Gitelman Syndrome Research Articles

1例儿童Gitelman综合征并矮小症的临床分析

1例儿童Gitelman综合征并矮小症的临床分析

Gitelman综合征1例并文献复习

Gitelman综合征1例并文献复习

Case of Gitelman syndrome in which hypokalemia was exacerbated by the combination of adrenaline β2 agonist and theophylline, and drug-induced QT prolongation occurred: initiatives for hypokalemia

Case of Gitelman syndrome in which hypokalemia was exacerbated by the combination of adrenaline β₂ agonist and theophylline, and drug-induced QT prolongation occurred: initiatives for hypokalemia

Mimicking Gitelman Syndrome with Proton Pump Inhibitors

Proton pump inhibitors (PPI) are widely used drugs for both prophylaxis and treatment of peptic ulcer and gastroesophageal reflux disease. Although electrolyte abnormalities are common, there is only a single report of Gitelman syndrome related to PPI in the literature. In this report, we described another case of a 58 years old woman with Gitelman-like electrolyte disturbances and metabolic alkalosis related to PPI usage. This case is important because of a new look of an old drug-related disorder mimicking a rare syndrome.

Phenotypic differences of mutation-negative cases in Gitelman syndrome clinically diagnosed in adulthood.

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school-aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation-negative cases in adults. A comprehensive screening of 168 genes, including GS-related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo-Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups.

Evolución de tubulopatías renales primarias diagnosticadas en edad pediátrica

Background and objectivePrimary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration and intercurrent complications. Patients and methodsObservational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. ResultsThe age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean±SD) was −1.39±1.49 at diagnosis and 1.07±1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an estimated glomerular filtration<90ml / min / 1.73m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and / or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. ConclusionsPrimary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of estimated glomerular filtration reduction and significant extrarenal complications derived or associated.

Clinical Gitelman Syndrome with Periodic Paralysis and Anemia

Gitelman syndrome is a rare, autosomal recessive, renal tubular salt-wasting disorder characterized by hypokalemia andmetabolic alkalosis combined with hypomagnesemia and hypocalciuria. A 13-year-old male patient came with acute flaccidparalysis, pain, and weakness in limb muscles. Laboratory results showed hypokalemia, hypocalcemia, hypomagnesemia,and metabolic alkalosis accompanied by anemia and elevated serum transaminases. An electrocardiogram test showed aprolonged QT wave. Physical examination showed blood pressure 118/68 mmHg; heart rate 95x/minute; respiration rate 262 x/minute; temperature 37.6⁰C, weight 80 kg, height 160 cm, and BMI 31.25 kg/M . Neurological examination weakness inthe lower limb, negative pathological reflex. Hematology examination showed Hb 9.8 g/dL, MCV 82.3 fL, MCH 26.8 pg,MCHC 32.5 g/dl, WBC 16.87x10³/μL, platelets 320 x10 /μL, serum iron 47 mg/dL, TIBC 229 mg/dL, ferritin 38.45 ng/mL.Peripheral blood smear showed hypochromic microcytic anemia. Blood gas pH 7.47; pCO2 39 mmHg; pO2 44 mmHg;HCO3- 28.4 mmol/l; Beecf 4.7 mmol/l; SO2 83%; AaDO2 114; thus supporting metabolic alkalosis. Cortisol level was 11.39ug/dL, ANA test result was positive at 17.2 IU/mL, the complement level was normal, dsDNA antigen was negative. Due tohypokalemia, hypocalcemia, hypomagnesemia, and metabolic alkalosis, this patient was diagnosed with Gitelmansyndrome with anemia. The diagnosis should be confirmed by molecular DNA diagnostic studies to identify mutations ofthe gene encoding the thiazide-sensitive Na-Cl-cotransporter.

Generation of a human induced pluripotent stem cell line (CMCi002-A) from a patient with Gitelman's syndrome.

We established a human induced pluripotent stem cells (hiPSC) line (CMCi002-A) from peripheral blood mononuclear cells (PBMCs) of 29-year-old male with Gitelman's syndrome (GIT) caused by the mutation of solute carrier family 12 member 3 (SLC12A3) gene using Sendai virus. The GIT-hiPSCs showed a typical human embryonic stem cell like morphology and expressed all pluripotency-associated markers, exhibited normal karyotype and were capable of differentiating into cells representative of three germ layers.

