- also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion.
-autosomal recessive
-great majority of cases GS is caused by mutations in the solute carrier family 12, member 3, SLC12A3 gene, which encodes the renal thiazide-sensitive sodium-chloride co-transporter NCC that is specifically expressed in the apical membrane of cells in the first part of the distal convoluted tubule (DCT)
-Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.
-Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria)
-Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.
-Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.
-GS patients usually present above six years of age and in many cases the diagnosis is only made at adult age. Most patients suffer from tetany, especially during periods of fever or when extra magnesium is lost due to vomiting or diarrhea. Paresthesias, especially in the face, frequently occur. Some patients experience severe fatigue interfering with daily activities, while others never complain of tiredness. The severity of fatigue in GS is not completely related to the degree of hypokalemia. In contrast to Bartter syndrome (a genetically distinct and clinically more severe tubular transport disorder, which shares the hypokalemic metabolic alkalosis with GS) polyuria is usually absent or only mild. In general, growth is normal in GS patients, however, it can be delayed in patients with severe hypokalemia and hypomagnesemia
-chondrocalcinosis, which is assumed to result from chronic hypomagnesemia. It causes swelling, local heat, and tenderness over the affected joints. In earlier clinical reports additional symptoms, such as ataxia, vertigo, and blurred vision have been reported
-salt craving, musculoskeletal symptoms such as tetany and cramps, muscle weakness and aches, and constitutional symptoms such as fatigue, generalized weakness and dizziness, and nocturia and polydipsia. In addition, measures of QOL were significantly lower in GS patients compared to controls.
-Potassium and magnesium depletion prolong the duration of the action potential of cardiomyocytes and consequently increase the risk for development of ventricular arrhythmia. Electrocardiograms of patients with Gitelman syndrome have shown that in about 50% of cases the QT interval is indeed slightly to moderately prolonged but, fortunately, is not associated with clinically relevant cardiac arrhythmias in the far majority of cases
-Blood pressure in GS patients is lower than in the general population, indicating that even the modest salt wasting of this disease reduces blood pressure. The results from a recent study in 35 GS-carriers (with one mutant gene allele) suggest that GS carriers also have lower blood pressure and may be protected from hypertension
-NaCl cotransporter (NCC) is a polypeptide of 1021 amino acids and the 2D-structure is predicted to contain 12 transmembrane domains and long intracellular amino- and carboxytermini.
-When less NaCl is reabsorped, more sodium will arrive in the collecting duct resulting in mild volume contraction. The reduced vascular volume activates the renin-angiotensin-aldosterone system, increasing renin activity and aldosterone levels. The elevated aldosterone levels give rise to increased electrogenic sodium reabsorption in the cortical collecting duct via the epithelial sodium channel (ENaC), defending salt homeostasis at the expense of increased secretion of potassium and hydrogen ions, thus resulting in hypokalemia and metabolic alkalosis. It has been shown that passive Ca2+ reabsorption in the proximal tubule and reduced abundance of the epithelial Mg2+ channel TRPM6, located in the DCT explains thiazide-induced hypocalciuria and hypomagnesemia, respectively
-Prostaglandin excretion is normal and plasma renin activity and plasma aldosterone concentration are only slightly elevated compared to Bartter syndrome
-Renal functional studies have demonstrated normal or slightly decreased urinary concentrating mechanism, but clearly reduced distal fractional chloride reabsorption during hypotonic saline infusion. GS patients have a blunted natriuretic response to hydrochlorothiazide administration but a prompt natriuresis after administration of furosemide, indicating that the defect in GS is located at the level of the distal tubule. DNA mutation analysis of the gene responsible for GS may confirm the diagnosis
-hypokalemia (fatigue, muscle weakness, constipation, cardiac arrhythmias)
-hypomagnesemia (tetany, cramps, paresthesias, joint and muscle pain)
- 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.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
-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
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