Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases.
Ontology highlight
ABSTRACT:
SUBMITTER: Kondo A
PROVIDER: S-EPMC8352941 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: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.
| S-EPMC2518128 | biostudies-literature
Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive salt-losing renal tubulopathy arising from mutations in the thiazide-sensitive Na-Cl cotransporter gene. Due to its low incidence and lack of awareness, GS can be easily misdiagnosed or missed in diagnosis.Case summaryA 24-year-old male presented with > 4 years of repeated limb weakness without any treatment. The previous day, the patient was bitten by ants and showed weakness of the lower limbs. The patient had hypokalemia (1.66-2.83 mmol/L), hypomagnesemia (0.4 mmol/L), hypocalciuria (1.51-2.46 mmol/d), metabolic alkalosis (7.47-7.54), normal blood pressure, and increased activity of aldosterone and plasma renin activity (PRA) (PRA 6.4 and 16.45 ng/mL/h and aldosterone 330.64 and 756.82 pg/mL in the supine and upright position, respectively). In addition, SLCI2A3 gene mutation with GS was diagnosed. Oral and intravenous supplementation with potassium and magnesium was initiated. Serum magnesium returned to 0.48 mmol/L and serum potassium returned to 3.08 mmol/L, alleviating the patient's fatigue symptoms.ConclusionGS should be considered in patients with hypokalemia complicated with hypomagnesemia. Genetic testing is essential to confirm the diagnosis.
| S-EPMC9258353 | biostudies-literature
Project description:Ethnicity recording across the National Health Service (NHS) has improved dramatically over the past decade. This study profiles the completeness, consistency and representativeness of routinely collected ethnicity data in both primary care and hospital settings.Completeness and consistency of ethnicity recording was examined in the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES), and the ethnic breakdown of the CPRD was compared with that of the 2011 UK censuses.27.1% of all patients in the CPRD (1990-2012) have ethnicity recorded. This proportion rises to 78.3% for patients registered since April 2006. The ethnic breakdown of the CPRD is comparable to the UK censuses. 79.4% of HES inpatients, 46.8% of outpatients and 26.8% of A&E patients had their ethnicity recorded. Amongst those with ethnicity recorded on >1 occasion, consistency was over 90% in all data sets except for HES inpatients. Combining CPRD and HES increased completeness to 97%, with 85% of patients having the same ethnicity recorded in both databases.Using CPRD ethnicity from 2006 onwards maximizes completeness and comparability with the UK population. High concordance within and across NHS sources suggests these data are of high value when examining the continuum of care. Poor completeness and consistency of A&E and outpatient data render these sources unreliable.
| S-EPMC4245896 | biostudies-other
Project description:Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.
| S-EPMC3065225 | biostudies-literature
Project description:BackgroundLeukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants.MethodsFrom 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database. Allele frequencies were estimated from Genome Aggregation Database. Allele frequencies for each gene were summed to generate a super allele frequency and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question.ResultsWe identified 4564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of one in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy was the RNA polymerase III-related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4733 live births, significantly higher than previous estimates.ConclusionsOur data are consistent with a significant underdiagnosis of leukodystrophy patients. An intriguing additional consideration is that there may be genetic modifiers that lead to weaker, absent, or adult-onset disease phenotypes.
| S-EPMC7506144 | biostudies-literature
Project description:Polycystic ovarian syndrome (PCOS) is thought to be the most common endocrine disorder found in women. Common symptoms include irregular menstrual cycle, polycystic ovaries, and hirsutism, as well as an increased risk for a multitude of conditions, including insulin resistance, dyslipidemia and infertility. The prevalence of polycystic ovarian syndrome is generally thought to be between 3% and 10% but it is widely unknown for specific subpopulations based on geographical location and race/ethnicity. Based on the high degree of variability and inconsistencies between the different diagnostic criteria, there is a unique challenge that exists when determining the prevalence of this syndrome. There are a large percentage of individuals that remain undiagnosed even after visiting multiple health care providers. Most studies conducted across the world are limited by small sample size, selection bias, and lack of comparability across studies. There have been very few studies that have examined the prevalence of polycystic ovary syndrome across the United States. Based on the National Institutes of Health (NIH)'s diagnostic criteria, there is a similar prevalence of PCOS documented across the United States, the United Kingdom, Spain, Greece, Australia, and Mexico. Other studies have shown some differences between geographical location and race. The existing data is not conclusive enough to determine whether or not there is any significant differences in the prevalence of PCOS across geographical location, racial or ethnic groups. This review will seek to determine the prevalence of polycystic ovarian syndrome based on geographical location and race/ethnicity.
