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Hypokalemic Periodic Paralysis

Synonyms: HOKPP, HypoPP

, MD, , MD, PhD, , MD, , MD, , PhD, , PhD, , PharmD, PhD, , MD, PhD, , PhD, and , MD, PhD.

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Initial Posting: ; Last Update: July 31, 2014.

Summary

Clinical characteristics.

Hypokalemic periodic paralysis (HOKPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (<2.5 mmol/L), and occasionally may develop late-onset proximal myopathy. The paralytic attacks are characterized by reversible flaccid paralysis usually leading to paraparesis or tetraparesis but typically sparing the respiratory muscles and heart. Acute paralytic crises usually last at least several hours and sometimes days. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are carbohydrate-rich meals and rest after exercise; rarely, cold-induced hypokalemic paralysis has been reported. The interval between crises may vary and may be prolonged by preventive treatment with potassium salts or acetazolamide. The age of onset of the first attack ranges from one to 20 years; the frequency of attacks is highest between ages 15 and 35 and then decreases with age. A variable myopathy develops in at least 25% of affected individuals and may result in a progressive fixed muscle weakness that manifests at variable ages as exercise intolerance predominantly in the lower limbs. It may occur independent of paralytic symptoms and may be the sole manifestation of HOKPP. Individuals with HOKPP are at increased risk for pre- or post-anesthetic weakness and may be at an increased risk for malignant hyperthermia – though not as great a risk as in individuals with true autosomal dominant malignant hyperthermia susceptibility (MHS).

Diagnosis/testing.

The diagnosis of HOKPP is based on a history of episodes of flaccid paralysis with rapid installation and spontaneous recovery; low serum concentration of potassium (0.9 to 3.0 mmol/L) during attacks, but not between attacks; the identification of typical precipitating factors (i.e., rest after a strong physical exertion, prolonged immobility); and a family history consistent with autosomal dominant inheritance. Of all individuals meeting diagnostic criteria for HOKPP, approximately 60% have pathogenic variants in CACNA1S, approximately 20% in SCN4A, and approximately 3.5% in KCNJ18.

Management.

Treatment of manifestations. Treatment varies depending on the intensity and duration of the paralytic attack. Minor attacks may resolve spontaneously. Moderate attacks may be self-treated in a non-medical setting by ingestion of oral potassium salts. Severe attacks typically require more intensive medical management with intravenous potassium infusion, serial measurement of serum potassium concentration, clinical evaluation of possible respiratory involvement, and continuous electrocardiogram monitoring. There is no known curative treatment for HOKPP-related myopathy; physiotherapy may help to maintain strength and motor skills.

Prevention of primary manifestations. The goal of preventive treatment is to reduce the frequency and intensity of paralytic attacks. This may be achieved by avoidance of triggering factors; adherance to a diet low in sodium and carbohydrate and rich in potassium; and oral potassium supplementation. If dietary intervention and oral potassium supplementation are not effective in preventing attacks, acetazolamide treatment may be necessary. However, acetazolamide may exacerbate attacks, in which case alternative treatments (e.g., dichlorphenamide, triamterene, spironolactone) may be used.

Prevention of secondary complications. Creating a safe environment includes informing companions of the risk of paralytic attacks, educating the affected individual to ask for medical help in case of an unusually severe attack, and home modification to prevent falls and accidents. Anesthetic complications, including malignant hyperthermia, should be prevented by strict control of serum potassium concentration; avoidance of large glucose loads; maintenance of body temperature and acid-base balance; and careful use of neuromuscular blocking agents with continuous monitoring of neuromuscular function. It is unknown whether prevention of paralytic attacks also prevents the development of myopathy.

Surveillance. The frequency of consultations is adapted to the individual's signs/symptoms and response to preventive treatment. Periodic neurologic examination with attention to muscle strength in the legs should be performed to detect permanent weakness associated with myopathy. For those taking acetazolamide, the following are indicated every three months: complete blood count, electrolytes, glucose, uric acid, and liver enzyme levels. Renal ultrasound should be performed annually.

