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Bartter syndrome and Gitelman syndrome

This is part of Rare diseases.

Diagnosis: Bartter syndrome and Gitelman syndrome

Synonyms: Primary renal tubular hypokalemic alkalosis, Hyperprostaglandin E syndrome, Familial hypokalemia-hypomagnesemia

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Date of publication: 2012-06-19

ICD 10 code

Version: 1.0

Bartter syndrome E26.8
Gitelman syndrome E83.4

The disease

Bartter syndrome and Gitelman syndrome are associated as they both concern hereditary changes in the ability of the kidneys to control the salt balance in the body. The syndromes are closely related but symptoms vary widely. There are four types of Bartter syndrome. The most serious forms of the syndrome are associated with serious symptoms requiring intensive medical interventions. However, most people with Gitelman syndrome and some people with the milder forms of Bartter syndrome are not significantly affected by their conditions.

Bartter syndrome was first described by American physician Frederic Bartter in the early 1960s. He described two children with delayed motor and intellectual development, impaired growth, severe thirst and impaired fluid balance. At the end of the 1970s it was understood that the cause of the disease was the kidneys’ impaired ability to retain salt. It was established shortly afterwards that some children were affected before birth while others were affected later and less severely. In 1966, American physician Hillel J Gitelman described the condition to which he gave his name after he had examined two adult sisters with potassium and magnesium deficiencies.

Occurrence

Bartter and Gitelman syndromes are equally rare, with an incidence of one or two per 100,000 inhabitants, indicating that there are between 100 and 200 individuals with the disease in Sweden. Bartter syndrome and Gitelman syndrome are found all over the world.

Cause

The cause of Bartter and Gitelman syndromes is a mutation in one of the genes controlling the production of (coding for) certain proteins which form a constituent part of ion channels. These ion channels manage the transport of sodium, potassium and chloride ions across cell membranes. (See figure 1.) Bartter syndrome is divided into types 1, 2, 3 and 4 depending on the protein which is affected. Genes mutated in Bartter syndrome types 1, 2, 3 and 4 are SLC12A1 (15q15-21), KCNJ1 (11q21-25), CLCNKB (1p36) and BSND (1p32.1) respectively. People with types 2 and 4 have similar symptoms and are described together in the”Symptoms” section. The same applies to types 1 and 3, which also resemble each other. The protein affected in Bartter type 4 also plays a role in the development of the inner ear, so a child with this type of the disease is born deaf.

Figure: Ion channels

Figure 1: Ion channels

The kidneys have many functions. They remove impurities from the blood, regulate blood pressure and maintain balances in the body’s levels of water, salts and trace elements. Each kidney is made up of approximately one million functional units named nephrons. A nephron consists of a network of blood capillaries (glomerulus, plural glomeruli) and a system of tubules. The glomeruli filter blood so that blood cells and blood proteins remain in the blood vessels while most of the fluid, containing salts and trace elements, is released into the tubules. Primary urine is processed in the tubules, where all products not treated as impurities are reabsorbed by the blood vessels. (See figure 2.) If tubules did not function, an adult would need to excrete approximately one hundred litres of urine per day and salt levels in the body would become uncontrolled, with life-threatening consequences.

Figure 2: Cross-section of the kidney.

Figure 2: Cross-section of the kidney.

Sodium and potassium are essential elements for the body. One important function of the kidneys is to ensure that excessive amounts of sodium are not released into the urine since sodium levels regulate fluid levels in the body. The hormones renin and aldosterone help by ensuring that sodium is reabsorbed from primary urine while potassium is excreted in urine. Potassium causes urine to be acidic, which makes the blood more alkaline (with raised pH levels). Levels of other substances in the body, including calcium and magnesium, are also controlled by the tubules of the kidneys. How much of these substances is retained, or lost in the urine, is regulated by sodium levels.

In both Bartter and Gitelman syndromes the ability to reabsorb sodium from primary urine is impaired, as mid-portions of tubules do not function normally. To some extent this is compensated for by increased production of renin and aldosterone, hormones which cause the latter portion of the tubules to absorb more sodium and excrete more potassium and acid in the urine. The consequence is that blood pH levels tend to rise and the kidneys’ ability to concentrate urine becomes impaired. Both diseases are characterised by varying degrees of potassium deficiency, excessive thirst, raised urine production and elevated blood pH levels. Calcium and magnesium balances are also affected.

Recently it has becomes possible to identify how different types of Bartter and Gitelman syndromes are associated with the impaired functionality of specific proteins in the kidneys. It is now also possible to identify the genetic mutations which cause changes in specific proteins.

