"Every Cloud Has a Silver Lining": How Three Rare Diseases Defend Themselves from COVID-19 and What We Have Learnt from It.

The process of SARS-CoV-2 infection, responsible for the COVID-19 pandemic, is carried out through different steps, with the interaction between ACE2 and Spike protein (S) being crucial. Besides of that, the acidic environment of endosomes seems to play a relevant role in the virus uptake into cells and its intracellular replication. Patients affected by two rare genetic tubulopathies, Gitelman's and Bartter's Syndromes, and a rare genetic metabolic disease, Fabry Disease, have shown intrinsic protection from SARS-CoV-2 infection and COVID-19 on account of specific intrinsic features that interfere with the virus uptake into cells and its intracellular replication, which will be reported and discussed in this paper, providing interesting insights for present and future research.

Gitelman syndrome and in vitro fertilization-embryo transfer: advancing preconception care in nephrology.

We report a case of a pregnant patient with Gitelman syndrome (GS) who conceived by in vitro fertilization-embryo transfer (IVF-ET). A 39-year-old woman was referred for hypokalemia, with a serum potassium level of 2.2 mEq/L. She had difficulty conceiving spontaneously. Because of her age, her hypokalemia could be exacerbated by pregnancy. We provided preconception care and managed her pregnancy by frozen-thawed embryo transfer with careful monitoring of the K levels. However, her serum K level dropped to 2.5 mEq/L at 8 weeks of gestation. It was expected that her K demand would increase with pregnancy; hence, she required hospitalization and a 1.5-fold increase in replacement dose to maintain her K levels. At 11 weeks of gestation, her serum K level rose to 3.0 mEq/L. The baby was born adequately sized after 38 weeks of gestation via vaginal delivery. The patient's K levels were stable during the postpartum period. Genetic testing revealed three heterozygous missense variants in SLC12A3 that were consistent with GS. In conclusion, preconception care and cooperation between internal medicine and obstetrics led to an excellent and successful delivery of an IVF fetus in an older patient with GS. There are no guidelines for electrolyte disorders in pregnancy, and only a few studies have reported on GS during pregnancy, including detailed postpartum assessments.

Genotype-phenotype correlations in children with Gitelman syndrome.

BACKGROUND: This study aimed to analyze genotype-phenotype correlations in children with Gitelman syndrome (GS). METHODS: This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. RESULTS: The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P = 0.049) during follow-up than those without truncating variants (n = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. CONCLUSIONS: Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.

A novel homozygous SLC12A3 mutation causing Gitelman syndrome with co-existent autoimmune thyroiditis: a case report and review of the literature.

Gitelman syndrome is a rare, autosomal recessively inherited tubulopathy manifesting with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Common symptoms include fatigue, myalgia, reduced performance capacity, tetany, paresthesia, and delayed growth. However, as reported in the literature, diagnosis in some patients is prompted by an incidental finding of hypokalemia. GS develops due to mutations in the SLC12A3 gene, which encodes the thiazide-sensitive Na-Cl cotransporter. Many variants in the SLC12A3 gene causing GS have been reported in literature. A new pathogenic homozygous mutation (c.2612G > T), absence of hypomagnesemia, and accompanying autoimmune thyroiditis are remarkable in our patient. There are a few Gitelman syndrome cases that are complicated with autoimmune thyroiditis in the literature. In this study, we present a case of Gitelman syndrome with a novel homozygous mutation and accompanying autoimmune thyroiditis and review of the literature.

Navigating the Multifaceted Intricacies of the Na+-Cl- cotransporter, a Highly Regulated and Key Effector in the Control of Hydromineral Homeostasis.

The Na+-Cl- cotransporter (NCC; SLC12A3) is a highly regulated integral membrane protein that is known to exist as 3 splice variants in primates. Its primary role in the kidney is to mediate the cosymport of Na+ and Cl- across the apical membrane of the distal convoluted tubule. Through this role and the involvement of other ion transport systems, NCC allows the systemic circulation to reclaim a fraction of the ultrafiltered Na+, K+, Cl- and Mg+ loads in exchange for Ca2+ and HCO3-. The physiological relevance of the Na+-Cl- cotransport mechanism in human is illustrated by the several abnormalities that result from NCC inactivation through the administration of thiazides or in the setting of hereditary disorders. The purpose of the current review is to discuss the molecular mechanisms and overall roles of Na+-Cl- cotransport as the main topics of interest. On reading the narrative proposed, one will realize that the knowledge gained in regard to these themes will continue to progress unrelentingly no matter how refined it has now become.

