NORD gratefully acknowledges Philip J. Klemmer, MD, Professor of Medicine, Division of Nephrology and Hypertension, UNC School of Medicine for assistance in updating this report.
Gitelman syndrome, also known as familial hypokalemia-hypomagnesemia, is a rare genetic disorder in which there is a specific defect in kidney function. This defect impairs the kidney’s ability to reabsorb salt and causes changes in various electrolyte concentrations as well as contraction of extracellular fluid volume (thus causing symptoms of dehydration). The electrolytes affected are primarily mineral ions, specifically potassium, calcium, magnesium, sodium, and chloride. Fundamentally, like Bartter’s syndrome, Gitelman syndrome is a salt wasting nephropathy. The symptoms and severity of the disorder can vary greatly from one person to another and can range from mild to severe. For unknown reasons, the onset of symptoms is frequently delayed until the second decade of life. Symptoms and severity can even vary greatly among members of the same family. Common symptoms can include episodes of fatigue, muscle weakness, and muscle cramps sometimes accompanied by gastrointestinal problems such as abdominal pain, nausea and vomiting. Some individuals may need to urinate frequently and will pass a large volume of urine (polyuria). This symptom is the result of failure to fully concentrate urine in the face of dehydration. Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene and are inherited in an autosomal recessive manner.
Gitelman syndrome is often discussed along with Bartter syndrome, a group of several disorders characterized by similar defects in kidney function leading to volume depletion and similar symptoms as is seen in Gitelman syndrome. Sometimes known as a variant of Bartter syndrome, Gitelman syndrome can show significant overlap with Bartter syndrome type 3; in specific cases, it is extremely difficult to distinguish between these disorders. Some researchers believe it is better to consider the Bartter syndrome and Gitelman syndrome as a spectrum of disease rather than distinct disorders. These disorders may be broadly classified as renal tubulopathies (because certain small tubes within the kidneys are affected), salt-wasting disorders (because affected individuals excrete excess amounts of salt), salt-losing tubulopathies or channelopathies (because the ion channels in the kidneys are affected). Gitelman syndrome causes metabolic abnormalities resembling treatment with high dosage of thiazide diuretics while Bartter syndrome resembles treatment with high dosage of loop diuretics.
Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize Gitelman syndrome. These terms refer to findings on laboratory tests rather than specific symptoms. Such terms include low levels of potassium in the blood (hypokalemia), low levels of chloride in the blood (hypochloremia), excess alkaline levels in the body (metabolic alkalosis), low levels of magnesium in the blood (hypomagnesemia), low levels of calcium in the urine (hypocalciuria), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia). The latter two laboratory findings are appropriate regulatory responses to dehydration caused by salt wasting kidney.disease.
Gitelman syndrome usually becomes apparent anywhere from late childhood (usually over the age of six) to early adulthood. The disorder is highly variable, even among individuals in the same family. Some people do not develop any symptoms (asymptomatic), while others can develop chronic issues that can impact their quality of life.
Muscle weakness, spasms, and cramps may occur and generally are more common in Gitelman syndrome than the related Bartter syndrome. Affected individuals may experiences episodes of fatigue, dizziness, fainting (due to low blood pressure), muscle weakness, muscle aches, cramps and spasms. Affected individuals may also experience a specific form of cramping spasms called tetany. Tetany is marked by cramping spasms of certain muscles, particularly those of the hands and feet, arms, legs and/or face. Tetany may be provoked by hyperventilation during periods of anxiety.
Symptomatic episodes may also be accompanied by abdominal pain, vomiting, diarrhea or constipation, and fever. Vomiting or diarrhea in a patient with Gitelman syndrome may lead to the misdiagnosis of eating disorder or cathartic abuse as the cause of hypokalemia. Falsely accusing a patient with Gitelman or Bartter syndrome of these behaviors can cause loss of trust as well as adverse psychological and emotional consequences. Measurement of urinary chloride will help differentiate Gitelman syndrome (high urinary chloride) from hypokalemia resulting from GI fluid losses. (urine chloride < 10 meQ/L). Seizures may also occur and in some people may be the initial reason they seek medical assistance. A loss of sensation or feeling of the face (facial paresthesia) characterized by numbness or tingling is common. Less often, tingling or numbness may affect the hands. The severity of fatigue can vary widely. Some individuals are severely fatigued to the point where it interferes with daily activities; other individuals never report fatigue as a specific symptom.