Gitelman syndrome, a rare condition: three clinical cases and pathophysiology review

Introduction: Gitelman syndrome (GS) is a renal tubular disorder characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. Clinical manifestations are nonspecific. Herein are reported three cases of GS with different age of onset, clinical manifestations, and management.Case Reports: Case 1 was a sixteen-year-old female, while Cases 2 and 3 presented at an atypical age (seven and eight years). Clinical manifestations mainly consisted of abdominal pain with vomits, together with past history of muscular weakness in Case 1. Diagnosis was based on usual electrolyte abnormalities, such as metabolic alkalosis with hypokalemia. Genetic diagnosis was confirmed in Case 3. Patients were treated with oral potassium, magnesium, and spironolactone, with symptom and electrolytic profile improvement.Discussion/Conclusions: GS is a rare condition that should be considered in cases of metabolic alkalosis and hypokalemia and all pediatricians should be aware of. Diagnosis is established based on biochemical profile and treatment response.

Investigation of Vestibular Function in Adult Patients with Gitelman Syndrome: Results of an Observational Study.

Gitelman syndrome (GS) is a rare salt-losing tubulopathy caused by an inactivating mutation in the SLC12A3 gene, encoding the thiazide-sensitive sodium chloride cotransporter (NCC). Patients with GS frequently complain of vertigo, usually attributed to hypovolemia. Because NCC is also located in the endolymphatic sac, we hypothesized that patients with GS might have vestibular dysfunction. Between April 2013 and September 2016, 20 (22%) out of 90 patients followed at the reference center complained of vertigo in the absence of orthostatic hypotension. Sixteen of them were referred to an otology department for investigation of vestibular function. The vertigo was of short duration and triggered in half of them by head rotation. Seven patients (44%) had a vestibular syndrome. Vestibular syndrome was defined: (1) clinically, as nystagmus triggered by the head shaking test (n = 5); and/or (2) paraclinically, as an abnormal video head impulse test (n = 0), abnormal kinetic test (n = 4) and/or abnormal bithermal caloric test (n = 3). Five patients had associated auditory signs (tinnitus, aural fullness or hearing loss). In conclusion, we found a high frequency of vestibular disorder in GS patients suffering from vertigo, suggesting a role of NCC in the inner ear. Referent physicians of these patients should be aware of this extrarenal manifestation that requires specific investigations and treatment.

Atteinte rénale au cours du syndrome de Sjögren

Primary Sjögren syndrome is an autoimmune disorder characterized by lymphoplasmacytic infiltration of the exocrine (salivary and lachrymal) glands resulting in sicca symptoms (dryness). Systemic complications can occur in primary Sjögren syndrome, but renal involvement is rare, affecting<10% patients. The most frequent form of nephropathy in primary Sjögren syndrome is tubulointerstitial nephritis, where infiltration of the kidney by plasma cells is a key feature and shows similarity to the lymphoplasmacytic infiltration of the salivary glands. Electrolyte disturbances may occur in primary Sjögren syndrome, such as renal distal tubular acidosis, diabetes insipidus, Gitelman syndrome, or Fanconi syndrome. Glomerular involvement is less frequently detected in patients with primary Sjögren syndrome, but can take the form of membranoproliferative glomerulonephritis secondary to cryoglobulinaemia. The renal prognosis in patients with primary Sjögren syndrome and TIN or glomerular disease is usually good, but the risk of chronic kidney disease remains significant for some patients. Appropriate screening must be performed at least once a year in patients with systemic primary Sjögren syndrome in order to facilitate the early detection of renal complications. In this Review, we discuss the epidemiology, pathophysiology, differential diagnosis, and treatment of renal disease in primary Sjögren syndrome.