A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease.

Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is a disorder that presents with hypokalemia and metabolic alkalosis resembling Gitelman syndrome (GS) due to secondary factors, such as lifestyle and /or medicines. Notably, PBS/PGS is more likely to cause renal dysfunction than GS. We report the first case of PBS/PGS due to long-term laxative abuse leading to end-stage kidney disease (ESKD). The patient was a 49-year-old woman with a history of constipation since school, who had used excessive doses of laxatives on her own judgment for nine years at least from 22 years of age. Two years later, blood tests revealed hypokalemia (serum K 3.1 mEq/L), and nine years later, the patient's renal function began to deteriorate (Cr-eGFR 48.7 mL/min/1.73 m2). Since abuse of laxatives was suspected as the cause, it was changed to the proper dosage of laxatives. At 33 years, the patient developed acute kidney injury (AKI), due to a urinary tract infection, and required intensive treatment, including hemodialysis. Although the patient was eventually weaned off dialysis, the renal function did not recover to pre-AKI levels. In suspected GS, comprehensive genetic testing for renal disease-related genes was performed; however, no obvious pathogenic variants were identified. Thereafter, despite decreasing the laxative doses and potassium supplementation, her renal function continued to decline. At 49 years, the patient developed ESKD and was started on maintenance hemodialysis. PBS/PGS is a disease that can lead to ESKD. An early diagnosis of PBS/PGS is crucial to prevent renal function deterioration, and the underlying causes should be removed immediately.

Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.

BACKGROUND: Potassium regulates the WNK (with no lysine kinase)-SPAK (STE20/SPS1-related proline/alanine-rich kinase) signaling axis, which in turn controls the phosphorylation and activation of the distal convoluted tubule thiazide-sensitive NCC (sodium-chloride cotransporter) for sodium-potassium balance. Although their roles in the kidney have not been investigated, it has been postulated that Cab39 (calcium-binding protein 39) or Cab39l (Cab39-like) is required for SPAK/OSR1 (oxidative stress response 1) activation. This study demonstrates how they control the WNK-SPAK/OSR1-NCC pathway. METHODS: We created a global knockout of Cab39l and a tamoxifen-inducible, NCC-driven, Cab39 knockout. The 2 lines were crossed to generate Cab39-DKO (Cab39 double knockout) animals. Mice were studied under control and low-potassium diet, which activates WNK-SPAK/OSR1-NCC phosphorylation. Western blots were used to assess the expression and phosphorylation of proteins. Blood and urine electrolytes were measured to test for compromised NCC function. Immunofluorescence studies were conducted to localize SPAK and OSR1. RESULTS: Both Cab39l and Cab39 are expressed in distal convoluted tubule, and only the elimination of both leads to a striking absence of NCC phosphorylation. Cab39-DKO mice exhibited a loss-of-NCC function, like in Gitelman syndrome. In contrast to the apical membrane colocalization of SPAK with NCC in wild-type mice, SPAK and OSR1 become confined to intracellular puncta in the Cab39-DKO mice. CONCLUSIONS: In the absence of Cab39 proteins, NCC cannot be phosphorylated, resulting in a Gitelman-like phenotype. Cab39 proteins function to localize SPAK at the apical membrane with NCC, reminiscent of the Cab39 yeast homolog function, translocating kinases during cytokinesis.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

Mitochondrial Dysfunction in Kidney Tubulopathies.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.

Pseudo-Gitelman Syndrome Presenting with Hypokalemic Metabolic Alkalosis and Hypocalciuria.

Pseudo-Bartter syndrome is a well-known differential diagnosis that needs to be excluded in cases of normotensive hypokalemic metabolic alkalosis. Pseudo-Bartter syndrome and pseudo-Gitelman syndrome are often collectively referred to as pseudo-Bartter/Gitelman syndrome; however, pseudo-Gitelman syndrome should be considered as a separate entity because Gitelman syndrome is characterized by hypocalciuria and hypomagnesemia, while Bartter syndrome is usually associated with hypercalciuria. Herein, we report the cases of two young adult female patients who presented with severe hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Diuretic or laxative abuse and self-induced vomiting were absent, and a chloride deficit and remarkable bicarbonaturia were observed. Initial sequencing studies for SLC12A3, CLCKNB, and KCNJ10 revealed no mutations, and whole-exome sequencing revealed no pathogenic variants. The metabolic alkalosis was saline-responsive in one case, and steroid therapy was necessary in the other to relieve chronic tubulointerstitial nephritis, which was diagnosed with kidney biopsy. A new category of pseudo-Gitelman syndrome should be defined, and various etiologies should be investigated.

