Gitelman syndrome (GS), also known as familial hypokalemia-hypomagnesemia, is a rare autosomal recessive inherited salt-wasting tubulopathy, occurring with a frequency of approximately 1:40,000. The disease is characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcuria. The cause is a transport defect in the distal convoluted tubule (DCT).
The phenotype of GS patients is extremely heterogeneous in terms of symptom onset and type and severity of biochemical abnormalities and clinical manifestations. Initial symptoms usually appear from late childhood (>6 years) into adulthood, with most patients presenting during adolescence. However, initial diagnoses can also occur within the neonatal period up to the seventh decade of life.
The disease may be asymptomatic or associated with mild symptoms, such as weakness, fatigue, craving for salt, thirst, or nocturia. GS patients often experience transient episodes of muscle weakness and tetany, which can be accompanied by abdominal pain, vomiting, and fever. Paresthesias, especially of the face, are also observed. Rare severe manifestations may present as early onset of disease under 6 years of age, growth retardation, chondrocalcinosis, seizures, and rhabdomyolysis. Hypokalemia and hypomagnesemia prolong the duration of the action potential in cardiomyocytes, increasing the risk for ventricular arrhythmias. ECGs of GS patients revealed that in about 50% of cases, the QT interval may be mildly to moderately prolonged.
In adult patients, loss-of-function variants in the SLC12A3 gene (solute carrier family 12 member 3), which encodes the renal thiazide-sensitive Na-Cl cotransporter (NCC) and is located on the long arm of chromosome 16 (16q13), are causative in about 80% of cases. This is specifically expressed on the apical membrane of cells of the distal convolute. The deficiency of functional NCC leads to the metabolic disorders, the consequence being severe electrolyte loss. Therapeutically, magnesium supplementation is recommended.
Most SLC12A3 alterations are missense and nonsense variants; however, frameshift, splice, and deep intronic variants as well as large genomic rearrangements have also been described. Variants are distributed throughout the gene. Genetic heterogeneity is also observed, and a small proportion of patients with the GS phenotype carry pathogenic variants in the CLCNKB gene. As such, Bartter syndrome (especially type III) should also be considered as a differential diagnosis. In addition, pathogenic variants in the HNF1B gene, which encodes the transcription factor HNF1-β, can cause GS-typical electrolyte abnormalities (especially hypomagnesemia).
References
Blanchard et al. 2017, Kidney Int 91:24 / Lee et al. 2016, J Korean Med Sci 31:47 / Nakhoul et al. 2012, Endocrine 41:53 / Vargas-Poussou et al. 2011, J Am Soc Nephrol 22:693 / Balavoine et al. 2011, Eur J Endocrinol 165:665