Agents/circumstances to avoid. Factors that trigger paralytic attacks (e.g., unusually strenuous effort, carbohydrate-rich meals, sweets, alcohol, prolonged immobility, oral or intravenous corticosteroids, glucose infusions) should be avoided when possible.

Evaluation of relatives at risk. When the family-specific pathogenic variant is known, molecular genetic testing of at-risk, asymptomatic family members can identify those at risk for unexpected acute paralysis and/or anesthetic complications.

Genetic counseling.

HOKPP is inherited in an autosomal dominant manner. Most individuals diagnosed with HOKPP have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant. Penetrance is about 90% in males and may be as low as 50% in females depending on the causative pathogenic variant. If the disease-causing allele has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the relevant gene or custom prenatal testing; however, requests for prenatal testing for conditions which (like HOKPP) do not affect intellect, are compatible with a nearly normal life, and have available treatment options are not common.

Diagnosis

Clinical Diagnosis

Hypokalemic periodic paralysis (HOKPP) can be a primary condition or a symptom of an overarching syndrome or disease (see Differential Diagnosis). This GeneReview focuses on primary HOKPP resulting from a genetic ion channel abnormality.

Consensus diagnostic criteria for primary hypokalemic periodic paralysis have been published in a Cochrane review [Sansone et al 2008]. The criteria:

  • Two or more attacks of muscle weakness with documented serum K <3.5 mEq/L
    OR
  • One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum K <3.5 mEq/L
    OR
  • Three of the following six clinical/laboratory features:
    • Onset in the first or second decade
    • Duration of attack (muscle weakness involving one or more limbs) longer than two hours
    • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress)
    • Improvement in symptoms with potassium intake
    • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation
    • Positive long exercise test (see Testing) [McManis et al 1986]
    AND
  • Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse)

For individuals who do not meet the diagnostic criteria above, a diagnosis of primary HOKPP may be suspected if an individual has the following symptoms and signs:

  • Decreased muscle tone (flaccidity)
  • Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles
  • Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes)
  • Concomitant hypokalemia that is usually pronounced (0.9-3.0 mmol/L)

The typical evolution of symptoms is as follows:

  • Rapid installation (over minutes or over hours)
  • Duration of several minutes to several days
  • Spontaneous recovery

Symptoms tend to occur under the following circumstances:

  • At rest after strong physical exertion
  • On awakening after a carbohydrate-rich meal the previous evening
  • After prolonged immobility (e.g., with long-distance travel)

Primary HOKPP may also be considered in individuals who have

  • A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs
  • A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics.

Testing

Clinical testing is often useful in making the diagnosis of primary hypokalemic periodic paralysis. However, the diagnosis cannot be established by clinical findings alone in the absence of a known family history of the condition.

In individuals who have had one or more paralytic episodes, several tests can be used to differentiate between primary HOKPP and the other possible causes.

Serum concentration of potassium during paralytic attack. During an attack, the serum concentration of potassium ranges from 0.9 to 3.0 mmol/L (normal range: 3.5-5.0 mmol/L).

Note: Measurement of the serum concentration of potassium during an attack is needed to classify a paralytic episode as hypokalemic.

Transtubular potassium concentration gradient and potassium-creatinine ratio during paralytic attack. The following can be used to distinguish between hypokalemia caused by renal (urinary) losses and hypokalemia caused by intracellular muscular shift of potassium (as occurs in primary HOKPP caused by a genetic ion channel defect) [Lin et al 2004]:

  • Urinary potassium concentration >20 mmol/L indicates urinary loss of potassium.
    Note: The threshold value of 20 mmol/L is not sufficient to distinguish between renal and non-renal hypokalemia.
  • Urinary potassium/creatinine ratio of >2.5 indicates urinary loss of potassium.
  • A transtubular potassium concentration gradient (TTKG) >3.0 suggests hypokalemia of renal origin.
    Note: The ratio: [urine potassium/plasma potassium]/[urine osmolality/blood osmolality]

Note: If a patient is already taking supplemental potassium, the urinary excretion of potassium is difficult to interpret, as high levels could be attributable to the supplementation.