Affected individuals may or may not experience excessive thirst (polydipsia) and a frequent need to urinate (polyuria) including the excessive need to urinate at night (nocturia). When these symptoms do occur they are usually mild. Blood pressure can be abnormally low (hypotension) in comparison to the general population. Affected individuals often crave salt or high-salt foods. Salt craving frequently begins in childhood and is helpful in making a correct diagnosis.
Some affected adults develop chondrocalcinosis, a condition characterized by the accumulation of calcium in the joints. Its development is thought to be related to hypomagnesemia. Affected joints may be swollen, tender, reddened, and warm to the touch. In some individuals, chondrocalcinosis and its complications are the only symptoms that develop.
Gitelman syndrome is generally considered to be a milder variant of Bartter syndrome, with symptoms often overlapping with Bartter syndrome type 3 (classic Bartter syndrome). Renal salt wasting is more severe and begins earlier in life in Bartter syndrome than in Gitelman syndrome. However, researchers have determined that in rare cases more severe complications can occur in the newborn (neonatal) period. In these cases, affected infants experience severe hypokalemia and hypomagnesemia, which can be associated with an increased need to urinate and passage of large amounts of urine (polyuria), diminished muscle tone (hypotonia), muscle spasms, growth delays and a failure to grow and gain weight as would be expected based on age and gender (failure to thrive). Earlier-onset, more severe cases have occurred in greater frequency in male infants than female infants.
In affected individuals who experience significant electrolyte imbalances, irregular heartbeats (cardiac arrhythmias) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death. These cardiac issues result from a prolonged QT interval. The QT-interval is measured on the electrocardiogram and, if prolonged, indicates that the heart muscle is taking longer than usual to recharge between beats.
Some affected individuals may develop the breakdown of muscle tissue causing the release of toxic content of muscle cells into the body fluids (rhabdomyolysis). Rhabdomyolysis is a serious condition that can potentially damage the kidneys. Additional symptoms have been reported in the medical literature but are quite rare. These symptoms include blurred vision, vertigo, and an impaired ability to coordinate voluntary movements (ataxia). A study from Yale indicated that Gitelman and Bartter syndrome have significant impact to quality of life (Cruz D et al., 2001).
In a study of a series of individuals with Gitelman syndrome (Berry et al. 2013), it was determined that affected individuals can develop abnormally high blood pressure (hypertension) later during life (median 55 years of age). This is counterintuitive in a salt-wasting disorder that can cause low blood pressure earlier in life. The exact reason for the development of hypertension is unknown, but may be related to prolonged exposure to renin and aldosterone levels (see Causes section below) and often occurs in the presence of traditional risk factors for hypertension. Some women have experienced severe potassium wasting during pregnancy and have required increased potassium and magnesium supplementation.
Most cases of Gitelman syndrome are caused by mutations in the SLC12A3 gene. In a minority of cases, mutations in the CLCNKB gene cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or not inserted in a tubule membrane properly. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of Gitelman syndrome, defective protein structure causes failure to reclaim filtered sodium and chloride (channelopathy). More severe salt wasting is caused by a defect in a different channel in Bartter syndrome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
The SLC12A3 gene that causes the majority of cases of Gitelman syndrome produces (encodes) a protein known as thiazide-sensitive NaCl cotransporter (NCC), which helps to transport salts through ion channels in the kidney. Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions, which include electrolytes such as potassium and sodium ions, in certain structures of the kidneys. Mutations in this gene result in abnormal functioning of the NCC protein that transports electrolytes through the ion channels. This abnormal functioning or channel inception in the tubular membrane prevents sodium and chloride (salt) from being reabsorbed (reclaimed) from the distal renal tubule. This causes salt and water wastage (negative balance) and results in volume depletion (dehydration). The kidney attempts to attenuate dehydration by activating the renin angiotensin aldosterone system (RAAS). Hypokalemia is the adverse consequence of RAAS activation. Because salt balance can never be fully achieved; the hypokalemia in Gitelman syndrome can only rarely be corrected.
The human kidney filters 180 liters of serum each day through selective filtration in glomeruli. All but 1-1.5 liters of this glomerular filtrate is selectively reclaimed) by renal tubules including the distal convoluted tubule (which functions abnormally in Gitelman syndrome) and the thick ascending limb (which functions abnormally in Bartter syndrome). Both abnormalities cause salt wasting and, in turn, symptoms related to dehydration as well as those due to secondary electrolyte disturbances (hypokalemia and hypomagnesemia.)
