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Nine V.a.m. Knoers - One of the best experts on this subject based on the ideXlab platform.
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Gitelman Syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Kidney International, 2017Co-Authors: Anne Blanchard, Nine V.a.m. Knoers, Detlef Bockenhauer, Davide Bolignano, Lorenzo Calò, Etienne Cosyns, Olivier Devuyst, David Ellison, Fiona Karet Frankl, Martin KonradAbstract:Gitelman Syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
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Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman Syndrome
European Journal of Human Genetics, 2012Co-Authors: Bob Glaudemans, Joost G J Hoenderop, Nine V.a.m. Knoers, René J. Bindels, Helger G Yntema, Pedro San-cristobal, Jeroen Schoots, Rolph Pfundt, Erik-j Kamsteeg, Lies H HoefslootAbstract:Gitelman Syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis in conjunction with significant hypomagnesemia and hypocalciuria. The GS phenotype is caused by mutations in the solute carrier family 12, member 3 ( SLC12A3 ) gene that encodes the thiazide-sensitive NaCl cotransporter (NCC). We analyzed DNA samples of 163 patients with a clinical suspicion of GS by direct sequencing of all 26 exons of the SLC12A3 gene. In total, 114 different mutations were identified, 31 of which have not been reported before. These novel variants include 3 deletions, 18 missense, 6 splice site and 4 nonsense mutations. We selected seven missense mutations to investigate their effect on NCC activity and plasma membrane localization by using the Xenopus laevis oocyte expression system. The Thr392Ile mutant did not display transport activity (probably class 2 mutation), while the Asn442Ser and Gln1030Arg NCC mutants showed decreased plasma membrane localization and consequently function, likely due to impaired trafficking (class 3 mutation). Even though the NaCl uptake was hampered for NCC mutants Glu121Asp, Pro751Leu, Ser475Cys and Tyr489His, the transporters reached the plasma membrane (class 4 mutation), suggesting an effect on NCC regulation or ion affinity. The present study shows the identification of 38 novel mutations in the SLC12A3 gene and provides insight into the mechanisms that regulate NCC.
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Gitelman Syndrome
Orphanet Journal of Rare Diseases, 2008Co-Authors: Nine V.a.m. Knoers, Elena N LevtchenkoAbstract:Gitelman Syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.
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Gitelman Syndrome
Orphanet Journal of Rare Diseases, 2008Co-Authors: Nine V.a.m. Knoers, Elena N LevtchenkoAbstract:Gitelman Syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia. GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3 , which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified. Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter Syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients. Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.
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novel mutations in the thiazide sensitive nacl cotransporter gene in patients with Gitelman Syndrome with predominant localization to the c terminal domain
Kidney International, 1998Co-Authors: Henny H. Lemmink, Lisa M Guaywoodford, Corinne Antignac, Nine V.a.m. Knoers, Lothar Karolyi, H Van Dijk, P Niaudet, Paul Goodyer, J C Carel, A HermesAbstract:Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman Syndrome. Gitelman Syndrome (familial hypokalemia-hypomagnesemia Syndrome) is an autosomal recessive inherited renal disorder characterized by defective tubular reabsorption of magnesium and potassium. In this study a group of 18 unrelated and 2 related Gitelman patients, collected from six different countries have been screened for mutations in the human thiazide-sensitive sodium-chloride cotransporter (SLC12A3) gene. Fourteen novel SLC12A3 mutations are presented along with six mutations described earlier, and three neutral polymorphisms. Among the tested patients are two who carry a total of three heterozygous SLC12A3 mutations. Two-thirds of the total number of mutant SLC12A3 alleles are amino acid substitutions. Most SLC12A3 gene mutations, 14 out of a total of 20, are localized at the intracellular carboxy-terminal domain of the NCCT protein. The pathogenicity of individual SLC12A3 mutations is based upon their predicted effect on SLC12A3 protein, and segregation in family members. Evolutionary conservation of substituted amino acid residues and their frequency in control chromosomes is presented. Identical mutations have been found in Gitelman families from different geographical origin, suggesting ancient mutations originating from a common ancestor. As yet, we have not found any evidence for a possible genotype-phenotype correlation.
