Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations

Abstract

Bartter and Gitelman syndromes (BS and GS) are inherited disorders resulting in defects in renal tubular handling of sodium, potassium and chloride. Previously considered as genotypic and phenotypic heterogeneous diseases, recent evidence suggests that they constitute a spectrum of disease caused by different genetic mutations with the molecular defects of chloride reabsorption originating at different sites of the nephron in each condition. Although they share some characteristic metabolic abnormalities such as hypokalemia, metabolic alkalosis, hyperplasia of the juxtaglomerular apparatus with hyperreninemia, hyperaldosteronism, the clinical and laboratory manifestations may not always allow distinction between them. Diuretics tests, measuring the changes in urinary fractional excretion of chloride from baseline after administration of either hydrochlorothiazide or furosemide show very little change (< 2.3%) in the fractional excretion of chloride from baseline in GS when compared with BS, except when BS is associated with KCNJ1 mutations where a good response to both diuretics exists. The diuretic test is not recommended for infants or young children with suspected BS because of a higher risk of volume depletion in such children. Clinical symptoms and biochemical markers of GS and classic form of BS (type III) may overlap and thus genetic analysis may specify the real cause of symptoms. However, although genetic analysis is available, its use remains limited because of limited availability, large gene dimensions, lack of hot-spot mutations, heavy workup time and costs involved. Furthermore, considerable overlap exists between the different genotypes and phenotypes. Although BS and GS usually have distinct presentations and are associated with specific gene mutations, there remains considerable overlap between their phenotypes and genotypes. Thus, they are better described as a spectrum of clinical manifestations caused by different gene mutations.

Keywords: Gitelman syndrome, Bartter syndrome, Potassium, Chloride, Magnesium, Metabolic alkalosis, Genetics

Core tip: As inherited disorders of renal tubular excretion and reabsorption of electrolytes, Bartter and Gitelman syndromes were previously considered as genotypic and phenotypic heterogeneous diseases. Although they share some characteristic features, the clinical and laboratory manifestations may not always allow distinction between them. Different genetic mutations inducing impairment of electrolytes transport across different sites of the nephron have been reported in each condition. However, considerable overlap exists between the different genotypes and phenotypes of these two conditions that are now better described as a spectrum of clinical manifestations caused by different gene mutations.