Gitelman syndrome is also known as familial hypokalemic hypomagnesaemia because hypokalemia is the most common phenomenon. Gitelman syndrome is estimated to have a prevalence of 1 in 40,000 homozygous people, and males and females are affected equally [1, 5]. Symptoms usually appear after six but may not be present until adolescence or adulthood. Usually, the diagnosis is made incidentally by detecting hypokalemia in a routine blood sample. Since hypokalemia can cause cardiac arrest, respiratory muscle paralysis, and death, early diagnosis of GS is essential . Diagnosis can be made fortuitously by detecting hypokalemia and hypomagnesemia during growth retardation identification. Patients may complain of fatigue, weakness, dizziness, thirst, muscle weakness or cramps, palpitations, and nocturia [3, 5].
Mutations in the SLC12A3 gene usually cause Gitelman syndrome. Less frequently, the condition is caused by mutations in the CLCNKB gene. More than 140 mutations in the SLC12A3 gene have been found in patients with GS [4, 6,7,8,9,10]. Three novel mutations, c.2 T > C, c.1609C > T and c.3055G > A, were identified by Wang et al. . Proteins produced from these genes are involved in the renal reabsorption of salt (NaCl) from the urine back into the bloodstream. Mutations in both genes impair the renal ability to reabsorb salt, resulting in an excess salt loss in the urine. Abnormalities in salt transport also affect the reabsorption of other ions, including potassium, magnesium, and calcium ions. The electrolyte imbalance underlies the basic features of GS . The SLC12A3 gene provides instructions for making a protein known as NCCT, which moves charged sodium and chloride atoms across cell membranes. NCCT is essential for normal renal function. Salt retention affects the body's fluid balance and helps maintain blood pressure. It is reported in the literature that 1% of the population is the carrier of the heterozygous SLC12A3 gene mutation . For a parent with GS, the risk of passing the abnormal gene to their offspring is low, 1 in 400, unless both parents are carriers of the disease .
In our first case, a c.1928C > T (p.Pro643Leu) homozygous mutation was detected in the SLC12A3 gene. In the literature, the c.1928C > T (p.Pro643Leu) missense variant has been reported rarely in patients with GS. Control data are unavailable for this variant, which is reported at a frequency of 0.001774 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro643Leu variant is classified as a variant of uncertain significance in GS [11,12,13,14]. This mutation would be expected to modify the protein structure and implicated in the loss of function of the NCCT of the distal tubule.
In our second case, a c.248G > A (p.Arg83Gln) homozygous mutation was detected in the SLC12A3 gene. This mutation is also not common among the SLC12A3 gene mutations. In a study, a c.248G > A (p.Arg83Gln) homozygous mutation in SLC12A3 has been reported in a 48-year-old male patient and his family . In this patient, weakness in the knee and Achilles tendons, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia, and chondrocalcinosis were detected.
In our third case, a c.1919A > G, p.N640S homozygous mutation was detected in the SLC12A3 gene. Although the gene mutation identified in this case has been reported in the literature, its relation to GS has not been identified. Numerous gene mutations are reported in a large series study . In this study, 448 index cases with the clinical diagnosis of GS were retrospectively screened for mutations in the SLC12A3 gene. Two affected alleles were detected in 315 (70%) of 448. However, 79 (25%) patients had homozygous mutations, and 236 (74.9%) patients had compound heterozygous mutations. In addition, only one mutant allele was detected in 81 (18%) patients and wild-type genotype in 52 (11.6%) patients.
There is no cure for GS. Treatment of GS includes supplements of potassium and magnesium. A high salt diet containing potassium and magnesium supplements to normalize blood levels is the basis of treatment . Severe potassium and magnesium deficiencies may require intravenous replacement. If low blood potassium levels cannot be raised sufficiently with oral supplements, aldosterone antagonists (spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride could reduce the urinary excretion of potassium [1, 2]. Indomethacin may also be used in patients with early onset of the disease, such as infants and children . Cardiac evaluation should be done to prevent dysrhythmias and to monitor QT intervals. In these patients, drugs that prolong the QT interval (macrolides, antihistamines, beta-2 agonists) should be avoided .