Bartter syndrome
Bartter syndrome is a rare, inherited disorder characterized by a defect in the kidney's reabsorption system, specifically in the thick ascending loop of Henle. This condition leads to excessive loss of essential electrolytes, including potassium, sodium, and chloride, resulting in symptoms such as muscle weakness, growth retardation, and energy imbalance. There are three main types of Bartter syndrome: neonatal Bartter syndrome, which is the most severe and often diagnosed prenatally; classic Bartter syndrome, which may be recognized by age two; and Gitelman syndrome, a milder form that generally manifests in later adolescence or adulthood. The condition is typically inherited through autosomal recessive patterns, but sporadic cases due to new mutations are also common.
Diagnosis involves evaluating electrolyte levels in blood and urine, as well as genetic testing to identify specific mutations. While there is no cure, management focuses on electrolyte and fluid replacement, and growth hormone may be used to address growth issues. Patients can often lead normal lives with appropriate treatment, although severe cases may lead to complications, including end-stage renal failure. Research into genetic analysis is ongoing, with the aim of finding better treatment options for Bartter syndrome and related disorders.
Bartter syndrome
ALSO KNOWN AS: Potassium wasting disease; Gitelman syndrome
DEFINITION Bartter syndrome describes a group of rare, inherited disorders that share a defect in the kidney’s reabsorption system known as the thick ascending loop of Henle. The abnormality causes excessive loss of fluid, potassium, sodium, and chloride in the urine, resulting in electrolyte imbalance, muscle weakness, and growth retardation. Three clinical types of Bartter syndrome have been identified; the neonatal type, the classic type, and Gitelman syndrome, a milder variant. The syndrome is named for Frederic Bartter, who described the combination of fluid loss, salt-wasting, and growth and muscle abnormalities in two patients in 1962.
Risk Factors
Bartter syndrome may be inherited by autosomal recessive transmission in which both parents carry a defective copy of the gene responsible for proteins that transport electrolytes across cell membranes in the nephron. Most cases appear to occur sporadically as new mutations, however, and are not familial.
Prevalence varies and may be related to the incidence of consanguineous marriage in the countries studied. In Costa Rica, the incidence is approximately 1.2 cases per 100,000 live births. Incidence is higher in Kuwait at 1.7 per 100,000. In Sweden, the prevalence is approximately 1.2 cases per 1,000,000. It is quite rare in the United States, and the precise incidence is unknown. There is no racial or gender preference.
Etiology and Genetics
In all three major Bartter types, defects in proteins responsible for the transport of fluid and electrolytes across cell membranes cause large volumes of urine and salts to pass through without being reabsorbed.
Neonatal Bartter syndrome is the most severe type and may be caused by defects in the NKCC2 (neonatal Type I) and ROMK (neonatal Type II) genes. Cases are often diagnosed prenatally as a result of the presence of excess amniotic fluid (polyhydramnios). After delivery, infants urinate excessively and may become critically dehydrated. They are not able to sustain normal serum electrolyte levels because of sodium, chloride, and potassium loss through the kidneys. A specific neonatal clinical syndrome (Types IV and V) is associated with sensorineural deafness and results from mutations in the BSND and CLCNKA-B genes.
Classic Bartter syndrome may present by age two but is often discovered later. The defect results from a mutation in the chloride-channel (CLCNKB) gene. This leads to the loss of sodium chloride and large volumes of fluid in the urine, as well as increased levels of the hormones angiotensin and prostaglandin E2.
Gitelman syndrome is a milder variant of Bartter syndrome and may appear in the teen or adult years. While it shares many of the characteristics of the classic type, it is differentiated by a consistent loss of serum magnesium caused by a defect in the NCCT gene.
Symptoms
Neonatal Bartter syndrome typically appears in the last trimester of pregnancy with maternal polyhydramnios (excess amniotic fluid) due to increased volume of fetal urine. If left untreated, infants will urinate excessively and become seriously dehydrated. Thirst increases, resulting in increased fluid intake. Vomiting is common, causing further dehydration and electrolyte imbalance. Short stature and growth delay are accompanied by typical triangular facies (facial expressions) with protruding ears. Intellectual disability may occur in severe cases.
