Cookies help us deliver our services. By using our services, you agree to our use of cookies. Learn more

Liddle's Syndrome

What is Liddle's Syndrome?

Liddle’s syndrome is a rare disease involving higher than normal kidney activity which leads to hypertension, or high blood pressure. A channel in the kidney epithelial layer, ENaC, normally functions by uptaking sodium ions and water from the kidneys’ filtrate and exporting them back into the bloodstream, exchanging them for the potassium ions from the blood. This process is known as reabsorption, and normally occurs in response to a low amount of sodium in the blood. Otherwise, any excess sodium ions would be removed from the kidneys through the urine. Liddle’s syndrome is caused by overactive ENaC channels, leading to too much removal of potassium ions from the bloodstream and increased levels of salt in the bloodstream. These elevated levels of sodium, or salt, in the blood lead to hypertension and hypokalemic metabolic alkalosis, or high blood pressure and high pH of the blood. Liddle’s syndrome is caused by a genetic mutation in the genes encoding the ENaC channel protein, and can be linked to an autosomal dominant inheritance pattern.

 

 

Synonyms

  • Pseudohyperaldosteronism
  • Pseudoprimary hyperaldosteronism

Liddle’s syndrome is a rare disease involving higher than normal kidney activity which leads to hypertension, or high blood pressure. A channel in the kidney epithelial layer, ENaC, normally functions by uptaking sodium ions and water from the kidneys’ filtrate and exporting them back into the bloodstream, exchanging them for the potassium ions from the blood. This process is known as reabsorption, and normally occurs in response to a low amount of sodium in the blood. Otherwise, any excess sodium ions would be removed from the kidneys through the urine. Liddle’s syndrome is caused by overactive ENaC channels, leading to too much removal of potassium ions from the bloodstream and increased levels of salt in the bloodstream. These elevated levels of sodium, or salt, in the blood lead to hypertension and hypokalemic metabolic alkalosis, or high blood pressure and high pH of the blood. Liddle’s syndrome is caused by a genetic mutation in the genes encoding the ENaC channel protein, and can be linked to an autosomal dominant inheritance pattern.

 

Acknowledgement of Liddle's Syndrome has not been added yet.

Among the world’s population, Liddle’s syndrome occurs with an unknown prevalence rate. This may be due to the difficulty in diagnosing a cause of hypertension across all age groups, as hypertension in individuals under 30 years old is more rare and is often treated with more scrutiny to understand the cause than in the older population. It is estimated that Liddle’s syndrome is the cause of about 0.9-1.5% cases of hypertension in people under 30. 

 

Name Abbreviation
Pseudohyperaldosteronism
Pseudoprimary hyperaldosteronism

The cause of Liddle’s syndrome is a mutation in the genes encoding the epithelial sodium channel, or ENaC, in the kidney. The “Na” in this acronym is attributed to the chemical formula for sodium, “Na”. This is an autosomal dominant inherited mutation (see Rareshare Guide on Genetic Inheritance). The genetic mutation of ENaC is a gain of function mutation (meaning the mutation increases activity) of the following genes that encode different components of the ENaC channel protein: SCNN1A, SCNN1B, and SCNN1G which encode the α, β, and γ subunits of ENaC respectively. When these genes are mutated, certain components of the protein they encode are not formed properly. This disrupts a process called ubiquitination, where normally ubiquitin (a small protein in the cell) attaches to other proteins such as ENaC channels. Other proteins in the cell normally recognize ubiquitin on the surface of proteins and target them for degradation, which is a normal and healthy way to control cellular pathways. When the ENaC channel proteins are not formed properly, they cannot be “marked” with ubiquitin. Without this check-and-balance process, more ENaC channel proteins are left in the membrane and thus the process of sodium uptake and potassium release is increased.

 

The most common and recognizable symptom of Liddle’s syndrome is early onset hypertension (high blood pressure) in people as young as 2 years old. Some symptoms associated with hypertension that lead to seeking medical treatment are headaches, fatigue, dizziness/fainting, and changes in vision. Long term hypertension can cause organ damage: left ventricular hypertrophy (increasing size of the left ventricular cavity in the heart), hypertensive retinopathy (damage to retina blood vessels in the eyes) and nephrosclerosis (damage to the kidney). 


Another key symptom specific to Liddle’s syndrome is hypokalemia, or low amounts of potassium ions in the blood leading to elevated pH levels of the blood. Hypokalemia symptoms can resemble muscle weakness or pain, fatigue, constipation, or heart palpitations.

