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Gitelman Syndrome

What it is, Causes, Treatment, and More

Author: Georgina Tiarks

Editors: Alyssa Haag, Emily Miao, PharmD

Illustrator: Jillian Dunbar

Copyeditor: David G. Walker

What is Gitelman syndrome?

Gitelman syndrome, also known as familial hypokalemia hypomagnesemia, is an inherited autosomal recessive kidney disorder that impacts the reabsorption of charged ions. Charged ions contain an unequal number of protons (i.e., positive charges) and electrons (i.e., negative charges). Examples of charged ions include electrolytes like potassium (K+), sodium (Na+), calcium (Ca+2), and magnesium (Mg+2). Within the kidney, tubules are responsible for reabsorbing and secreting charged ions to maintain balanced electrolyte concentrations. Gitelman syndrome affects the thiazide-sensitive sodium-chloride cotransporter at the distal convoluted tubule. The distal convoluted tubule is responsible for reabsorbing around 5% of NaCl, commonly known as salt. This impairment of the cotransporter results in reduced sodium and chloride reabsorption into the body. In addition, other transporters are impacted, resulting in further electrolyte abnormalities, including elevated bicarbonate levels (i.e., metabolic alkalosis), low potassium (i.e., hypokalemia), low magnesium (i.e., hypomagnesemia), and elevated calcium (i.e., hypercalcemia).

How rare is Gitelman syndrome?

Gitelman syndrome is a rare kidney disorder that typically affects around 1 in 40,000 individuals globally.

What causes Gitelman syndrome?

Gitelman syndrome is most commonly caused by missense mutations in the SLC12A3 gene on chromosome 16p. Less commonly, it may also result from mutations in the CLCNKB gene. These mutations occur in an autosomal recessive inheritance pattern, which means that in order to develop the disorder, both copies of the gene must be mutated.

What are the signs and symptoms of Gitelman syndrome?

The signs and symptoms of Gitelman syndrome typically mimic the effects of persistent thiazide diuretic use (e.g., hydrochlorothiazide). These may include increased thirst (i.e., polydipsia) and salt cravings, caused by increased sodium excretion. Individuals may also experience an increased frequency of urination (i.e., polyuria) or an increased urge to urinate at night (i.e., nocturia). In some rare cases, an individual may develop low blood pressure (i.e., hypotension) due to excess sodium excretion.

Other electrolyte abnormalities caused by Gitelman syndrome, such as hypokalemia and hypomagnesemia, may lead to muscle weakness or tetany (i.e., muscle cramping). In addition to these symptoms, individuals may also experience nausea, vomiting, and abdominal pain. In more rare situations, cardiac arrhythmias may occur due to electrolyte disturbances.

Symptoms typically first appear in adolescents and adulthood but may sometimes present as early as childhood.

How is Gitelman syndrome diagnosed?

Gitelman is diagnosed through a variety of methods. Initially, the individual’s medical history and a thorough review of symptoms will be used to narrow down the diagnosis. Due to the genetic nature of the disease, other family members may have similar symptoms or be previously diagnosed. A physical exam may then be performed to assess for muscle cramps and weakness. Blood work may show hypokalemia (i.e., low potassium), hypomagnesemia (i.e., low magnesium), hypochloremia (i.e., low chloride), and hypercalcemia (i.e., elevated calcium). In addition, hypocalciuria (i.e., low urinary calcium) and elevated urinary chloride would further support a diagnosis of Gitelman. Lab work may also show high levels of renin (i.e hyperreninemia) and high levels of aldosterone (i.e hyperaldosteronemia) due to the body’s compensatory responses. Often, diagnosis of Gitelman syndrome relies on excluding other possible causes. A definitive diagnosis of Gitelman syndrome requires performing genetic testing to show the specific gene mutations.

A common differential diagnosis is Bartter syndrome, which presents similarly to Gitelman. Both Bartter and Gitelman syndromes are classified as renal tubulopathies, or salt-wasting disorders, due to their impact on electrolyte reabsorption. Unlike Gitelman though, Bartter syndrome affects the sodium-potassium-chloride cotransporter at the thick ascending loop of Henle. Urinary and serum calcium levels may help to differentiate between Bartter and Gitelman syndromes. Bartter syndrome would cause elevated urinary calcium (i.e. hypercalciuria), whereas Gitelman would result in low urinary calcium (i.e. hypocalciuria) and elevated serum calcium (i.e. hypercalcemia).

How is Gitelman syndrome treated?

Due to the genetic nature of Gitelman syndrome, there are no curative treatment options and, currently, only management therapies are available. Gitelman syndrome may be managed by using potassium-sparing diuretics, such as amiloride or spironolactone. In most cases, potassium-sparing diuretics are administered in higher doses than would typically be used for other disorders. This can help to raise serum potassium, correct metabolic alkalosis, and reverse hypomagnesemia. Additionally, an individual may be placed on potassium, sodium chloride, and magnesium supplements.

What are the most important facts to know about Gitelman syndrome?

Gitelman syndrome, an autosomal recessive renal tubular disorder that affects the thiazide-sensitive sodium-chloride cotransporter, is a rare condition that occurs in 1 out of 40,000 individuals globally. Unlike other renal disorders, symptoms of Gitelman syndrome often begin in adolescence or adulthood. Gitelman syndrome causes electrolyte abnormalities, such as hypokalemia, hypomagnesemia, hypochloremia, and hypercalcemia. Individuals may experience muscle weakness, abdominal pain, nausea, excess thirst, salt cravings, and increased urinary frequency. In more severe cases, it may result in cardiac arrhythmias. Diagnosis of Gitelman is heavily reliant on labwork, accurate history, and physical examination as well as excluding other possible causes. However, in order to make a definitive diagnosis of Gitelman syndrome, genetic testing is necessary.

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