Henny H. Lemmink - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the thiazide sensitive nacl cotransporter gene in patients with Gitelman Syndrome with predominant localization to the c terminal domain
Kidney International, 1998Co-Authors: Henny H. Lemmink, Lisa M Guaywoodford, Corinne Antignac, Nine V.a.m. Knoers, Lothar Karolyi, H Van Dijk, P Niaudet, Paul Goodyer, J C Carel, A HermesAbstract:Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman Syndrome. Gitelman Syndrome (familial hypokalemia-hypomagnesemia Syndrome) is an autosomal recessive inherited renal disorder characterized by defective tubular reabsorption of magnesium and potassium. In this study a group of 18 unrelated and 2 related Gitelman patients, collected from six different countries have been screened for mutations in the human thiazide-sensitive sodium-chloride cotransporter (SLC12A3) gene. Fourteen novel SLC12A3 mutations are presented along with six mutations described earlier, and three neutral polymorphisms. Among the tested patients are two who carry a total of three heterozygous SLC12A3 mutations. Two-thirds of the total number of mutant SLC12A3 alleles are amino acid substitutions. Most SLC12A3 gene mutations, 14 out of a total of 20, are localized at the intracellular carboxy-terminal domain of the NCCT protein. The pathogenicity of individual SLC12A3 mutations is based upon their predicted effect on SLC12A3 protein, and segregation in family members. Evolutionary conservation of substituted amino acid residues and their frequency in control chromosomes is presented. Identical mutations have been found in Gitelman families from different geographical origin, suggesting ancient mutations originating from a common ancestor. As yet, we have not found any evidence for a possible genotype-phenotype correlation.
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linkage of Gitelman Syndrome to the thiazide sensitive sodium chloride cotransporter gene with identification of mutations in dutch families
Pediatric Nephrology, 1996Co-Authors: Henny H. Lemmink, Steven C Hebert, H Van Dijk, L P W J Van Den Heuvel, G F M Merkx, Tineke J Smilde, Peter E M Taschner, L A H Monnens, Nine V.a.m. KnoersAbstract:Gitelman Syndrome is a mostly autosomal recessive disorder affecting the renal tubular function associated with hypokalemia and hypomagnesemia. Functional studies point to a defect in the distal renal tubule in the thiazide-sensitive, electroneutral sodium-chloride co-transporter (TSC). Based upon the localization of a 2.6 cDNA encoding the human TSC to chromosome 16q13, polymorphic markers spanning the region from 16p12 to 16q21 were tested for linkage to the Gitelman Syndrome locus in three Dutch families with autosomal recessive inheritance of this disorder. Using two-point linkage analysis, a maximum LOD score (Zmax of 4.49 (at theta = 0.00) was found for the marker D16S408. One crucial recombination event places the Gitelman Syndrome locus distal to D16S419 at 16q12-13. Subsequently we have tested our group of Gitelman patients for mutations in the human TSC gene. Two mutations were identified in three Gitelman families. Our study confirms that the human TSC gene is involved in Gitelman Syndrome. Patients from three Gitelman families reveal two identical human TSC mutations, suggesting these families share a common ancestor.
Kandai Nozu - One of the best experts on this subject based on the ideXlab platform.
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a case of Gitelman Syndrome that was difficult to distinguish from hypokalemic periodic paralysis caused by graves disease
Journal of Nippon Medical School, 2019Co-Authors: Takeshi Oba, Kandai Nozu, Kazumoto Iijima, Shunsuke Kobayashi, Yuko Nakamura, Mototsugu Nagao, Izumi Fukuda, Hitoshi SugiharaAbstract:A 21-year-old man presented with hyperthyroidism and hypokalemia and was treated for thyrotoxic hypokalemic periodic paralysis caused by Graves' disease. Thyroid function soon normalized but hypokalemia persisted. Laboratory data revealed hyperreninemic hyperaldosteronism and metabolic alkalosis consistent with Gitelman Syndrome. The patient was found to have a previously unreported compound heterozygous mutation of T180K and L858H in the SLC12A3 gene, and Gitelman Syndrome was diagnosed. He was started on eplerenone to control serum potassium level. Alternative diagnoses should be considered when electrolyte imbalances persist after disease resolution.