Thyroid Function in 35 Patients with Gitelman Syndrome

Objective. In this study, we aimed to analyze thyroid function and related risk factors for thyroid dysfunction in 35 patients with Gitelman syndrome (GS). Methods. This study included 35 patients with GS who were referred to West China Hospital of Sichuan University from Aug 2013 to Jan 2018. General patient characteristics were collected, and thyroid function was assessed. To evaluate the potential contribution of hypokalemia to thyroid dysfunction, 636 patients who were clinically diagnosed with primary aldosteronism (PA) during the same period were included as the control group; these patients were divided into a hypokalemia group ( N = 528 ) and a normokalemia group ( N = 108 ). Logistic regression was used to screen for significant determinants of thyroid dysfunction in the GS patients. Results. Patients with GS had a significantly different prevalence of subclinical hypothyroidism, hypothyroidism, and hyperthyroidism than patients with hypokalemic PA and normokalemic PA (28.6%, 2.9%, and 11.4% vs. 15.5%, 6.1%, and 0.7% vs. 8.3%, 4.6%, and 2.8%, P &lt; 0.001 ). No significant difference was observed in the distribution of thyroid function between the hypokalemic PA group and the normokalemic PA group ( P &gt; 0.05 ). No significant differences were seen in the positive rates of thyrotropin receptor antibody (TRAb), thyroglobulin antibody (TGAb), and thyroid peroxidase antibody (TPOAb) among the three groups ( P &gt; 0.05 ). In the logistic regression, only sex (OR, 7.4; 95% CI, 1.555-35.479; P = 0.012 ) was significantly correlated with thyroid dysfunction in GS patients. Conclusion. GS is complicated with a greater rate of thyroid dysfunction than primary aldosteronism. The risk of thyroid dysfunction in female patients with GS is higher than that in male patients.

A Rare Case of Hypokalemia Induced Rhabdomyolysis Secondary to Gitelman Syndrome: An Easily Overlooked Inherited Tubulopathy

Hypokalemia is a common clinical problem in endocrinologists’ and nephrologists’ practice. There are many obvious causes of hypokalemia such as diarrhea, vomiting or diuretics abuse. Other causes such as tubulopathies are rarely observed and their diagnosis is more challenging. There are many inherited and acquired tubulopathies causing hypokalemia, sometimes severe and life-threatening. We report a case of a middle aged female patient who presented with weakness of upper and lower limbs, muscle pain and oliguria. On evaluation, she had hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria and diagnosis of Gitelman syndrome was established. In addition, she had acute kidney injury (AKI ) due to rhabdomyolysis secondary to hypokalemia. A short review on the etiology, pathogenesis and management of Gitelman syndrome is presented.&#x0D; J MEDICINE JUL 2020; 21 (2) : 105-108

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter.

Among the electroneutral Na+-dependent chloride transporters, NKCC1 had until now evaded identification as a protein causing human diseases. The closely related SLC12A transporters, NKCC2 and NCC have been identified some 25 years ago as responsible for Bartter and Gitelman syndromes: two renal-dependent salt wasting disorders. Absence of disease was most surprising since the NKCC1 knockout mouse was shown in 1999 to be viable, albeit with a wide range of deleterious phenotypes. Here we summarize the work of the past 5 years that introduced us to clinical cases involving NKCC1. The most striking cases are of 3 children with inherited mutations, who have complete absence of NKCC1 expression. These cases establish that lack of NKCC1 causes deafness; CFTR-like secretory defects with mucus accumulation in lung and intestine; severe xerostomia, hypotonia, dysmorphic facial features, and severe neurodevelopmental disorder. Another intriguing case is of a patient with a dominant deleterious SLC12A2 allele. This de novo mutation introduced a premature stop codon leading to a truncated protein. This mutant transporter seems to exert dominant-negative effect on wild-type transporter only in epithelial cells. The patient who suffers from lung, bladder, intestine, pancreas, and multiple endocrine abnormalities has, however, normal hearing and cognition. Finally, new reports substantiate the haploinsufficiency prediction of the SLC12A2 gene. Cases with single allele mutations in SLC12A2 have been linked to hearing loss and neurodevelopmental disorders.

NaCl cotransporter activity and Mg2+ handling by the distal convoluted tubule.

