Hypokalemic Periodic Paralysis Research Articles

Neurological manifestations of hypokalemia: a case report

Hypokalemic Periodic Paralysis (HPP) is a neurological manifestation of hypokalemia, with a prevalence of 1 in 100,000. HPP is recognized by the sudden onset of muscle paralysis and low serum potassium. Due to its various causes, it may be misdiagnosed and neglected.
 We present a case of 42-year-old Asian female with weakness of both legs and cramps. The weakness was felt upon awakening from sleep. She also complained of palpitation, tiredness, sweating, heat intolerance, and hand tremors. In the recent weeks, her appetite increased.
 Periodic paralysis (PP) is characterized by bursts of painless muscle weakening. A possible cause of periodic paralysis is hypokalemia which was found in our case. Hyperthyroid is classified into potassium depletion by extra renal route which was found in this case. Management
 When managing a patient with sudden onset weakness or paralysis, it is crucial to consider the possibility of periodic paralysis. HPP is a rare but serious medical emergency. This should be suspected in any patient presenting with sudden muscle weakness. Prompt correction of any abnormalities in potassium levels can lead to rapid and complete symptom resolution. To avoid persistent or recurrent paralysis, any underlying causes should be effectively managed wherever possible.
 Keywords: Hypokalemia; Paralysis; Hyperthyroid; Hypokalemic Periodic Paralysis
 Citation: Puspamaniar VA, Firdha AA, Azizah N, Hidayati HB. Neurological manifestations of hypokalemia: a case report. Anaesth. pain intensive care 2024;28(1):187−190; DOI: 10.35975/apic.v28i1.2387
 Received: September 03, 2023; Reviewed: September 16, 2023; Accepted: September 19, 2023

A Curious Case of Quadriplegia

Background: Hypokalemic periodic paralysis (HPP) is an uncommon disorder of the muscle marked by intermittent weakness of muscles , which, in severe cases, can progress to respiratory failure. It is frequently associated with renal tubular acidosis, a condition that can manifest in connection with systemic disorders like Sjögren’s syndrome and thyroid disorders.  Case Presentation: A 58-years-old woman presented to the hospital with weakness in all extremities. The patient exhibited motor strength of 0/5 in all limbs. The ECG revealed sinus bradycardia and hypokalemia changes. Laboratory tests showed hypokalemia, metabolic acidosis with a high anion gap, urine pH of more than 5.5, FT4 levels at 6.9 ng/dL, TSH levels at 25.03 IU/mL, Anti-TPO antibodies positive, and a positive SS-A (Ro), Ro-52, SS-B (La) in the ANA profile, indicative of Sjogren's syndrome. Patient has previously experienced similar issues and also has a confirmed diagnosis of hypothyroidism.  Discussion: The patient received diagnoses of hypokalemic periodic paralysis(HPP), Sjögren's syndrome, and renal tubular acidosis due to findings of hypokalemia, metabolic acidosis, elevated urine pH, and a positive ANA profile.  Conclusion: Distal renal tubular acidosis secondary to Sjögren’s syndrome can rarely present as HPP.

349 Atypical hypokalemic periodic paralysis secondary to Conn syndrome

349 Atypical hypokalemic periodic paralysis secondary to Conn syndrome

LAPORAN KASUS: HIPOKALEMIA PERIODIK PARALISIS

Hypokalemic periodic paralysis is one form of rare periodic paralysis that can result in sudden weakness. Comprehensive examination is required to determine the management in such cases. This case report discusses a 26-year-old woman who presented to the hospital with a sudden complaint of weakness in all limbs and no neurological deficits. The patient had a history of being admitted three times in the past year with the same complaint. Laboratory results revealed significantly low potassium levels. Although rare, periodic paralysis must be promptly distinguished from other causes of weakness and paralysis. Immediate and appropriate actions are crucial. After rapid administration of potassium through a central vein, the limb weakness disappeared. The patient had a history of three admissions with severe hypokalemia. Abdominal ultrasound revealed mild right hydronephrosis. In this case, the patient fully recovered after receiving both oral and intravenous potassium supplementation with strict ECG monitoring in the ICU. The patient returned to the ward after 2 days in the ICU and was subsequently referred to a nephrology specialist for the management of the observed hydronephrosis. This is important to identify the underlying cause of recurrent hypokalemic paralysis

