The challenges of diagnosis and management of Gitelman syndrome

Abstract

Gitelman syndrome is an inherited tubulopathy characterized by renal salt wasting from the distal convoluted tubule. Defects in the sodium chloride cotransporter (encoded by SLC12A3) underlie this autosomal recessive condition. This article focuses on the specific challenges of diagnosing and treating Gitelman syndrome, with use of an illustrative case report. Symptoms relate to decreased serum potassium and magnesium levels, which include muscle weakness, tetany, fatigue and palpitations. Sudden cardiac deaths have been reported. Making a diagnosis may be difficult given its rarity but is important. A knowledge of the serum and urine biochemical picture is vital to distinguish it from a broad differential diagnosis, and application of genetic testing can resolve difficult cases. There is a group of Gitelman syndrome heterozygous carriers that experience symptoms and electrolyte disturbance and these patients should be managed in a similar way, though here genetic investigations become key in securing a difficult diagnosis. Potassium and magnesium replacement is the cornerstone of treatment, though practically this can be hard for patients to manage and often does not fully relieve symptoms even when serum levels are normalized. Challenges arise due to the lack of randomized controlled trials focussing on treatment of this rare disease; hence, clinicians endorse strategies in line with correction of the underlying pathophysiology such as sodium loading or pharmacological treatments, which seem to help some patients. Focussed dietary advice and knowing the best tolerated preparations of potassium and magnesium medications are useful tools for the physician, as well as an awareness of the specific burdens that this patient group face in order to signpost appropriate support.

Clinical and Genetic Features in 31 Serial Chinese Children With Gitelman Syndrome

“…However, the phenotype of GS is highly variable and is linked to quality of life. Currently, a diagnosis of GS is based on clinical symptoms, biochemical abnormalities (i.e., normal/lower blood pressure, increased activity of the renin–angiotensin–aldosterone system, metabolic alkalosis, hypomagnesemia, and hypocalciuria), and genetic testing ( 5 ). Recently, next-generation sequencing (NGS) has begun to play an increasingly important role in the diagnosis of GS.…”

Gitelman Syndrome: A Rare Case of Hypokalaemia and a Novel Mutation

“…DISCUSSION GS, also known as familial hypokalaemia-hypomagnesaemia, is a renal tubulopathy resulting from loss-of-function mutations in the thiazidesensitive apical sodium-chloride cotransporter (NCCT). The prevalence is estimated to be 1:40,000 and mutations in the SLC12A3 gene underlie this tubulopathy, which are inherited in an autosomal recessive fashion [1][2][3] . GS is characterized by hypokalaemia, hypomagnesaemia, hypocalciuria and metabolic alkalosis [1,2] .…”

“…The prevalence is estimated to be 1:40,000 and mutations in the SLC12A3 gene underlie this tubulopathy, which are inherited in an autosomal recessive fashion [1][2][3] . GS is characterized by hypokalaemia, hypomagnesaemia, hypocalciuria and metabolic alkalosis [1,2] . Decreased reabsorption of sodium chloride in the distal convoluted tubule results in an increased distal tubular flow rate leading to increased potassium secretion through enhanced "maxi" potassium channel activity.…”

“…Clinical features are generally unspecific, including palpitations, muscle weakness, cramps and hypotension. The age of onset is usually around adolescence and early adulthood [1] . The differential diagnosis includes other renal tubulopathies, namely Bartter syndrome.…”

“…Potassium-sparing diuretics may be used as adjunctive therapy to increase potassium reabsorption in the nephron; however, they may worsen volume depletion, particularly in patients with low dietary sodium intake. ACE inhibitor and NSAID use is controversial and not routinely recommended [1] . This clinical case stands out for the rarity of a syndrome that presents itself as a severe hypokalaemia.…”