hypokalemic periodic paralysis ( hokpp ) is an autosomal dominant disorder characterized by recurrent episodes of reversible flaccid paralysis with concomitant hypokalemia and it is the most common form of primary periodic paralysis1 ) . symptoms begin in the first or second decades of life and the severity varies greatly in terms of frequency and duration of paralytic attacks . well - known precipitating factors are a carbohydrate - rich meal , rest after strenuous exercise , emotional stress , and preceding infections2 ) . the diagnosis of hokpp is made if there are recurrent attacks of paralysis and hypokalemia , without any apparent cause for hypokalemia1 ) . patients with hokpp can be grouped according to the underlying molecular genetic defects ; hokpp type 1 ( online mendelian inheritance in man [ omim ] 170400 ) is due to mutations in the -subunit of the dhp - receptor ( cacna1s)gene3 ) and hokpp type 2 ( omim 613345 ) is due to mutations in the -subunit of the sodium channel ( scn4a ) gene4 ) . although there are no significant differences in clinical presentation between the two groups , difference in response to treatment with certain scn4a gene mutation has been reported5 ) . we report two patients diagnosed with hokpp type 1 and type 2 after identifying p.arg528his mutation of the cacna1s and p.arg672his mutation of the scn4a , respectively . he had a history of transient lower extremity weakness fo llowing an upper respiratory infection 2 years ago . the patient was unable to move his limbs when he got up from a nap . he denied any recent weight change , diarrhea , chest pain , or heat intolerance . he had no significant past medical history , except the transient weakness 2 years ago . his family history revealed no similar episodes and no other significant illnesses other than the hypothyroidism of the patient 's mother . a clinical examination revealed normal vital signs ( blood pressure , 120/66 mmhg ; heart rate , 94 beats / min ; respiration rate , 20 breaths / min ; body temperature , 36 ) , unremarkable cardiopulmonary examinations , and no thyroid enlargement . a neurological examination revealed symmetric upper and lower extremity weakness ( grade iii / v ) and decreased deep tendon reflex . sensory change , muscular atrophy , myotonia , and pyramidal tract signs were not present . laboratory tests including thyroid function test , routine chemistry ( blood urea nitrogen [ bun ] , 11 mg / dl ; creatinine , 0.8 mg / dl ) , electrolyte ( sodium , 140 mmol / l ; chloride , 106 mmol / l ; bicarbonate , 20 mmol / l ) , complete blood count , urinalysis ( ph 6.0 ) , and urine chemistry were normal except for a serum potassium level of 1.9 ( 3.5 to 5.5 an electrocardiogram revealed typical findings of hypokalemia such as st segment depression , t wave flattening , and u waves . intravenous potassium ( 20 meq/10 ml ) mixed with normal saline ( 240 ml , concentration 80 after the intravenous replacement , oral potassium chloride supplementation was started ( k - contin 600 mg bid ) . the patient 's symptoms completely resolved the next day with intravenous and oral potassium replacement . studies to reveal the cause of hypokalemia at the outpatient clinic including serum renin and aldosterone were normal . after the first episode , the patient was started on an oral potassium supplement and had yearly attacks of paralysis with concomittant hypokalemia during the next 3 years . however , the number of attacks increased to twice per month in the recent few months without an identifiable cause . the paralytic attacks decreased after treatment with acetazolamide and the patients was attack - free for 3 months . direct sequencing of exons 11 and 30 of cacna1s and exon 12 of scn4a were performed as an initial step of genetic diagnosis . a heterozygous c.1583g > a ( p.arg528his ) mutation of cacna1s exon 11 was identified ( fig . 1 ) . a 15-year - old male presented to the emergency department with sudden onset lower extremity weakness . he denied any recent weight change , diarrhea , chest pain , or heat intolerance . he had no significant past medical history , except an incidentally detected transient microscopic hematuria at the age of 7 and acute appendicitis at the age of 8 . his family history revealed no similar episodes and no other significant illnesses . a clinical examination revealed normal vital signs ( blood pressure , 128/84 mmhg ; heart rate , 70 beats / min ; respiration rate , 20 breaths / min , body temperature , 36.6 ) , unremarkable cardiopulmonary examinations , and no thyroid enlargement . a neurological examination revealed upper symmetric and lower extremity weakness ( upper , grade iii / v ; lower , grade ii / v ) and an absent deep tendon reflex . sensory change , muscular atrophy , myotonia , and pyramidal tract signs were not present . laboratory tests including thyroid function test , routine chemistry ( bun , 11 mg / dl ; creatinine , 0.77 mg / dl ) , electrolyte ( sodium , 140 mmol / l ; chloride , 106 mmol / l ; bicarbonate , 20 mmol / l ) , complete blood count , urinalysis ( ph 6.0 ) , and urine chemistry were normal except for a serum potassium level of 2.3 ( 3.5 to 5.5 intravenous potassium ( 20 meq/10 ml ) mixed with normal saline ( 490 ml , concentration 40 meq / l ) was infused over five hours while monitoring the electrocardiogram . after the intravenous replacement , oral potassium chloride supplementation was started ( k - contin 600 mg bid ) . serum potassium level immediately after the intravenous replacement and the next day was 3.0 and 5.2 studies to reveal the cause of hypokalemia at the outpatient clinic , including serum renin and