Liddle syndrome is a rare genetic disorder characterized by malfunction of an ion channel primarily expressed in renal tubules. This condition leads to electrolyte imbalances and severe hypertension at an early age.
LS is a genetic disorder and renal regulation of serum levels of sodium and potassium is disturbed from an early age. However, hypokalemia, metabolic alkalosis and hypertension may not cause any symptoms in pediatric or adolescent patients and unless there is a familial history of LS - which frequently is the case - affected individuals may not seek medical attention. Of note, de novo mutations of genes encoding for ENaC subunits have been reported and thus, lack of a familial history of LS does not rule out this syndrome  . Here, either symptoms induced by electrolyte imbalances or dysregulation of blood pressure (e.g., fatigue and weakness) prompt patients to consult their physician or the former are detected during routine examinations.
None of the aforementioned symptoms should be considered an exclusion criterion; also, electrolyte imbalances and hypertension may be very mild. In such atypical cases, a family history of early-onset hypertension and severe cardiovascular events may be required to bring about the suspicion of LS.
It is not uncommon that a tentative diagnosis of LS is only made after hypertension cannot be reduced with standard medication.
Entire Body System
High blood pressure in Liddle syndrome can be severe and associated with low potassium, fatigue, and weakness. It is also called pseudoaldosteronism. References United States. National Institutes of Health. U.S. National Library of Medicine. [rxlist.com]
High blood pressure in Liddle syndrome can be severe and associated with low potassium, fatigue, and weakness. It is also called pseudoaldosteronism. Reviewed on 9/7/2018 REFERENCE: United States. National Institutes of Health. U.S. [medicinenet.com]
We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]
Adults are affected with severe hypokalemia, weakness, fatigue, heart palpitations, or muscle weakness. Synonyms Pseudohyperaldosteronism; Liddle’s Syndrome. [accessanesthesiology.mhmedical.com]
Patients are often asymptomatic. Renal impairment may occur due to hypertension. Muscle weakness in combination with severe hypertension has been reported in elderly population with the syndrome . [ohsu.pure.elsevier.com]
Individuals may remain asymptomatic for up to 40 years, but Liddle syndrome can also be diagnosed as early as 12 years in a majority of cases. [lecturio.com]
Severe and reproducible low-renin hypertension responsive to salt restriction and amiloride-thiazide therapy in a 13-year-old otherwise asymptomatic boy suggested Liddle syndrome. [ncbi.nlm.nih.gov]
Typically patients are asymptomatic other than hypertension, which is hopefully identified in childhood. Quiz questions Promoted articles (advertising) [radiopaedia.org]
It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008. Signs and symptoms Children with Liddle syndrome are frequently asymptomatic. [en.wikipedia.org]
[…] and proliferation. rs1458038 FGF5 4q21.21 Fibroblast growth factor 5, involved in embryonic development, cell growth, morphogenesis, tissue repair, tumour growth and invasion. rs13107325 SLC39A8 4q24 Mitochondrial cellular import of zinc, involved in inflammation [cardiogen.com.ar]
Cardio-Lipidology Cardio-Renal Diabetes Angiology Frontier Anti-aging Science Arthritis―運動器疾患と炎症― Bella Pelle CANCER BOARD of the BREAST CANCER BOARD乳癌 CARDIAC PRACTICE Cardio-Coagulation Cardio-Lipidology Cardio-Renal Diabetes Clinical Respiration Coagulation & Inflammation [med.m-review.co.jp]
Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep. 2017;21:1009–1020. doi:10.1016/j.celrep.2017.10.002 59. Van Beusecum JP, Barbaro NR, McDowell Z, et al. [dovepress.com]
High salt activates CD11c + antigen-presenting cells via SGK (serum glucocorticoid kinase) 1 to promote renal inflammation and salt-sensitive hypertension. Hypertension. 2019 Sep;74(3):555-563. doi: 10.1161/HYPERTENSIONAHA.119.12761. [rarediseases.org]
- Short Stature
Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis. [ 8 ] Other features include: Short stature. [patient.info]
Age of onset: typically < 3 years Clinical features Features of rickets (e.g., short stature, bowing of legs) Dental abscesses Calcification of soft tissues (tendons, ligaments, and joint capsules) Deafness Arnold-Chiari malformations Diagnostics Laboratory [amboss.com]