The cause of the delayed motor and cognitive development of many children with Bartter syndrome, particularly type 4, is not fully understood. One possible cause is that the protein affected plays a role in the nervous system. In addition, a difficult neonatal period may negatively influence a child’s future development.

Gitelman syndrome is caused by a mutation in gene SLC12A3, which is located on chromosome 16 (16q13).

Heredity

The inheritance pattern of both Bartter syndrome and Gitelman syndrome is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent), in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

In Bartter syndrome types 2 and 4, symptoms present at birth, indicating a severe form of the disease. In types 1 and 3 symptoms usually manifest during early childhood and in isolated cases may be scarcely noticeable. Not every individual with Gitelman syndrome experiences symptoms. When symptoms do manifest, they usually do so in the teens.

Bartter syndrome types 2 and 4

Children with these syndrome types have impaired pre-natal kidney function. Reduced kidney function results in increased urine production, leading in turn to excessive amounts of amniotic fluid. Birth is often premature, which in itself is associated with increased risks to the child. During the first days and weeks of life, the child loses excessive amounts of fluid and salts. If these fluids and salts are not replaced there is a risk of cardiac arrhythmia or serious dehydration.

Some children with Bartter syndrome have characteristic facial features including a broad forehead and large eyes and ears.

Anomalies in fluid and salt balances are life-long, causing children and adults with the syndrome to urinate and drink excessively. In some people, especially those with Bartter syndrome type 4, there is a risk that the kidneys’ ability to remove impurities from the blood will gradually decline, leading to renal insufficiency. Renal insufficiency may start in the neonatal period or during early childhood; it may be moderate or so severe that the child requires dialysis or a kidney transplant. The severity of renal insufficiency determines the severity of the associated conditions, which include restricted growth, anaemia and calcium imbalances.

The impaired ability to concentrate urine leads to excessive thirst and a risk of dehydration. Dehydration can cause constipation or feverish episodes. In type 2, the child often has elevated levels of calcium in the urine, which many cause calcification in the kidneys. This has a negative effect on kidney function.

In type 4, cognitive and motor development are primarily affected. They result in the child learning to stand, walk and talk later than other children. In this type of the disease the child is deaf from birth.

Growth is often impaired and it is common for children with types 2 and 4 to be short as adults, particularly if they develop renal failure.

Bartter syndrome types 1 and 3

In types 1 and 3 symptoms usually present during the first years of life, but sometimes onset is later. Some people with these types have only mild symptoms.

The most common symptoms are increased thirst and urine production. Children often wish to drink large quantities at frequent intervals throughout the day. They urinate excessively, which increases the risk of dehydration. Signs are constipation, feelings of sickness, vomiting and elevated body temperature. Many children also crave salt.

Growth is often delayed when compared to a normal growth curve, which may become apparent during the child’s first year. Older children often experience muscle pain, muscle weakness and tiredness. Puberty may be delayed.

In type 1 in particular, there is a risk of calcification in the kidneys, which may lead to kidney stones and impaired kidney function.

Gitelman syndrome

Not every individual with Gitelman syndrome experiences symptoms. Those who develop symptoms usually do so in their teens. Periodically recurring episodes of muscle weakness and muscle cramps are common, sometimes combined with abdominal pains and feelings of nausea. Muscle symptoms are the result of magnesium deficiency and are usually most troublesome when associated with stomach problems, as magnesium is lost through vomiting and diarrhoea. Another common symptom is a transient loss of feeling in the face. Some people with Gitelman syndrome feel generally tired or tire easily. Growth and development are normal and thirst is often no more pronounced than in healthy individuals.

Adults with the condition may be affected by swollen and tender joints as a result of chondrocalcinosis (false gout), caused by the deposit of calcium crystals in the joints.

Diagnosis

Bartter and Gitelman syndromes are associated with potassium deficiency and elevated pH levels in the blood. Urine contains high concentrations of sodium and potassium. Levels of hormones renin and aldosterone are often elevated. A DNA analysis can usually confirm the diagnosis.

Carrier diagnosis, pre-natal diagnosis and embryo diagnosis are all possible if the mutation in the family has been identified.

