Gitelman syndrome is a rare genetic disorder of the kidneys that typically presents in teenage or early adult years and affects approximately 1 in 40,000 individuals.¹ It shares many features with a similar condition known as Bartter syndrome.² The kidneys are the main filtration units of the body and are responsible for controlling levels of salt and water in the body. As such, the symptoms of Gitelman syndrome are related to difficulty regulating salts in the bloodstream. These salts are referred to as electrolytes, and this article will focus on electrolyte imbalances (salt levels that are too high or too low) as a result of the genetic mutations found in Gitelman syndrome.

Why are electrolytes important?

Electrolytes are the salts in the body that are essential for nearly every bodily function. Everything that you do consciously and unconsciously uses electrolytes, from your heart pumping, your gut digesting food, using muscles to walk around, and the firing of neurons in your brain allowing you to think—to name just a few of these functions.³ Electrolytes have to be maintained at a constant level, as too much of an increase or decrease in these levels can affect the delicate balance of the body (known as homeostasis).

What causes Gitelman syndrome?

The genetic origin

Gitelman syndrome is most commonly caused by genetic mutations, with an affected individual inheriting copies of the mutated gene from both parents. Every cell in your body has two copies of each gene, one from each parent. If an individual has one copy of the affected gene and one copy of a normal (or unaffected) gene, they will not develop Gitelman syndrome. This is known as being a heterozygous carrier for the affected gene, and even though affected individuals are rare (with both genes affected by the mutation and called homozygous), it is estimated that 1% of the population are heterozygous carriers of an affected gene that could be passed onto their offspring[iv].⁴ However, in some exceptional cases, these mutations are not inherited and can develop spontaneously by chance as an individual ages.⁵

There are several genes that, if mutated, can cause Gitelman syndrome, but the most common mutation is in the SLC12A3 gene.^6,7 This gene is responsible for making a protein, which will go on to form a structure called the thiazide-sensitive sodium chloride transporter (often abbreviated to the NCC transporter), which is a vital part of the functioning of the kidney.

Understanding normal kidney function

Kidney functions to filter all of the blood that circulates through the body, removing toxins and waste products while retaining important components such as water, some electrolytes, and sugars.⁸ It is made up of nearly 1 million specialised ‘mini-sieves’ called nephrons. As blood flows into each nephron, its components are split; the thin, watery fluid known as plasma (which contains all of the electrolytes as well as other dissolvable substances such as sugars) enters the body of the nephron, and the larger material (including the blood cells and large proteins) cannot get through. As the plasma flows along, several proteins in the walls of the nephron (such as the NCC transporter) will pick up electrolytes and return them to the blood. Anything left at the end of the nephron will drain from the kidney into the bladder and be excreted as urine.

How kidney function changes in Gitelman syndrome

In Gitelman syndrome, the mutations result in faulty NCC transporters that cannot perform the role of returning electrolytes to the blood.⁹ As a result, the body loses far more potassium and magnesium than an unaffected individual would, resulting in low levels of both of these salts (hypokalaemia and hypomagnesaemia, respectively). It also indirectly prevents potassium from returning to the bloodstream, as sodium is typically exchanged to allow potassium to be taken up; due to this genetic mutation, there is not enough sodium taken up to facilitate this.¹⁰

What are the electrolyte disturbances caused by Gitelman syndrome?

Hypokalaemia

This refers to low levels of potassium in the blood. A mild reduction in potassium can cause muscle weakness, cramping, and fatigue, but if levels drop by a significant amount, abnormal heart rhythms (arrhythmias) can occur. A severe, uncontrolled arrhythmia caused by very low potassium can be fatal if not identified and treated promptly.¹¹

Hypomagnesemia

This refers to low levels of magnesium in the blood as a result of being unable to reabsorb filtered magnesium in the kidney. Symptoms typically include:¹²

• Muscle cramps or twitches
• Diarrhoea
• Fatigue
• Confusion

In cases of severe low levels of magnesium, individuals can develop abnormal heart rhythms (arrhythmias) and seizures.

Hypocalciuria

This refers to low levels of calcium in the urine. If the urinary levels are low, this indicates that the body is not managing to remove calcium from the blood, so levels of calcium in the blood are actually very high (hypercalcaemia). Hypercalcaemia can carry its own problems, including:

• Excessive thirst (polydipsia)
• Changes to patterns of urination (polyuria and nocturia)
• Constipation
• Joint and muscle pain
• Confusion

In severe cases, it can even cause cardiac arrhythmias.¹³ The feature of hypocalciuria is often used to distinguish Gitelman syndrome from the similar condition of Bartlett syndrome.