Serum concentration of thyroid-stimulating hormone and free thyroxine and triiodothyronine may distinguish between primary HOKPP and thyrotoxic periodic paralysis (TPP) (see Differential Diagnosis).

Electromyogram (EMG). Muscle electrophysiologic testing must be performed during an interictal period. Protocols for implementation [Fournier et al 2004] and interpretation [Tan et al 2011] have been published. EMG testing includes:

  • Assessment for myotonic discharges
  • Repeated short exercise tests
  • A long exercise test (the principal discriminating test for primary periodic paralysis)

The diagnosis of primary hypokalemic periodic paralysis relies on:

  • The absence of myotonic discharges
    Note: One family with combined heat-induced myotonia and cold-induced hypokalemic periodic paralysis has been described [Sugiura et al 2000].
  • The presence of a progressive and marked decrease in the amplitude of compound motor action potentials (CMAP) during a long exercise test [McManis et al 1986].

During an attack, EMG findings are not specific; EMG demonstrates a reduced number of motor units and possibly myopathic abnormalities.

Between attacks, EMG may exhibit myopathic abnormalities in individuals with fixed myopathy.

Specific exercise tests can assist with the diagnosis of periodic paralyses and nondystrophic myotonias [Fournier et al 2004]:

  • Short exercise test (SET). SET consists of recording evoked compound muscle action potential (CMAP) every ten seconds over one minute after a short effort (5-12 seconds) [Streib 1987].
  • Long exercise test (LET). LET consists of recording evoked CMAP over 30-45 minutes, every one to two minutes and then every five minutes, after a long effort (2-5 minutes, with brief 3- to 4-second rest periods every 15-45 seconds) [McManis et al 1986].

Five patterns (I-V) of abnormal responses to SET and/or LET in periodic paralyses and nondystrophic myotonias have been described [Fournier et al 2004]. Genetically defined periodic paralyses specifically result in:

  • Pattern IV (no or rare myotonic discharges, increase of CMAP on SET, immediate increase and late marked decrease in LET), more commonly seen in the hyperkalemic type
    OR
  • Pattern V (no myotonic discharges, normal response to SET, no immediate increase but late marked decrease in LET), more commonly seen in the hypokalemic type

A false negative normal pattern may be noted in some individuals who have a pathogenic variant, especially in asymptomatic individuals or those who have not recently had a paralytic attack [Tengan et al 2004].

A decrease of at least 30% in CMAP amplitude and surface on LET is diagnostic for HOKPP. A decrease of less than 30% and greater than 20% is less specific and may indicate a different diagnosis. This decrease corresponds to pattern IV (with initial increment) and pattern V.

Muscle biopsy. Muscle biopsy is not necessary when the diagnosis is that of one or several recurrent paralytic episodes.

Molecular Genetic Testing

Genes. Three genes are associated with primary HOKPP. All three genes encode subunits of ion channels that are primarily expressed in skeletal muscle cells (see Molecular Genetics).

  • CACNA1S
  • SCN4A
  • KCNJ18

Evidence for possible locus heterogeneity. No other loci are known to be associated with primary HOKPP. One study suggested that pathogenic variants in another potassium channel gene, KCNE3, cause HOKPP [Abbott et al 2001] and thyrotoxic periodic paralysis [Dias Da Silva et al 2002a]; two further studies did not support this hypothesis, showing that this missense variant is present in 0.8%-1.5% of the healthy population [Sternberg et al 2003, Jurkat-Rott & Lehmann-Horn 2004]. Therefore, KCNE3 variants do not appear to be associated with primary HOKPP.

Molecular genetic testing is summarized in Table 1 and Table 2 (pdf) and in Figure 1.

Figure 1. . Localization of pathogenic missense variants of the S4 segments of Cav 1.

Figure 1.

Localization of pathogenic missense variants of the S4 segments of Cav 1.1 and Nav 1.4 that have been reported. Most are associated with HOKPP and account for nearly all genetically characterized cases of HOKPP.

