fetal urine we assayed electrolytes, beta‐2 microglobulin, and total protein. Results are presented in Table 1 in comparison with two fetal urine controls (one with renal failure and one with normal renal function, both performed because of megacystis). Electrolytes were significantly increased in Bartter Syndrome compared with controls (P < 0.001). A weekly check‐up was planned. The patient delivered a girl at 33.6 weeks of gestation. The baby presented clinical and laboratory signs of Bartter Syndrome. Postnatal screening for Bartter Syndrome mutations detected a homozygous mutation in the SLC12A1 gene. Table 1 Fetal urine and amniotic fluid electrolytes (mmol/L), β2‐microglobulin (β2 m), and total protein in Bartter Syndrome and controls
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Prenatal Diagnosis, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract:Objective Bartter Syndrome is a severe inherited tubulopathy characterized by postnatal salt wasting, severe polyuria, dehydration, failure to thrive and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following the onset of severe polyhydramnios in the second trimester. We studied amniotic fluid aldosterone concentration in Bartter Syndrome and in controls. Methods Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of prenatally suspected and postnatally confirmed Bartter Syndrome (22 with identified mutations): and 72 gestational age matched controls presenting with polyhydramnios and 72 without polyhydramnios. Amniotic fluid aldosterone was compared between the three groups. Results The median amniotic fluid aldosterone concentration in the Bartter Syndrome group (90 pg/mL) was not different from that in the controls with polyhydramnios (90 pg/mL, P = 0.33) or without polyhydramnios (87 pg/mL, P = 0.41). Conclusion Amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter Syndrome. © 2015 John Wiley & Sons, Ltd.
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Bartter Syndrome Prenatal Diagnosis Based on Amniotic Fluid Biochemical Analysis
Pediatric Research, 2010Co-Authors: Arnaud Garnier, Georges Deschênes, Rosa Vargas-poussou, Sophie Dreux, Jeanfrancois Oury, Alexandra Benachi, Francoise MullerAbstract:Bartter Syndrome is an autosomic recessive disease characterized by severe polyuria and sodium renal loss. The responsible genes encode proteins involved in electrolyte tubular reabsorption. Prenatal manifestations, mainly recurrent polyhydramnios because of fetal polyuria, lead to premature delivery. After birth, polyuria leads to life-threatening dehydration. Prenatal genetic diagnosis needs an index case. The aim of this study was to analyze amniotic fluid biochemistry for the prediction of Bartter Syndrome. We retrospectively studied 16 amniotic fluids of Bartter Syndrome-affected fetuses diagnosed after birth, only six of them being genetically proven. We assayed total proteins, alpha-fetoprotein, and electrolytes and defined a Bartter index corresponding to the multiplication of total protein and of alpha-fetoprotein. Results were compared with two control groups matched for gestational age—non-Bartter polyhydramnios ( n = 30) and nonpolyhydramnios ( n = 60). In Bartter Syndrome, we observed significant differences ( p < 0.0001) for protein amniotic fluid levels when compared with the two control groups (1.55 g/L, 3.9 g/L, and 5.2 g/L, respectively) and low Bartter index (0.16, 0.82, and 1.0, respectively). No statistical difference was observed for electrolytes. In conclusion, Bartter Syndrome can be prenatally suspected on amniotic fluid biochemistry (sensitivity 93% and specificity 100%), allowing appropriate management before and after birth.
Rosa Vargas-poussou - One of the best experts on this subject based on the ideXlab platform.
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ClC-K chloride channels: emerging pathophysiology of Bartter Syndrome type 3
AJP Renal Physiology, 2015Co-Authors: Olga Andrini, Rosa Vargas-poussou, Mathilde Keck, Rodolfo Briones, Stéphane Lourdel, Jacques TeulonAbstract:The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter Syndrome type 3, one of the four variants of Bartter Syndrome in the genetically based nomenclature. All forms of Bartter Syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism, but Bartter Syndrome type 3 has the most heterogeneous presentation, extending from severe to very mild. A relatively large number of CLCNKB mutations have been reported, including gene deletions and nonsense or missense mutations. However, only 20 CLCNKB mutations have been functionally analyzed, due to technical difficulties regarding ClC-Kb functional expression in heterologous systems. This review provides an overview of recent progress in the functional consequences of CLCNKB mutations on ClC-Kb chloride channel activity. It has been observed that 1) all ClC-Kb mutants have an impaired expression at the membrane; and 2) a minority of the mutants combines reduced membrane expression with altered pH-dependent channel gating. Although further investigation is needed to fully characterize disease pathogenesis, Bartter Syndrome type 3 probably belongs to the large family of conformational diseases, in which the mutations destabilize channel structure, inducing ClC-Kb retention in the endoplasmic reticulum and accelerated channel degradation.
