What are the other Names for this Condition? (Also known as/Symptoms)

• Bartter Disease
• Juxtaglomerular Hyperplasia with Secondary Aldosteronism
• Salt-Wasting Nephropathy due to Bartter Syndrome

What is Bartter Syndrome? (Definition/Background Information)

• Bartter Syndrome is a genetic disorder characterized by imbalances of ions, such as sodium, chloride, and potassium, within the body
• The disorder is classified based on the time of onset into the following categories:
  • Antenatal Bartter Syndrome: It is recognizable before birth and can potentially be life-threatening
  • Classic Bartter Syndrome: It is not as severe and has an onset during early infancy
  • Gitelman Syndrome: This condition has an onset during adolescence or early adulthood, and it may not be as severe as the other forms of Bartter Syndrome
• Bartter Syndrome is caused by mutations in the SLC12A1, KCNJ1, CLCNKB, CLCNKA, and BSND genes. Since this is a genetic condition, a family history of Bartter Syndrome is a major risk factor for developing the condition
• The genes implicated in Bartter Syndrome are involved in the proper functioning of the kidneys through salt reabsorption. Mutations in these genes can cause a loss of salt in the urine
• Some of the symptoms of Bartter Syndrome are increased urine volume, increased urine frequency, dehydration, constipation, reduced potassium levels, weak bones, and muscle spasms
• The syndrome can lead to potential complications such as developmental delays, progressive kidney failure, and risk of arrhythmia with resultant sudden cardiac death
• The treatment options for Bartter Syndrome include suitable lifestyle measures, such as eating foods rich in sodium and potassium and drinking plenty of water. Other measures include taking potassium supplements, medications to prevent potassium loss from kidneys, and if required, kidney transplantation in case of end-stage renal disease
• Currently, there are no effective means of preventing Bartter Syndrome; however, genetic testing and counselling might help parents prepare for and understand the disorder better. Prompt and continued treatment may also help prevent complications due to Bartter Syndrome
• Bartter Syndrome is currently not curable, but it is only manageable through appropriate medical support. In neonates, the condition can be very serious and life-threatening
• The long-term prognosis for Bartter Syndrome is guarded in light of the possibility for progressive kidney disease and kidney failure. Without treatment, the mortality and morbidity rates are reported to be high

Who gets Bartter Syndrome? (Age and Sex Distribution)

• Bartter Syndrome is a rare genetic disorder with a greater prevalence in Costa Rica and Kuwait than other countries
  • Costa Rica: 1.2 cases per 100,000 live births
  • Kuwait: 1.7 cases per 100,000 live births; over 50% of the cases occur in families with marriages between close relatives
• Worldwide, the disorder is believed to affect 1 in every 1,000,000 individual, with a varying prevalence based on the geographic location
• The onset of the syndrome may be before or immediately after birth (antenatal or neonatal), in early infancy (Classic Bartter Syndrome), or during adolescence/early adulthood (when it is termed Gitelman Syndrome)
• Both males and females can be affected and no gender preference is seen

What are the Risk Factors for Bartter Syndrome? (Predisposing Factors)

• A major risk factor for developing Bartter Syndrome is a family history of the condition
• Individuals with consanguineous relations are at a higher risk

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Bartter Syndrome? (Etiology)

Bartter Syndrome is believed to be caused by mutations in a number of genes, 5 of which have been characterized so far. The genes are SLC12A1, KCNJ1, CLCNKB, CLCNKA, and BSND genes.

• Based on the age of onset, severity of symptoms, and the genes involved, the disease can be classified into the following groups:
  • Type I Bartter Syndrome: Neonatal/antenatal, often life-threatening, and caused by mutation(s) in SLC12A1 gene
  • Type II Bartter Syndrome: Neonatal/antenatal, often life-threatening, and caused by mutation(s) in KCNJ1 gene
  • Type III Bartter Syndrome: Classic type, less severe, and caused by mutation(s) in CLCNKB gene
  • Type IV Bartter Syndrome: Neonatal/antenatal, often serious, caused by mutation(s) in the BSND gene or a combination of mutations in CLCNKA and CLCNKB genes
• These genes are necessary for the reabsorption of salt by the kidneys, and therefore, normal functioning of the organ. Mutations in any of these genes may lead to impaired salt reabsorption, resulting in excess salt in urine (when it is termed salt-wasting)
• Salt-wasting could impact the regulation of other important ions in the body, such as potassium and calcium, leading to an ionic imbalance
• Bartter Syndrome is inherited in an autosomal recessive manner; in which both copies of the causative gene in an individual need to be defective in order for the disease to manifest itself
• In some cases of Bartter Syndrome, the responsible genes have not yet been identified. Active research is currently ongoing to identify and characterize these genes

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Bartter Syndrome?

The signs and symptoms of Bartter Syndrome can begin during the fetal stage, in early infancy, during adolescence, or even in early adulthood. The following are the typical signs and symptoms observed in individuals with the condition at different stages of onset:

• Antenatal stage:
  • Polyhydramnios or increased amniotic fluid surrounding the fetus
  • It can result in premature birth
• Neonatal stage:
  • Failure to grow and issues with gain weight (failure to thrive)
  • Dehydration
  • Vomiting
• In infancy and early childhood:
  • Failure to grow and gain weight in an age appropriate manner
  • Increased urine production and frequent urination
  • Loss of salt in urine with resultant dehydration
  • Constipation
  • Weak bones due to calcium loss (osteopenia), calcium deposit in the kidneys, and hardening of kidney tissues
  • Loss of potassium (hypokalemia)
  • Muscle weakness
  • Tiredness
  • Abnormal changes in the brain affecting brain function
  • Hearing loss, on rare occasions
• Late childhood, adolescence, early adulthood stage:
  • A craving for salt
  • Slow growth
  • Muscle weakness, painful cramps or spasms (tetany)
  • Dizziness
  • Prickly sensation on skin (parasthesia), particularly on the face
  • Low blood pressure
  • Painful joints (a condition called chondrocalcinosis, where calcium crystals get deposited in the joints)
  • Fatigue

How is Bartter Syndrome Diagnosed?

An accurate diagnosis of Bartter Syndrome may be performed based on the following tests and analyses:

• A thorough physical examination
• An evaluation of family history of the condition
• An assessment of the signs and symptoms
• Blood tests to check for levels of the following:
  • Potassium, which is usually low
  • Renin and aldosterone, which may be elevated
  • Chloride, which is usually low
  • Metabolic alkalosis, by measuring serum electrolytes and blood gases in the arteries
• Urine tests to check for elevated levels of potassium, calcium, and chloride, indicative of salt loss
• Blood pressure
• Biopsy of kidney tissue

Prenatal diagnosis of the condition may be performed by genetic testing of fetal cells, for the presence of mutations.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis

What are the possible Complications of Bartter Syndrome?

The potential complications of Bartter Syndrome can include

• Developmental delays
• Decreased bone mineral density
• Formation of gallbladder stones
• Kidney disease and kidney/renal failure
• Risk of irregular heartbeats (arrhythmia)

How is Bartter Syndrome Treated?

The treatment options for Bartter Syndrome may include the following:

• Taking sodium and potassium rich foods or supplements
• Keeping oneself hydrated
• Use of medicines to prevent the loss of potassium from the kidneys
• Aldosterone antagonists such as angiotensin-converting enzyme inhibitors
• Diuretic spironolactone to prevent loss of potassium
• Indomethacin, for decreasing prostaglandin excretion
• Growth hormone injections, in order to help achieve normal growth and treat short stature
• Calcium or magnesium supplements for tetany, if warranted
• Kidney transplantation, when renal failure or end-stage renal disease develops

How can Bartter Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent Bartter Syndrome, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess the risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Bartter Syndrome

Besides the above-mentioned factors, the following may be considered:

• Maintain proper dietary control and regularly include foods that are rich in sodium and potassium
• Individuals with this syndrome should take care to avoid dehydration, which can help prevent complications from arising due to excessive loss of salt
• Regular medical screening at periodic intervals with tests, and physical examinations are strongly recommended
• Children and adolescents should be closely monitored, so that they do not miss their medications. This can help prevent serious complications from developing in them

What is the Prognosis of Bartter Syndrome? (Outcomes/Resolutions)

• Bartter Syndrome is an incurable condition. It can be managed through proper treatment and continued care
• In neonates and infants, the condition can be severe and life-threatening
• Children may be able to catch up on growth, reaching age-appropriate statures/development
• The long-term prognosis of Bartter Syndrome is guarded, owing to the possibility of progressive renal failure. Without early and adequate treatment, the morbidity and mortality from Bartter Syndrome is higher

Additional and Relevant Useful Information for Bartter Syndrome:

In the USA, more than 75% of cases of Bartter Syndrome are seen in individuals of African-American descent.