RARE DISEASE
Genetic periodic paralysis
Genetic periodic paralysis
Genetic periodic paralysis
Drug discovery
0
drugs
With orphan designations
Overview
Genetic periodic paralysis encompasses rare autosomal dominant channelopathies (CACNA1S, SCN4A, KCNJ2 mutations) causing episodic flaccid paralysis. Four subtypes exist: hypokalemic (HypoPP), hyperkalemic (HyperPP), thyrotoxic, and Andersen-Tawil syndrome. Attacks are triggered by exertion, carbohydrate intake, or stress. Diagnosis combines serum potassium levels during episodes, genetic testing, and exclusion of secondary causes. Treatment focuses on acute potassium correction and long-term prophylaxis with carbonic anhydrase inhibitors (e.g., acetazolamide) [1][3][6][9].
Burden
Progressive permanent myopathy develops in 25-50% of patients with aging [9][12][17].
Andersen-Tawil syndrome carries arrhythmia risks (prolonged QT interval) requiring cardiac surveillance [1][12].
Frequent attacks disrupt daily function, with treatment costs and disability contributing to reduced quality of life [6][12][19].
Therapies
Acute: Oral/IV potassium for HypoPP; β2-agonists (salbutamol) for HyperPP [3][6][12].
Prevention: Carbonic anhydrase inhibitors (dichlorphenamide/acetazolamide), potassium-sparing diuretics, and low-carbohydrate diets [3][9][12].
Lifestyle: Avoid triggers (e.g., fasting, strenuous exercise); ECG monitoring in Andersen-Tawil syndrome [1][3][12].
Categories: rare genetic diseases
Research Papers
199 drug discovery papers about Genetic periodic paralysis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
199 drug discovery papers about Genetic periodic paralysis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Late-Onset Episodic Weakness With Hyperkalemia Suggestive of Hyperkalemic Periodic Paralysis
A rare late-onset presentation of episodic weakness associated with hyperkalemia is described in a 72-year-old male with concurrent early-stage chronic lymphocytic leukemia. He experienced frequent episodes of generalized muscle weakness accompanied by loss of speech, shortness of breath, and fatigue, with a documented serum potassium level of 6.5 mmol/L obtained within 30 minutes of an attack. Treatment with acetazolamide and dietary modification was associated with a substantial reduction in episode frequency and improved functional status, although persistent fatigue remained. The clinical presentation was suggestive of hyperkalemic periodic paralysis, but a definitive diagnosis was limited by the patient's exceptionally late age at onset, negative genetic testing, lack of specialized exercise testing, and absence of electrophysiologic testing during an attack. This case emphasizes the importance of considering hyperkalemic periodic paralysis in the differential diagnosis of episodic weakness while simultaneously evaluating alternative neuromuscular, metabolic, hematologic, and paraneoplastic causes. Treatment response to acetazolamide and dietary modification was considered supportive of but not necessarily diagnostic of an inherited channelopathy.
2026-07-30 | Atypical Andersen-Tawil Syndrome in an Asymptomatic Child With Bidirectional Ventricular Tachycardia and Incipient Tachycardiomyopathy.
Bidirectional ventricular tachycardia is a rare electrocardiographic (ECG) finding, associated with a restricted group of clinical conditions, particularly hereditary channelopathies. An 11-year-old girl, asymptomatic from a cardiovascular point of view, was identified by family screening after detection in her father of a pathogenic variant in the KCNJ2 gene. The admission ECG showed bidirectional ventricular tachycardia. Clinical investigation revealed periodic paralysis and skeletal dysmorphisms, confirming a diagnosis of Andersen-Tawil syndrome. Pharmacological treatment significantly reduced the arrhythmic burden, with reverse ventricular remodeling at follow-up. This case illustrates the central role of ECG as a diagnostic tool in rare cardiovascular diseases, allowing early recognition, targeted genetic investigation, and prevention of arrhythmia-induced cardiomyopathy. Bidirectional ventricular tachycardia is a distinct ECG pattern that should raise suspicion of Andersen-Tawil syndrome and warrants genetic evaluation with cascade family screening. In this patient, the combination of propafenone and beta-blocker therapy was associated with suppression of bidirectional ventricular tachycardia, significant reduction in ventricular arrhythmic load, and reversal of tachycardiomyopathy, suggesting a potential therapeutic alternative when flecainide is not available.
2026-07-01 | Polymorphic ventricular tachycardia with mutation in KCNJ2: case report.