Gitelman syndrome affects males and females in equally. The disorder occurs in approximately 1 in 40,000 Caucasian individuals. However, many cases of these disorders may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of Gitelman syndrome in the general population. The prevalence of individuals with one mutated copy of a gene (known as heterozygotes or carriers of the disease) is approximately 1% of European populations. These heterozygotes may enjoy a benefit of a small degree of salt wasting: they have lower blood pressures than the general population.
A diagnosis of Gitelman syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected after other more common causes of hypokalemia and metabolic acidosis are ruled out.
Clinical Testing and Workup
Laboratory tests that are used to diagnose Gitelman syndrome include blood tests to determine serum electrolyte levels, specifically low serum concentrations of magnesium and potassium and/or elevated serum concentrations of renin, and aldosterone. Urine electrolyte measurement seeks to determine the presence inappropriately high urine potassium in the face of hypokalemia. Low urine chloride should always suggest GI losses from vomiting and/or diarrhea. Low urinary calcium is comparable with a diagnosis of Gitelman syndrome. Hypertension in a hypokalemic patient who is not taking diuretics should always suggest primary hyperaldosteronism, not Gitelman or Bartter syndromes.
Molecular genetic testing can confirm a diagnosis of Gitelman syndrome. Genetic testing can detect mutations in the specific genes known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Generally, genetic testing is not needed to make a diagnosis.
The treatment of Gitelman syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, kidney specialists (nephrologists or pediatric nephrologists), cardiologists, social workers and other healthcare professionals may need to systematically and comprehensively plan individual’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Because this is a rare disease, even well trained private practice or academic nephrologists may have little experience diagnosing or treating this disease.
Individuals who do not develop symptoms (asymptomatic) often do not require treatment, but it is recommended that they receive outpatient monitoring one or twice a year. They should be aware that they will be prone to rapidly become dehydrated should they experience vomiting or diarrhea from GI illness. They may require saline and intravenous potassium supplementation during these illnesses. All individuals with Gitelman syndrome are encouraged to follow a high-sodium chloride added diet. Dietary potassium should also be high. Dried fruit is an excellent source of supplemental potassium. Such a diet can help reduce exposure to potassium chloride supplements which irritate the stomach lining. These patents should never be treated with ACE inhibitors or ARBs.
There is no cure for Gitelman syndrome. The mainstay of treatment for affected individuals is a high salt diet with oral potassium and magnesium supplements. Potassium rich foods such as dried fruit are helpful. Magnesium supplements in single large doses cause diarrhea and should be avoided. Magnesium supplements should be taken in small frequent (4-6 times/ day) in order to avoid magnesium associated diarrhea which may worsen hypokalemia and symptoms of volume depletion. For many individuals, lifelong daily supplementation with magnesium is recommended. In some cases, during severe muscle cramps, magnesium has been given intravenously. In general, the goal of therapy should always be attenuation of symptoms rather than normalization of electrolyte abnormalities. Because of the risk of infection and thrombosis, central catheters should be discouraged.
Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone, eplerenone or amiloride. These drugs are mild diuretics that spare potassium excretion. While these agents improve hypokalemia, they rarely normalize serum potassium concentrations. The goal of therapy is to improve symptoms not to normalize laboratory abnormalities. When chondrocalcinosis causes symptoms, supplementation with magnesium, pain medications and/or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may be beneficial.
A specific nonsteroidal anti-inflammatory drug (NSAID) known as indomethacin has been used to treat some infants and children with Gitelman syndrome. This drug is commonly used to treat individuals with Bartter syndrome, but is being used more often in Gitelman syndrome, particularly to treat growth deficiency in severe, early-onset forms of the disorder.
Affected individuals may be encouraged to undergo a cardiac workup to screen for risk factors for cardiac arrhythmias. Individuals with a prolonged QT interval should avoid drugs that prolong the QT interval. For a list of such drugs, contact the Sudden Arrhythmia Death Syndromes Foundation.
Finally, the initial report of two patients with Gitelman syndrome by Hillel Gitelman and associates at the University of North Carolina at Chapel Hill in 1966 opened the door to understanding the role of the kidney’s handling of salt in not only rare genetic diseases but more importantly in high blood pressure which effects millions of people world- wide. Dr. Gitelman showed that a well- studied orphan disease can open our eyes to more wide spread health issues. (http://www.sads.org/).
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