Patients with classic Bartter syndrome have excess urine production and increased fluid intake, along with low serum electrolytes, particularly potassium, but symptoms are milder than in the neonatal type. Blood pressure is typically low to normal and kidney function remains normal if the disease is treated. However, there have been cases proceeding to end-stage renal failure. Metabolic alkalosis, weakness, and vomiting may occur.
Gitelman syndrome is commonly asymptomatic and may be found incidentally when routine blood studies demonstrate low serum magnesium.
Screening and Diagnosis
There is currently no prenatal genetic screening for Bartter syndrome. If it is suspected prenatally, amniotic fluid can be assessed for elevated electrolyte levels. Renal ultrasound may show renal calcium deposits, as well as enlarged kidneys as a result of polyuria.
Evaluation of potassium, sodium, calcium, and magnesium levels in blood and urine is essential. Patients are likely to have low serum levels (most notably of potassium) and elevated urine levels. Low serum magnesium levels are typical of Gitelman syndrome. A complete blood count (CBC) may show hemoconcentration as a result of fluid loss. Renal function may be normal or may decrease over time as a result of chronic potassium wasting. Genetic analysis may pinpoint the specific gene defect on a case-by-case basis.
Treatment and Therapy
There is no cure for Bartter syndrome. Medical treatment focuses on electrolyte and fluid replacement. Electrolyte supplements are given, as well as specific medications to counteract increases in aldosterone and prostaglandins. Short stature and growth retardation have been successfully treated with growth hormone supplementation.
Patients who have received kidney transplants for end-stage renal failure (usually for reasons other than Bartter syndrome) have found their abnormalities corrected following the transplant. This may be because the genetic defect in Bartter syndrome is present only in the kidneys.
In 2023, researchers working at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center developed a way to use long-read sequencing to provide a more detailed analysis of the genome of patients with Bartter syndrome. Unlike short-read sequencing, which is unable to read the long stretches of genetic material that are affected in Bartter syndrome, long-read sequencing can read tens of thousands of genetic base pairs. This allowed researchers to detect eight unique gene deletions associated with the syndrome, giving rise to a hypothesis that the condition may be caused by separate events within the same genetic background. The researchers will use this new finding to investigate new ways to treat not only Bartter's syndrome but also other rare genetic disorders.
Prevention and Outcomes
There is no known prevention for Bartter syndrome. Early diagnosis and treatment of children with Bartter syndrome may prevent short stature and normalize electrolyte imbalance. The severity of disease depends on the degree of dysfunction in the loop of Henle. With proper management, prognosis is good and patients may lead normal lives.
Further Reading
Bartter, F. C., P. Pronove, and J. R. Gill. “Hyperplasia of the Juxtaglomerular Complex with Hyperaldosteronism and Hypokalemic Alkalosis.” American Journal of Medicine 33 (1962): 811–28. Print
"Bartter Syndrome." Genetics Home Reference. Natl. Lib. of Medicine, Feb. 2011. Web. 30 Nov. 2015.
"Bartter Syndrome." MedlinePlus. Natl. Lib. of Medicine, 11 July 2013. Web. 30 Nov. 2015.
Kleta, R., and D. Bockenhauer. “Bartter Syndromes and Other Salt-Losing Tubulopathies.” Nephron Physiology 104.2 (2006): 73–80. Print.
LaRosa, Christopher J. "Bartter Syndrome and Gitelman Syndrome." Merck Manual Consumer Version. Merck Sharp & Dohme, n.d. Web. 30 Nov. 2015.
Rudin, A. “Barrter’s Syndrome: A Review of Twenty-eight Patients Followed for Ten Years.” Acta Medica Scandinavica224.2 (1988): 165–71. Print.
Tschernoster, N., et al. "Long-Read Sequencing Identifies a Common Transposition Haplotype Predisposing for CLCNKB Deletions." Genome Medicine, vol. 15, no. 62, 23 Aug. 2023, doi.org/10.1186/s13073-023-01215-1. Accessed 9 Sept. 2024.