Liddle syndrome is an inherited form of high blood pressure (hypertension). This condition is characterized by severe hypertension that begins unusually early in life, often in childhood, although some affected individuals are not diagnosed until adulthood. Some people with Liddle syndrome have no additional signs or symptoms, especially in childhood. Over time, however, untreated hypertension can lead to heart disease or stroke, which may be fatal.

In addition to hypertension, affected individuals can have low levels of potassium in the blood (hypokalemia). Signs and symptoms of hypokalemia include muscle weakness or pain, fatigue, constipation, or heart palpitations. The shortage of potassium can also raise the pH of the blood, a condition known as metabolic alkalosis.

Liddle syndrome is a rare condition, although its prevalence is unknown. The condition has been found in populations worldwide.

Liddle syndrome is caused by mutations in the SCNN1B or SCNN1G gene. Each of these genes provides instructions for making a piece (subunit) of a protein complex called the epithelial sodium channel (ENaC). These channels are found at the surface of certain cells called epithelial cells in many tissues of the body, including the kidneys, where the channels transport sodium into cells.

In the kidney, ENaC channels open in response to signals that sodium levels in the blood are too low, which allows sodium to flow into cells. From the kidney cells, this sodium is returned to the bloodstream (a process called reabsorption) rather than being removed from the body in urine.

Mutations in the SCNN1B or SCNN1G gene change the structure of the respective ENaC subunit. The changes alter a region of the subunit that is involved in signaling for its breakdown (degradation) when it is no longer needed. As a result of the mutations, the subunit proteins are not degraded, and more ENaC channels remain at the cell surface. The increase in channels at the cell surface abnormally increases the reabsorption of sodium (followed by water), which leads to hypertension. Reabsorption of sodium into the blood is linked with removal of potassium from the blood, so excess sodium reabsorption leads to hypokalemia.

Genetic Testing Information

• Genetic Testing Registry: Liddle syndrome

Genetic and Rare Diseases Information Center

• Liddle syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• LIDDLE SYNDROME 1; LIDLS1

Scientific Articles on PubMed

• PubMed

• Bogdanovic R, Kuburovic V, Stajic N, Mughal SS, Hilger A, Ninic S, Prijic S, Ludwig M. Liddle syndrome in a Serbian family and literature review of underlying mutations. Eur J Pediatr. 2012 Mar;171(3):471-8. doi: 10.1007/s00431-011-1581-8. Epub 2011 Sep 29. Citation on PubMed
• Corvol P. Liddle's syndrome: heritable human hypertension caused by mutations in the Beta subunit of the epithelial sodium channel. J Endocrinol Invest. 1995 Jul-Aug;18(7):592-4. doi: 10.1007/BF03349775. No abstract available. Citation on PubMed
• Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995 Sep;11(1):76-82. doi: 10.1038/ng0995-76. Citation on PubMed
• Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP. A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11495-9. doi: 10.1073/pnas.92.25.11495. Citation on PubMed or Free article on PubMed Central
• Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001 Feb 23;104(4):545-56. doi: 10.1016/s0092-8674(01)00241-0. No abstract available. Citation on PubMed
• Rotin D. Role of the UPS in Liddle syndrome. BMC Biochem. 2008 Oct 21;9 Suppl 1(Suppl 1):S5. doi: 10.1186/1471-2091-9-S1-S5. Citation on PubMed or Free article on PubMed Central
• Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, Rossier BC. Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J. 1996 May 15;15(10):2381-7. Citation on PubMed or Free article on PubMed Central
• Smith JH, Lindor NM, Rabinstein AA. Cerebrovascular consequences of pseudohyperaldosteronism. J Clin Hypertens (Greenwich). 2012 Aug;14(8):547-52. doi: 10.1111/j.1751-7176.2012.00639.x. Epub 2012 May 3. Citation on PubMed
• Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ. Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel. Cell. 1995 Dec 15;83(6):969-78. doi: 10.1016/0092-8674(95)90212-0. Citation on PubMed
• Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D. WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J. 1996 May 15;15(10):2371-80. Citation on PubMed or Free article on PubMed Central
• Warnock DG. Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci. 2001 Dec;322(6):302-7. doi: 10.1097/00000441-200112000-00002. Citation on PubMed