Liddle's Syndrome Research Articles

Challenges in diagnosing and treating Liddle syndrome in resource-limited settings: A case report from Indonesia

Liddle syndrome, a rare form of monogenic hypertension, poses significant diagnostic and therapeutic challenges due to its phenotypic variability and the need for genetic testing. The rarity of the condition, coupled with the limited availability of first-line treatments such as epithelial sodium channel (ENaC) blockers, makes this case report particularly urgent and novel, highlighting alternative management strategies in resource-limited settings. The aim of this case report was to present the diagnostic challenges, therapeutic strategies, and clinical outcomes of a patient with Liddle syndrome who did not have access to ENaC blockers, emphasizing the importance of early recognition and personalized treatment. A 35-year-old female presented with resistant hypertension (190/100 mmHg) and bilateral limb weakness. Laboratory results revealed persistent hypokalemia, hypernatremia, and metabolic alkalosis. Low aldosterone levels, alongside clinical and family history, led to the diagnosis of Liddle syndrome. Genetic testing was not conducted due to resource limitations, and ENaC blockers were unavailable. The patients were managed with a combination of alternative antihypertensive agents, potassium supplementation, and a low-sodium diet. Although this approach led to modest improvements in blood pressure and motor strength, persistent hypokalemia and hypernatremia underscored the suboptimal control of the syndrome's underlying pathophysiology in the absence of ENaC blockers. This case highlights the challenges faced in resource-limited settings and the need for innovative strategies to manage rare conditions like Liddle syndrome. Liddle syndrome's diagnostic and therapeutic challenges underscore the critical importance of early recognition and access to targeted therapies. In the absence of ENaC blockers, alternative treatment strategies can provide some benefit, but they often fall short of optimal management. This case emphasizes the need for enhanced clinical awareness, improved access to genetic testing, and the development of personalized treatment approaches to achieve better patient outcomes.

6568 A Novel Case of Liddle Syndrome in Siblings: Insights into a Rare Genetic Mutation

Abstract Disclosure: A.B. Humrickhouse: None. M. Peltsverger: None. Introduction: Liddle syndrome (LS) is an inherited form of hypertension caused by a mutation in the epithelialsodium channel (ENaC). This condition is characterized by hypertension (HTN), hypokalemia,hyporeninemia, and metabolic alkalosis, although clinical presentation can vary. Asymptomaticearly-onset HTN is common, and if left undiagnosed, it can lead to advanced renal disease,cardiovascular complications, stroke, and even sudden death. Treatment typically involves theadministration of ENaC blockers such as amiloride and triamterene. We present a novel case ofLS in two siblings resulting from a missense mutation in the SCNN1B gene. Case Presentation: The patient is a 24-year-old Hispanic female who presented for evaluation of poorly controlledHTN and severe hypokalemia of 2.9 mmol/L during the first trimester of pregnancy. She wasdiagnosed with HTN at age eighteen. The family history was notable for resistant HTN in herfather and younger brother. Biochemical evaluation revealed normal plasma-free metanephrinesand 24-hour urine-free cortisol. Low plasma renin activity (0.530 ng/mL/hr) and aldosterone(<1.0 ng/dL) were detected on multiple tests. The urine-free cortisol-to-cortisone ratio was <0.5,excluding the diagnosis of apparent mineralocorticoid excess syndrome. The diagnosis of LS wasconfirmed by genetic analysis, which identified a novel heterozygous mutation, c.1859 A>G(Tyr620Cys), in the SCNN1B gene, which had not been reported in the literature to date. Thesame mutation was identified in her brother. The patient was treated with a high dose ofamiloride (15 mg daily), which controlled her HTN and hypokalemia throughout her pregnancy. Discussion: LS is an autosomal dominant disorder with genetic heterogeneity. It is characterized by HTN,low plasma aldosterone and renin activity, and increased potassium excretion. This leads tohypokalemia and metabolic alkalosis. LS is caused by germline mutations found in theSCNN1A, SCNN1B, and SCNN1G genes, which encode the alpha, beta, and gamma subunits ofthe ENaC channel. These mutations lead to enhanced sodium reabsorption in the kidneys,independent of aldosterone. Our patient was diagnosed with hypertension at the age of 18.However, the diagnosis of LS was not made until six years later when she presented during herfirst trimester of pregnancy. Treatment with amiloride effectively controlled her hypertension andhypokalemia, which allowed her to deliver a healthy child. Amiloride was also prescribed for thepatient's brother. A combination of biochemical analysis and genetic testing enables a betterunderstanding of the various clinical presentations, ensuring appropriate treatment andprevention of end-organ damage. Genetic counseling is essential for families affected by LS. Presentation: 6/1/2024