Polymorphic ventricular tachycardia (VT), particularly in the absence of structural heart disease, has a strong genetic foundation primarily rooted in mutations affecting cardiac ion channels and associated regulatory proteins. Here, we report two patients with polymorphic VT harboring potassium channel subfamily J member 2 (KCNJ2) gene mutations. The first case is a 13-year-old girl presenting with periodic paralysis, polymorphic VT, and a prolonged QT interval. She was sequentially treated with metoprolol, verapamil, amiodarone, moricizine, and mexiletine, along with three radiofrequency catheter ablation sessions, but the therapeutic effect was unsatisfactory. Genetic testing revealed a de novo c.406T > C (p.S136P) variant in the KCNJ2 gene. During a 10-year follow-up period, she never experienced syncope. The second patient is a 5-year-old boy presenting with thumb adduction, polymorphic VT, and a prolonged QT interval. He was treated sequentially with metoprolol and flecainide, and his premature ventricular contraction burden decreased significantly after flecainide therapy. Genetic testing identified a de novo c.652C > T (p.A218T) variant in the KCNJ2 gene. This case report updates our understanding of KCNJ2 gene mutations. Arrhythmias due to KCNJ2 mutations respond poorly to antiarrhythmic drugs, but flecainide may be a promising therapeutic option. Arrhythmias associated with KCNJ2 mutations tend to have a more benign clinical course, but identifying mutation carriers at risk of life-threatening arrhythmias remains challenging.
2026-06-08 | T-Cell Acute Lymphoblastic Leukemia in a Young Patient With Andersen-Tawil Syndrome Successfully and Safely Treated With Intensive Chemotherapy Including Potential Precipitating Drugs: A Case Report After 3.5 Years of Follow-up.
Andersen-Tawil syndrome (ATS) is a rare, hereditary channelopathy characterized by periodic paralysis, cardiac arrhythmias, and sometimes developmental anomalies. No association with hematologic malignancies has previously been reported. We describe the case of a 27-year-old man with genetically confirmed Type 1 ATS who developed T-cell acute lymphoblastic leukemia. He was treated according to the GRAALL-2014 protocol and achieved sustained complete molecular remission without allogeneic transplantation after 3.5 years of follow-up. Management required careful adaptation to mitigate ATS-related risks. Specifically, QT-prolonging and neurotoxic agents were avoided or substituted, glucose infusions were minimized, and acetazolamide was introduced early. Despite exposure to high-dose corticosteroids and anthracyclines, only moderate, self-limited paralytic episodes occurred during intensive phases. During maintenance, ventricular ectopy and QT prolongation prompted chemotherapy dose adjustments and beta-blocker therapy, leading to rapid normalization. This case highlights the feasibility of delivering intensive chemotherapy in ATS with tailored supportive care. Although likely coincidental, this unprecedented association raises questions about potential links between ion channel dysfunction and leukemogenesis.
2026-05-01 | A51-21 Navigating the Challenges of Hypokalemic Periodic Paralysis
Abstract Introduction Hypokalemic periodic paralysis (HPP) is a rare autosomal dominant channelopathy characterized by transient episodes of muscle weakness or paralysis due to intracellular potassium shift and resultant hypokalemia. Attacks are often triggered by rest after exercise, high-carbohydrate meals, or stress. Although typically reversible with potassium repletion, recurrent episodes and variable responses to therapy make management challenging. We present a case of genetically confirmed HPP that illustrates diagnostic and therapeutic difficulties in long-term care. Case Report A 41-year-old man with a known family history of HPP presented with progressive, symmetric weakness of both lower and upper extremities over several hours despite taking over-the-counter potassium supplements. On arrival, his potassium was critically low at 1.9 mmol/L. He was admitted to the intensive care unit for cardiac monitoring and treated with intravenous and oral potassium, resulting in gradual recovery of strength and normalization of serum potassium. Despite careful repletion and counseling, he re-presented two months later with recurrent paralysis following strenuous physical activity and a carbohydrate-rich meal. Repeat labs confirmed hypokalemia (2.2 mmol/L) with otherwise normal electrolytes and thyroid function. Genetic testing identified a pathogenic CACNA1S mutation consistent with familial HPP. Long-term management included initiation of acetazolamide, dietary modification emphasizing low-glycemic carbohydrate intake, and structured outpatient monitoring to minimize recurrence. Discussion HPP arises from mutations in voltage-gated calcium or sodium channel genes (CACNA1S or SCN4A), leading to aberrant membrane excitability and intracellular potassium sequestration. The condition typically manifests in adolescence or early adulthood, with frequency and severity of attacks often declining with age. Acute management centers on cautious potassium repletion to restore muscle function while avoiding rebound hyperkalemia. Preventive therapy with carbonic anhydrase inhibitors such as acetazolamide or dichlorphenamide reduces attack frequency by stabilizing membrane excitability.This case underscores the unpredictable nature of potassium fluctuations even with close monitoring and adherence. Variability in absorption, dietary intake, and genetic phenotype can complicate potassium regulation, emphasizing the need for individualized replacement strategies. Broader awareness of HPP among clinicians is critical, as early recognition and tailored preventive care can significantly reduce morbidity and hospitalizations. This abstract is funded by: None