aldosterone , were normal . the patient was started on spironolactone and he had no further attacks for the last 4 months . direct sequencing of exons 11 and 30 of cacna1s and exon 12 of scn4a were performed as an initial step of genetic diagnosis . a heterozygous c.2015g > a ( p.arg672his ) mutation of scn4a exon 12 was identified ( fig . he had a history of transient lower extremity weakness fo llowing an upper respiratory infection 2 years ago . the patient was unable to move his limbs when he got up from a nap . he denied any recent weight change , diarrhea , chest pain , or heat intolerance . he had no significant past medical history , except the transient weakness 2 years ago . his family history revealed no similar episodes and no other significant illnesses other than the hypothyroidism of the patient 's mother . a clinical examination revealed normal vital signs ( blood pressure , 120/66 mmhg ; heart rate , 94 beats / min ; respiration rate , 20 breaths / min ; body temperature , 36 ) , unremarkable cardiopulmonary examinations , and no thyroid enlargement . a neurological examination revealed symmetric upper and lower extremity weakness ( grade iii / v ) and decreased deep tendon reflex . sensory change , muscular atrophy , myotonia , and pyramidal tract signs were not present . laboratory tests including thyroid function test , routine chemistry ( blood urea nitrogen [ bun ] , 11 mg / dl ; creatinine , 0.8 mg / dl ) , electrolyte ( sodium , 140 mmol / l ; chloride , 106 mmol / l ; bicarbonate , 20 mmol / l ) , complete blood count , urinalysis ( ph 6.0 ) , and urine chemistry were normal except for a serum potassium level of 1.9 ( 3.5 to 5.5 an electrocardiogram revealed typical findings of hypokalemia such as st segment depression , t wave flattening , and u waves . intravenous potassium ( 20 meq/10 ml ) mixed with normal saline ( 240 ml , concentration 80 after the intravenous replacement , oral potassium chloride supplementation was started ( k - contin 600 mg bid ) . the patient 's symptoms completely resolved the next day with intravenous and oral potassium replacement . studies to reveal the cause of hypokalemia at the outpatient clinic including serum renin and aldosterone were normal . after the first episode , the patient was started on an oral potassium supplement and had yearly attacks of paralysis with concomittant hypokalemia during the next 3 years . however , the number of attacks increased to twice per month in the recent few months without an identifiable cause . the paralytic attacks decreased after treatment with acetazolamide and the patients was attack - free for 3 months . direct sequencing of exons 11 and 30 of cacna1s and exon 12 of scn4a were performed as an initial step of genetic diagnosis . a heterozygous c.1583g > a ( p.arg528his ) mutation of cacna1s exon 11 was identified ( fig . a 15-year - old male presented to the emergency department with sudden onset lower extremity weakness . he denied any recent weight change , diarrhea , chest pain , or heat intolerance . he had no significant past medical history , except an incidentally detected transient microscopic hematuria at the age of 7 and acute appendicitis at the age of 8 . his family history revealed no similar episodes and no other significant illnesses . a clinical examination revealed normal vital signs ( blood pressure , 128/84 mmhg ; heart rate , 70 beats / min ; respiration rate , 20 breaths / min , body temperature , 36.6 ) , unremarkable cardiopulmonary examinations , and no thyroid enlargement . a neurological examination revealed upper symmetric and lower extremity weakness ( upper , grade iii / v ; lower , grade ii / v ) and an absent deep tendon reflex . sensory change , muscular atrophy , myotonia , and pyramidal tract signs were not present . laboratory tests including thyroid function test , routine chemistry ( bun , 11 mg / dl ; creatinine , 0.77 mg / dl ) , electrolyte ( sodium , 140 mmol / l ; chloride , 106 mmol / l ; bicarbonate , 20 mmol / l ) , complete blood count , urinalysis ( ph 6.0 ) , and urine chemistry were normal except for a serum potassium level of 2.3 ( 3.5 to 5.5 intravenous potassium ( 20 meq/10 ml ) mixed with normal saline ( 490 ml , concentration 40 meq / l ) was infused over five hours while monitoring the electrocardiogram . after the intravenous replacement , oral potassium chloride supplementation was started ( k - contin 600 mg bid ) . serum potassium level immediately after the intravenous replacement and the next day was 3.0 and 5.2 studies to reveal the cause of hypokalemia at the outpatient clinic , including serum renin and aldosterone , were normal . the patient was started on spironolactone and he had no further attacks for the last 4 months . direct sequencing of exons 11 and 30 of cacna1s and exon 12 of scn4a were performed as an initial step of genetic diagnosis . a heterozygous c.2015g > a ( p.arg672his ) mutation of scn4a exon 12 was identified ( fig . typical clinical presentation of hokpp is recurrent attacks of flaccid paralysis and hypokalemia beginning in the first two decades1 ) . two different genes , cacna1s and scn4a , are identified as responsible for the molecular genetic cause of hokpp type 1 and type 2 , respectively3,4 ) . there are reports of genotype - phenotype correlations in certain mutations regarding the age of onset , frequency or duration of attacks , and triggering factors6 ) . however , there were no differences between the cacna1s and scn4a group in terms of clinical presentations including the age of onset , attacks of flaccid paralysis and hypokalemia , precipitating factors , and outcomes2,7 ) . the two patients in