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Clinical and Genetic Characteristics in Patients With Gitelman Syndrome
Elsevier, 2019Co-Authors: Junya Fujimura, Tomoko Horinouchi, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Keita Nakanishi, China Nagano, Nana Sakakibara, Koichi Nakanishi, Yuko ShimaAbstract:Introduction: Gitelman Syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most often diagnosed by chance blood test. Aside from that, some cases are also diagnosed from tetanic symptoms associated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroid dysfunction and short stature are known, but the incidence rates for these complications have not yet been elucidated. In addition, no genotype–phenotype correlation has been identified in GS. Methods: We examined the clinical characteristics and genotype–phenotype correlation in genetically proven GS cases with homozygous or compound heterozygous variants in SLC12A3 (n = 185). Results: In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), or short stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrile convulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT prolongation was detected. Among 29 cases with short stature, 10 were diagnosed with growth hormone (GH) deficiency and GH replacement therapy started. Interestingly, there was a strong correlation in serum magnesium levels between cases with p.Arg642Cys and/or p.Leu858His and cases without these variants, which are mutational hotspots in the Japanese population (1.76 mg/dl vs. 1.43 mg/dl, P < 0.001). Conclusion: This study has revealed, for the first time, clinical characteristics in genetically proven GS cases in the Japanese population, including prevalence of complications. Patients with hypokalemia detected by chance blood test should have gene tests performed. Patients with GS need attention for developing extrarenal complications, such as short stature, febrile convulsion, thyroid dysfunction, epilepsy, or QT prolongation. It was also revealed for the first time that hypomagnesemia was not severe in some variants in SLC12A3. Keywords: febrile convulsion, QT prolongation, salt-losing tubulopathy, SLC12A3, thyroi
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Congenital chloride diarrhea needs to be distinguished from Bartter and Gitelman Syndrome
Journal of Human Genetics, 2018Co-Authors: Natsuki Matsunoshita, Azusa Kawaguchi, Masahide Yoshikane, Naoya Fujita, Shingo Ishimori, Naoya Morisada, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Tomoko HorinouchiAbstract:Pseudo-Bartter/Gitelman Syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter Syndrome (BS) or Gitelman Syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.
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differential diagnosis of bartter Syndrome Gitelman Syndrome and pseudo bartter Gitelman Syndrome based on clinical characteristics
Genetics in Medicine, 2016Co-Authors: Natsuki Matsunoshita, Naoya Morisada, Kandai Nozu, Shogo Minamikawa, Akemi Shono, Yoshimi Nozu, Naohiro Kamiyoshi, Hiromi Ohtsubo, Takeshi Ninchoji, Tomohiko YamamuraAbstract:Differential diagnosis of Bartter Syndrome, Gitelman Syndrome, and pseudo–Bartter/Gitelman Syndrome based on clinical characteristics
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a deep intronic mutation in the slc12a3 gene leads to Gitelman Syndrome
Pediatric Research, 2009Co-Authors: Kandai Nozu, Koichi Nakanishi, Kazumoto Iijima, Yoshimi Nozu, Ei Ikegami, Takehide Imai, Hiroshi Kaito, Norishige Yoshikawa, Masafumi MatsuoAbstract:Many mutations have been detected in the SLC12A3 gene of Gitelman Syndrome (GS, OMIM 263800) patients. In previous studies, only one mutant allele was detected in approximately 20 to 41% of patients with GS; however, the exact reason for the nonidentification has not been established. In this study, we used RT-PCR using mRNA to investigate for the first time transcript abnormalities caused by deep intronic mutation. Direct sequencing analysis of leukocyte DNA identified one base insertion in exon 6 (c.818_819insG), but no mutation was detected in another allele. We analyzed RNA extracted from leukocytes and urine sediments and detected unknown sequence containing 238bp between exons 13 and 14. The genomic DNA analysis of intron 13 revealed a single-base substitution (c.1670-191C>T) that creates a new donor splice site within the intron resulting in the inclusion of a novel cryptic exon in mRNA. This is the first report of creation of a splice site by a deep intronic single-nucleotide change in GS and the first report to detect the onset mechanism in a patient with GS and missing mutation in one allele. This molecular onset mechanism may partly explain the poor success rate of mutation detection in both alleles of patients with GS.
