Gitelman syndrome

GS is characterised by hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. The first symptoms usually appear from late childhood (>6 years) to adulthood, with most patients presenting in adolescence. The disease can be asymptomatic or associated with mild symptoms such as weakness, fatigue, salt cravings, thirst or nocturia. Rare severe manifestations may present as early onset under 6 years of age, growth retardation, chondrocalcinosis, seizures, rhabdomyolysis and ventricular arrhythmias. Phenotypic severity is highly variable: affected siblings sharing identical SLC12A3 genotypes may show markedly different clinical pictures, ranging from mildly symptomatic presentations to incapacitating muscular and cardiac complications.

GS prevalence is estimated at 1 to 10 per 40,000 and potentially higher in Asia. GS is arguably the most frequent hereditary tubulopathy.

Gitelman syndrome is caused by biallelic germline pathogenic variants in SLC12A3. This gene encodes the renal thiazide-sensitive Na-Cl cotransporter (NCC), which is specifically expressed on the apical membrane of cells of the distal convoluted tubule where it mediates reabsorption of sodium and chloride. Loss of transporter function results in renal salt wasting, secondary activation of the renin-angiotensin-aldosterone system, and the characteristic biochemical pattern of hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria.

Gitelman syndrome is inherited in an autosomal recessive manner. Heterozygous carriers are clinically unaffected. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Clinical and biochemical criteria were formalized at the 2017 KDIGO Controversies Conference. Meeting these criteria establishes the clinical diagnosis. Characteristic findings comprise chronic hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria, hyperreninaemia, hyperaldosteronism, and normal or low blood pressure. The hydrochlorothiazide chloride-clearance test, with a blunted natriuretic response, distinguishes Gitelman from Bartter syndrome where genetic testing is non-diagnostic.

• Establishing the diagnosis: Identification of biallelic germline pathogenic variants confirms the molecular diagnosis when clinical and biochemical findings are suggestive.
• Informing clinical management: a confirmed molecular diagnosis is a prerequisite for individualised clinical management and long-term care planning.
• Family member testing: Once the familial pathogenic variants are known, targeted molecular testing of at-risk relatives is possible and supports reproductive planning.

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• Blanchard A, Bockenhauer D, Bolignano D, Calò LA, Cosyns E, Devuyst O, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2017;91(1):24-33. PMID: .
• Schlingmann KP, de Baaij JHF. The genetic spectrum of Gitelman(-like) syndromes. Curr Opin Nephrol Hypertens. 2022;31(5):508-515. PMID: .