High carbohydrate diet induced hypokalemic periodic paralysis: A case report

Hypokalemic periodic paralysis (HypoKPP) is a rare disorder characterised by the sudden onset of muscle weakness associated with low serum potassium levels. A 54-year-old man was admitted to the hospital with an abrupt onset of weakness in his right upper and lower extremities which slowly progressed to involve his left upper and lower extremities. He reported having consumed a carbohydrate-rich meal the day before the episode. Laboratory tests indicated severe hypokalemia with a serum potassium level of 2.3 mEq/L. He was treated with intravenous potassium chloride and his paralysis resolved after correction of hypokalemia. The patient was discharged on potassium supplementation and dietary guidelines were advised.

Primary Hyperaldosteronism is An Unusual Cause of Periodic Paralysis: a case report

Primary hyperaldosteronism a synonym for Conn's syndrome is characterized by hypernatremia, arterial hypertension, and, in certain situations, potentially fatal hypokalemia. A rare class of neuromuscular disorders known as periodic paralysis (PP) is brought on by an affection of the skeletal muscle's ion channels. In patients with hypokalaemic PP, potassium levels are normal in between attacks, but they remain low in those with secondary hypokalaemic PP. Although secondary causes of PP have been documented in the literature, the majority of cases are hereditary. We report the case of a 46-year-old man who had a history of hypertension and was admitted to the neurology ward after experiencing sudden-onset weakness in all four limbs, primarily affecting the lower limbs, two days earlier. This present case demonstrates a peculiar and severe primary hyperaldosteronism manifested by PP. Bangladesh J Medicine 2024; 35(1): 42-46

Crossover randomized controlled trial of bumetanide to rescue an attack of exercise induced hand weakness in hypokalaemic periodic paralysis

The aim of this study was to establish whether bumetanide can abort an acute attack of weakness in patients with HypoPP. This was a randomised, double-blind, cross-over, placebo-controlled phase II clinical trial. Focal attack of weakness was induced by isometric exercise of ADM followed by rest (McManis protocol). Participants had two study visits and received either placebo or 2 mg bumetanide at attack onset (defined as 40 % decrement in the abductor digiti minimi CMAP amplitude from peak). CMAP measurements assessed attack severity and duration. Nine participants completed both visits. CMAP percentage of peak amplitudes in the bumetanide (40.6 %) versus placebo (34.9 %) group at 1hr following treatment did not differ significantly (estimated effect difference 5.9 % (95 % CI: (-5.7 %; 17.5 %), p = 0.27, primary outcome). CMAP amplitudes assessed by the area under the curve for early (0–2hr post-treatment) and late (2–4 h post-treatment) efficacy were not statistically different between bumetanide and placebo (early effect estimate 0.043, p = 0.3; late effect estimate 0.085, p = 0.1). Two participants recovered from the attack following bumetanide intake; none recovered following placebo. Bumetanide was well tolerated but not efficacious to rescue a focal attack in an immobilised hand in the majority of patients, although data supports further studies of this agent.

Delayed Neurotoxic Paralysis with Confounding Hypokalaemia

Snakebite is a major health issue in India and developing nations across the globe. Common krait bites are associated with delayed paralysis and locked-in syndrome. Locked-in syndrome has been documented among patients of snakebite. Our case is unique due to the confounding effect of hypokalaemia which may confuse the physician as hypokalaemic periodic paralysis (HPP), a rare genetic condition which can also be precipitated by a stressful event such as snakebite. To the best of our knowledge, we could not associate the presence of hypokalaemia in patients of neurotoxic snakebite. As krait bite are often not associated with the history of having witnessed, a snake due to its nocturnal habit and painless bite, such hypokalaemia should not lead the physician to misdiagnose this snakebite as severe HPP. We urge our fellow researchers to look out for similar findings in their patients. Key messages: Locked-in syndrome in snakebites can be due to the effect of the venom in blood onto the ventral pons. To the best of our knowledge, we could not associate the presence of hypokalaemia in patients of neurotoxic snakebite. We presume this hypokalaemia to be nutritional in origin. As krait bites are often not associated with the history of having witnessed, a snake due to its nocturnal habit and painless bite, such hypokalaemia should not lead the physician to misdiagnose this snakebite as severe HPP. Keywords: Case report, Hypokalaemia, Neurotoxic, Snake envenomation

Prevalence and risk factors of low vitamin D levels in children and adolescents with familial hypokalemic periodic paralysis.

Vitamin D deficiency was highly prevalent in children with HOKPP, and vitamin D levels correlated with various disease characteristics. We recommend routine screening for vitamin D levels in these patients to address this prevalent deficiency. Considering the high prevalence of vitamin D deficiency observed, further research on other diseases characterized by reversible immobility is warranted. • A correlation between immobility and low serum vitamin D levels has been established. However, the vitamin D status of patients with familial hypokalemic periodic paralysis (HOKPP) who experience periods of reversible immobility remains unknown. • Vitamin D deficiency was highly prevalent in children with HOKPP, and vitamin D levels correlated with various disease characteristics.

SAT507 New Onset Graves’ Thyrotoxicosis Complicated by Hypokalemic Periodic Paralysis: A Late Sequela of COVID- 19 Infection

Abstract Disclosure: E. Askar: None. H. Basharat: None. L. Lotfi: None. Y. Jamal: None. Background: Thyrotoxic periodic paralysis (TPP)is a rare endocrine emergency identified by hypokalemia and ascending symmetrical paralysis of extremities. If left untreated, it can lead to cardiopulmonary collapse. There are cases in the literature highlighting that Covid-19 infection or Covid vaccination can cause hypokalemic periodic paralysis with or without thyroid dysfunction. To our knowledge, four cases of Covid induced TPP and three cases of TPP after Covid vaccination have been reported in the literature. In all cases, the patients developed TPP soon after (within two months) Covid-19 infection or vaccination. However, we describe a case of a young, healthy euthyroid male who developed TPP as an initial manifestation of new-onset Graves' disease after five months of Covid infection. Even though Covid-19 infection has been known to cause thyroid dysfunction, especially subacute thyroiditis, there have only been a few case reports of Covid induced Graves' disease presenting as TPP at initial diagnosis. Clinical Case: A 37-year-old Asian male with no past medical history presented to the emergency department with lower extremity paralysis, palpitations, tremors and diaphoresis one day prior to presentation. He was diagnosed with mild COVID 19 infection, five months prior to presentation. Since then, he has been having intermittent palpitations but did not have any other symptoms. Vital signs on admission revealed heart rate of 100 beats/min, respiratory rate of 16 breaths/min, blood pressure of 131/66 mmHg, temperature of 97.5°F and oxygen saturation of 98% on room air. Physical examination was significant for an anxious young male with tender enlarged thyroid gland. There was positive thyroid bruit. Pemberton sign was negative. Muscle strength of 1/5 in bilateral lower extremities with brisk deep tendon reflexes and tremors in both hands were noticed. Laboratory studies showed white blood cell count of 13.07 (3.80-10.50 x 109/L), serum potassium of 1.4 mmol/L (3.5-5.3) and thyroid stimulating hormone of <0.01 mIU/L (0.358-3.74), free thyroxine of 5.5 ng/dl (0.9-1.8), total Triiodothyronine of 438 ng/dl (80-200) and positive thyroid stimulating immunoglobin of 4.22 IU/l (0.00-0.55) confirming Graves' disease as a diagnosis causing thyrotoxicosis with periodic paralysis. Patient did not have any history of thyroid disease with no available previous thyroid function tests. Patient was admitted to intensive care unit. Judicious repletion of potassium was done and he was started on propranolol 40 mg daily and methimazole 30 mg daily that lead to resolution of his paralysis and hyperthyroid symptoms. Conclusion: Here we report a case of new onset Graves' disease with TTP after COVID 19 increasing the likelihood that Covid 19 is a direct cause of new onset autoimmune thyroid illness. More studies are required to identify the mechanism and to confirm if the relationship is causal. Presentation Date: Saturday, June 17, 2023