Table 1.

Summary of Molecular Genetic Testing Used in Hypokalemic Periodic Paralysis

Gene 1Proportion of Hypokalemic Periodic Paralysis
Attributed to Mutation of This Gene
Test Method
CACNA1S~60% 2Sequence analysis 3, 4
SCN4A~20% 2Sequence analysis 3, 4
KCNJ18~3.5% 2Sequence analysis 3, 4
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

See Table 2 (pdf).

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Some laboratories may perform targeted sequence analysis of common pathogenic variants or of select exons prior to sequence analysis of the gene. See Table 2 and Testing Strategy.

Testing Strategy

To confirm/establish the diagnosis in a proband

Sequential molecular genetic testing. One approach to molecular genetic testing is targeted analysis of select exons for pathogenic variants, followed by full gene sequencing, if a pathogenic variant is not identified. This may be particularly useful for CACNA1S, which has 44 exons. Nearly all pathogenic variants are located in exons that encode for S4 helices (i.e., exons 4, 11, 21, and 30 in CACNA1S and exons 5, 12, 13, 18, and 24 in SCN4A; see Table 2).

1.

Testing for common pathogenic variants in exons 11 and 30 of CACNA1S and exon 12 of SCN4A by targeted analysis or sequencing of select exons may be considered first (see Table 2).

2.

If no pathogenic variant is identified, targeted testing for pathogenic variants in exons 4 and 21 of CACNA1S and exons 5, 13, 18, and 24 of SCN4A may be considered next (see Table 2).

3.

If no pathogenic variant is identified, full gene sequence analysis of SCN4A and CACNA1S may be considered. Reevaluation of the affected individual and genetic testing for syndromic HOKPP is another option to consider (see Differential Diagnosis).

4.

If no pathogenic variant is identified, sequence analysis of KCNJ18 may be considered (see Table 2).

Multi-gene panel. Another approach to molecular genetic testing is use of a multi-gene panel in which some or all of the genes leading to primary and/or syndromic HOKPP are sequenced simultaneously. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in a given affected individual also varies.

Clinical Characteristics

Clinical Description

Large-scale studies of the natural history of primary hypokalemic periodic paralysis have rarely been performed. Thus, knowledge of the natural history relies largely on personal observations and on individual cases that have been published with a retrospective description of the individual disease history.

Pattern of attacks. The natural history and expressivity vary greatly over time. Frequency ranges from a single occurrence of a paralytic attack that may be triggered by exceptional circumstances (extreme physical effort, specific medical intervention) to spontaneous recurrent attacks of variable frequency (ranging from multiple attacks daily to less frequent attacks). This pattern may more or less be linked to identifiable temporal and behavioral circumstances, and may evolve over years.

Triggers of paralytic attacks. There may be identifiable triggers for paralytic attacks in hypokalemic periodic paralysis. In a cohort study by Miller et al [2004], affected individuals were given a list of triggers and asked which trigger applied to their own case. Note: The percentages of affected individuals who reported the following as triggers are from the study by Miller et al [2004].

  • Cessation of effort following strenuous exercise (e.g., football match) may trigger a paralytic attack. Approximately 67% of affected individuals identified exercise as a trigger.
  • Carbohydrate-rich evening meals followed by nocturnal rest may result in an immobilizing paralytic attack in the morning. Approximately 45% of affected individuals identified heavy meals or sweets as a trigger.
  • Additional triggers reported by affected individuals:
    • Cold: ~24%
    • Stress: ~12%
    • Salt: ~11%
  • Prolonged immobility was not proposed in the list of triggers in the study by Miller et al [2004].

Age of onset of paralytic attacks. Two cohort studies have addressed this issue [Sternberg et al 2001, Miller et al 2004].

  • The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Disease onset is not likely after 30 years of age.
  • Symptom onset is correlated with sex (younger age of onset for girls than for boys) and with the specific underlying pathogenic variant (see Genotype-Phenotype Correlations).

