Abstract:
Gitelman syndrome (GS) is an autosomal-recessive renal tubular disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, secondary hyperreninemic aldosteronism, and low blood pressure.1–3 GS patients are usually diagnosed relatively late, because malaise, low blood pressure, hypokalemia, hypocalciuria, and hypomagnesemia are difficult to categorize clinically. Inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium chloride cotransporter (NCCT) cause GS.2 The investigators used the criteria of Bettinelli et al4 to identify patients with GS. More than 100 SLC12A3 mutations have been described.3 Most are missense mutations substituting conserved amino acid residues within putative functional domains of NCCT, whereas nonsense, frameshift, and splice site defects and gene rearrangements are less frequent. GS is clinically variable (men are more severely affected than women), and the combination of mutations present in each allele may determine phenotype variability.3 A heterozygous carrier state for 30 different inactivating mutations in NCCT, as well as genes responsible for Bartter syndrome, is associated with reduced blood pressure risk of hypertension in the general population.5 Approximately 80% of the mutation carriers had systolic blood pressure values below the mean of the entire 5124-subject cohort of the Framingham Heart Study. The mean blood pressure reduction in carriers averaged −6.3 mm Hg for the systolic and −3.4 mm Hg for the diastolic blood pressures, similar to values obtained with chronic thiazide treatment. There was a 60% reduction in the risk of developing hypertension by age 60 years. Thus, rare alleles that affect renal salt handling and blood pressure in the general population could account for a substantial fraction of blood pressure variation.5 We encountered 2 patients and then found others in our database who illustrate the importance of NCCT on blood pressure variability and, therefore, hypertension.