Liddle Syndrome and Recurrent Spontaneous Coronary Artery Dissection

Liddle Syndrome and Recurrent Spontaneous Coronary Artery Dissection

Liddle Syndrome in a Family Presenting with Early-Onset Hypertension, Sudden Death, and Bilateral Kidney Cysts

Liddle Syndrome in a Family Presenting with Early-Onset Hypertension, Sudden Death, and Bilateral Kidney Cysts

Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

A Rare Case of Apparent Mineralocorticoid Excess Presenting as Endocrine Hypertension

A 3-year-old boy presented with polyuria and polydipsia for 18 months, along with growth failure. He was born prematurely, at 34 weeks of gestation, with a low birth weight. On examination, the child was severely underweight and hypertensive. Clinical history and evaluation could not identify any secondary causes of hypertension. There was no significant family history. An endocrine workup was planned, considering hypokalemia and metabolic alkalosis. This demonstrated hyporeninemic hypoaldosteronism and raised the possibility of apparent mineralocorticoid excess (AME) and Liddle syndrome. Clinical exome sequence analysis of HSD11B2 revealed a homozygous mutation in exon 5 (911A>G; p.His304Arg), which resulted in a missense mutation that confirmed the diagnosis of AME. A novel homozygous variant was found in the HSD11B2 gene in a subject with early onset hypertension associated with hypokalemic metabolic alkalosis, establishing the diagnosis of AME.

310 Unexplained CKD With Unexpected Finding of Liddle Syndrome

310 Unexplained CKD With Unexpected Finding of Liddle Syndrome

Reverse Phenotypes of Patients with Genetically Confirmed Liddle Syndrome.

Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from gain-of-function variants in the epithelial Na + channel (ENaC). Efficient treatment with ENaC inhibitors is available, but the phenotypic spectrum of genetically confirmed Liddle syndrome is unknown, and some patients may remain undiagnosed and at risk of inefficient treatment. In this study, we used a reverse phenotyping approach to investigate the Liddle syndrome phenotypic spectrum and genotype-phenotype correlations. Pubmed, Embase, Scopus, and the Human Gene Mutation Database were searched for articles reporting Liddle syndrome variants. The genetic variants were systematically classified to identify patients with genetically confirmed Liddle syndrome. We identified 62 articles describing 45 unique variants within 86 Liddle syndrome families, and phenotypic data were pooled for 268 patients with confirmed Liddle syndrome. The Liddle syndrome variants localized to exon 13 of SCNN1B and SCNN1G , disrupting the PPPxY motif critical for downregulating ENaC activity. Hypertension sensitive to ENaC inhibition was present in 97% of adults carrying Liddle syndrome variants while hypokalemia, metabolic alkalosis, and plasma renin and aldosterone suppression showed incomplete penetrance. In addition, 95% and 55% of patients had a family history of hypertension or cerebrovascular events, respectively. The genotype had minor phenotypic effects; however, probands compared with relatives showed significant phenotypic discrepancies consistent with selection bias for initial genetic screening. Patients with genetically confirmed Liddle syndrome displayed a phenotypic spectrum, with ENaC-sensitive hypertension and family history of hypertension being the most common features. The phenotype seemed independent of the specific gene or variant type involved.