A novel CACNA1S gene variant in a child with hypokalemic periodic paralysis: a case report and literature review

BackgroundThe CACNA1S gene encodes the alpha 1 S-subunit of the voltage-gated calcium channel, which is primarily expressed in the skeletal muscle cells. Pathogenic variants of CACNA1S can cause hypokalemic periodic paralysis (HypoPP), malignant hyperthermia susceptibility, and congenital myopathy. We aimed to study the clinical and molecular features of a male child with a CACNA1S variant and depict the molecular sub-regional characteristics of different phenotypes associated with CACNA1S variants.Case presentationWe presented a case of HypoPP with recurrent muscle weakness and hypokalemia. Genetic analyses of the family members revealed that the proband had a novel c.497 C > A (p.Ala166Asp) variant of CACNA1S, which was inherited from his father. The diagnosis of HypoPP was established in the proband as he met the consensus diagnostic criteria. The patient and his parents were informed to avoid the classical triggers of HypoPP. The attacks of the patient are prevented by lifestyle changes and nutritional counseling. We also showed the molecular sub-regional location of the variants of CACNA1S which was associated with different phenotypes.ConclusionsOur results identified a new variant of CACNA1S and expanded the spectrum of variants associated with HypoPP. Early genetic diagnosis can help avoid diagnostic delays, perform genetic counseling, provide proper treatment, and reduce morbidity and mortality.

Hypokalemic Periodic Paralysis: A Case Report

Introduction: Hypokalemic Periodic Paralysis is one form of Periodic Paralysis, a rare group of disorders that can cause sudden onset weakness. Although rare, Periodic paralysis must be differentiated from other causes of weakness and paralysis so that the proper treatment can be initiated quickly. Case Report: A 72 year-old elderly male presented to the emergency room with sudden onset of paralysis. He had no respiratory or swallowing difficulty and was able to move his neck and facial muscles. Neurologic exam revealed flaccid paralysis bilateral lower extremities which involved the proximal and distal muscles. Sensation was intact but deep tendon reflexes were slightly diminished to 3 out of 4 throughout. RFT deranged with serum creatinine level of 1.7 (0.6- 1.2mg/dl), potassium level of 1.6 (3.5–5 mmol/L), magnesium level of 0.9 (1.3-2.1meq/l). Electrocardiogram revealed bradycardia and left axis deviation. Two hours after initiation of intravenous potassium replacement, the patient's neurologic symptoms started resolving. The patient was diagnosed with Hypokalemic Periodic Paralysis and was started on calcium channel blocker for control of blood pressure. He was discharged home with an appointment to follow up. Conclusion: Periodic Paralysis should be kept in mind when a patient comes with sudden onset weakness or paralysis, especially when other diseases have been ruled out. It can be life threatening if the treatment is improper, but intervention and subsequent correction of potassium abnormalities can clear the symptoms completely. The underlying etiology should be searched properly to avoid recurrence or persistence of the paralysis.