Gitelman Syndrome Manifesting With Acute Hypokalemic Paralysis: A Case Report.

Gitelman syndrome (GS) is a rare renal tubulopathy, classically characterized by renal salt wasting and metabolic alkalosis. It is usually an incidental diagnosis, being asymptomatic or with mild symptoms. GS manifesting with acute flaccid paralysis is extremely uncommon. We report a case of GS that mimicked Guillain-Barré syndrome (GBS), manifesting with acute hypokalemic paralysis. A middle-aged male with no known comorbidities presented to our center with paresthesias of all four limbs for one month and progressive, asymmetric limb weakness over the past eight days. Neurological examination revealed hypotonia, global areflexia, and power ranging from 3/5 to 4/5 in all four limbs, leading to our initial clinical diagnosis of GBS. Our patient's laboratory panel revealed hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalcemia, characteristic of GS. Additionally, he had significantly elevated creatine phosphokinase, suggestive of rhabdomyolysis. Further urine studies revealed renal potassium wasting, confirming the diagnosis of GS. Whole exome genome sequencing for common causative genes and workup for autoimmune disease were both negative. With gradual electrolyte correction, the patient rapidly improved symptomatically. Our case highlights an uncommon initial presentation of GS and emphasizes the need for more literature on its manifestations from the Indian subcontinent.

Heart's Dangerous Symphony: Torsade De Pointes Unleashed by Gitelman Syndrome-Induced Hypomagnesemia.

Gitelman syndrome (GS) is a rare autosomal recessive salt-losing renal tubular disorder associated with a mutation of SLC12A3 or CLCNKB genes which encodes the thiazide-sensitive sodium-chloride co-transporter (NCCT) in the distal renal tubule. It is inherited as an autosomal recessive disorder. Hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation are characteristics of GS. GS is often misdiagnosed or underdiagnosed owing to its low incidence and lack of awareness. Its prevalence is estimated to be around 1-10 per 40,000 people. We report a case of cardiac arrest secondary to torsade de pointes (TdP) because of GS-induced hypomagnesemia. Our case highlights the importance of clinicians being aware of the potential electrolyte abnormalities and complications associated with GS, as it can lead to catastrophic consequences if not identified and corrected earlier.

Gitelman Syndrome and Hypertension: A Case Report.

In a patient with persistent hypokalemia, it is important to consider Gitelman syndrome, a rare, salt-wasting tubulopathy inherited in an autosomal recessive pattern. Gitelman syndrome leads to electrolyte abnormalities like hypokalemia, hypomagnesemia, and metabolic alkalosis. Typical clinical features include muscle cramps, fatigue, polydipsia, and salt cravings. Our case involves a female patient in her early 40s who visited the endocrinology clinic with symptoms of polyuria, constipation, muscle weakness, and fatigue. Electrolyte abnormalities included hypokalemia, hypomagnesemia, hypochloremia, and hyperreninemia. Initial tests, such as renal function tests, renal ultrasound, and CT scan, yielded normal results. Differential diagnosis of Gitelman syndrome and Bartter syndrome was considered due to the mutual electrolyte abnormalities of hypokalemia and metabolic alkalosis. Bartter syndrome was ruled out in our patient due to the presence of hypomagnesemia, which indicates a different defective receptor. Ultimately, genetic testing would be necessary to confirm the diagnosis of Gitelman syndrome considering the characteristic electrolyte disturbances and classic clinical presentation of fatigue, weakness, and salt craving.

Ocular manifestations of the genetic renal tubulopathies.

BACKGROUND: The genetic tubulopathies are rare and heterogenous disorders that are often difficult to identify. This study examined the tubulopathy-causing genes for ocular associations that suggested their genetic basis and, in some cases, the affected gene. METHODS: Sixty-seven genes from the Genomics England renal tubulopathy panel were reviewed for ocular features, and for retinal expression in the Human Protein Atlas and an ocular phenotype in mouse models in the Mouse Genome Informatics database. The genes resulted in disease affecting the proximal tubules (n = 24); the thick ascending limb of the loop of Henle (n = 10); the distal convoluted tubule (n = 15); or the collecting duct (n = 18). RESULTS: Twenty-five of the tubulopathy-associated genes (37%) had ocular features reported in human disease, 49 (73%) were expressed in the retina, although often at low levels, and 16 (24%) of the corresponding mouse models had an ocular phenotype. Ocular abnormalities were more common in genes affected in the proximal tubulopathies (17/24, 71%) than elsewhere (7/43, 16%). They included structural features (coloboma, microphthalmia); refractive errors (myopia, astigmatism); crystal deposition (in oxalosis, cystinosis) and sclerochoroidal calcification (in Bartter, Gitelman syndromes). Retinal atrophy was common in the mitochondrial-associated tubulopathies. Structural abnormalities and crystal deposition were present from childhood, but sclerochoroidal calcification typically occurred after middle age. CONCLUSIONS: Ocular abnormalities are uncommon in the genetic tubulopathies but may be helpful in recognizing the underlying genetic disease. The retinal expression and mouse phenotype data suggest that further ocular associations may become apparent with additional reports. Early identification may be necessary to monitor and treat visual complications.

Spectrum of variants in a large Chinese Gitelman syndrome cohort.

Gitelman syndrome (GS) is caused by SLC12A3 biallelic variants. A previous study showed that large rearrangements (LRGs) of SLC12A3 accounted for the low sensitivity of genetic testing. However, a systematic screening for LRGs in Chinese GS patients is lacking. Massively parallel sequencing (MPS) and multiplex ligation-dependent probe amplification (MLPA) were performed to sequence the genomic DNA of patients with clinically diagnosed GS. Of 165 index cases, MPS identified 151 cases with two or more affected alleles and 14 cases with one variant allele. LRGs were detected by MLPA in 20 out of 27 cases, including 15 cases with suspected LRGs by MPS. Among these 20 cases with LRGs, the results of MPS and MLPA were identical in only 8 cases. Additional LRGs in 6 cases were detected by MLPA alone. In 6 cases, E4_E6del was identified by MPS, while E4_E5del and Intron6del were identified by MLPA. Among the 102 distinct variants, 30 are novel. LRGs were found in 20 cases (12.1%). LRGs were found in 12.1% of our Chinese GS patients cohort. We show that MPS and MLPA are two complementary techniques with the ability to improve the diagnostic yield of GS.

Two Brothers from Macedonia with Gitelman Syndrome.

Gitelman syndrome (GS) is a rare renal tubulopathy with an autosomal recessive mode of inheritance, caused by biallelic pathogenic variants in the SLC12A3 gene. The clinical features may overlap with other disorders, such as Bartter syndrome type 3, HNF1B nephropathy or even mitochondrial disease, but can be distinguished by molecular genetic analysis. Here we report on two preschool brothers, who presented with a several months' history of episodes of carpopedal spasms and muscle aches. The biochemical analyses revealed hypokalemia and hypomagnesemia without metabolic alkalosis. A 24-h urine sample demonstrated hypocalciuria. The molecular analyses showed that both patients were heterozygous for 3 (likely) pathogenic variants in SLC12A3: c.1805_1806del; p. (Tyr602Cysfs*31), c.2660+1G>A and c.2944 A>T; p. (Ile982Phe). Analysis of the parents showed that the mother was heterozygous for the c.2944 A>T p.(Ile982Phe) variant, and the father carried the other 2 variants (c.1805_1806del and c.2660+1G>A). Herein we present two children in a family from N. Macedonia with clinical manifestations and electrolyte imbalances suggestive of GS. The results of the tubulopathy next generation sequencing (NGS) panel confirmed the diagnosis. The boys are treated with a high salt diet and oral potassium and magnesium supplements.

Gitelman Syndrome: A Case Report.

Gitelman syndrome is a rare hereditary tubulopathy characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this case report, we describe a 21-year-old male who presented with myalgias, asthenia, general muscle weakness, and hypokalemia after receiving oral potassium supplementation for six months. Additional biochemical studies showed hypomagnesemia, metabolic alkalosis, and increased urinary potassium and magnesium excretion. Calcium urinary excretion was within the normal range, but 25-hydroxycholecalciferol levels were low. Systolic arterial hypertension was found, probably reflecting chronic hyperreninemic hyperaldosteronism. Genetic testing for SCL12A3 mutations identified a pathogenic variant in homozygosity, which confirmed the Gitelman syndrome diagnosis. Treatment with chronic potassium and magnesium oral supplementation was started, as well as eplerenone and amiloride, with sustained correction of hypokalemia and hypomagnesemia.