Alberto Bettinelli - One of the best experts on this subject based on the ideXlab platform.
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renal phosphate handling in Gitelman Syndrome the results of a case control study
Pediatric Nephrology, 2013Co-Authors: Cristina Vigano, Marie Louise Syrén, Mario G. Bianchetti, Chiara Amoruso, Francesco Barretta, Giuseppe Minnici, W Albisetti, Alberto BettinelliAbstract:Background Patients with Gitelman Syndrome, a hereditary salt-wasting tubulopathy, have loss-of-function mutations in the SLC12A3 gene coding for the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule. Since the bulk of filtered phosphate is reabsorbed in the proximal tubule, renal phosphate wasting is considered exceptional in Gitelman Syndrome.
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Early appearance of hypokalemia in Gitelman Syndrome.
Pediatric nephrology (Berlin Germany), 2010Co-Authors: Fabiana Tammaro, Marie Louise Syrén, Silvana Tedeschi, Alberto Bettinelli, Donatella Cattarelli, Alessandra Cavazza, Carla Colombo, Mario G. BianchettiAbstract:Inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive co-transporter causes Gitelman Syndrome. The main features of this Syndrome include normal or low blood pressure, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and hyperreninemia. These patients are at low risk for preterm birth and do not present with symptoms before school age. As a consequence, the condition is usually diagnosed in late childhood or in adult life. We report on four patients, two pairs of prematurely born twins, in whom hypokalemia was demonstrated early in life. In these children, a tendency towards hypokalemia was first noted during the third week of life. Overt hypokalemia subsequently appeared associated with normal blood pressure, hypochloremia, hyperreninemia, and an inappropriately high fractional excretion of potassium and chloride. Molecular biology studies failed to detect mutations in the SLC12A1, KCNJ1, and CLCNKB genes responsible for the Bartter Syndromes type I, II and III, respectively. Compound heterozygous mutations in the SLC12A3 gene were detected in both pairs of twins: a frameshift mutation in exon 10 (c.1196_1202dup7bp), leading to the truncated protein p.Ser402X, and a missense mutation in exon 11, p.Ser475Cys (c.1424C>G) in the first pair; two missense mutations, p.Thr392Ile (c.1175C>T) in exon 9 and p.Ser615Leu in exon 15 (c.1844C>T), in the second pair. In conclusion, the diagnosis of Gitelman Syndrome deserves consideration in infants with unexplained hypokalemia.
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novel molecular variants of the na cl cotransporter gene are responsible for Gitelman Syndrome
American Journal of Human Genetics, 1996Co-Authors: Nadia Mastroianni, Alberto Bettinelli, Mario G. Bianchetti, G Colussi, M De Fusco, F Sereni, Andrea Ballabio, Giorgio CasariAbstract:A hereditary defect of the distal tubule accounts for the clinical features of Gitelman Syndrome (GS), an autosomal recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Recently, we cloned the cDNA coding for the human Na-Cl thiazide-sensitive cotransporter (TSC; also known as ?NCCT? or ?SLC12A3?) as a possible candidate for GS, and Simon et al., independently, described mutations in patients with GS. Now, we show 12 additional mutations consistent with a loss of function of the Na-Cl cotransporter in GS. Two missense replacements, R209W and P349L, are common to both studies and could represent ancient mutations. The other mutations include three deletions, two insertions, and six missense mutations. When all mutations from both studies are considered, missense mutations seem to be more frequently localized within the intracellular domains of the molecule, rather than in transmembrane or extracellular domains. One family, previously reported as a GS form with dominant inheritance, has proved to be recessive, with the affected child being a compound heterozygote. A highly informative intragenic tetranucleotide marker, useful for molecular diagnostic studies, has been identified at the acceptor splice site of exon 9.