Frequency of paralytic episodes

  • In a cohort study by Miller et al [2004], the mean frequency of paralytic attacks was seven per month (2 per week), with a range of one attack per day to one attack each trimester.
  • In general, the frequency of attacks peaks and then decreases with age – a finding that could be attributable to any or a combination of the following: better knowledge of the disease leading to avoidance of attack triggers, medical preventive treatments, or the natural evolution of the susceptibility of muscle to attacks.

Duration of paralytic episodes

  • In the cohort study by Miller et al [2004], the duration of a paralytic episode ranged from one hour to 72 hours, with a mean duration of nearly 24 hours.
  • Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack.

Potassium levels during paralytic episodes

  • The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by Sternberg et al [2001] and as 2.3 mmol/L in a cohort study by Miller et al [2004]. The lowest reported value was 1.2 mmol/L.
  • Occasionally, normal potassium values are noted. Whether the ictal potassium level depends on the specific underlying pathogenic variant is as yet unknown.

Permanent reversible fluctuating weakness. Most individuals have normal muscle strength and physical activity during the interictal period between paralytic attacks, but in some affected individuals and in some stages of the disease, there may be long-lasting permanent fluctuating weakness manifesting as abortive paralytic attacks occurring in rapid succession over a long period (weeks, months). Such attacks may respond to acetazolamide treatment (see Treatment of Manifestations).

Permanent fixed weakness. The development of permanent fixed weakness due to myopathic muscle changes appears to vary widely from one individual to another. Rarely, early signs of myopathy (e.g., Achille’s tendon shortening or scoliosis) may be present in childhood – possibly the result of more severe pathogenic variants.

No sufficiently large long-term study has addressed the frequency, age of development, and factors (e.g., sex of the affected individual, specific pathogenic variant present) associated with permanent fixed muscle weakness.

  • In a study of 11 affected individuals from the same pedigree ranging from age 33 to 74 years, Links et al [1990] showed that all demonstrated either morphologic (on muscle biopsy), radiologic (through CT scan of muscles), or clinical signs of myopathy:
    • The authors concluded that primary HOKPP is a myopathy with permanent muscle weakness of late onset that develops in all affected individuals independent of the history of paralytic attacks.
    • Whether this is true for all individuals with primary HOKPP, or for this particular pedigree with its particular (unknown) pathogenic variant, remains a question.
  • Some figures have been calculated by Sternberg et al [2001] from his cohort: the frequency of fixed permanent weakness among individuals of any age with molecularly proven HOKPP was 28%, and the age at which permanent weakness was identified ranged from eight to 66 years, with a mean age of 39 years.
  • From a survey in which participants were recruited by a patient support group, Cavel-Greant et al [2012] collected data from 46 individuals with a clinical diagnosis of HOKPP. Their mean age was 55 years.
    • Of the 46, nearly 90% reported fatigue and difficulties with daily activities and mild exercise; nearly 50% needed mobility aids.
    • However, as no longitudinal prospective study has been performed, the risk for permanent muscle weakness as it pertains to age and the particular pathogenic variant present is unknown.

In some individuals, primary hypokalemic periodic paralysis may be revealed solely by a permanent weakness due to a progressive limb-girdle myopathy with no history of paralytic episodes. The diagnosis may be considered if paralytic episodes are present in family members, whereas in simplex cases (i.e., single occurrence in a family) the diagnosis is often revealed only after muscle biopsy.

Respiratory involvement and fatal outcome. The involvement of respiratory muscles during paralytic attacks is a rare but life-threatening complication of primary HOKPP. There are three possible life-threatening elements of paralytic attacks:

  • Hypokalemia leading to possible cardiac dysrythmia
  • Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency
  • Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool)

The correlation of specific pathogenic variants with a higher frequency of respiratory involvement in paralytic attacks and of possible fatal outcome is still to be proven (see Genotype-Phenotype Correlations).