The genetic disease Gitelman syndrome, knockout mice, and pharmacological blockade with thiazide diuretics have revealed that reduced activity of the NaCl cotransporter (NCC) promotes renal Mg2+ wasting. NCC is expressed along the distal convoluted tubule (DCT), and its activity determines Mg2+ entry into DCT cells through transient receptor potential channel subfamily M member 6 (TRPM6). Several other genetic forms of hypomagnesemia lower the drive for Mg2+ entry by inhibiting activity of basolateral Na+-K+-ATPase, and reduced NCC activity may do the same. Lower intracellular Mg2+ may promote further Mg2+ loss by directly decreasing activity of Na+-K+-ATPase. Lower intracellular Mg2+ may also lower Na+-K+-ATPase indirectly by downregulating NCC. Lower NCC activity also induces atrophy of DCT cells, decreasing the available number of TRPM6 channels. Conversely, a mouse model with increased NCC activity was recently shown to display normal Mg2+ handling. Moreover, recent studies have identified calcineurin and uromodulin (UMOD) as regulators of both NCC and Mg2+ handling by the DCT. Calcineurin inhibitors paradoxically cause hypomagnesemia in a state of NCC activation, but this may be related to direct effects on TRPM6 gene expression. In Umod-/- mice, the cause of hypomagnesemia may be partly due to both decreased NCC expression and lower TRPM6 expression on the cell surface. This mini-review discusses these new findings and the possible role of altered Na+ flux through NCC and ultimately Na+-K+-ATPase in Mg2+ reabsorption by the DCT.

Gitelman Syndrome: A Rare Cause of Persistent Hypokalemia

Gitelman syndrome is a rare autosomal recessive renal tubular disease, caused by mutations in the SLC12A3 gene, which encodes the renal thiazide-sensitive sodium-chloride cotransporter (NCCT) in the distal renal convoluted tubule. We present a 48-years-old male referred to our observation after being considered not suitable to a previous proposed surgery due to persistent hypokalemia. No valued symptoms were described. Laboratory tests showed metabolic alkalosis, hypomagnesemia, hypokalemia and secondary hyperaldosteronism. Genetic test was performed and sequence analysis of the SLC12A3 gene revealed a homozygous mutation confirming this disease. The aim of this report is to remind and increase awareness of the existence of GS, manage the condition properly and consider the risk of disease recurrence to the next generations.

Differential diagnosis of perinatal Bartter, Bartter and Gitelman syndromes.

The common finding of hypokalemic alkalosis in several unrelated disorders may confound the early diagnosis of salt-losing tubulopathy (SLT). Antenatal Bartter syndrome (BS) must be considered in idiopathic early-onset polyhydramnios. Fetal megabladder in BS may allow its distinction from third-trimester polyhydramnios that occurs in congenital chloride diarrhea (CCD). Fetal megacolon occurs in CCD while fecal chloride >90 mEq/L in infants is diagnostic. Failure-to-thrive, polydipsia and polyuria in early childhood are the hallmarks of classic BS. Unlike BS, there is low urinary chloride in hypokalemic alkalosis of intractable emesis and cystic fibrosis. Rarely, renal salt wasting may result from cystinosis, Dent disease, disorders of paracellular claudin-10b and Kir4.1 potassium-channel deficiency. Acquired BS may result from calcimimetic up-regulation of a calcium-sensing receptor or autoantibody inactivation of sodium chloride co-transporters in Sjögren syndrome. A relatively common event of heterozygous gene mutations for Gitelman syndrome increases the likelihood of its random occurrence in certain diseases of adult onset. Finally, diuretic abuse is the most common differential diagnosis of SLT. Unlike the persistent elevation in BS, urinary chloride concentration losses waxes and wanes on day-to-day assessment in patients with diuretic misuse.

Spectrum of Mutations in 106 Chinese Patients with Gitelman Syndrome

Spectrum of Mutations in 106 Chinese Patients with Gitelman Syndrome

Recurrent SLC12A3 Mutations in Taiwanese Families with Gitelman Syndrome: A Rapid Detection for the Higher Prevalence

Recurrent SLC12A3 Mutations in Taiwanese Families with Gitelman Syndrome: A Rapid Detection for the Higher Prevalence

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