Tomohiko Yamamura - One of the best experts on this subject based on the ideXlab platform.
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examination of the predicted prevalence of Gitelman Syndrome by ethnicity based on genome databases
Scientific Reports, 2021Co-Authors: Atsushi Kondo, Tomoko Horinouchi, Tomohiko Yamamura, China Nagano, Nana Sakakibara, Shinya Ishiko, Takashi Omori, Yuya Aoto, Rini Rossanti, Sadayuki NagaiAbstract:Gitelman Syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman Syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy-Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman Syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.
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Clinical and Genetic Characteristics in Patients With Gitelman Syndrome
Elsevier, 2019Co-Authors: Junya Fujimura, Tomoko Horinouchi, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Keita Nakanishi, China Nagano, Nana Sakakibara, Koichi Nakanishi, Yuko ShimaAbstract:Introduction: Gitelman Syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most often diagnosed by chance blood test. Aside from that, some cases are also diagnosed from tetanic symptoms associated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroid dysfunction and short stature are known, but the incidence rates for these complications have not yet been elucidated. In addition, no genotype–phenotype correlation has been identified in GS. Methods: We examined the clinical characteristics and genotype–phenotype correlation in genetically proven GS cases with homozygous or compound heterozygous variants in SLC12A3 (n = 185). Results: In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), or short stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrile convulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT prolongation was detected. Among 29 cases with short stature, 10 were diagnosed with growth hormone (GH) deficiency and GH replacement therapy started. Interestingly, there was a strong correlation in serum magnesium levels between cases with p.Arg642Cys and/or p.Leu858His and cases without these variants, which are mutational hotspots in the Japanese population (1.76 mg/dl vs. 1.43 mg/dl, P < 0.001). Conclusion: This study has revealed, for the first time, clinical characteristics in genetically proven GS cases in the Japanese population, including prevalence of complications. Patients with hypokalemia detected by chance blood test should have gene tests performed. Patients with GS need attention for developing extrarenal complications, such as short stature, febrile convulsion, thyroid dysfunction, epilepsy, or QT prolongation. It was also revealed for the first time that hypomagnesemia was not severe in some variants in SLC12A3. Keywords: febrile convulsion, QT prolongation, salt-losing tubulopathy, SLC12A3, thyroi
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Congenital chloride diarrhea needs to be distinguished from Bartter and Gitelman Syndrome
Journal of Human Genetics, 2018Co-Authors: Natsuki Matsunoshita, Azusa Kawaguchi, Masahide Yoshikane, Naoya Fujita, Shingo Ishimori, Naoya Morisada, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Tomoko HorinouchiAbstract:Pseudo-Bartter/Gitelman Syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter Syndrome (BS) or Gitelman Syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.
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differential diagnosis of bartter Syndrome Gitelman Syndrome and pseudo bartter Gitelman Syndrome based on clinical characteristics
Genetics in Medicine, 2016Co-Authors: Natsuki Matsunoshita, Naoya Morisada, Kandai Nozu, Shogo Minamikawa, Akemi Shono, Yoshimi Nozu, Naohiro Kamiyoshi, Hiromi Ohtsubo, Takeshi Ninchoji, Tomohiko YamamuraAbstract:Differential diagnosis of Bartter Syndrome, Gitelman Syndrome, and pseudo–Bartter/Gitelman Syndrome based on clinical characteristics