Malignant hyperthermia. Individuals with HOKPP are at increased risk (of unknown magnitude) for malignant hyperthermia, though not as great a risk as in those individuals with true autosomal dominant malignant hyperthermia susceptibility. Three individuals with HOKPP who developed malignant hyperthermia have been reported to date [Lambert et al 1994, Rajabally & El Lahawi 2002, Marchant et al 2004]; however, in one individual, the cause was clearly a coincidental pathogenic variant in RYR1 [Marchant et al 2004] (see Prevention of Secondary Complications).

Increased risk for pre- or post-anesthetic weakness. Individuals with HOKPP are often reported to have pre- or post-anesthetic weakness [Siler & Discavage 1975, Horton 1977, Melnick et al 1983], the risk for which requires preventive measures and careful anesthetic follow up (see Management).

Muscle histology. Histologic findings associated with the myopathy in HOKPP may depend on the specific pathogenic variant. In individuals with the c.1583G>A CACNA1S variant, the usual finding is vacuoles. Two male members of a family with the c.2014C>G SCNA4 variant presented only with tubular aggregates [Sternberg et al 2001].

For more information on muscle histology click here.

Genotype-Phenotype Correlations

Table 3.

Summary of Observations on the Two Most Prevalent Pathogenic Variants in CACNA1S

c.1583G>A (p.Arg528His)c.3716G>A (p.Arg1239His)
% of individuals
with HOKPP
Mean age of
first attack
Mean ictal
hypokalemia
Need for aid
w/daily activities
(railing, chair, or
cane)
Improvement by
acetazolamide

Age of onset of paralytic attacks for other pathogenic variants. Retrospective analysis of a significant number of probands with the c.1583G>A or c.3716G>A pathogenic variant in CACNA1S or the c.2015G>A pathogenic variant in SCN4A allows definition of trends for the age of onset for each pathogenic variant:

Serum concentration of potassium during paralytic attacks and potassium sensitivity. In the series of Miller et al [2004], the serum concentration of potassium noted during paralytic attacks is the lowest for the c.3716G>A pathogenic variant in CACNA1S (1.9±0.4 mmol/L), higher for the SCN4A pathogenic variants (2.2±0.8 mmol/L), and still higher for the c.1583G>A pathogenic variant in CACNA1S (2.9±0.7 mmol/L). Conversely, Sternberg et al [2001] found that the serum concentration of potassium during attacks was lower for individuals with the c.1583G>A pathogenic variant (1.69±0.49 mmol/L) than for individuals with the c.3716G>A pathogenic variant (2.23±0.86 mmol/L).

Frequency, duration, and triggering factors of paralytic attacks. Miller et al [2004] showed that:

  • Frequency of attacks did not differ among symptomatic individuals with the c.1583G>A or c.3716G>A pathogenic variant in CACNA1S or with SCN4A pathogenic variants.
  • Duration of attacks was shorter in individuals with SCN4A pathogenic variants (average: 1 hour) than in individuals with either CACNA1S pathogenic variant (average: 10 hours).
  • The most frequent trigger of attacks was:

Response to acetazolamide treatment

  • Acetazolamide is effective in preventing or shortening paralytic attacks in 60% of individuals with the CACN1AS pathogenic variants c.1583G>A and c.3716G>A, as compared to 16% of individuals with SCN4A pathogenic variants.
  • Acetazolamide aggravates frequency and intensity of crises in individuals with the c.2014C>G and c.2014C>A pathogenic variants in SCNA4, with arginine-to-glycine or arginine-to-serine CACNA1S and SCN4A pathogenic variants; it may be effective in individuals with other SCN4A pathogenic variants [Venance et al 2004].
  • Treatment with acetazolamide resulted in exacerbation of symptoms in several individuals in a family with the c.2014C>G pathogenic variant [Sternberg et al 2001] and one individual with the c.2014C>A pathogenic variant [Bendahhou et al 2001]. However, Venance et al [2004] found that in at least four individuals with either the c.2006G>A or the c.2014C>A pathogenic variant in SNC4A, acetazolamide treatment resulted in improved symptoms.
  • Treatment was not effective in a Chinese individual with the c.2015G>A pathogenic variant [Ke et al 2006].

