Gitelman Syndrome, Orphanet Journal of Rare Diseases

Genetic counseling

Genetic counseling is important. Since GS is an autosomal recessive trait, the recurrence risk for parents with an affected child is 25%. If the parents already have other children, who are not obviously affected, it is not absolutely sure that they do not have GS because clinical symptoms can appear later in life. If the parents are eager to know the status of the other child(ren) and in case the molecular defect in their affected child has been elucidated, DNA-analysis in the other child(ren) may be performed. Adult patients with GS have a low risk of having children with GS (~1 in 400) unless the patient and his/her partner are consanguineous. Although technically feasible, antenatal diagnosis for GS is not advised and as yet has never been asked for because of the good prognosis in the majority of patients.

Management including treatment

Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring (generally by nephrologists) with low frequency (1–2 times per year). At each visit complaints related to hypokalemia (fatigue, muscle weakness, constipation, cardiac arrhythmias) and hypomagnesemia (tetany, cramps, paresthesias, joint and muscle pain) as well as serum levels of K+, bicarbonate and Mg2+ should be evaluated. In view of the assumption that chondrocalcinosis is due to magnesium deficiency (magnesium is a co-factor of various pyrophospatases, including alkaline phosphatase), there is a clear argument for lifelong supplementation of magnesium. Normalization of serum magnesium is difficult to achieve since high doses of magnesium cause diarrhea. The bio-availability of magnesium preparations is different. Magnesium-oxide and magnesium-sulfate have a significantly lower bio-availability compared to magnesium-chloride, magnesium-lactate and magnesium-aspartate. We recommend the administration of magnesium-chloride orally to compensate for renal Mg2+ and Cl- losses. Initial daily dose is 3 mmol Mg/m2/24 hrs or 4–5 mg/kg/24 hrs. This dose should be divided in 3–4 administrations to avoid diarrhea and has to be adjusted according to serum magnesium levels. The dose usually has to be increased during periods of undercurrent infections especially those accompanied by vomiting and diarrhea. In case of acute tetany, 20% MgCl2 should be administered intravenously (0.1 mmol Mg/kg per dose) and can be repeated every 6 hours.

Complaints related to chondrocalcinosis (mainly pseudogout attacks) are caused by the deposition of calcium pyrophosphate dehydrate crystals in synovium and the synovial fluid and can be reduced by Mg2+ supplementation [17]. The symptoms can be controlled by non-steroidal anti-inflammatory drugs (NSAID) and joint surgery is generally not required.

If symptomatic hypokalemia is not corrected by MgCl2 administration, it can be treated by drugs that antagonize the activity of aldosterone or block the sodium channel ENaC in the collecting duct. We prefer the combination of amiloride (5–10 mg/1.73 m2/day) with KCl (1–3 mmol/kg/day divided in 3–4 doses). Amiloride should be started with caution in order to avoid hypotension.

Growth and puberty delay in some patients with severe GS can be corrected by adequate Mg and K supplementation and a growth-promoting effect of indomethacin was also reported in GS patients [18]. Cardiac work-up is recommended to screen for risk factors of cardiac arrhythmias. All patients with GS are encouraged to maintain a high-sodium and high potassium diet.

Prognosis

In general, the long-term prognosis of Gitelman syndrome is excellent. However, the severity of fatigue may seriously hamper some patients in their daily activities. Progression to renal insufficiency is extremely rare in GS. As yet, only one patient who developed chronic renal insufficiency and subsequent progression to end-stage renal disease has been reported [19].

Abbreviations

GS: Gitelman syndrome; QOL: Quality of life; DCT: Distal convoluted tubule; NCC: Thiazide-sensitive NaCl cotransporter; TAL: Thick ascending limb of Henle’s loop; ENaC: Epithelial sodium channel; TRPM6: Transient receptor potential channel subfamily M, member 6; NSAID; Non-steroidal anti-inflammatory drugs.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

The authors contributed to this review article. They read and approved the final version of the manuscript.

Gitelman HJ, Graham JB, Welt LG: A new familial disorder characterized by hypokalemia and hypomagnesemia.

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