Last updated: 10/7/2024
Years published: 1988, 1989, 1995, 1997, 1999, 2006, 2007, 2016, 2019, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and 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.
Summary
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. The age of onset of overt symptoms can range from before birth to adulthood. Bartter syndrome is caused by changes (variants) in one of several different genes. Treatment is aimed at correcting the electrolyte imbalances using supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs) and diuretics.
Introduction
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 gene variant. 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 variants. The most common classification system for these disorders is based upon the underlying genetic variant 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.
Bartter syndrome is a rare genetic disorder that affects kidney function, leading to imbalances in electrolytes such as potassium, chloride and sodium. Symptoms, onset and severity can vary greatly among individuals, even in those with the same subtype. Some people may experience mild symptoms, while others may face severe, life-threatening complications, often starting before birth.
There are 5 subtypes of Bartter syndrome, all resulting from various variants impacting the movement of sodium, potassium and chloride through the tubular cell.
Gitelman syndrome was initially considered a subtype of Bartter syndrome due to similar symptoms, but it is now generally considered a separate entity thanks to advancements in molecular genetics, which revealed distinct genetic variants causing each condition. Therefore, Gitelman syndrome is not currently classified as a subtype of Bartter syndrome, but rather a related disorder with overlapping features.
Below are the main symptoms associated with the different subtypes of Bartter syndrome:
Bartter Syndrome Type 1:
Bartter Syndrome Type 2:
Bartter Syndrome Type 3 (Classic Bartter Syndrome):
Bartter Syndrome Type 4:
Bartter Syndrome Type 5:
Each subtype of Bartter syndrome follows a unique course and the management of symptoms may differ based on the severity and specific symptoms present.
Generally, Bartter syndrome 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.
Bartter syndromes are caused by changes (pathogenic variants) in the SLC12A1 gene (type 1), KCNJ1 gene (type 2), CLCNKB gene (type 3), BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B) and the MAGED2 gene (type 5). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.
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).
Variants 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.
Bartter syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.
Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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.
X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
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 a high level of amniotic fluid (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 identifying the variants in the genes associated with the different subtypes can confirm a diagnosis.
Treatment
The treatment of the Bartter syndromes is directed toward the specific symptoms that are apparent in each affected person. 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 the most adequate 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. 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. The treatment typically includes:
In stressful situations, blood electrolytes can change rapidly, requiring prompt intravenous treatment
Bartter syndrome is difficult to treat and has no complete cure available to date. Untreated cases are associated with severe health problems, especially from chronic kidney disease. Overall, most affected people can lead normal lives with strict compliance with their treatment plan. Early recognition and treatment in childhood can prevent growth delay.
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TEXTBOOKS
Chaudhry S, Pyne L, Rabbat C, Zawadzki J, Drabczyk R. Bartter and Gitelman Syndromes. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.14.5.6.
Scholl UI, Lifton RP. Molecular Genetics of Gitelman’s and Bartter’s Syndromes and Their Implication for Blood Pressure Variation. In: Genetic Diseases of the Kidney, Lifton RP, Somlo S, Giebisch GH, Seldin DW, editors. 2009 Elsevier, New York, NY. Pp. 229-247.
Hodgson DM, Zingman LV, Terzic A. Bartter Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:309-311.
JOURNAL ARTICLES
R A, Upendra Bhatia S, Narayan K, Mohammed S, Yelkur P. An Unusual Presentation of Failure to Thrive in a Toddler: Bartter Syndrome. Cureus. 2024;16(8):e67289. Published 2024 Aug 20. doi:10.7759/cureus.67289
Thimm C, Adjaye J. Untangling the uncertain role of overactivation of the renin-angiotensin-aldosterone system with the aging process based on sodium wasting human models. Int J Mol Sci. 2024 Aug 28;25(17):9332. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11394713/
Zhou L, Chen X, Xiong J, Lei L. A mosaic mutation in the CLCNKB gene causing Bartter syndrome: A case report. Front Pediatr. 2023 Apr 17;11:1034923. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149701/
Blanchard A, Vargas-Poussou R, Vallet M, et al. Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. Am Soc Nephrol. 2015;26:468-475. https://www.ncbi.nlm.nih.gov/pubmed/25012174
Al Shibli A, Narchi H. Bartter and Gitelman syndromes: spectrum of clinical manifestations caused by different mutations. World J Methodol. 2015;5:55-61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482822/
Seyberth HW. Pathophysiology and clinical presentations of salt-losing tubulopathies. Pediatr Nephrol. 2015;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/26178649
Kintu B Brightwell A. Episodic seasonal pseudo-bartter syndrome in cystic fibrosis. Paediatr Respir Rev. 2014;15:19-21. https://www.ncbi.nlm.nih.gov/pubmed/24821548
Ellison DH. Adaptation in Gitelman syndrome: “we just want to pump you up.” Clin J Am Soc Nephrol. 2012;7(3):379-382. https://www.ncbi.nlm.nih.gov/pubmed/22344514
Vieira H, Mendes L, Mendes P, Esteves da Silva J. Classic Bartter syndrome: a rare cause of failure of thrive in a child. BMJ Case Rep. 2012;2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448348/
Seyberth HM, Schlingmannn KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011;26:1789-1802. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163795/
Nozu K, Iijima K, Kanda K, et al. The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies. J Clin Endocrinol Metab. 2010;95:E511-588. https://www.ncbi.nlm.nih.gov/pubmed?term=20810575
Cortesi C, Lava SA, Bettinelli A, et al. Cardiac arrhythmias and rhabdomyolysis in Bartter-Gitelman patients. Pediatr Nephrol. 2010;25:2005-2008. https://www.ncbi.nlm.nih.gov/pubmed/20549246
Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol. 2006;104:73-80. https://www.ncbi.nlm.nih.gov/pubmed/16785747
Vezzoli G, Arcidiacono T, Paloschi V, et al. Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J Nephrol. 2006;19:525-528. https://www.ncbi.nlm.nih.gov/pubmed/17048213
Amirlak I, Dawson KP. Bartter syndrome: an overview. QJM. 2000;93:207-215. https://www.ncbi.nlm.nih.gov/pubmed/10787448
INTERNET
Bokhari SRA, Zulfiqar H, Mansur A. Bartter Syndrome. [Updated 2023 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK442019 Accessed Oct 3, 2024.
Ellison DH and Konrad M. Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations. UpToDate. Last updated: Jun 03, 2024. Available at: https://www.uptodate.com/contents/bartter-and-gitelman-syndromes Accessed Oct 7, 2024.
LaRosa CJ. Bartter and Gitelman Syndrome. Merck Manual Consumer Version. Dec 2022. Available at: https://www.merckmanuals.com/professional/pediatrics/congenital-renal-transport-abnormalities/bartter-syndrome-and-gitelman-syndrome Accessed Oct 7, 2024.
Frassetto LA, Lo LJ. Bartter syndrome. Medscape. Updated: May 11, 2023. Available at: https://emedicine.medscape.com/article/238670-overview Accessed Oct 7, 2024.
Antenatal Bartter syndrome type 2. Online Mendelian Inheritance in Man (OMIM). 07/02/2013. https://omim.org/clinicalSynopsis/241200 Accessed Oct 7, 2024.
Bartter syndrome type 1. Orphanet. 2024. https://www.orpha.net/en/disease/detail/620217 Accessed Oct 7, 2024.
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