Clinical Features and Mutations in Children with Liddle Syndrome: A Systematic Review of Case Reports

Abstract Background: Liddle syndrome, an autosomal dominant condition, is a rare cause of hypertension, resulting from gain-of-function mutation in genes which encode the subunits of the epithelial sodium channel (ENaC). Objective: The present systematic review focuses on clinical features, genes involved, mutations, and pharmacological management. Methods: A comprehensive search was done in major databases, PubMed and Google Scholar using defined search terms encompassing case reports or case series on Liddle syndrome. The identified reports underwent screening by three different authors for inclusion and exclusion criteria. Results: In total, 44 cases were included from 35 articles. The median age of the children was 14 years, with a slightly higher proportion of males 63.63% (28/44). The most common clinical feature was hypertension (97.7%). Hypertension was controlled in all patients using ENaC channel blockers, amiloride, or triamterene. Conclusion: This is one of the first reviews collating data on Liddle syndrome. Mutations in SCNN1B were most common, with hypertension being the most consistent clinical feature.

Monogenic Hypertension Linked to the Renin-Angiotensin-Aldosterone System.

Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon's syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options.

Liddle Syndrome Caused by Loss-of-Function Mutations in the Ubiquitin Ligase NEDD4L

Liddle Syndrome Caused by Loss-of-Function Mutations in the Ubiquitin Ligase NEDD4L

Therapeutic management of congenital forms of endocrine hypertension.

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism, congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.

Clinical Overview and Treatment of Hypokalemia in Pediatric Patients: A Narrative Literature Review

Hypokalemia is a condition in which the blood potassium levels are below the normal range, which is typically between 3.5 and 5.0 mEq/L. Potassium is an essential electrolyte that plays a critical role in many physiological processes in the body, including nerve and muscle function, heart rhythm, and acid-base balance. This literature review aimed to describe the clinical and current management aspects of hypokalemia in pediatric patients. The pathophysiology of hypokalemia involves a disturbance in the balance of potassium in the body, which can occur due to several mechanisms, including reduced intake of potassium-rich foods, increased loss of potassium, and redistribution of potassium. In children, clinical symptoms of hypokalemia may include weakness and fatigue, abdominal discomfort, cardiac symptoms, respiratory symptoms, neurological symptoms, polyuria, and renal symptoms. There are several diseases and conditions that can cause hypokalemia in children, including renal tubular acidosis, prolonged diarrhea, cystic fibrosis, hyperaldosteronism, malnutrition, medication, type 1 Bartter syndrome, type 2 Bartter syndrome, and Liddle syndrome. Some options for hypokalemia treatment are potassium supplements, a potassium-rich diet, intravenous potassium, and treating underlying conditions. In conclusion, hypokalemia is an overview of the underlying disease and requires immediate management. Understanding the pathophysiology of hypokalemia will increase the accuracy of diagnosis and accelerate hypokalemia intervention in children, as well as prevent complications due to hypokalemia.

A FRAMESHIFT MUTATION IN THE SCNN1B GENE CAUSING LIDDLE SYNDROME AND A GENOTYPE-PHENOTYPE CORRELATION OF 18 CASES WITH THE P603 RESIDUE VARIANT