Novel compound heterozygous variants of SLC12A3 gene in a Chinese patient with Gitelman syndrome: a case report.

Background: The Gitelman syndrome (GS) is an autosomal recessive disorder of renal tubular salt handling. Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation, and is caused by variants in the SLC12A3 gene. Gitelman syndrome has a heterogeneous phenotype, which may or may not include a range of clinical signs, posing certain difficulties for clinical diagnosis. Case presentation: A 49-year-old man was admitted to our hospital due to muscular weakness. The patient's history revealed previous recurrent muscular weakness events associated with hypokalemia, featured by a minimum serum potassium value of 2.3 mmol/L. The reported male patient had persistent hypokalemia, hypocalciuria and normal blood pressure, without presenting obvious metabolic alkalosis, growth retardation, hypomagnesemia, hypochloremia or RAAS activation. We performed whole-exome sequencing and identified a novel compound heterozygous variant in the SLC12A3 gene, c.965-1_976delGCGGACATTTTTGinsACCGAAAATTTT in exon8 and c.1112T>C in exon9 in the proband. Conclusion: This is a study to report a heterogeneous phenotype Gitelman syndrome with a novel pathogenic compound heterozygous variant in the SLC12A3 gene. This genetic study expands the variants spectrum, and improve the diagnostic accuracy of Gitelman syndrome. Meanwhile, further functional studies are required to investigate the pathophysiological mechanisms of Gitelman syndrome.

Molecular complexity analysis of the diagnosis of Gitelman syndrome in China.

Gitelman syndrome (GS) is an autosomal recessive renal tubal disease characterized by hypomagnesemia, hypokalemia, and hypocalciuria. The disease is caused by defects in the SLC12A3 gene, which encodes the thiazide diuretic-sensitive sodium chloride cotransporter (NCCT). In this study, a 20-year-old female patient with recurrent hypokalemia was tested for a hypokalemia-related panel using Next Generation Sequencing. Pedigree analysis was performed on her parents (non-consanguineous) and sister using Sanger sequencing. The results revealed that the patient carried compound heterozygous variants of the SLC12A3 gene: c.179C > T (p.T60M) and c.1001G > A (p.R334Q). Furthermore, her asymptomatic 6-year-old sister also carried both mutations. While the p.T60M mutation had been reported previously, the p.R334Q mutation was novel, and amino acid position 334 was identified as a mutation hotspot. Our findings provide an accurate molecular diagnosis that is essential for the diagnosis, counseling, and management of not only the symptomatic patient but also her asymptomatic sister. This study contributes to our understanding of the GS, which has a prevalence of approximately 1 in 40,000 and a heterozygous mutation carrier rate of 1% in Caucasians. Specifically, we observed a compound heterozygous mutation of the SLC12A3 gene in a 20-year-old female patient presenting with clinical symptoms consistent with GS.

Sudden cardiac arrest in a child with Gitelman syndrome: a case report and literature review.

Salt-losing tubulopathies are well-recognised diseases predisposing to metabolic disturbances in affected patients. One of the most severe complications can be life-threatening arrhythmias causing sudden cardiac arrest. We present here the first case of a pediatric patient with Gitelman syndrome associated sudden cardiac arrest without precipitating event. A 10-year-old boy collapsed due to ventricular fibrillation in the Prague tram. Lay cardiopulmonary resuscitation was initiated and external defibrillation restored sinus rhythm within minutes. Initial laboratory examination revealed severe hypokalemia requiring large amounts of electrolyte supplementation. Genetic testing focused to tubulopathies was performed and the diagnosis of Gitelman syndrome was made following the identification of two pathogenic variants in SLC12A3 gene (c.2633 + 1G>A and c.2221G>A). Implantable cardioverter-defibrillator was implanted to prevent sudden cardiac death. The patient was in a good clinical condition with satisfactory electrolyte serum levels at the last follow-up. Causes of electrolyte abnormalities in children should be identified early to prevent the development of rare but potentially fatal complications.