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논문분류	춘계학술대회 초록집
제목	Gitelman syndrome
저자	Nine Knoers
출판정보	2020; 2020(1):
키워드	Gitelman syndrome \| SLC12A3 \| NCC \| Phenotypic variability \| hypomagnesemia
초록	Gitelman syndrome (OMIM 263800) is an autosomal recessive salt-losing renal tubulopathy characterized by hypokalemic metabolic alkalosis in conjunction with hypomagnesemia and hypocalciuria. With an estimated prevalence of 1 to 10 per 40.000, and a heterozygote carrier frequency of 1% in the Caucasian population, Gitelman syndrome is one of the most frequent inherited renal tubular disorders. In Asia, the disease is probably even more prevalent with a heterozygote carrier frequency up to 3%. The Gitelman syndrome phenotype can be observed from the age of 6 years, but in most instances the diagnosis is made during adulthood. The phenotype is extremely variable; the most common symptoms seen in more than 50% of cases are salt craving, muscle weakness, tetany, fatigue, dizziness, nocturia, palpitations, paresthesia, thirst, polydipsia, and low blood pressure. Other prominent symptoms, seen in 20-50% of cases are fainting, polyuria, arthralgia, chondrocalcinosis, prolonged QT, and febrile episodes. Remarkably, some patients are completely asymptomatic and in these patients the disease is detected fortuitously. There are a few case reports of Gitelman syndrome presenting already before 2 years of age. The Gitelman syndrome phenotype is in most cases caused by bi-allelic loss-of-function mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. A minority (3-5%) of Gitelman syndrome patients has bi-allelic loss-of-function mutations in CLCNKB, encoding the chloride channel subunit b (ClC-Kb). Both mutations in NCC as well as in ClC-Kb lead to disruption of NaCl reabsorption in the DCT, resulting in increased sodium delivery to the collecting duct and mild volume contraction. Hypovolemia will, via stimulation of the renin-angiotensin-aldosterone system, increase sodium reabsorption in the collecting duct, maintaining sodium homeostasis at the expense of increased secretion of potassium and hydrogen ions, and an attendant hypokalemia and metabolic alkalosis. Enhanced passive Ca2+ reabsorption in the proximal tubule and reduced abundance of the epithelial Mg 2+ channel TRPM6, located in the DCT, are suggested to explain the hypocalciuria and hypomagnesemia, respectively. In my presentation, I will update you on the genetics of Gitelman syndrome. At present, more than 500 different disease-causing mutations in SLC12A3 have been reported. Of these mutations several are common in Asia: p.Arg642Cys, p.Leu858His, and p.Thr60Met. I will also discuss the differential diagnosis of Gitelman syndrome and how genetic testing can help in differentiating Gitelman syndrome from phenocopies. I will elaborate on studies that try to explain the high phenotypic variability of Gitelman syndrome and I will explain why Gitelman syndrome cannot be considered a benign tubulopathy. Finally, I will review the current management, further therapeutic options and the long-term prognosis of Gitelman syndrome.
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