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CLCNKB mutations causing mild Bartter Syndrome profoundly alter the pH and Ca2+ dependence of ClC-Kb channels
Pflügers Archiv European Journal of Physiology, 2014Co-Authors: Olga Andrini, Mathilde Keck, Rodolfo Briones, Stéphane Lourdel, Sébastien L'hoste, Lamisse Mansour-hendili, Teddy Grand, Francisco Sepúlveda, Anne Blanchard, Rosa Vargas-poussouAbstract:ClC-Kb, a member of the ClC family of Cl(-) channels/transporters, plays a major role in the absorption of NaCl in the distal nephron. CLCNKB mutations cause Bartter Syndrome type 3, a hereditary renal salt-wasting tubulopathy. Here, we investigate the functional consequences of a Val to Met substitution at position 170 (V170M, α helix F), which was detected in eight patients displaying a mild phenotype. Conductance and surface expression were reduced by ~40-50 %. The regulation of channel activity by external H(+) and Ca(2+) is a characteristic property of ClC-Kb. Inhibition by external H(+) was dramatically altered, with pKH shifting from 7.6 to 6.0. Stimulation by external Ca(2+) on the other hand was no longer detectable at pH 7.4, but was still present at acidic pH values. Functionally, these regulatory modifications partly counterbalance the reduced surface expression by rendering V170M hyperactive. Pathogenic Met170 seems to interact with another methionine on α helix H (Met227) since diverse mutations at this site partly removed pH sensitivity alterations of V170M ClC-Kb. Exploring other disease-associated mutations, we found that a Pro to Leu substitution at position 124 (α helix D, Simon et al., Nat Genet 1997, 17:171-178) had functional consequences similar to those of V170M. In conclusion, we report here for the first time that ClC-Kb disease-causing mutations located around the selectivity filter can result in both reduced surface expression and hyperactivity in heterologous expression systems. This interplay must be considered when analyzing the mild phenotype of patients with type 3 Bartter Syndrome.
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Bartter Syndrome Prenatal Diagnosis Based on Amniotic Fluid Biochemical Analysis
Pediatric Research, 2010Co-Authors: Arnaud Garnier, Georges Deschênes, Rosa Vargas-poussou, Sophie Dreux, Jeanfrancois Oury, Alexandra Benachi, Francoise MullerAbstract:Bartter Syndrome is an autosomic recessive disease characterized by severe polyuria and sodium renal loss. The responsible genes encode proteins involved in electrolyte tubular reabsorption. Prenatal manifestations, mainly recurrent polyhydramnios because of fetal polyuria, lead to premature delivery. After birth, polyuria leads to life-threatening dehydration. Prenatal genetic diagnosis needs an index case. The aim of this study was to analyze amniotic fluid biochemistry for the prediction of Bartter Syndrome. We retrospectively studied 16 amniotic fluids of Bartter Syndrome-affected fetuses diagnosed after birth, only six of them being genetically proven. We assayed total proteins, alpha-fetoprotein, and electrolytes and defined a Bartter index corresponding to the multiplication of total protein and of alpha-fetoprotein. Results were compared with two control groups matched for gestational age—non-Bartter polyhydramnios ( n = 30) and nonpolyhydramnios ( n = 60). In Bartter Syndrome, we observed significant differences ( p < 0.0001) for protein amniotic fluid levels when compared with the two control groups (1.55 g/L, 3.9 g/L, and 5.2 g/L, respectively) and low Bartter index (0.16, 0.82, and 1.0, respectively). No statistical difference was observed for electrolytes. In conclusion, Bartter Syndrome can be prenatally suspected on amniotic fluid biochemistry (sensitivity 93% and specificity 100%), allowing appropriate management before and after birth.
