Bartter Syndrome

Bartter syndrome is a general term for a group of rare genetic disorders that affects the kidneys, in which specific defects  impair the transport of certain electrolytes, particularly sodium, potassium, and chloride, in the cells of the kidney's tubules. These defects can lead to an imbalance of these electrolytes in the body, which can cause a range of symptoms and health problems.

There are several different types of Bartter syndrome, each caused by mutations in specific genes involved in electrolyte transport in the kidney.

► 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. Treatment is aimed at correcting the electrolyte imbalances through the use of supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs; analgesic and anti-inflammatory, e.g. iboprofen) and diuretics (promote urine production and urination, e.g. furosemide).

• Facial Features: Triangular-shaped face, prominent forehead, large eyes, pointed ears, "pouting" expression.
• Growth Issues: Failure to thrive, growth delays, and potential short stature.
• Complications: Electrolyte imbalances may lead to cardiac arrhythmias, paralysis, and, in severe cases, sudden cardiac arrest or death.
• Renal Complications: Elevated calcium levels in urine, nephrocalcinosis, and the potential for kidney function impairment.

1. Bartter Syndrome Types 1, 2, 4a, and 4b:

   • Age of Onset: Early (before birth).
   • Symptoms: Severe symptoms include polyhydramnios, premature birth, excessive urination (polyuria), fever, dehydration. Types 4A and 4B also involve congenital sensorineural deafness.
   • Developmental Impact: Cognitive and motor development may be affected, possibly related to prematurity.

2. Bartter Syndrome Type 3:

   • Onset: Can present before birth with milder symptoms or in infancy/early childhood with growth problems.

3. Bartter Syndrome Type 5:

   • Manifestation: Excess amniotic fluid (polyhydramnios), severe enough to cause premature birth.
   • Resolution: Kidney symptoms spontaneously resolve after birth without treatment.
   • Demographics: Predominantly occurs in boys due to X-chromosome gene.

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/ the same gen mutation. Some individuals may have mild cases; others may experience severe, potentially life-threatening complications, at birth.

Common features and symptoms of Bartter syndrome may include:

• Dehydration: Due to excessive loss of salt and water in the urine.
• Muscle Weakness: Particularly in the legs.
• Kidney Stones: An increased risk of developing kidney stones.
• Growth Failure: Children with Bartter syndrome may have poor growth.
• Polyuria: Excessive urination.
• Polydipsia: Excessive thirst.
• Hypotension: Low blood pressure.
• Hypokalemia: Low levels of potassium in the blood.
• Metabolic Alkalosis: A condition where the body's pH becomes too high due to excessive loss of acid in the urine.

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.

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 plan an affect child’s treatment systematically and comprehensively. 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.

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.

Due to 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 shown to be effective, but can have severe side effects, especially in premature babies with regards to perforation in the intestinal tract, especially the stomach. 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 

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.

• It may be that these drugs lead to a significant loss of sodium and must therefore be combined with a simultaneous intake of an appropriate sodium chloride supplement. 

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.

• 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.

Especially in Bartter syndrome type 3, magnesium supplementation may be used to treat muscle spasms or tetany.