Gitelman syndrome is an autosomal recessive kidney disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter (also known as NCC, NCCT, or TSC) located in the distal convoluted tubule of the kidney. This symporter is a channel responsible for the transport of multiple electrolytes such as sodium, chloride, calcium, magnesium, and potassium.
|Synonyms||Primary renal tubular hypokalemic hypomagnesemia with hypocalciuria|
|A model of transport mechanisms in the distal convoluted tubule. Sodium chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leaves the cell through the basolateral Cl− channel (ClC-Kb), and the Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman's syndrome.|
Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive hypokalemic metabolic alkalosis, but it derives from a mutation to the NKCC2 found in the thick ascending limb of the loop of Henle.
Signs and symptomsEdit
Affected individuals may not have symptoms in some cases. Symptomatic individuals present with symptoms identical to those of patients who are on thiazide diuretics, given that the affected transporter is the exact target of thiazides.
Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine. In contrast to people with Gordon's syndrome, those affected by Gitelman's syndrome generally have low or normal blood pressure. Individuals affected by Gitelman's syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability. Though cravings for salt are most common and severe, cravings for sour foods (e.g. vinegar, lemons, and sour figs) have been noted in some persons affected. More severe symptoms such as seizures, tetany, and paralysis have been reported. Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram and cases of sudden cardiac death have been reported due to low potassium levels. Phenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated.
Most Gitelman syndrome cases are linked to inactivating mutations in the SLC12A3 gene resulting in a loss of function of the encoded thiazide-sensitive sodium-chloride co-transporter (NCCT). This genetic mutation in the SLC12A3 is present in 80% of adults with Gitelman syndrome. More than 180 mutations of this transporter protein have been described. This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na-Ca exchanger and apical calcium channel.
When the sodium-chloride cotransporter is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favorable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, leading to a low level of magnesium in the blood.
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Most asymptomatic individuals with Gitelman syndrome can be monitored without medical treatment. Potassium and magnesium supplementation to normalize low blood levels of potassium and magnesium is the mainstay of treatment. Large doses of potassium and magnesium are often necessary to adequately replace the electrolytes lost in the urine. Diarrhea is a common side effect of oral magnesium which can make oral replacement difficult but dividing the dose to 3-4 times a day is better tolerated. Severe deficits of potassium and magnesium require intravenous replacement. If low blood potassium levels are not sufficiently replaced with oral replacement, aldosterone antagonists (such as spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride can be used to decrease urinary wasting of potassium.
Gitelman syndrome is estimated to have a prevalence of 1 in 40,000 people.
The disorder is named for Hillel J. Gitelman (1932– January 12, 2015), an American nephrologist working at University of North Carolina School of Medicine. He first described it in 1966, after observing a pair of sisters with the disorder. He and his colleagues later cloned the gene responsible.
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