NORD gratefully acknowledges Detlef Bockenhauer, MD, PhD, Prof. of Paediatric Nephrology, UCL Centre for Nephrology, Honorary Consultant Great Ormond Street Hospital for Children NHS Foundation Trust, London, England, for assistance in the preparation of this report.
Bartter syndrome is a general term for a group of rare genetic disorders in which there are specific defects in kidney function. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, calcium, magnesium, sodium, and chloride. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. Age of onset of overt symptoms can range from before birth to adulthood. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Most subtypes of Bartter syndrome are inherited in an autosomal recessive manner. Treatment is aimed at correcting the electrolyte imbalances through the use of supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs) and diuretics.
Bartter syndrome was first described in the medical literature in the 1960s by Dr. Frederic Bartter. Through the years, different terminology has been used to describe these disorders. Some researchers classify these disorders based on their clinical appearance, while others classify them based on the underlying mutated gene. The different terminology and classification systems can be confusing. Bartter syndrome can be variably classified as a renal tubulopathy (because certain small tubes within the kidneys are affected), a salt-wasting disorder (because affected individuals excrete excess amounts of salt), a salt-losing tubulopathy, and a channelopathy (because the ion channels in the kidneys are affected). Although Bartter syndrome can be broken down into subtypes based on the underlying gene or symptomatology, considerable overlap of symptoms and disease presentation exists among the subtypes and Bartter syndrome may be best thought of as spectrum of disease caused by several different gene mutations. The most common classification system for these disorders is based upon the underlying genetic mutation: Batter syndrome type 1, type 2, type 3, type 4a and 4b as well as Gitelman syndrome. The term antenatal (before birth) Bartter syndrome refers to those cases who present before birth and is typically associated with types 1, 2, 4a and 4b. These disorders are also known as hyperprostaglandin E syndromes because they are associated with elevated levels of fatty compounds known as prostaglandins. Bartter syndrome type 3 is also known as classic Bartter syndrome. Gitelman syndrome, which has considerable clinical overlap with Bartter syndrome type 3, is often grouped with the Bartter syndromes. NORD has a separate report on Gitelman syndrome. A new classification system classifies these disorders based upon the specific part of the kidney that is affected. This includes three subtypes – loop disorders (affecting the loop of Henle); DCT disorders (affecting the distal convoluted tube; and combined loop/DCT disorders. (For more information on these kidney structures see the Causes section below.) Loop disorders include Bartter syndromes type 1 and 2. DCT disorders includes Gitelman syndrome. Loop/DCT disorders include Bartter syndrome types 3, 4a and 4b.
The age of onset, severity and specific symptoms associated with Bartter syndrome can vary greatly from one person to another, even among individuals who have the same subtype. Some individuals may have mild cases; others may experience severe, potentially life-threatening complications, at birth.
Generally, Bartter syndromes types 1, 2, 4a, and 4b are associated with an early age of onset and more severe symptoms. Bartter syndrome type 3 and Gitelman syndrome generally have milder symptoms and a later age of onset. However, this is not a universal, absolute rule and exceptions exist. Therefore, affected individuals may not have all of the symptoms discussed below and certain symptoms, which are more prevalent with one subtype of Bartter syndrome, can occur in another subtype. It is important to note that every case is unique and will follow its own course.
Most medical sources will use specific terminology to describe the electrolyte imbalances that characterize the Bartter syndromes. 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), high levels of renin in the blood (hyperreninemia), and high levels of aldosterone in the blood (hyperaldosteronemia).
Classic Bartter syndrome and Gitelman syndrome (DCT disorders types 1 and 2) usually present in school age or adolescence. Some affected individuals may only have mild symptoms. Common symptoms include muscle weakness, cramping, spasms and fatigue. Excessive thirst (polydipsia), excessive urination (polyuria), and the need to urinate at night (nocturia) may also occur. Despite excessive fluid intake, frequent urination can lead to dehydration. Some children may crave salt. Additional symptoms that may occur include constipation, vomiting, elevated body temperature, lethargy, and a general feeling of poor health.
As children grow older, their growth rate may be below what would be expected based upon their age and gender (growth retardation). If left untreated, affected individuals may be shorter than would be expected as adults (short stature). Some children may experience delays in the reaching developmental milestones (developmental delays).
The signs and symptoms of the antenatal Bartter syndromes, also known as Bartter syndromes 1 and 2 and Bartter syndromes 4a and 4b, can be seen before birth (antenatal period). Abnormal kidney function in utero can lead to excessive urine production and an abnormal buildup of amniotic fluid around the developing fetus (polyhydramnios). Birth is often premature. In the newborn period, affected infants may experience excessive urination (polyuria) and life-threatening episodes of fever and dehydration. Vomiting and diarrhea may also occur.
Some affected infants may have characteristic facial features including a triangularly-shaped face, prominent forehead, large eyes, prominent, pointed ears, and a “pouting” expression because of drooping of the corners of the mouth. In some cases, these distinctive features may be absent or so mild as to go unnoticed. Affected infants may fail to grow and gain weight as would be expected based upon age and gender (failure to thrive). Growth delays and growth retardation may be seen as affected children age, and final adult height may be shorter than would otherwise be expected (short stature).
In some 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.
Some infants and children may develop excess levels of calcium in the kidney (nephrocalcinosis). In mild cases, there may not be any associated symptoms or minor symptoms including blood in the urine, vomiting, or fever. Affected individuals may pass stones made up of calcium. Calcium buildup (calcification) in the kidneys can eventually affect kidney function.
In Bartter syndrome types 4A and 4B, affected infants cannot hear from birth due to an impaired ability of the auditory nerves to transmit sensory input to the brain (congenital sensorineural deafness). In some cases, cognitive and motor development is also affected and affected children may experience delays in reaching certain developmental milestones.
Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the ClC-Kb gene (type 3), the BSND gene (type 4A), or both the ClC-Ka and CIC-Kb genes (type 4B). Gitelman syndrome is caused by mutations in the SLC12A3 gene. 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Bartter and Gitelman syndrome are inherited in an autosomal recessive manner.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females.
Most of the genes involved in Bartter syndrome produce (encode) proteins that are required for the proper health and function of the kidneys. One of the different functions of the kidney is maintaining a specific volume and composition of body fluids through the reabsorption of salts and minerals that conduct electrical impulses in the body (electrolytes). Electrolytes are necessary for various functions in the body including muscle contraction, energy generation, and most major biochemical reactions in the body. The kidneys maintain electrolyte balance by filtering the blood. Hair-sized structures called nephrons are the basic filtering units of the kidneys and filter blood from the urine. Each nephron consists of a glomerulus and a renal tubule. The renal tubule reabsorbs electrolytes such as sodium, chloride and potassium into the blood to ensure that not too much is lost through the urine. The renal tubule is broken down into four parts known as the proximal convoluted tube, the loop of Henle, the distal convoluted tube (DCT), and the collecting duct. In Bartter and Gitelman syndromes the loop of Henle and/or the distal convoluted tubule are affected by the disorder.
The loop of Henle accounts for a significant percentage of the salt and mineral reabsorption in the body. It also plays a role in urine concentration. The DCT plays a lesser role in salt reabsorption and also has a role in functions necessary to maintain chemical balance in the body (e.g. potassium secretion). When one part of the distal nephron does not function properly, another part can compensate. The severity of loss of function in the loop of Henle and/or the DCT determines how the kidneys can adapt to compensate.
Mutations in the genes involved in Bartter and Gitelman syndrome result in abnormal functioning of the ion channels or proteins involved in the transport of electrolytes back into the bloodstream. This abnormal functioning prevents sodium and chloride (salt) from being reabsorbed from the urine. This causes too much salt and water to be expelled from the body through the urine. In turn, either directly or indirectly, other electrolytes such as potassium, magnesium, and calcium are also affected. Thus, the proper balance of electrolytes in the body is disrupted, which can cause the body to try and compensate by producing other substances (e.g. certain hormones and proteins such as aldosterone and renin) leading to excess levels of those substances and further upsetting the electrolyte, fluid and hormonal balances in the body. These imbalances ultimately lead to the various symptoms of the Bartter syndromes.
The Bartter syndromes affect males and females in equal numbers. They are estimated to affect approximately one in 1,000,000 people in the general population. However, many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Bartter syndromes can occur in individuals of any race or ethnic background.
A diagnosis of one of the Bartter syndromes is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Workup
Laboratory tests that are used to diagnose these disorders include blood tests to determine serum electrolyte levels, specifically magnesium, renin, and aldosterone levels and urine tests to determine the presence of prostaglandin E2 and urine electrolytes, including elevated levels of sodium and potassium.
The antenatal subtypes of Bartter syndrome can be diagnosed before birth (prenatally) when polyhydramnios is detected without the presence of associated congenital malformations, and elevated levels of chloride and aldosterone are detected in the amniotic fluid.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in specific genes known to cause the Bartter syndromes, but is only available as a diagnostic service at specialized laboratories.
The treatment of the Bartter syndromes 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), social workers, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
There is no cure for these disorders, which require lifelong administration of certain supplements and medications. The mainstay of treatment is restoring the proper balance of fluids and electrolytes in the body. This includes potassium chloride supplementation to help correct electrolyte imbalances. Potassium chloride supplementation is preferred to salt supplementation because of the corresponding chloride deficiencies. Some infants with severe, life-threatening loop disorders (antenatal Bartter syndromes) may require salt and water replacement via a central vein catheter. Because aggressive fluid replacement may worsen polyuria, treatment with a drug that prevents the production of prostaglandin 2 such as indomethacin.
Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID). This drug reduces prostaglandin levels in the body, thereby reducing excess urine production and the need for potassium supplements. Indomethacin has generally been effective and well tolerated in individuals with Bartter syndromes.
Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone or amiloride. These drugs increase the excretion of water in urine, but retain potassium preventing potassium (hypokalemia). They have not always proven effective in treating hypokalemia and they may worsen the loss of salt in the body (renal salt wasting).
Drugs that inhibit or block the renin-aldosterone-angiotensin system (RAAS inhibitors) have been used to treat individuals with Bartter syndromes in addition to other therapies (adjunct therapy). RAAS inhibitors include aldosterone antagonists, angiotensin II receptor blockers, and angiotensin-converting enzyme (ACE) inhibitors. These drugs can prevent the secretion of aldosterone from the adrenal glands and counteract the effects of renin on the kidneys, thereby reducing potassium loss. Use of these drugs needs to be monitored because they may lower blood pressure, which may already be low in individuals with Bartter syndromes, and can potentially impact kidney and cardiovascular function.
Growth hormone therapy has been successful for the treatment of growth retardation and short stature potentially associated with Bartter syndrome.
In some cases, calcium and/or magnesium supplementation is required to treat muscle spasms or tetany.
Adequate salt and water intake is necessary. Affected individuals have a large appetite for salt due to salt cravings. Affected individuals may be encouraged to eat foods that are high in potassium.
Cochlear implants can be used to treat deafness associated with Bartter syndromes type 4A and 4B.
In stressful situations, blood electrolytes can change rapidly, require prompt intravenous treatment. Stressful situations can include surgical procedures, trauma, and the presence of another type of disease or infection (intercurrent disease).
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