As for short stature, I'm only 5 foot 1 and my mother is 4 foot 10 so I'm curious if this is why I failed to grow. I am anxious to get this genetic testing behind me and move forward with a true diagnosis. [medhelp.org]
Muscle weakness this can be in the form of abdominal muscle weakness associated with constipation, weakness if chest muscles leading to dyspnea. Slight exertion or exercise may become intolerable. Palpitation. [tandurust.com]
From 13.5 years, the patient has been complaining of headache and dyspnea during exercises. His BP was stable at 160/100 mmHg. Hypertrophy of the left ventricular myocardium and angiopathy of the retinal vessels were revealed. [bmcnephrol.biomedcentral.com]
[…] e.g., hyperparathyroidism, vitamin D toxicity, sarcoidosis) Medullary sponge kidney Chronic obstructive uropathy Sickle cell nephropathy Wilson's disease Drugs: ifosfamide, amphotericin B, lithium, NSAIDs Clinical features Nephrocalcinosis Polyuria → polydipsia [amboss.com]
At a Glance The clinical presentation is that of polyuria and polydipsia, failure to thrive, and systemic hypertension in infancy and/or early childhood. [cancertherapyadvisor.com]
The patient was otherwise asymptomatic and denied polyuria, polydipsia, diarrhea, nausea, vomiting, anorexia, and alcohol abuse. The patient denied smoking tobacco, abusing alcohol, using drugs, or excessive intake of licorice or chewing tobacco. [utswim.wordpress.com]
[…] hypokalaemia in Bartter's syndrome and Gitelman's syndrome may abruptly become life-threatening under certain aggravating conditions. [ 10 ] True Bartter's syndrome patients usually present aged >5 years with signs of vascular volume depletion, polyuria, and polydipsia [patient.info]
Resistant hypertension can cause muscle weakness, polyuria, and polydipsia due to hypokalemia. [statpearls.com]
- Abdominal Pain
Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis. [ 8 ] Other features include: Short stature. [patient.info]
led us to suspect other forms of secondary hypertension. [ec.bioscientifica.com]
Renal impairment may occur due to hypertension. Muscle weakness in combination with severe hypertension has been reported in elderly population with the syndrome . [ohsu.pure.elsevier.com]
Description Liddle syndrome is an inherited form of high blood pressure (hypertension). [medlineplus.gov]
[…] in Chinese early-onset hypertensive patients. [statpearls.com]
A total of 10/29 members in this pedigree were clinically diagnosed with hypertension. III-10 (sibling of the proband) was diagnosed with hypertension at the age of 20. [spandidos-publications.com]
- Heart Failure
Failure and Transplantation Cardiology Nita Ahuja MD, MBA Gastrointestinal Surgical Oncology, General Surgery, Minimally Invasive Surgery, Sarcoma and Connective Tissue Surgical Oncology Paul Aiello MD Radiology, Diagnostic Radiology Joseph Akar MD, [yalemedicine.org]
Unrecognised or uncontrolled high blood pressure can lead to stroke, heart failure, eyesight problems and kidney damage (including end-stage kidney disease). All of these can be prevented by early recognition and good blood pressure control. [ukkidney.org]
Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation. 2008 Oct 14. 118(16):1643-50. [Medline]. [medscape.com]
- Chest Pain
This have been very distressing for me because I feel exhausted all the time and I'm concerned I could end up it the ER again with chest pains or worse I could end up dead. [medhelp.org]
The patient had no history of blurred vision, chest tightness, chest pain, proteinuria, hematuria or edema. Furthermore, daily urine volume was normal. The basic metabolic panel revealed that potassium level was 3.4 mmol/l. [spandidos-publications.com]
Bronchiectasis,Liddle Syndrome, Pseudohypoaldosteronism AD,AR 100 56 of 56 SCNN1G Bronchiectasis With Or Without Elevated Sweat Chloride, Liddle Syndrome, Pseudohypoaldosteronism AD,AR 100 28 of 28 *Inheritance: AD: Autosomal Dominant; AR: Autosomal [igenomix.fr]
These channels are found on the surface of epithelial cells found in the kidneys, lungs, and sweat glands. The ENaC transports sodium ions from the adjacent lumen into the epithelial cells that line the lumen. [en.wikipedia.org]
These channels are found at the surface of epithelial cells in many tissues of the body, including the kidneys, lungs, and sweat glands. The ENaC channel transports sodium into epithelial cells. [genetics.ouhsc.edu]
