Gitelman Syndrome

Gitelman syndrome (GS) is an autosomal recessive, salt-losing tubulopathy characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism. Gitelman syndrome is also referred to as familial hypokalemia-hypomagnesemia. GS is perhaps the most common inherited tubulopathy, with a prevalence of 1 to 10 per 40,000 and potentially more in Asia. The disorder is caused by biallelic inactivating mutations. Both hypomagnesemia and hypocalciuria are highly suggestive of the clinical diagnosis of GS; however, hypomagnesemia may be absent, and hypocalciuria is highly variable. In some cases, it becomes difficult to use clinical and biological features to distinguish GS from other salt-losing nephropathies. Genetic testing is increasingly becoming more available for GS; however, it remains expensive. GS has been considered a benign tubulopathy for a long time, usually presenting during adolescence or adulthood. Often, the condition may remain asymptomatic or present with mild or nonspecific symptoms. However, studies have challenged this idea by emphasizing the disorder's phenotypic variation and potential severity. Cruz et al. argued that GS is associated with a significantly reduced quality of life, similar to patients with congestive heart failure or diabetes. Severe presentation, such as early-onset (before age six years), chondrocalcinosis, growth retardation, tetany, seizures, rhabdomyolysis, and ventricular arrhythmia, have been described. Of note, in many cases of severe manifestation, the diagnosis of GS was made on a clinical rather than a genetic basis, potentially creating confusion with similar disorders. Many treatment options are available; however, evidence supporting the tolerability, efficacy, and safety of these management options (either as a standalone therapy or as an adjunct) in GS patients is limited. Information regarding the long-term outcomes of Gitelman syndrome is lacking. Long-term consequences such as chronic kidney disease, chondrocalcinosis, cardiac arrhythmias, secondary hypertension, and treatment during pregnancy need to be considered. Much insight has been gained since its genetic elucidation in 1996, yet mystery still surrounds GS. More efforts are required to substantiate issues, such as diagnostic criteria and methods, phenotypic heterogeneity, clinical workup and follow-up, clinical manifestations, nature and severity of the biochemical abnormalities, and treatment and long-term consequences of the disease.