Have you ever wondered how one disease can have so many symptoms? How such different symptoms can be linked to the same problem? Both of these phenomena are possible because our bodies are made of highly interconnected systems that rely on the same forms of energy and nutrition to carry out their functions. Considering this, it suddenly becomes much clearer as to how the removal of these energy sources can have very significant effects on different systems of the body.

In this article, we will explore the broad range of symptoms connected to Gitelman syndrome and explain the role magnesium (or the lack of it) plays in causing these symptoms. 

Overview of gitelman syndrome

What is gitelman syndrome? 

Gitelman syndrome is an inherited genetic disorder that affects the kidneys' ability to filter and excrete key minerals, such as salt, potassium, and magnesium. The syndrome is named after Dr Hiller Gitelman, who initially identified the gene responsible for causing the disorder. Whilst there are a variety of treatments available for this disorder, some of the symptoms can be severe and lead to further complications if not treated. 

Symptoms of gitelman syndrome

Reduced or complete loss of kidney function leads to higher amounts of salt, magnesium, and potassium being excreted in urine (rather than being reabsorbed into the blood), causing levels of salt, magnesium, and potassium in the blood to drop. This can have a broad range of symptoms, including:^1,2

Symptoms associated with low salt (sodium) levels include:

• Hypotension (low blood pressure), which can lead to dizziness or light-headedness
• Cravings for foods high in sodium, such as crackers or pickles
• Increased thirst

Symptoms associated with low potassium levels include:

• Irregular heartbeat (arrhythmias)
• Heart palpitations
• Feeling faint

Symptoms associated with low magnesium levels include:

• Muscle cramps
• Fatigue, especially whilst exercising
• Stunted growth
• Seizures

What causes gitelman syndrome?

It is important to understand how the kidney functions normally to filter out waste from our blood before exploring the consequences of when this goes wrong as in Gitelman syndrome. 

Role of the kidney tubules

The kidney is made up of a series of small tubules that possess unique structures to help filter out waste from our blood whilst retaining important minerals. These tubules are called nephrons and can be further divided into smaller subsections, which are described below.

Glomerulus/renal corpuscle 

When the blood enters the kidney, it enters the glomerulus and is effectively filtered through a series of sieves. What remains after this sieving is called the filtrate; the filtrate normally contains a mixture of waste (urea), water, vitamins, minerals, and solutes such as salt and magnesium. The filtrate then enters the tubular system. As the filtrate passes through the tubular system, different amounts of its non-waste components will be reabsorbed into the blood, depending on what the body needs. Whatever isn’t needed is kept in the filtrate to be excreted from the body in the form of urine. 

Proximal convoluted tubule 

The proximal tubule is where the majority of the filtrate returns to the blood via a process called reabsorption. This process aims to reabsorb and retain water, proteins, vitamins, and electrolytes to meet the body’s needs. 

Loop of henle 

This area is where the most salt and water is reabsorbed back into the blood. As the filtrate passes through the different sections of the kidney, it becomes increasingly concentrated and the proportion of waste products increases. If we are dehydrated, more water is reabsorbed (explaining why our urine becomes more concentrated) as it is needed to maintain the internal balance. If we drink too much water, more salt is absorbed, and more water is excreted (meaning we make large amounts of dilute urine).

Distal convoluted tubule 

This area is where the most magnesium and potassium (alongside other minerals) are reabsorbed back into the blood. The reabsorption of magnesium and potassium is controlled by a series of transporters that can recognise them and sense differences in their levels in the blood and the filtrate. In Gitelman Syndrome, one of these transporters is faulty - preventing these minerals from re-entering the blood. Consequently, they remain in the filtrate and are excreted in the urine.

Collecting duct 

This area is where the filtrate in the tubules collects and forms the final urine output. 

Figure: (Simple diagram of the subsections of a nephron)

Genetic basis of gitelman syndrome

Gitelman syndrome is a genetic disorder affecting the tubular system of the kidneys. This means that Gitelman syndrome can be described as a ‘tubulopathy’. Specifically, Gitelman syndrome is caused by mutations in the genes that encode transporters in the distal convoluted tubule. 

One of the genes mutated in Gitelman syndrome, SLC12A3, encodes a sodium chloride cotransporter in the distal convoluted tubule.¹ This cotransporter sits at the boundary between the tubular system and the blood acts like a gate and can recognise both sodium and chloride ions. When it comes into contact with sodium or chloride, it can open to allow these minerals to re-enter the blood. This process is known as selective reabsorption. 

Another gene implicated in Gitelman syndrome, TRPM6 encodes a magnesium transporter located in the distal convoluted tubule.¹ TRPM6 behaves similarly to the sodium chloride cotransporter SLC12A3, opening to allow magnesium back into the blood when it is needed. 

In Gitelman syndrome, these 2 genes are mutated, and the cotransporters are unable to function properly. As a result, the gates do not open, meaning that lots of salt and magnesium remain in the tubular system and are excreted from our bodies. As the movement of water is directly linked to the movement of salt, lots of water also remains in the tubular system and is excreted from our body. Understanding how these genetic mutations cause these nutrient deficiencies can help us explain the symptoms of Gitelman syndrome, and work out how to treat it.

The importance of magnesium in gitelman syndrome

Role of magnesium in the body

Magnesium is an important mineral in our body. It is needed for many biological and cellular functions including neuron signalling, generating energy and bone formation. Most of the magnesium we obtain from our diet is excreted, so it is very important that we can correctly regulate the reabsorption of magnesium and maintain normal bodily functions. As detailed above, the kidneys have highly specialised nephrons which can control the amount of magnesium that is excreted into urine or reabsorbed back into our blood. Most of this control occurs in the distal convoluted tubule of the nephron. 

Hypomagnesemia

The threshold for hypomagnesemia (low blood magnesium) is less than 1.7mg/dL of magnesium in the blood.² This deficiency can happen due to having insufficient magnesium in the diet. Certain medications can also reduce magnesium availability in our body insufficiencies, as well as genetic disorders of the kidney including Gitelman syndrome. 

The lack of magnesium available in the body for those with Gitelman syndrome can help to explain some of the symptoms of the disorder. The lack of magnesium in the blood is called hypomagnesemia and can be linked to many different symptoms of Gitelman Syndrome.

These symptoms can range in severity. As magnesium is needed for energy production, tiredness, fatigue and muscle cramps are common symptoms for those with Gitelman Syndrome.³ Magnesium is needed for proper nerve function so some people with Gitelman syndrome may experience numbness or tingling sensations. More severe symptoms including heart attacks can occur in individuals with Gitelman Syndrome due to the role magnesium plays in normal heart functions. Although these instances are rare, the central roles magnesium plays in our body, prolonged depletion of it can quickly escalate these symptoms. 

Luckily, hypomagnesemia can be treated easily with magnesium supplements, which can be administered via oral tablets or injections depending on the severity of your symptoms. Dosages must be carefully calculated, as excessive doses can cause diarrhoea.⁴ Nonetheless, this treatment is highly successful and able to alleviate many of the symptoms of Gitelman syndrome.

Summary

Magnesium is very important for the normal functioning of our bodies, as it is involved in many cellular processes. Our kidneys are responsible for maintaining the correct amount of magnesium in our body, but their function is disrupted by diseases such as Gitelman syndrome, which causes magnesium transporters in the kidney to become dysfunctional. This can cause individuals to experience hypomagnesemia, which can cause a broad range of seemingly unconnected symptoms. Now that we have linked many of the symptoms of Gitelman disease to hypomagnesemia, they can easily be managed with magnesium supplements - minimising its impact on patients’ daily lives.