Bartter syndrome types 2 och 4

Blood and urine levels of potassium, sodium and chloride are abnormal, with high levels in the urine and low levels in the blood. Abnormal levels can be measured during the neonatal period. The exception occurs in type 2, where potassium levels in the blood may be extremely high during the first week of life. Calcium levels in urine can also be high, mainly in type 2. Already in the neonatal period auditory tests can establish that a child with type 4 is deaf. The presence of calcium deposits in the kidneys can be established with the help of an ultrasound examination. Renal insufficiency is diagnosed with the help of blood tests and clearance tests. (A creatinine clearance test is used to help evaluate the rate and efficiency of kidney filtration.)

Bartter syndrome types 1 och 3

People with types 1 and 3 of the syndrome show the same abnormal values in blood and urine as people with types 2 and 4, but symptoms present later. Increased amounts of calcium are excreted in the urine, although renal failure occurs only in exceptional cases. The excretion of calcium seldom causes calcium deposits or kidney stones.

Gitelman syndrome

In Gitelman syndrome abnormalities in the pH levels of the blood can be mild, and may only be detected after repeated tests. However, potassium levels may be lower than normal and blood magnesium levels are often very low. Urine samples reveal that abnormally large amounts of magnesium are being excreted in the urine. Approximately half of all people with Gitelman syndrome have minor changes in the electrical conduction of the heart (due to electrolyte imbalance), which can be established in an electrocardiogram (ECG).

Treatment/interventions

Bartter syndrome types 2 and 4

In the neonatal period it is essential to replace fluids and salts which have been lost in the urine and to monitor the child carefully to ensure that neither serious dehydration nor salt imbalance occurs. Apart from breast milk, additional fluid is given either intravenously, or via a thin tube through the nose directly into the stomach. It is usually necessary to give supplementary sodium and potassium. Initially, they are often given intravenously, but subsequently are administered by mouth several times a day. Appropriate dosage causes no side effects while a potentially life-threatening salt imbalance is prevented.

Neonates with type 2 may, at times during the first week of life, have extremely high levels of potassium and may require medication to reduce the risk of serious cardiac arrhythmia. After this period these children require daily potassium supplements.

As neonates, children with types 2 and 4 require careful monitoring at a hospital. Blood tests are taken daily, the heart is monitored by ECG and volumes of fluid ingested and excreted are measured. Children are usually premature and need extra care and monitoring to prevent complications associated with under-developed organs.

Sometimes medication such as indometacine, which inhibits prostaglandin production, reduces excessive urine production and the need for potassium supplements. Side effects may include nausea and the erosion of the mucus membrane of the stomach, causing dyspepsia and stomach ulcers.

ACE (angiotensin converting enzyme) inhibitors, a medication affecting blood pressure, can also reduce potassium loss by counteracting the effect of renin on the kidneys.

Despite potassium supplements, it is often not possible to achieve normal potassium blood levels, and levels just below normal are acceptable. This treatment does not usually entail risk as long as the child does not suffer from diarrhoea or vomiting, or takes medication affecting the electrical conduction of the heart. Some children also require magnesium supplements.

As people with Bartter syndrome are always at risk of dehydration causing serious deficiencies in salt levels, it is important they seek medical assistance if they experience gastrointestinal problems, and they should ensure their fluid intake is adequate.

Patients affected by renal insufficiency require further medication and treatment. The amount of medication depends on the degree of insufficiency.

In type 4, deafness in children can be treated with a cochlear implant inserted into the skull under the skin behind the ear. A cochlear implant transmits signals directly to the auditory nerve. In this way, an otherwise completely deaf child can begin to hear and then often learns to speak. Children usually have the procedure at approximately one year of age. It is important to offer complementary communication methods, including sign language.

In order to stimulate the child’s development and help compensate for loss of function, some children with type 4 require early habilitation. It is important the child has contact with a habilitation team with expertise in auditory impairments as well as knowledge of the way deafness affects interaction with, and participation in, community and social life. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Measures may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information on support offered by the local authority, and advice on adapting accommodation and other environments. The family may also need help in coordinating different forms of assistance.

Habilitation plans are based on existing needs. For children with type 4, a functioning form of communication is a priority, as this is a pre-condition for the child’s successful development.

Continued habilitation may be required into adulthood, depending on the needs of the individual.

Bartter syndrome types 1 and 3

People with types 1 and 3 require daily potassium supplements. Many also require additional sodium, and they are at risk of dehydration if they do not drink sufficient fluids. As with other patients with Barrter syndrome, it is not always possible to maintain normal levels of potassium. For that reason it is important that people with types 1 and 3 contact medical services if affected by gastrointestinal problems or are at risk of dehydration.