oligonucleotides
2024-03-25 | Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7
Abstract Objective Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. Methods and results We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis. Conclusion This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing. Graphical Abstract
small molecules
2026-08-14 | Late-Onset Episodic Weakness With Hyperkalemia Suggestive of Hyperkalemic Periodic Paralysis
A rare late-onset presentation of episodic weakness associated with hyperkalemia is described in a 72-year-old male with concurrent early-stage chronic lymphocytic leukemia. He experienced frequent episodes of generalized muscle weakness accompanied by loss of speech, shortness of breath, and fatigue, with a documented serum potassium level of 6.5 mmol/L obtained within 30 minutes of an attack. Treatment with acetazolamide and dietary modification was associated with a substantial reduction in episode frequency and improved functional status, although persistent fatigue remained. The clinical presentation was suggestive of hyperkalemic periodic paralysis, but a definitive diagnosis was limited by the patient's exceptionally late age at onset, negative genetic testing, lack of specialized exercise testing, and absence of electrophysiologic testing during an attack. This case emphasizes the importance of considering hyperkalemic periodic paralysis in the differential diagnosis of episodic weakness while simultaneously evaluating alternative neuromuscular, metabolic, hematologic, and paraneoplastic causes. Treatment response to acetazolamide and dietary modification was considered supportive of but not necessarily diagnostic of an inherited channelopathy.
2026-07-30 | Atypical Andersen-Tawil Syndrome in an Asymptomatic Child With Bidirectional Ventricular Tachycardia and Incipient Tachycardiomyopathy.
Bidirectional ventricular tachycardia is a rare electrocardiographic (ECG) finding, associated with a restricted group of clinical conditions, particularly hereditary channelopathies. An 11-year-old girl, asymptomatic from a cardiovascular point of view, was identified by family screening after detection in her father of a pathogenic variant in the KCNJ2 gene. The admission ECG showed bidirectional ventricular tachycardia. Clinical investigation revealed periodic paralysis and skeletal dysmorphisms, confirming a diagnosis of Andersen-Tawil syndrome. Pharmacological treatment significantly reduced the arrhythmic burden, with reverse ventricular remodeling at follow-up. This case illustrates the central role of ECG as a diagnostic tool in rare cardiovascular diseases, allowing early recognition, targeted genetic investigation, and prevention of arrhythmia-induced cardiomyopathy. Bidirectional ventricular tachycardia is a distinct ECG pattern that should raise suspicion of Andersen-Tawil syndrome and warrants genetic evaluation with cascade family screening. In this patient, the combination of propafenone and beta-blocker therapy was associated with suppression of bidirectional ventricular tachycardia, significant reduction in ventricular arrhythmic load, and reversal of tachycardiomyopathy, suggesting a potential therapeutic alternative when flecainide is not available.
2026-07-01 | Polymorphic ventricular tachycardia with mutation in KCNJ2: case report.
Polymorphic ventricular tachycardia (VT), particularly in the absence of structural heart disease, has a strong genetic foundation primarily rooted in mutations affecting cardiac ion channels and associated regulatory proteins. Here, we report two patients with polymorphic VT harboring potassium channel subfamily J member 2 (KCNJ2) gene mutations. The first case is a 13-year-old girl presenting with periodic paralysis, polymorphic VT, and a prolonged QT interval. She was sequentially treated with metoprolol, verapamil, amiodarone, moricizine, and mexiletine, along with three radiofrequency catheter ablation sessions, but the therapeutic effect was unsatisfactory. Genetic testing revealed a de novo c.406T > C (p.S136P) variant in the KCNJ2 gene. During a 10-year follow-up period, she never experienced syncope. The second patient is a 5-year-old boy presenting with thumb adduction, polymorphic VT, and a prolonged QT interval. He was treated sequentially with metoprolol and flecainide, and his premature ventricular contraction burden decreased significantly after flecainide therapy. Genetic testing identified a de novo c.652C > T (p.A218T) variant in the KCNJ2 gene. This case report updates our understanding of KCNJ2 gene mutations. Arrhythmias due to KCNJ2 mutations respond poorly to antiarrhythmic drugs, but flecainide may be a promising therapeutic option. Arrhythmias associated with KCNJ2 mutations tend to have a more benign clinical course, but identifying mutation carriers at risk of life-threatening arrhythmias remains challenging.