Early onset hypertension in young people is rare and requires critical examination by a physician in order to determine the cause. More specifically, people under 30 years old with resistant hypertension are tested for Liddle’s syndrome, which is described by the American Heart Association as “blood pressure that remains above goal despite optimal doses of 3 antihypertensive agents of different classes, one ideally being a diuretic”. Diagnosis of Liddle’s syndrome causing hypertension involves identification of symptoms, analysis of family history, laboratory testing, and finally genetic testing.

In order for a diagnosis of Liddle’s Syndrome to be determined, the cause of hypertension must be distinguished from other rare disorders or causes of hypertension (high blood pressure). Some key symptoms that are found in only individuals with Liddle’s hypertension are suppressed renin (an enzyme that controls salt levels in the body) and suppressed aldosterone (a hormone that controls salt levels and blood pressure). Two common tests are used to determine Liddle’s syndrome, followed by genetic testing confirmation:

  1. Urine tests - analysis of ion content in the urine to determine proper kidney function; low sodium levels and high potassium levels in the urine are indicators for Liddle’s syndrome

  2. Improvement of hypertension in response to potassium sparing diuretics (amiloride) - a class of medicine that causes urination without the loss of potassium ions, meaning that they are still in the bloodstream and lowering the alkaline levels which are features of Liddle’s syndrome

Treatment of Liddle’s syndrome focuses on lowering blood pressure by controlling sodium and potassium ion levels in the bloodstream. This involves pharmaceuticals targeting the over-activated ENaC channels in the kidney. These medications, called potassium sparing diuretics, target and block ENaC channels in the kidneys and prevent sodium reabsorption and loss of potassium in the urine. Amiloride is the most common of these diuretics prescribed for Liddle’s syndrome, and while triamterene may also be effective it often requires a larger and more frequent dosage. A different diuretic, spironolactone, once prescribed for this cause of hypertension is actually how Liddle’s syndrome got its name. A physician named Grant Liddle was the first to determine that spironolactone was ineffective against this particular type of hypertension, and thus is no longer used as a therapeutic. Amiloride paired with a low-salt diet is the current treatment prescribed for Liddle’s syndrome.

As the treatment regimen for Liddle’s syndrome has been perfected in recent years, many individuals with early diagnosis and treatment of Liddle’s syndrome have a good prognosis. Often, Liddle’s syndrome is diagnosed before age 30 because symptoms of hypertension are less common in young people, which can increase the potential of a good prognosis. Left untreated, Liddle’s syndrome can lead to cardiovascular complications and damage to the kidneys, which worsens the prognosis with time. 

 

Tips or Suggestions of Liddle's Syndrome has not been added yet.
Logo

Liddle's Syndrome community discussions will be posted here.

There are no new discussions. Start one now!!

Community Resources
Title Description Date Link

Clinical Trials


Cords registry

CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access.

Enrolling is easy.

  1. Complete the screening form.
  2. Review the informed consent.
  3. Answer the permission and data sharing questions.

After these steps, the enrollment process is complete. All other questions are voluntary. However, these questions are important to patients and their families to create awareness as well as to researchers to study rare diseases. This is why we ask our participants to update their information annually or anytime changes to their information occur.

Researchers can contact CoRDS to determine if the registry contains participants with the rare disease they are researching. If the researcher determines there is a sufficient number of participants or data on the rare disease of interest within the registry, the researcher can apply for access. Upon approval from the CoRDS Scientific Advisory Board, CoRDS staff will reach out to participants on behalf of the researcher. It is then up to the participant to determine if they would like to join the study.

Visit sanfordresearch.org/CoRDS to enroll.

Community Leaders

 

Expert Questions

Ask a question

Community User List

test


Start a Community


Don't See Your Condition On Rareshare?

Start your own! With a worldwide network of 8,000 users, you won't be the only member of your community for long.

FAQ


Have questions about rareshare?

Visit our Frequently Asked Questions page to find the answers to some of the most commonly asked questions.

Discussion Forum

Logo

Liddle's Syndrome community discussions will be posted here.

There are no new discussions. Start one now!!


Communities

Our Communities

Join Rareshare to meet other people that have been touched by rare diseases. Learn, engage, and grow with our communities.

FIND YOUR COMMUNITY
Physicians

Our Resources

Our rare disease resources include e-books and podcasts

VIEW OUR EBOOKS

LISTEN TO OUR PODCASTS

VIEW OUR GUIDES

Leaders

Our Community Leaders

Community leaders are active users that have been touched by the rare disease that they are a part of. Not only are they there to help facilitate conversations and provide new information that is relevant for the group, but they are there for you and to let you know you have a support system on Rareshare.