Gitelman syndrome

Not everyone with Gitleman syndrome requires treatment. For many individuals, supplements of magnesium and potassium in tablet form are appropriate. In many cases magnesium is best given in three or four doses every day to minimize the risk of side effects including diarrhoea. Nevertheless, it may not always be possible to normalise magnesium levels. During periods of infection it is often appropriate to increase the dosage as the body can lose additional amounts of magnesium. In the case of acute muscle cramps it can sometimes be necessary to administer magnesium intravenously.

Adults with Gitelman syndrome who have chondrocalcinosis require magnesium supplements as well as pain relief and/or non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen.

Others

Many people with Bartter or Gitelman syndromes crave salty foods and are encouraged to eat foods containing large amounts of sodium and potassium. If required, advice on appropriate nutrition can be provided by a dietician.

Certain medications lower levels of potassium in the blood, affecting the electrical conduction of the heart. These include asthma medicines containing salbutamol and beta blockers (a common type of medication affecting blood pressure). It is important that people with Bartter and Gitelman syndromes are not prescribed these medications. If they do take them, they should be monitored with great care.

Practical advice

Extreme or prolonged bouts of physical activity are inadvisable for individuals with Bartter and Gitelman syndromes.

National and regional resources in Sweden

Bartter and Gitelman syndromes are often diagnosed in childhood. As these are rare diseases, specialist clinics with extensive experience of paediatric diseases should be contacted. In Sweden, relevant expertise is to be found at the Renal Unit of The Queen Silvia Children’s Hospital in Gothenburg, The Astrid Lindgren Childrens’ Hospital in Huddinge, Uppsala University Children’s Hospital and Skåne University Hospital in Lund.

Cochlear implant procedures are carried out at several Swedish university hospitals.

Resource personnel

Paediatricians

Associate Professor Gianni Celsi, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: gianni.ennio.celsi@akademiska.se.

Associate Professor Sverker Hansson, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: sverker.hansson@vgregion.se.

Associate Professor Tryggve Nevéus, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: tryggve.neveus@akademiska.se.

Senior Physician Svante Swerkersson, Paediatric Medicine, Skaraborg Hospital, SE-541 85 Skövde, Sweden. Tel: +46 500 43 10 00, email: svante.swerkersson@vgregion.se.

Physician

Associate Professor Peter Barany, Renal Clinic, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

The Swedish Kidney Association, Sturegatan 4 A, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 546 40 500, fax: +46 8 546 40 504, email: info@njurforbundet.se, www.njurforbundet.se.

HRF, The Swedish Hearing Loss Association, Gävlegatan 16, Box 6605, SE-113 84 Stockholm, Sweden. Tel: +46 8 457 55 00, text telephone: +46 8 457 55 01, fax: +46 8 457 55 03, email: hrf@hrf.se, www.hrf.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

International research is under way to test the capability of new medication to control salt levels in the kidneys.

Information material

An information leaflet on Bartter syndrome and Gitelman syndrome summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-11-23). Address: SE-120 88 Stockholm. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Bartter FC, Pronove P, Gill R, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 1962; 33: 811-828.

Brochard K, Boyer O, Blanchard A, Loirat C, Niaudet P, Macher MA et al. Phenotype–genotype correlation in antenatal and neonatal variants of Bartter syndrome. Nephrol Dial Transplant 2009; 24: 1455-1464.

Fahlke C, Fischer M. Physiology and pathyphysiology of ClC-K/barttin channels. Front Physiol 2010; 1: 155.

Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Tran Assoc Am Physicians 1966; 79: 221-235.

Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol 2006; 104: 73-80.

Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008; 3: 22.

Landau D, Shalev H, Ohaly M, Carmi R. Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder. Am J Genet 1995; 59: 454-9.
Proesmans W. Threading through the mizmaze of Bartter syndrome. Pediatr Nephrol 2006; 21: 902.

Puricelli E, Bettinelli A, Borsa N, Sironi F, Mattiello C, Tammaro F et al. Long-term follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant 2010; 25: 2976-2981.

Rudin A. Batters syndrome. A review of 28 patients followed for 10 years. Acta Med Scand 1988; 224: 165-171.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: bartter syndrome, gitelman syndrome

Orphanet (European database)
www.orpha.net/consor/cgi-bin/index.php 
Search: bartter syndrome, gitelman syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical experts who wrote the draft of this material are Associate Professor Tryggve Nevéus and Associate Professor Gianni Celsi, Uppsala University Children’s Hospital.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2012-06-19
Version: 1.0
Publication date of the Swedish version: 2011-12-29

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.