Symptoms : Children and adolescents affected with Liddle syndrome may show symptoms of hypertension like increase in heartbeat, profuse sweating and sudden increase in blood pressure. [diseasespictures.com]
Pseudohypoaldosteronism, Bronchiectasis with or without elevated sweat chloride AD/AR 8 20 Non-coding variants covered by Liddle Syndrome Panel Gene Genomic location HG19 HGVS RefSeq RS-number Test strength The strengths of this test include: CAP and [blueprintgenetics.com]
Although the condition may not be associated with signs and symptoms initially, untreated hypertension can eventually lead to heart disease or stroke. [rarediseases.info.nih.gov]
Over time, however, untreated hypertension can lead to heart disease or stroke, which may be fatal. [medicalvideos.com]
Events contain heart failure, stroke, and all-cause death. [frontiersin.org]
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). [medlineplus.gov]
Muscle weakness and neuromuscular irritability may occur especially in Gitelman's syndrome. Can also present in utero with resulting prematurity or polyhydramnios. [patient.info]
The symptom triad of hypokalemia, metabolic alkalosis and hypertension in a child or adolescent is highly suspicious of LS. Consequently, patients (or their parents) should be queried for similar pathologies that may have been diagnosed in family members. Also, additional laboratory analyses of blood samples should be carried out. They may reveal hypernatremia and reduced levels of renin and aldosterone. The latter is of diagnostic importance since the main differential diagnoses are distinct forms of hyperaldosteronism. In primary aldosteronism or Conn syndrome, an increased production of adrenal aldosterone causes renin concentrations to diminish; in secondary aldosteronism, restriction of renal blood flow induces augmented renin and aldosterone levels. Furthermore, hypokalemia and metabolic alkalosis may be triggered by genetic disorders like Bartter syndrome and Gitelman syndrome, but hypertension is not characteristic for these diseases .
Urine samples may be analyzed and should confirm the aforementioned electrolyte imbalances, i.e., LS patients excrete a lot of potassium, but reduced quantities of sodium and aldosterone.
Definitive diagnosis of LS requires a genetic screen and identification of the underlying gene mutation. Both SCNN1B and SCNN1G should be examined and sequencing results should be revised for any of those gene defects known to induce LS. However, gene variants that have not yet been related to this disease should also be considered as possible sources of ENaC malfunction .
Diagnosis of LS should prompt the physical examination of the patient's relatives, of those family members pertaining to previous as well as to following generations .
Dietary adaptions, mainly salt restriction, and inhibition of mutated sodium channels by potassium-sparing diuretics are the mainstays of LS therapy. Although this therapeutic approach is symptomatic rather than causative, it counteracts the effects of increased sodium reabsorption at the level of the channelopathy and thus prevents consequent serum electrolyte imbalances and hypertension. Amiloride and triamterene are the drugs of choice and are administered at doses of up to 20 and 300 mg per day, respectively. Lower doses may suffice; the individual dose should be adjusted to the patient's response to treatment.
If patients follow dietary recommendations and comply with drug intake, serum electrolyte levels and blood pressure should normalize. Regular follow-ups including measurement of blood pressure, serum potassium and assessment of acid-base balance are strongly recommended.
Of note, spironolactone and eplerenone are not effective against LS-associated hypertension, since ENaC activity does not depend on aldosterone and patients do indeed present reduced serum aldosterone concentrations.
An early diagnosis and timely initiation of an adequate treatment largely contributes to avoid severe complications resulting from hypertension. Indeed, dietary adjustments and life-long administration of potassium sparing diuretics is generally sufficient to reestablish physiological serum electrolyte concentrations and blood pressure. Life expectancy of LS patients receiving the aforementioned treatment is normal or near to normal.
In contrast, untreated LS may be associated with severe cardiovascular sequelae and even sudden death before the age of 40 .