2026-06-08 | T-Cell Acute Lymphoblastic Leukemia in a Young Patient With Andersen-Tawil Syndrome Successfully and Safely Treated With Intensive Chemotherapy Including Potential Precipitating Drugs: A Case Report After 3.5 Years of Follow-up.
Andersen-Tawil syndrome (ATS) is a rare, hereditary channelopathy characterized by periodic paralysis, cardiac arrhythmias, and sometimes developmental anomalies. No association with hematologic malignancies has previously been reported. We describe the case of a 27-year-old man with genetically confirmed Type 1 ATS who developed T-cell acute lymphoblastic leukemia. He was treated according to the GRAALL-2014 protocol and achieved sustained complete molecular remission without allogeneic transplantation after 3.5 years of follow-up. Management required careful adaptation to mitigate ATS-related risks. Specifically, QT-prolonging and neurotoxic agents were avoided or substituted, glucose infusions were minimized, and acetazolamide was introduced early. Despite exposure to high-dose corticosteroids and anthracyclines, only moderate, self-limited paralytic episodes occurred during intensive phases. During maintenance, ventricular ectopy and QT prolongation prompted chemotherapy dose adjustments and beta-blocker therapy, leading to rapid normalization. This case highlights the feasibility of delivering intensive chemotherapy in ATS with tailored supportive care. Although likely coincidental, this unprecedented association raises questions about potential links between ion channel dysfunction and leukemogenesis.
2026-05-01 | A51-21 Navigating the Challenges of Hypokalemic Periodic Paralysis
Abstract Introduction Hypokalemic periodic paralysis (HPP) is a rare autosomal dominant channelopathy characterized by transient episodes of muscle weakness or paralysis due to intracellular potassium shift and resultant hypokalemia. Attacks are often triggered by rest after exercise, high-carbohydrate meals, or stress. Although typically reversible with potassium repletion, recurrent episodes and variable responses to therapy make management challenging. We present a case of genetically confirmed HPP that illustrates diagnostic and therapeutic difficulties in long-term care. Case Report A 41-year-old man with a known family history of HPP presented with progressive, symmetric weakness of both lower and upper extremities over several hours despite taking over-the-counter potassium supplements. On arrival, his potassium was critically low at 1.9 mmol/L. He was admitted to the intensive care unit for cardiac monitoring and treated with intravenous and oral potassium, resulting in gradual recovery of strength and normalization of serum potassium. Despite careful repletion and counseling, he re-presented two months later with recurrent paralysis following strenuous physical activity and a carbohydrate-rich meal. Repeat labs confirmed hypokalemia (2.2 mmol/L) with otherwise normal electrolytes and thyroid function. Genetic testing identified a pathogenic CACNA1S mutation consistent with familial HPP. Long-term management included initiation of acetazolamide, dietary modification emphasizing low-glycemic carbohydrate intake, and structured outpatient monitoring to minimize recurrence. Discussion HPP arises from mutations in voltage-gated calcium or sodium channel genes (CACNA1S or SCN4A), leading to aberrant membrane excitability and intracellular potassium sequestration. The condition typically manifests in adolescence or early adulthood, with frequency and severity of attacks often declining with age. Acute management centers on cautious potassium repletion to restore muscle function while avoiding rebound hyperkalemia. Preventive therapy with carbonic anhydrase inhibitors such as acetazolamide or dichlorphenamide reduces attack frequency by stabilizing membrane excitability.This case underscores the unpredictable nature of potassium fluctuations even with close monitoring and adherence. Variability in absorption, dietary intake, and genetic phenotype can complicate potassium regulation, emphasizing the need for individualized replacement strategies. Broader awareness of HPP among clinicians is critical, as early recognition and tailored preventive care can significantly reduce morbidity and hospitalizations. This abstract is funded by: None
oligonucleotides
2024-03-25 | Transcriptome and open chromatin analysis reveals the process of myocardial cell development and key pathogenic target proteins in Long QT syndrome type 7
Abstract Objective Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. Methods and results We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis. Conclusion This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing. Graphical Abstract
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