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Novel Molecular Variants of the Na-K-2Cl Cotransporter Gene Are Responsible for Antenatal Bartter Syndrome
American journal of human genetics, 1998Co-Authors: Rosa Vargas-poussou, Martin Vollmer, Delphine Feldmann, L. Kelly, L.p.w.j. Van Den Heuvel, L. Tebourbi, Matthias Brandis, Lothar Károlyi, Steven C. HebertAbstract:Antenatal Bartter Syndrome is a variant of inherited renal-tubular disorders associated with hypokalemic alkalosis. This disorder typically presents as a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark of this variant is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. We have analyzed 15 probands belonging to 13 families and have performed SSCP analysis of the coding sequence and the exon-intron boundaries of the NKCC2 gene; and we report 14 novel mutations in patients with antenatal Bartter Syndrome, as well as the identification of three isoforms of human NKCC2 that arise from alternative splicing.
Rosa Vargaspoussou - One of the best experts on this subject based on the ideXlab platform.
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Annales De Biologie Clinique, 2017Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract: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.
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fetal urine biochemistry in antenatal Bartter Syndrome a case report
Clinical Case Reports, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Jeanfrancois Oury, Isabelle Czerkiewicz, Dominique Mahieucaputo, Francoise MullerAbstract:Bartter Syndrome is a severe inherited tubulopathy responsible for renal salt wasting. It is caused by alterations in ion channels located in the thick ascending limb of Henle's loop. Five mutations in four genes – SLC12A1, KCNJ1, CLCNKB, and BSND – coding for transporters and one specific mutation (L125Q) in the CASR gene, which encodes the calcium‐sensing receptor, have been identified 1, 2. First described in 1962 3, two presentations are currently recognized. The classic form develops in childhood and is characterized by severe polyuria, dehydration, hypokalemic metabolic alkalosis, secondary hyper‐aldosteronism, and hypercalciuria sometimes leading to nephrocalcinosis. The second presentation is antenatal, more severe 4, 5 and is revealed by refractory polyhydramnios (caused by fetal polyuria) during the second trimester of pregnancy, without morphological anomalies. The major consequences are preterm birth, growth retardation, and severe dehydration at birth due to salt loss. In children with Bartter Syndrome, urinalysis highlights increased sodium, potassium, chloride and calcium excretion, and as a consequence hyponatremia, hypochloremia, and hypokalemia 4, 6. However, until now, no studies have been published about fetal urinalysis in antenatal Bartter Syndrome. A 28‐year‐old woman in a consanguineous marriage (first cousins), gravida 1, para 0, presented severe polyhydramnios at routine ultrasound examination at 22.6 weeks of amenorrhea. Megacystis was observed in a female fetus, without any other malformation. After genetic counseling, invasive procedures were offered to the parents and accepted: amniotic fluid sampling for karyotyping and biochemistry and fetal urine sampling for renal function evaluation. The karyotype was normal, 46,XX. A second amniocentesis was secondarily performed at 26.3 weeks for amniodrainage. Amniotic fluid alpha‐fetoprotein and total protein were decreased at both 22.6 and 26.3 weeks (Table 1), giving a Bartter index (total protein expressed in g/L x alpha‐fetoprotein in MoM) of 0.85 and 0.71, respectively 7. These values were strongly suggestive of Bartter Syndrome. In fetal urine we assayed electrolytes, beta‐2 microglobulin, and total protein. Results are presented in Table 1 in comparison with two fetal urine controls (one with renal failure and one with normal renal function, both performed because of megacystis). Electrolytes were significantly increased in Bartter Syndrome compared with controls (P < 0.001). A weekly check‐up was planned. The patient delivered a girl at 33.6 weeks of gestation. The baby presented clinical and laboratory signs of Bartter Syndrome. Postnatal screening for Bartter Syndrome mutations detected a homozygous mutation in the SLC12A1 gene. Table 1 Fetal urine and amniotic fluid electrolytes (mmol/L), β2‐microglobulin (β2 m), and total protein in Bartter Syndrome and controls
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prenatal diagnosis of Bartter Syndrome amniotic fluid aldosterone
Prenatal Diagnosis, 2016Co-Authors: Myriam Rachid, Rosa Vargaspoussou, Georges Deschênes, Sophie Dreux, Isabelle Czerkiewicz, Gauthier Pean De Ponfilly, D Chevenne, J F Oury, Francoise MullerAbstract:Objective Bartter Syndrome is a severe inherited tubulopathy characterized by postnatal salt wasting, severe polyuria, dehydration, failure to thrive and secondary hyperaldosteronism. Prenatally, the disease is usually discovered following the onset of severe polyhydramnios in the second trimester. We studied amniotic fluid aldosterone concentration in Bartter Syndrome and in controls. Methods Amniotic fluid aldosterone was assayed by radioimmunoassay. We undertook a retrospective case-control study based on 36 cases of prenatally suspected and postnatally confirmed Bartter Syndrome (22 with identified mutations): and 72 gestational age matched controls presenting with polyhydramnios and 72 without polyhydramnios. Amniotic fluid aldosterone was compared between the three groups. Results The median amniotic fluid aldosterone concentration in the Bartter Syndrome group (90 pg/mL) was not different from that in the controls with polyhydramnios (90 pg/mL, P = 0.33) or without polyhydramnios (87 pg/mL, P = 0.41). Conclusion Amniotic fluid aldosterone assay cannot be used for prenatal diagnosis of Bartter Syndrome. © 2015 John Wiley & Sons, Ltd.