Three distinct subunits - an α, β, γ subunit, respectively - form this heterotrimeric channel. Every subunit consists of intracellular NH2- and COOH-termini, two transmembrane helices and an extracellular loop. According to current knowledge, both β and γ subunits may negatively regulate channel activity by targeting the receptor for ubiquitination and induction of degradation . This hypothesis is supported by the fact that mutations of those genes encoding for these subunits have been related with LS ; these genes are designated SCNN1B and SCNN1G. All gene defects associated with this pathology are gain-of-function mutations.
Gene mutations associated with LS are inherited with an autosomal dominant trait.
LS is a very rare disease, although familial prevalence may be high due to dominant inheritance. To date, gene defects associated with this syndrome have only been reported for a few dozen families and even less isolated cases.
As has been indicated above, LS is associated with mutations of the β or γ subunit of ENaC, an ion channel that is expressed in distinct parts of the renal tubule system. It is located on the apical surface of epithelial cells lining the respective tubules and allows for reabsorption of sodium ions along the electrochemical gradient. Lateral and basal sodium efflux and return to the circulation is mediated by Na+/K+-ATPase pumps expressed on the respective surfaces of the epithelial cell. Here, three sodium ions are exchanged for two potassium ions.
In LS, β or γ subunits of ENaC lose their affinity for Nedd4, an ubiquitin ligase that marks the ion channel for ubiquitination, endocytotic uptake and degradation. Presumably, this alteration of binding properties is provoked by mutations affecting conserved proline-rich regions in COOH-termini of the respective subunits. If Nedd4 binding cannot occur, ion channel internalization is not induced and the cell-surface half-life is significantly prolonged . This results in a net-overexpression of ENaC.
Epithelial sodium channels constitute the rate-limiting step in sodium reabsorption. According to the aforementioned mechanisms, constitutive activity of excess amounts of ENaC leads to enhanced luminal absorption and basal efflux of sodium as well as elevated intracellular potassium concentrations. Moreover, lumen-negative electrical potentials caused by the aforementioned ion movements induces release of cations into the lumen of the renal tubule. Potassium and hydrogen ions account for the majority of these cations and thus, LS patients present with hypokalemia and metabolic alkalosis. Hypernatremia may be observed in affected individuals. Because elevated sodium concentrations provoke an increased osmotic pressure in extracellular fluids, passive reabsorption of water augments and volume-mediated hypertension results from those pathophysiological events described above. Because hyponatremia and hypovolemia are the main stimulants for secretion of renin and aldosterone, plasma levels of these hormones are typically diminished in LS patients.
ENaC can be blocked with distinct compounds, e.g., with amiloride or triamterene. Thus, such potassium sparing diuretics are the treatment of choice for LS patients.
Affected families may benefit from genetic counseling, particularly because inheritance of one mutated gene suffices to induce LS.
Early diagnosis assures initiation of treatment in a timely manner and helps to prevent cardiovascular complications. Furthermore, patients diagnosed with LS can increase the efficacy of their medication by keeping a diet low in sodium.
Liddle syndrome (LS) is a rare genetic disorder that is inherited with an autosomal dominant trait. To date, several mutations of genes encoding for subunits of the amiloride-sensitive epithelial sodium channel ENaC have been related to LS. This ion channel is mainly expressed in renal collecting tubules, but it can also be found in more proximal parts of the tubule system as well as in the respiratory and gastrointestinal tract . Thus, LS pertains to the large group of channelopathies.
The disease has first been described by Grant W. Liddle and colleagues who referred to it as "ectopic ACTH syndrome" . And indeed, increased serum levels of ACTH that may be seen in patients suffering from primary hyperaldosteronism or Conn syndrome, for instance, cause symptoms similar to those observed in LS: decreased serum concentrations of renin and aldosterone, hypokalemia and metabolic alkalosis as well as hypertension. Therefore, the term pseudohyperaldosteronism is sometimes used as an alternative designation for LS, although the former comprises additional etiologic factors and pathogenetic mechanisms.
LS patients present with the above mentioned symptoms at an early age, typically in childhood or adolescence . Because young LS patients may feel just fine, the disease may also remain undetected until adulthood if pathological alterations of blood pressure or blood biochemistry are not encountered during routine screens. The latter are thus indicated in patients with a family history of early-onset hypertension and possibly sudden death in young adulthood. If left untreated, such severe cardiovascular complications are very common.
