June 25, 2019
Years published: 1988, 1989, 1995, 1997, 1999, 2006, 2007, 2016, 2019
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. 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 as listed above. 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 were sometimes also called hyperprostaglandin E syndromes because they are associated with elevated levels of compounds known as prostaglandins, which act as signaling molecules in our body. Bartter syndrome type 3 is sometimes also referred to as classic Bartter syndrome. Gitelman syndrome, which has considerable clinical overlap with Bartter syndrome, especially type 3, is sometimes grouped with the Bartter syndromes. NORD has a separate report on Gitelman syndrome.
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 (before birth) age of onset and more severe symptoms. Bartter syndrome type 3 can also present before birth, but usually with milder symptoms (see below) and many patients with this subtype present in infancy or early childhood with growth problems. 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).
Symptoms can vary substantially. 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.
A special form is Bartter type 5: it manifests with excess amniotic fluid (polyhydramnios), that is typically severe leading to premature birth. In some instances, prematurity is so early that the baby is not viable outside the mother’s womb. Yet, within weeks of being born all the kidney symptoms of high urine output and electrolyte loss resolve spontaneously without any need for treatment. The gene underlying this condition is on the X-chromosome, so Bartter syndrome type 5 occurs predominantly in boys.
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, severe complications, such as irregular heartbeats (cardiac arrhythmias) or muscle weakness (paralysis) may develop. Although rare, if untreated, these cardiac arrhythmias can potentially progress to cause sudden cardiac arrest and potentially sudden death.
Patients with Bartter syndromes type 1 and 2 typically have elevated levels of calcium in the urine which can lead to the deposition 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 may 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. This is likely related to the degree of prematurity.
Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the CLCNKB gene (type 3), the BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B). 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 syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.
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 abnormal copies of a gene, one from each parent. If an individual inherits one normal copy and one copy 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.
This is however different for the X-linked Bartter syndrome type 5, as a boy only has one X-chromosome, which he inherits from the mother. If the mother is a carrier for a mutation in MAGED2, then there is a 50% risk that she passes this on to her children. If she passes it on to a daughter, then she will be a carrier, as well, as a daughter also inherits a normal copy of MAGED2 on the X-chromosome she receives from the father. But if she passes it on to a boy, then he will be affected, as he does not have a second normal copy, for he receives the Y-chromosome from the father. Very rarely, girls who are carriers can also have disease manifestations, but it is typically much milder than in boys.
Most of the genes involved in Bartter syndrome produce (encode) proteins that are required for the proper 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 nerve firing, 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 functional units of the kidneys and there are roughly a million of these in our kidneys. Each nephron consists of a glomerulus and a renal tubule. The glomeruli filter the blood and in an adult create a primary urine volume of about 100 ml/min (or roughly 150litres per day). This is called the glomerular filtration rate (GFR). The renal tubule then reabsorbs most of this filtrate, including electrolytes such as sodium, chloride and potassium back into the blood to ensure that not too much is lost through the urine. The renal tubule contains four main segments known as the proximal convoluted tube, the loop of Henle, the distal convoluted tube (DCT), and the collecting duct. Bartter syndrome is primarily a disorder in the loop of Henle, but the distal convoluted tubule can also be affected in some subtypes.
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 segment of the distal nephron does not function properly, others try to compensate. An important segment for compensation is the collecting duct, where especially the sodium that has not been reabsorbed upstream is taken up, but this occurs in exchange for potassium and acid. It is this compensation that generates the typical electrolyte abnormalities of Bartter syndrome, the low potassium and the alkalosis (lack of acid).
Mutations in the genes involved in Bartter 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, and it is this balance which is critical for the normal functioning of our 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 100,000 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 potassium, chloride, bicarbonate, magnesium, renin, and aldosterone levels and urine tests to determine the presence of prostaglandin E2 and urine electrolytes, including sodium, chloride, potassium, calcium and magnesium.
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) and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended 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 typically includes sodium and potassium chloride supplementation to help correct electrolyte imbalances. Potassium chloride supplementation is preferred to other forms of potassium salts because of the corresponding chloride deficiencies. Some infants with severe, life-threatening loop disorders (antenatal Bartter syndromes) may require intravenous salt and water replacement. Because the elevated levels of prostaglandins aggravate the polyuria and electrolyte abnormalities, treatment typically includes a drug that decreases the production of these such as indomethacin, ibuprofen or celecoxib. These drugs are also called nonsteroidal anti-inflammatory drug (NSAID). Indomethacin has generally been used and shown to be effective in individuals with Bartter syndromes, but can have severe side effects, especially in premature babies with regards to perforation in the intestinal tract, especially the stomach. If used, it is recommended to do so in combination with a stomach acid blocker. Newer forms of NSAID, such as celecoxib (also called “COX2 inhibitors”) have a much lower risk of these intestinal side effects and have also been shown to be effective in Bartter syndrome, but there is less experience in their use. With increasing age, Bartter syndrome tends to get easier to manage and control. The most difficult period is usually the first year(s) of life. As there is also concern that long-term use of NSIAD may affect kidney function, these medications often get reduced or weaned off over the years.
Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone or amiloride. These drugs increase the excretion of sodium in urine, but retain potassium and acid thereby improving low potassium levels in the blood (hypokalemia) and alkalosis. Yet, because they worsen the loss of sodium, they risk low blood pressure and potentially even collapse (hypovolemic shock) and it is usually recommended to take these together with adequate sodium chloride supplementation.
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 and acid loss. But, like the potassium-sparing diuretics, they may dangerously lower blood pressure, which may already be low in individuals with Bartter syndromes, and can potentially impact kidney and cardiovascular function. Thus, their use should be carefully considered and monitored and the drugs must be stopped, if the patient has additional salt losses, e.g. from diarrhea and/or vomiting.
Successful use of growth hormone therapy has been reported in some cases for the treatment of growth retardation and short stature potentially associated with Bartter syndrome.
Especially in Bartter syndrome type 3, magnesium supplementation may be used to treat muscle spasms or tetany.
Adequate salt and water intake is necessary. Affected individuals typically have a large appetite for salt due to salt cravings and should be encouraged to indulge in salty foods.
Affected individuals may also 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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