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clc k chloride channels emerging pathophysiology of Bartter Syndrome type 3
American Journal of Physiology-renal Physiology, 2015Co-Authors: Olga Andrini, Rosa Vargaspoussou, Mathilde Keck, Rodolfo Briones, Stéphane Lourdel, Jacques TeulonAbstract:The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter Syndrome type 3, one of the four variants of Bartter Syndrome in the genetically based nomenclature...
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mutations in the chloride channel gene clcnkb as a cause of classic Bartter Syndrome
Journal of The American Society of Nephrology, 2000Co-Authors: Martin Konrad, L P W J Van Den Heuvel, Rosa Vargaspoussou, A Lakings, Nikola Jeck, Henny H. Lemmink, Corinne Antignac, Martin Vollmer, Georges Deschênes, Lisa M GuaywoodfordAbstract:Abstract. Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: ( 1 ) the Gitelman variant of Bartter Syndrome (GS); ( 2 ) hyperprostaglandin E Syndrome, the antenatal variant of Bartter Syndrome (HPS/aBS); and ( 3 ) the classic Bartter Syndrome (cBS). Hypokalemic metabolic alkalosis and renal salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypomagnesemia are specific clinical features of Gitelman Syndrome, while HPS/aBS is a life-threatening disorder of the newborn with polyhydramnios, premature delivery, hyposthenuria, and nephrocalcinosis. The Gitelman variant is uniformly caused by mutations in the gene for the thiazide-sensitive NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, while HPS/aBS is caused by mutations in the gene for either the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1) . Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis. In this study, the screening for CLCNKB mutations showed 20 different mutations in the affected children from 30 families. The clinical characterization revealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neonatal period to almost asymptomatic patients diagnosed during adolescence. This study adds 16 novel mutations to the nine already described, providing further evidence that mutations in the gene for the basolateral chloride channel CLC-Kb are the molecular basis of classic Bartter Syndrome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype.
Hannsjörg W. Seyberth - One of the best experts on this subject based on the ideXlab platform.
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classification and rescue of romk mutations underlying hyperprostaglandin e Syndrome antenatal Bartter Syndrome
Kidney International, 2003Co-Authors: Melanie Peters, Saskia Ermert, Ulla Pechmann, Christian Derst, Karl Peter Schlingmann, Nikola Jeck, Stefanie Weber, Siegfried Waldegger, Hannsjörg W. Seyberth, Martin KonradAbstract:Classification and rescue of ROMK mutations underlying hyperprostaglandin E Syndrome/antenatal Bartter Syndrome. Background Mutations in the renal K + channel ROMK (Kir 1.1) cause hyperprostaglandin E Syndrome/antenatal Bartter Syndrome (HPS/aBS), a severe tubular disorder leading to renal salt and water wasting. Several studies confirmed the predominance of alterations of current properties in ROMK mutants. However, in most of these studies, analysis was restricted to nonmammalian cells and electrophysiologic methods. Therefore, for the majority of ROMK mutations, disturbances in protein trafficking remained unclear. The aim of the present study was the evaluation of different pathogenic mechanisms of 20 naturally occurring ROMK mutations with consecutive classification into mutational classes and identification of distinct rescue mechanisms according to the underlying defect. Methods Mutated ROMK potassium channels were expressed in Xenopus oocytes and a human kidney cell line and analyzed by two electrode voltage clamp analysis, immunofluorescence, and Western blot analysis. Results We identified 14 out of 20 ROMK mutations that did not reach the cell surface, indicating defective membrane trafficking. High expression levels rescued six out of 14 ROMK mutants, leading to significant K + currents. In addition, two early inframe stop mutations could be rescued by aminoglycosides, resulting in full-length ROMK and correct trafficking to the plasma membrane in a subset of transfected cells. Conclusion In contrast to previous reports, most of the investigated ROMK mutations displayed a trafficking defect that might be rescued by pharmacologic agents acting as molecular chaperones. The evaluation of different disease-causing mechanisms will be essential for establishing new and more specific therapeutic strategies for HPS/aBS patients.