| S-EPMC6266413 | biostudies-other
Project description:OBJECTIVE:Impaired glucose metabolism and insulin sensitivity have been reported in patients with Gitelman syndrome (GS), but insulin secretion and the related mechanisms are not well understood. DESIGN AND METHODS:The serum glucose levels, insulin secretion and insulin sensitivity were evaluated in patients with GS (n?=?28), patients with type 2 diabetes mellitus (DM) and healthy individuals (n?=?20 in both groups) using an oral glucose tolerance test. Serum and urine sodium, potassium and creatinine levels were measured at 0, 30, 60, 120 and 180?min after an oral glucose load was administered. RESULTS:The areas under the serum glucose curves were higher in the GS patients than those in the healthy controls (17.4?±?5.1?mmol·h/L vs 14.5?±?2.8?mmol·h/L, P?=?0.02) but lower than those in the DM patients (24.8?±?5.3?mmol·h/L, P?<?0.001). The areas under the serum insulin curves and the insulin secretion indexes in GS patients were higher than those in DM patients and lower than those in healthy subjects. The insulin secretion-sensitivity index of GS patients was between that of healthy subjects and DM patients, but the insulin sensitivity indices were not different among the three groups. After one hour of glucose administration, the serum potassium level significantly decreased from baseline, and the urinary potassium-to-creatinine ratio increased gradually and peaked at 2?h. CONCLUSIONS:Glucose metabolism and insulin secretion were impaired in GS patients, but insulin sensitivity was comparable between GS patients and patients with type 2 DM. After administration of an oral glucose load, the plasma potassium level decreased in GS patients due to the increased excretion of potassium in the urine.
| S-EPMC5632718 | biostudies-literature
Project description:IntroductionGitelman 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.MethodsWe examined the clinical characteristics and genotype-phenotype correlation in genetically proven GS cases with homozygous or compound heterozygous variants in SLC12A3 (n = 185).ResultsIn 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).ConclusionThis 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.
| S-EPMC6308995 | biostudies-literature
Project description:Polymorphisms in the gene encoding sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) associate with hypertension susceptibility in humans. SPAK interacts with WNK kinases to regulate the Na(+)-K(+)-2Cl(-) and Na(+)-Cl(-) co-transporters [collectively, N(K)CC]. Mutations in WNK1/4 and N(K)CC can cause changes in BP and dyskalemia in humans, but the physiologic role of SPAK in vivo is unknown. We generated and analyzed SPAK-null mice by targeting disruption of exons 9 and 10 of SPAK. Compared with SPAK(+/+) littermates, SPAK(+/-) mice exhibited hypotension without significant electrolyte abnormalities, and SPAK(-/-) mice not only exhibited hypotension but also recapitulated Gitelman syndrome with hypokalemia, hypomagnesemia, and hypocalciuria. In the kidney tissues of SPAK(-/-) mice, the expression of total and phosphorylated (p-)NCC was markedly decreased, but that of p-OSR1, total NKCC2, and p-NKCC2 was significantly increased. We observed a blunted response to thiazide but normal response to furosemide in SPAK(-/-) mice. In aortic tissues, total NKCC1 expression was increased but p-NKCC1 was decreased in SPAK-deficient mice. Both SPAK(+/-) and SPAK(-/-) mice had impaired responses to the selective α(1)-adrenergic agonist phenylephrine and the NKCC1 inhibitor bumetanide, suggesting that impaired aortic contractility may contribute to the hypotension of SPAK-null mice. In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation. SPAK may be a promising target for antihypertensive therapy.
| S-EPMC3014002 | biostudies-literature
Project description:The data paper is becoming a popular way for researchers to publish their research data. The growing numbers of data papers and journals hosting them have made them an important data source for understanding how research data is published and reused. One barrier to this research agenda is a lack of knowledge as to how data journals and their publications are indexed in the scholarly databases used for quantitative analysis. To address this gap, this study examines how a list of 18 exclusively data journals (i.e., journals that primarily accept data papers) are indexed in four popular scholarly databases: the Web of Science, Scopus, Dimensions, and OpenAlex. We investigate how comprehensively these databases cover the selected data journals and, in particular, how they present the document type information of data papers. We find that the coverage of data papers, as well as their document type information, is highly inconsistent across databases, which creates major challenges for future efforts to study them quantitatively, which should be addressed in the future.
| S-EPMC10600123 | biostudies-literature