Hypokalemic periodic paralysis: a 3-year follow-up study

Background and objectivesPrimary hypokalemic periodic paralysis (HypoPP) is an inherited channelopathy most commonly caused by mutations in CACNA1S. HypoPP can present with different phenotypes: periodic paralysis (PP), permanent muscle weakness (PW), and mixed weakness (MW) with both periodic and permanent weakness. Little is known about the natural history of HypoPP.MethodsIn this 3-year follow-up study, we used the MRC scale for manual muscle strength testing and whole-body muscle MRI (Mercuri score) to assess disease progression in individuals with HypoPP-causing mutations in CACNA1S.ResultsWe included 25 men (mean age 43 years, range 18–76 years) and 12 women (mean age 42 years, range 18–76 years). Two participants were asymptomatic, 21 had PP, 12 MW, and two PW. The median number of months between baseline and follow-up was 42 (range 26–52). Muscle strength declined in 11 patients during follow-up. Four of the patients with a decline in muscle strength had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis. Fat replacement of muscles increased in 27 patients during follow-up. Eight of the patients with increased fat replacement had no attacks of paralysis during follow-up, and two of these patients had never had attacks of paralysis.DiscussionThe study demonstrates that HypoPP can be a progressive myopathy in both patients with and without attacks of paralysis.

Kidney manifestations of pediatric Sjögren's syndrome.

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.

Clinical features and recovery pattern of secondary hypokalaemic paralysis.

Information regarding frequency, details of neurological signs and recovery patterns of patients with secondary hypokalaemic paralysis (HP) is limited. This study aimed to analyse the frequency, aetiology, clinical features and recovery patterns of patients with secondary HP. The clinical and laboratory records of 18 consecutive patients with secondary HP aged ≥ 18years admitted to our hospital between April 2011 and March 2022 were reviewed. Patients with inherited hypokalaemic periodic paralysis were excluded. Of the 18 patients, 16 had a common aetiology: chronic alcoholism, diarrhoea or an imbalanced diet. Initial symptoms, such as fatigue, were often atypical. Three patients had prominent asymmetric limb weakness and four had predominant upper limb weakness. On admission, the mean serum potassium and creatine kinase (CK) levels of the patients were 1.90mmol/L and 4488U/mL, respectively. Ten patients (56%) had decreased potassium levels after admission, despite potassium replacement treatment (rebound hypokalaemia). Twelve patients presented with increased CK levels even after 2-5days (delayed hyperCKaemia). Low serum magnesium levels significantly correlated with rebound hypokalaemia. Secondary HP can be caused by a variety of conditions, but mainly occurs due to lifestyle conditions/disorders. Secondary HP often presents with atypical symptoms, and the initial symptoms can be non-specific. Rebound hypokalaemia and delayed hyperCKaemia are common in secondary HP, despite potassium replacement. As such, careful serial monitoring is needed for patients with secondary HP.

Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.

The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features. A total of 45 participants and eight healthy controls were enrolled and underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale. A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty-one (69%) had weakness, and 9 (20%) required a gait-aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri-tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness. We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.

Potential Benefit of Channel Activators in Loss-of-Function Primary Potassium Channelopathies Causing Heredoataxia.

Potassium channels (KCN) are transmembrane complexes that regulate the resting membrane potential and the duration of action potentials in cells. The opening of KCN brings about an efflux of K+ ions that induces cell repolarization after depolarization, returns the transmembrane potential to its resting state, and enables for continuous spiking ability. The aim of this work was to assess the role of KCN dysfunction in the pathogenesis of hereditary ataxias and the mechanisms of action of KCN opening agents (KCO). In consequence, a review of the ad hoc medical literature was performed. Among hereditary KCN diseases causing ataxia, mutated Kv3.3, Kv4.3, and Kv1.1 channels provoke spinocerebellar ataxia (SCA) type 13, SCA19/22, and episodic ataxia type 1 (EA1), respectively. The K+ efflux was found to be reduced in experimental models of these diseases, resulting in abnormally prolonged depolarization and incomplete repolarization, thereby interfering with repetitive discharges in the cells. Hence, substances able to promote normal spiking activity in the cerebellum could provide symptomatic benefit. Although drugs used in clinical practice do not activate Kv3.3 or Kv4.3 directly, available KCO probably could ameliorate ataxic symptoms in SCA13 and SCA19/22, as verified with acetazolamide in EA1, and retigabine in a mouse model of hypokalemic periodic paralysis. To summarize, ataxia could possibly be improved by non-specific KCO in SCA13 and SCA19/22. The identification of new specific KCO agents will undoubtedly constitute a promising therapeutic strategy for these diseases.