this report , who carried the mutation in different causative genes , also manifested a similar clinical presentation of hokpp . the exact pathophysiologic mechanisms how these mutations in cacna1s and scn4a genes produce prolonged muscle paralysis are not identified . however , paradoxical sustained muscle membrane depolarization in response to hypokalemia was demonstrated in both calcium channel and sodium channel mutations8 - 10 ) . the voltagegated calcium channel located in the t - tubule of the skeletal muscle fiber ( cav 1.1 ) has a function of excitation and contraction coupling . the p.arg528his mutation substitutes the positively charged arginine to lesser charged histidine , in the s4 segment of domain ii , which is thought to be a voltage sensor of the channel . this substitution resulted in reduced calcium current density and rate of activation , finally causing reduced excitability11 ) . tricarico et al.12 ) showed reduced open probability and conductance states and hypothesized that abnormal potassium channel conductance resulted from altered calcium homeostasis . the " loss - of - function " feature of smaller currents and slower activation was demonstrated from cardiac rabbit mutant channel which contained mutation of segment 4/domain ii13 ) . the voltagedependent sodium channel of the skeletal muscle ( nav 1.4 ) has a function of action potential generation in response to membrane depolarization , which finally resulted in muscle contraction . rudel et al.14 ) showed reduced excitability and increased sodium conductance in response to hypokalemia , and suggested these findings were the basic defects in hokpp type 2 . the p.arg672his mutation resulted in reduced current and enhanced inactivation which finally caused impaired muscle contraction9,15 ) . the authors of these reports suggested that this depolarization causes paralysis in both types of hokpp8 - 12 ) . although the clinical presentation did not vary significantly between the two groups of hokpp , there are reports of different responses to treatment with acetazolamide in patients carrying a certain mutation of the scn4a . the frequency and severity of attacks increased in some patients with p.arg672gly and p.arg672ser mutations of the scn4a gene after treatment with acetazolamide4,5,16 ) . on the contrary , report , patient 1 who harbored a cacna1s mutation ( p.arg528his ) showed good response to the potassium supplement having only 2 attacks in 3 years . however , the attacks occurred more frequently without any identifiable cause resulting in 2 to 3 attacks a month . this finding is concordant with previous reports that acetazolamide is frequently effective in patients with the cacna1s gene mutation . acute attacks are treated with potassium replacement to normalize serum potassium and to shorten the duration of the attacks . an oral potassium supplement , acetazolamide , and spironolactone are used to prevent recurrent paralytic episodes with varying degrees of effectiveness2 ) . treatment with acetazolamide should be initiated carefully because of the risk of worsening symptoms in patients with certain genotypes . molecular genetic analysis of case series studies revealed that 65 to 80% of the hokpp cases are caused by the mutation in the cacna1s and scn4a ( cacna1s , 55 to 70% and scn4a , 8 to 10%)1,6,17 ) . the mutations identified in this study are the most common mutation of the cacna1s and the scn4a gene1 ) . a study done in korea revealed that the cacna1s and the scn4a mutation were responsible for hokpp in 75% and 25% of the patients , respectively , and the most frequent mutation was p.arg528his for hokpp17 ) . molecular genetic diagnosis is usually made after the clinical diagnosis of hokpp in patients with periodic paralysis . sternberg et al.2 ) proposed a testing strategy of sequencing exons 11 and 30 of cacna1s and exons 12 and 18 of scn4a , based on the frequency of pathogenic mutations identified . patient 2 was diagnosed hokpp 2 immediately after his first attack of paralysis and hypokalemia . molecular genetic diagnosis must be made for all patients with hokpp because genetic counseling is very important . moreover , we can increase the diagnostic yield by applying the testing strategy based on the genotype frequency of the population . the patients in this report presented with similar clinical manifestation of acute paralysis and hypokalemia . however , molecular genetic analysis revealed mutations in different causative genes ( cacna1s and scn4a ) . preventive treatment with acetazolamide was effective in patient 1 who harbored p.arg528his mutation in the cacna1s . molecular genetic diagnosis was made after the first episode in patient 2 and p.arg672his mutation was identified in the scn4a .
primary hypokalemic periodic paralysis ( hokpp ) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia . 
 hokpp is divided into type 1 and type 2 based on the causative gene . 
 although 2 different ion channels have been identified as the molecular genetic cause of hokpp , the clinical manifestations between the 2 groups are similar . 
 we report the cases of 2 patients with hokpp who both presented with typical clinical manifestations , but with mutations in 2 different genes ( cacna1sp.arg528his and scn4a p.arg672his ) . despite the similar clinical manifestations , there were differences in the response to acetazolamide treatment between certain genotypes of scn4a mutations and cacna1s mutations . 
 we identified p.arg672his in the scn4a gene of patient 2 immediately after the first attack through a molecular genetic testing strategy . 
 molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment .