Gitelman syndrome: a review of clinical features, genetic diagnosis and therapeutic management

ABSTRACT

Introduction: Gitelman syndrome (GS) is an autosomal recessive primary tubular disorder caused by a defective function of the sodium chloride cotransporter (NCC), sited in the distal convoluted tubule, sensitive to thiazides and encoded by the SLC12A3 gene. GS causes a wide spectrum of clinical manifestations associated with a rather homogeneous biochemical profile characterized by hypokalemic metabolic alkalosis, hypomagnesemia, in the face of inappropriately high urinary magnesium elimination, and very low urinary calcium. The reason for the lack of phenotype – genotype correlation, the underlying genetic defect and the pathophysiological mechanisms of some manifestations are not clear.

Areas covered: This review describes the genetic and molecular bases of GS, discusses the clinical and biochemical findings, including the effect on blood pressure, and provides therapeutic indications.

Expert opinion: GS raises several intriguing issues. The underlying gene defect is unknown in some patients with typical manifestations of the disease, which prompts to the involvement of additional genes regulating NCC. The large phenotypic variability occurs even within members of the same family sharing the same gene mutation and similar environmental conditions. Patients with severe symptoms are difficult to control adequately in spite of sodium chloride, potassium and magnesium supplementation and the administration of potassium-sparing diuretics.

KEYWORDS:

• Gitelman syndrome
• hypokalemia
• hypomagnesemia
• genetics
• blood pressure
• treatment

Article highlights

• Gitelman syndrome (GS) is a salt-loss primary tubulopathy

• The underlying causal disorder of GS lies in the SLC12A3 gene

• The molecular basis of GS consists in a loss of function of the thiazide-sensitive NCC protein responsible for the reabsorption of sodium chloride in the distal convoluted tubule

• The phenotype of GS is highly variable

• GS is biochemically characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria

• The relationship of GS with blood pressure is not clear

• Treatment of GS depends on the severity of the clinical manifestations

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (PI14/00702) and Fondos Feder.