A rare complication of a relatively common disease: periodic paralysis caused by thyrotoxicosis

Thyrotoxic periodic paralysis is a sporadic form of hypo-kalemic periodic paralysis and it is most commonly presents as sudden onset weakness in the proximal muscles. It is a disorder most commonly seen in Asian men which is characterised by abrupt onset of hypo-kalemia and paralysis and it is primarily affects lower extremities and is secondary to thyrotoxicosis. It is due to an intracellular shift of potassium induced by thyroid hormone sensitisation of Na/K ATPase rather than depletion of total potassium. The absence of a family history, male predilection and, presentation in second to fourth decade of life and signs of thyrotoxicosis and sinus tachycardia help in the diagnosis of the disorder. The age of onset is later and corresponded with age of incidence of thyrotoxicosis. It is very essential to diagnose TPP early and treat appropriately.

Hypokalemic periodic paralysis as the first sign of thyrotoxicosis- a rare case report from Somalia

BackgroundThyrotoxic hypokalemic periodic paralysis (THPP) is a rare complication of hyperthyroidism characterized by thyrotoxicosis, hypokalemia, and paralysis. It is the most common form of acquired periodic paralysis. THPP is precipitated by strenuous exercise, a high carbohydrate diet, stress, infection, alcohol, albuterol, and corticosteroid therapy. It is most common in Asian men with hyperthyroidism and exceptionally rare in black people.Case PresentationA 29-year-old man was admitted to the emergency department in Somalia with a sudden onset of paralysis after a high carbohydrate meal. Laboratory investigations showed low serum potassium 1.8 mEq/l (3.5–4.5), and biochemical thyrotoxicosis with TSH 0.006 miu/l (0.35–5.1), total T3 3.2 ng/ml (0.9–2.8) and total T4 13.5 ng/ml (0.6–1.2). He was successfully treated with potassium chloride infusion and an antithyroid drug, methimazole.ConclusionTo prevent life-threatening cardiac and respiratory complications, it is critical to consider and diagnose THPP early, even in populations where the condition is rare.

Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.

Hypokalemic periodic paralysis (HypoPP) is a rare genetic disease associated with mutations in CACNA1S or SCN4A, encoding Cav1.1 or Nav1.4, respectively. Most HypoPP-associated missense changes occur at the arginine residues within the voltage-sensing domain (VSD) of these channels. It is established that such mutations destroy the hydrophobic seal separating the external water and the internal cytosolic crevices, resulting in the generation of aberrant leak currents called gating pore currents. Presently, the gating pore currents are thought to underlie HypoPP. Here, we generated HEK293T-based HypoPP-model cell lines with the Sleeping Beauty transposon system that co-express mouse inward-rectifier potassium channel (mKir2.1) and HypoPP2-associated Nav1.4 variants. Whole cell patch-clamp measurements confirmed that mKir2.1 successfully hyperpolarized the membrane potential to comparable levels to myofibers, and that some Nav1.4 variants induced notable proton-based gating pore currents. Importantly, we succeeded in fluorometrically measuring the gating pore currents in these variants using a ratiometric pH indicator, SNARF-4F. Our optical method provides a potential in vitro platform for high-throughput drug screen, not only for HypoPP but also for other channelopathies caused by VSD mutations.