Objective: Liddle syndrome is an autosomal dominant form of monogenic hypertension caused by mutation of the SCNN1A, SCNN1B, and SCNN1G genes, which respectively encode various subunits of the epithelial sodium channel. In this report, we describe a frameshift mutation in SCNN1B in a Chinese family with early-onset hypertension and hypokalemia. Design and method: DNA was extracted from leucocytes in peripheral blood obtained from all family members. Whole-exome sequencing and Sanger sequencing were performed to verify the candidate variant and conduct co-segregation analysis. We also reviewed the clinical and biochemical characteristics of patients with the same mutation described in the literature and performed a genotype–phenotype correlation analysis. Results: Whole-exome sequencing identified a c.1806dupG frameshift variant in SCNN1B leading to substitution of alanine for proline at position 603 and premature emergence of a stop codon at position 607. Phenotypic heterogeneity is evident in patients with the mutation reported in the literature and is reflected in the proportions with hypertension (94.4%), hypokalemia (58.9%), hypoaldosteronemia (52.9%), and hyporeninemia (41.1%). Patients with the mutation have a good response to targeted ENaC inhibitor therapy. Conclusions: We have identified a frameshift mutation (c.1806dupG) in SCNN1B in a Chinese family characterized by early-onset hypertension and hypokalemia. Confirmatory genetic testing is necessary and targeted therapy should be used to prevent premature onset of clinical endpoints events in patients suspected to have mutation. Genotype-phenotype correlation analysis involving the P603 residue variant provides further evidence of phenotypic heterogeneity and guidance for clinical management of Liddle syndrome.

Recording Sodium Self-Inhibition of Epithelial Sodium Channels Using Automated Electrophysiology in Xenopus Oocytes.

The epithelial sodium channel (ENaC) is a key regulator of sodium homeostasis that contributes to blood pressure control. ENaC open probability is adjusted by extracellular sodium ions, a mechanism referred to as sodium self-inhibition (SSI). With a growing number of identified ENaC gene variants associated with hypertension, there is an increasing demand for medium- to high-throughput assays allowing the detection of alterations in ENaC activity and SSI. We evaluated a commercially available automated two-electrode voltage-clamp (TEVC) system that records transmembrane currents of ENaC-expressing Xenopus oocytes in 96-well microtiter plates. We employed guinea pig, human and Xenopus laevis ENaC orthologs that display specific magnitudes of SSI. While demonstrating some limitations over traditional TEVC systems with customized perfusion chambers, the automated TEVC system was able to detect the established SSI characteristics of the employed ENaC orthologs. We were able to confirm a reduced SSI in a gene variant, leading to C479R substitution in the human α-ENaC subunit that has been reported in Liddle syndrome. In conclusion, automated TEVC in Xenopus oocytes can detect SSI of ENaC orthologs and variants associated with hypertension. For precise mechanistic and kinetic analyses of SSI, optimization for faster solution exchange rates is recommended.

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

The Epithelial Sodium Channel-An Underestimated Drug Target.

Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

Clinical Overview and Treatment of Hypokalemia in Pediatric Patients: A Narrative Literature Review

Hypokalemia is a condition in which the blood potassium levels are below the normal range, which is typically between 3.5 and 5.0 mEq/L. Potassium is an essential electrolyte that plays a critical role in many physiological processes in the body, including nerve and muscle function, heart rhythm, and acid-base balance. This literature review aimed to describe the clinical and current management aspects of hypokalemia in pediatric patients. The pathophysiology of hypokalemia involves a disturbance in the balance of potassium in the body, which can occur due to several mechanisms, including reduced intake of potassium-rich foods, increased loss of potassium, and redistribution of potassium. In children, clinical symptoms of hypokalemia may include weakness and fatigue, abdominal discomfort, cardiac symptoms, respiratory symptoms, neurological symptoms, polyuria, and renal symptoms. There are several diseases and conditions that can cause hypokalemia in children, including renal tubular acidosis, prolonged diarrhea, cystic fibrosis, hyperaldosteronism, malnutrition, medication, type 1 Bartter syndrome, type 2 Bartter syndrome, and Liddle syndrome. Some options for hypokalemia treatment are potassium supplements, a potassium-rich diet, intravenous potassium, and treating underlying conditions. In conclusion, hypokalemia is an overview of the underlying disease and requires immediate management. Understanding the pathophysiology of hypokalemia will increase the accuracy of diagnosis and accelerate hypokalemia intervention in children, as well as prevent complications due to hypokalemia.

A Case of Juvenile Hypertension Diagnosed as Liddle Syndrome, Initially Suspected of Primary Aldosteronism

A Case of Juvenile Hypertension Diagnosed as Liddle Syndrome, Initially Suspected of Primary Aldosteronism