Therapy consists in administration of potassium-sparing diuretics like amiloride or triamterene. These drugs block ENaC and thus counteract the effects of gain-of-function mutations that cause LS. Both electrolyte imbalances and hypertension can be corrected. Life expectancy of adequately treated LS patients is near normal.
LS patients suffer from malfunction of an ion channel expressed in their kidneys. In simple terms, the kidneys' function is to produce primary urine (in great amounts, since this is merely filtrated blood) and to reabsorb the vast majority of electrolytes and water before passing it on to ureters and urinary bladder.
Many different proteins are involved in this process, one of them being the sodium channel ENaC that is expressed in epithelial cells lining the distal parts of the renal tubule system. In LS, gene defects lead to an abnormally high activity of ENaC. Here, epithelial cells reabsorb great amounts of sodium through ENaC, transport those ions through the cell and exchange them on their basal side for potassium. However, the exchange rate slightly favors sodium, i.e., more sodium ends up in the patient's circulation than potassium in their urine. Water passively diffuses to the site of higher ion concentrations, i.e., to the blood. Additionally, the aforedescribed ion movements are associated with loss of hydrogen ions into the lumen of renal tubules.
According to those mechanisms mentioned before, LS patients present with hypertension (due to increased renal absorption of water and subsequent increment of fluid volume), hypokalemia (loss of potassium), metabolic alkalosis (loss of hydrogen) and possibly hypernatremia (enhanced reabsorption of sodium).
Because LS is a genetic disorder, those conditions manifest at an early age, most frequently in adolescence. They are commonly detected during routine screens. Also, a familial history of early-onset hypertension may (and should) prompt parents to have their child checked.
Even in the absence of a familial history of LS, the symptom triad of hypokalemia, metabolic alkalosis and hypertension in a child or adolescent is highly suspicious of LS. Additional laboratory analyses of blood samples will reveal low renin and aldosterone levels and thus support this tentative diagnose. Definitive diagnosis does require identification of the underlying gene mutation, though.
Diagnosis of LS should lead to physical examination of the patient's relatives, of those family members pertaining to previous as well as to following generations.
The overactive ion channel ENaC can be blocked by administration of potassium-sparing diuretics like amiloride or triamterene. This medication has to be used throughout life and needs to be combined with a low-sodium diet. Following these recommendations, hypertension and electrolyte imbalances can be corrected. Thus, adequately treated LS patients have a normal life expectancy.
- Nesterov V, Krueger B, Bertog M, Dahlmann A, Palmisano R, Korbmacher C. In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron. Hypertension. 2016; 67(6):1256-1262.
- Liddle GW, Bledsoe T, Coppage WS Jr. A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Assoc Am Physicians. 1963; 76:199-213.
- Bogdanovic R, Kuburovic V, Stajic N, et al. Liddle syndrome in a Serbian family and literature review of underlying mutations. Eur J Pediatr. 2012; 171(3):471-478.
- Malbert-Colas L, Nicolas G, Galand C, Lecomte MC, Dhermy D. Identification of new partners of the epithelial sodium channel alpha subunit. C R Biol. 2003; 326(7):615-624.
- Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995; 11(1):76-82.
- Lu C, Pribanic S, Debonneville A, Jiang C, Rotin D. The PY motif of ENaC, mutated in Liddle syndrome, regulates channel internalization, sorting and mobilization from subapical pool. Traffic. 2007; 8(9):1246-1264.
- Hansson JH, Schild L, Lu Y, et al. 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; 92(25):11495-11499.
- Yang KQ, Lu CX, Xiao Y, et al. A novel frameshift mutation of epithelial sodium channel beta-subunit leads to Liddle syndrome in an isolated case. Clin Endocrinol (Oxf). 2015; 82(4):611-614.
- Jain G, Ong S, Warnock DG. Genetic disorders of potassium homeostasis. Semin Nephrol. 2013; 33(3):300-309.
- Findling JW, Raff H, Hansson JH, Lifton RP. Liddle's syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. J Clin Endocrinol Metab. 1997; 82(4):1071-1074.