Metabolic alkalosis

This refers to a reduction in the acidity of the blood. This is due to rising levels of bicarbonate (an important molecule the body uses to regulate the acidity of the blood), which are increased as a consequence of the faulty NCC transporter protein in the kidney. This causes the pH of the blood to rise (and become dangerously alkaline), which we refer to as metabolic alkalosis. This can cause dizziness, confusion, muscle twitches, and cramping.¹⁴

What are the symptoms of electrolyte disturbance in Gitelman syndrome?

Although there are many possible symptoms, the most typical examples include:¹⁵

• Weakness and fatigue
• Muscle cramps
• Thirst
• Salt craving
• Needing to urinate frequently (polyuria)
• Being woken up at night with the need to urinate (nocturia)

How is Gitelman syndrome diagnosed?

A healthcare provider will commonly assess the following:¹⁶

• The clinical picture—from speaking to and examining you, the symptoms and signs discussed in the previous section can be identified by an appropriately trained healthcare provider
• Laboratory Tests— this can include blood tests checking for key electrolytes in the blood (such as potassium, magnesium and calcium) and urine analysis checking the same electrolytes
• Genetic Testing — although clinical and biochemical tests discussed can help narrow down the list of causes, the definitive diagnosis can only be made by checking for the common mutations in Gitelman syndrome, such as the SLC12A3 variant¹⁷

How are these electrolyte imbalances typically managed?

There is currently no cure for Gitelman syndrome. Instead, the focus is on the management of the symptoms caused by the condition, which means managing the side effects of the electrolyte disturbance. Typical management strategies include:

Dietary changes

Some individuals may be able to manage their disease by maintaining a high-salt diet and including foods rich in potassium and magnesium.

Replacing electrolytes the body cannot absorb

 This can take the form of oral potassium and magnesium supplements, either as tablets or oral sachet medications that can be dissolved in water. Note that if both magnesium and potassium are low, it is often recommended to replace the magnesium first.^18,19

Choosing alternative medication 

 Certain drugs that you may already be taking, including thiazide diuretics, laxatives and certain antibiotics, can make electrolyte imbalances more pronounced, so your healthcare provider may switch you to an alternative drug regimen. ^20,21

Pharmacological Interventions

This can include the use of diuretics to prevent potassium loss, including spironolactone and amiloride, although these medications can cause side effects including dizziness and muscle stiffness. In cases of extreme electrolyte deficiency, intravenous doses of key electrolytes such as magnesium or potassium may be given.^22,23

How are patients with Gitelman syndrome followed up?

To ensure that the disease is being optimally managed, your healthcare provider will often check your kidney function with blood and urinary tests and make adjustments to your current treatment regimen accordingly. Please be aware that many drugs come with side effects, so please discuss this thoroughly with your healthcare provider before committing to a prolonged course. Note that a lack of adherence to the recommended therapy may result in worsening of your condition.

It is important that you are aware of the common signs of the electrolyte disturbances discussed above and seek medical input sooner if you are concerned.

What are the complications of not treating these electrolyte disorders?

Complications, although rare, can occur and are linked to extremes of high or low electrolyte levels, the most concerning of which affect the heart and nervous system. They include:²⁴

• Arrhythmias (abnormal heartbeats)
• Low blood pressure
• Muscle weaknesses

When should I see my doctor?

If you do not have a diagnosis and are experiencing any of the discussed symptoms, seeking further investigation from your healthcare provider would be recommended. Many of these symptoms overlap with other medical disorders, although early assessment would be recommended regardless of the underlying cause. If you have a diagnosis of Gitelman syndrome and are experiencing worsening of existing symptoms or new symptoms, prompt assessment is recommended.

Summary

Gitelman syndrome is a genetic disorder affecting the kidneys. It can lead to deranged electrolyte levels in the blood, which can manifest as fatigue, muscle cramps, and heart disorders, including abnormal blood pressure and irregular heart rhythms. Management focuses on the control of symptoms with dietary changes, supplements, and medication if necessary. Regular engagement with your healthcare provider will allow for optimum control of your disease.