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role of cyclooxygenase 2 in hyperprostaglandin e Syndrome antenatal Bartter Syndrome
Kidney International, 2002Co-Authors: Stephan C Reinalter, Nikola Jeck, Hannsjörg W. Seyberth, Rolf M Nusing, Christoph Brochhausen, Bernhard Watzer, Martin KomhoffAbstract:Role of cyclooxygenase-2 in hyperprostaglandin E Syndrome/antenatal Bartter Syndrome. Background Hyperprostaglandin E Syndrome/antenatal Bartter Syndrome (HPS/aBS) is a congenital salt-losing tubulopathy with an induced expression of cyclooxygenase-2 (COX-2) in the macula densa probably leading to hyperreninemia. Inhibition of stimulated prostaglandin E 2 (PGE 2 ) formation with indomethacin results in a significant improvement of clinical symptoms and is therefore standard therapy. Using the COX-2 selective inhibitor rofecoxib, we investigated the role of COX-2 in the pathophysiology of HPS/aBS. Methods Six clinically well-characterized patients with HPS/aBS (3 girls) were enrolled into the study. Four patients had mutations in the renal potassium channel ROMK, one patient in the furosemide-sensitive cotransporter NKCC2, whereas in one patient no molecular abnormality could be detected. Median age was 15.8 years (range: 9.1 to 19.0 years). Patients were evaluated on indomethacin treatment, 3 days after indomethacin withdrawal, and after 4 days of treatment with rofecoxib. Therapeutic drug monitoring was performed. Results COX-2-selectivity of rofecoxib was confirmed in vivo and ex vivo. Both indomethacin and rofecoxib ameliorated clinical symptoms, the typical laboratory findings, and significantly suppressed PGE 2 and PGE-M excretion to normal values while it was elevated under withdrawal conditions. Rofecoxib suppressed hyperreninemia to a similar extent as indomethacin. Conclusion In patients with HPS/aBS, excessive PGE 2 synthesis and hyperreninemia is dependent on COX-2 activity. This observation proves the stimulatory role of COX-2 on renin-secretion in salt-depletion in humans. Clinical long-term efficacy and potential side effects of rofecoxib need to be evaluated in a larger cohort of HPS/aBS-patients.
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pathogenetic role of cyclooxygenase 2 in hyperprostaglandin e Syndrome antenatal Bartter Syndrome therapeutic use of the cyclooxygenase 2 inhibitor nimesulide
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Rolf M Nusing, Melanie Peters, Stephan C Reinalter, Martin Komhoff, Hannsjörg W. SeyberthAbstract:Patients with hyperprostaglandin E Syndrome/antenatal Bartter Syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E Syndrome/antenatal Bartter Syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E Syndrome/antenatal Bartter Syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E Syndrome/antenatal Bartter Syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.
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mutations in the romk gene in antenatal Bartter Syndrome are associated with impaired k channel function
Biochemical and Biophysical Research Communications, 1997Co-Authors: Christian Derst, Martin Konrad, Georges Deschênes, Lothar Károlyi, Arnold Kockerling, Jurgen Daut, Andreas Karschin, Hannsjörg W. SeyberthAbstract:Children with the antenatal variant of Bartter Syndrome present the typical pattern of impaired salt reabsorption in the thick ascending limb of Henle's loop (TALH) resulting in marked ante- and postnatal salt wasting. In some of these patients mutations in the renal potassium channel ROMK (KCNJ1) have been found. We analyzed the electrophysiological function of five recently described ROMK channel mutations (V72E, D108H, P110L, A198T and V315G). In whole cell patch clamp recordings wildtype rat ROMK1 exhibited K+currents of >1 nA at a membrane potential of 100 mV when transfected into COS-7 kidney cells. These currents were sensitive to external Ba2+and internal Mg2+, which are typical features of the inwardly rectifying KIRchannel. In contrast mutated ROMK1 cDNAs expressed either no or only infrequently small currents (<200 pA). Loss of tubular K+channel function probably prevents apical membrane potassium recycling with secondary inhibition of Na-K-2Cl-cotransport in the TALH. We conclude that mutations in the potassium channel ROMK are the primary events causing renal salt wasting in a subset of patients with the antenatal variant of Bartter Syndrome.
