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      Clinical Severity of Gitelman Syndrome Determined by Serum Magnesium

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          Abstract

          Background/Aims: Normomagnesemia is considered atypical in Gitelman syndrome (GS). Here, we describe clinical, pathological and genetic characteristics in Chinese GS patients with or without hypomagnesemia in order to determine whether serum magnesium concentration indicates the severity of the disease. Methods: 7 normomagnesemic and 25 hypomagnesemic GS patients who were confirmed by direct sequencing of SLC12A3 gene were included. Clinical manifestation and laboratory tests were documented. Supine and upright plasma renin activity, angiotensin II and aldosterone were determined by radioimmunoassay. Transient receptor potential channel melastatin subtype 6 (TRPM6) was detected by immunohistochemistry in paraffin-embedded renal biopsy sections of 12 GS patients. 14 patients with glomerular minor lesion served as controls. The distribution of the mutations on the predicted NCC protein was analyzed and compared between two subgroups. Results: Clinical manifestations, electrolyte abnormalities, metabolic alkalosis and renin-angiotensin-aldosterone system activation were found to be milder in normomagnesemic compared with the hypomagnesemic group. Compared with glomerular minor lesion controls, the TRPM6-positive area was significantly decreased in hypomagnesemic patients (4.96 ± 1.88 vs. 8.63 ± 2.67%) while it was near normal (7.82 ± 5.23%) in 2 normomagnesemic GS patients. A higher percentage of intracellular mutations was observed in normomagnesemic patients than hypomagnesemic patients (92.31 vs. 56.52%, p = 0.02). Conclusions: Normomagnesemia is not rare in GS. Serum magnesium may indicate the severity of GS.

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          Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.

          Electroneutral cation-Cl(-) cotransporters compose a family of solute carriers in which cation (Na(+) or K(+)) movement through the plasma membrane is always accompanied by Cl(-) in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na(+)-Cl(-) cotransporter, two genes encoding loop diuretic-sensitive Na(+)-K(+)-2Cl(-) cotransporters, and four genes encoding K(+)-Cl(-) cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl(-) concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.
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            Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter.

            Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter (NCC). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K+) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS--less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB. Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
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              A thiazide test for the diagnosis of renal tubular hypokalemic disorders.

              Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2014
                May 2014
                23 April 2014
                : 39
                : 4
                : 357-366
                Affiliations
                aDepartment of Nephrology and bDepartment of Endocrinology and Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, and cState Key Laboratory of Medical Genetics, Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
                Author notes
                *Limeng Chen and Min Nie, Peking Union Medical College Hospital, No. 1, Shuaifuyan, Wangfujing St, Beijing 100730 (China), E-Mail chenlimeng@pumch.cn and nm_pumch@aliyun.com
                Article
                360773 Am J Nephrol 2014;39:357-366
                10.1159/000360773
                24776766
                5cb1c7c6-517b-4a29-baf0-02626ea5a607
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 22 December 2013
                : 16 February 2014
                Page count
                Figures: 4, Tables: 4, Pages: 10
                Categories
                Original Report: Patient-Oriented, Translational Research

                Cardiovascular Medicine,Nephrology
                Hypomagnesemia,TRPM6,Gitelman syndrome,Normomagnesemia
                Cardiovascular Medicine, Nephrology
                Hypomagnesemia, TRPM6, Gitelman syndrome, Normomagnesemia

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