Abstract
Gitelman syndrome (OMIM #263800) is an autosomal recessive renal tubular disorder due to loss of function mutations of SLC12A3 gene, encoding the thiazide-inhibitable, electroneutral Na+-Cl– cotransporter (NCC) of the distal convoluted tubule. Clinical consequences include chronic normotensive hypokalemic alkalosis, hypomagnesemia, hypocalciuria, polyuria/nocturia, chronic asthenia, muscular cramps, chondrocalcinosis and rarely cardiac arrhythmias.Impaired reabsorption of glomerular filtrate through NCC drives compensatory reabsorption of Na+ in more distal tubular segments (connecting and cortical collecting tubules) via both the «electrogenic» channel ENa (which also enhances tubular secretion of potassium and protons, explaining the hypokalemic alkalosis), and pendrin-dependent electroneutral NaCl reabsorption. Thus volume depletion is seldom severe in these patients.There exists wide variability and severity of clinical symptoms between subjects, ranging from an almost asymptomatic disease to a severely disabling one. More than 400 SLC12A3 mutations have been so far described, evenly distributed along the protein sequence and without any hot spot. Mutation detection rate by gene sequencing actually is about 80 %. There are no genotype-phenotype correlations.Commonly considered a benign condition, Gitelman syndrome may be associated with reduced quality of life, increased medicalization and high hospitalization rate.
Highlights
Gitelman syndrome (GS; OMIM # 263800) is a renal tubular disorder mechanistically linked to impaired function of the electroneutral Na+-Cl– cotransporter (NCC) expressed in the apical membrane of distal convoluted tubule (DCT) cells
In GS NCC mutations result in reduced NaCl reabsorption in DCT, which drives electrogenic Na+ reabsorption downstream this tubular segments, mostly the connecting tubule (CNT) and collecting tubule (CCT), enhancing potassium and proton secretion, which is the basis for the typical hypokalemic alkalosis in GS
Clinical manifestations include muscular cramps/tetanic crisis, asthenia, polyuria/nocturia, chondrocalcinosis; normal/low blood pressure is an important feature in the differential diagnosis with hypertensive hypokalemic disorders
Summary
Gitelman syndrome (GS; OMIM # 263800) is a renal tubular disorder mechanistically linked to impaired function of the electroneutral Na+-Cl– cotransporter (NCC) expressed in the apical membrane of distal convoluted tubule (DCT) cells. In GS NCC mutations result in reduced NaCl reabsorption in DCT, which drives electrogenic Na+ reabsorption downstream this tubular segments, mostly the CNT and CCT, enhancing potassium and proton secretion, which is the basis for the typical hypokalemic alkalosis in GS. Though GS may be viewed as a chronic diuretic state, there are specificities of GS in comparison with chronic diuretic users (Colussi et al, 1992b): patients with GS, like patients with Bartter syndrome, show «resistance» to angiotensin II and other vasoconstrictors (and do not have peripheral vasoconstriction) (Sartori et al 2007), and, at variance with diuretic users, have normal GFR and are not hyperuricemic; this finding is useful to differentiate GS from «pseudo-Bartter» syndrome from surreptitious diuretic intake (Colussi et al, 1992b) It is unclear whether the absence of renal vasoconstriction in GS, despite relative hypovolemia, may be explained by enhanced renal prostaglandin production (Sartori et al, 2007). 50 mmol/day (personal data), and «hypovolemic crises» usually do not occur in the absence of superimposed conditions, such as protracted diarrhoea and/or vomiting
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