Respiratory phenotype

Arginine-to-glycine substitutions in CACNA1S as well as SCN4A appear more likely to have the following phenotypic correlates:

  • Complete penetrance in men and women
  • No or worsening effect of acetazolamide
  • Propensity to develop myopathy

Penetrance

The penetrance of HOKPP appears to depend on the specific pathogenic variant and the gender of the affected individual. In general, among individuals with pathogenic variants, females have fewer symptoms than males:

CACNA1S

SCN4A

Anticipation

Anticipation is not observed.

Nomenclature

Names for hypokalemic periodic paralysis no longer in use include the following:

  • Cavaré-Romberg syndrome
  • Cavaré-Westphal syndrome
  • Cavaré-Romberg-Westphal syndrome
  • Westphal's disease
  • Westphal's neurosis

The disease was mostly known as Westphal's disease, as Karl Friedrich Otto Westphal (1833-1890) first described extensively and convincingly the main characteristics of the disease, which had previously been described as "periodic palsy" by Musgrave in 1727, Cavaré in 1853, and Romberg in 1857. Hartwig reported a case of palsy with muscle inexcitability provoked by rest after exercise in 1875. Westphal described a simplex case (i.e., single occurrence in a family); it was not until 1887 that a dominant pedigree was described by Cousot.

Familial versus sporadic HOKPP. Hypokalemic periodic paralysis may be familial (f-HOKPP) or sporadic (s-HOKPP), meaning that the affected individual has no known family history of HOKPP. Sporadic cases may be due to a de novo pathogenic variant, to pathogenic variants with incomplete penetrance in other family members with the variant, or to as-yet unexplained factors. Pathogenic variants in the same genes may lead to either f-HOKPP or s-HOKPP.

HOKPP1 versus HOKPP2. HOKPP1 and HOKPP2 are hypokalemic periodic paralysis linked respectively to CACNA1S and SCN4A pathogenic variants. Some authors use the terms “HOKPP type 1” and “HOKPP type 2”. However, this could wrongly suggest that there are two clinical types of HOKPP. In fact, HOKPP1 and HOKPP2 are not distinct clinically.

Prevalence

The prevalence of HOKPP is unknown but thought to be approximately 1:100,000.

Differential Diagnosis

The following signs and symptoms suggest a diagnosis other than sporadic HOKPP:

  • Associated sensory symptoms, including pain or tenderness
    • Sensory loss could suggest polyneuropathy such as Guillain-Barré syndrome
    • Pain could suggest myositis; however, some individuals with HOKPP report paralytic episodes as painful
  • Urinary retention or constipation; these signs may be observed in other causes of acute or subacute paralysis
  • Associated symptoms that suggest myasthenia or involvement of the neuromuscular junction, including:
    • Ptosis
    • Diplopia
    • Dysphagia
    • Dysarthria
  • Alteration or loss of cousciousness
  • Abnormal movement
  • History of fever days before an attack, which could suggest poliomyelitis or other virus-caused paralysis
  • History of back pain days before an attack, which could suggest acute transverse myelitis
  • History of tick bite, which could suggest tick paralysis

Hypokalemic periodic paralysis (HOKPP) is the most common cause of periodic paralysis. Four major differential diagnoses exist (see Table 5).

Table 5.

The Different Categories of Periodic Paralyses (PP) with Primitive Membrane Excitability Disorder and Associated Findings

HOKPPNormoPPHYPPATSTPP
Age at first attacksLate in 1st decade or in 2nd decade1st years of lifeVariable, dependent on onset of thyrotoxicosis
Main triggersThyrotoxicosis
Extramuscular expressionnonenoneNoneCardiac arrhythmia; DysmorphyPossible manifestations of thyrotoxicosis
Prevention of paralysis attacksACZACZACZ
Curative treatmentNoneNoneNoneNoneTreatment of thyroid disorder
Known causal or susceptibility gene(s)CACNA1S;
SCN4A;
KCNJ18 (sporadic cases)
SCN4ASCN4AKCNJ2KCNJ18
Defective ion channel(s)Cav 1.1;
Nav 1.4;
Kir 6.2
Nav 1.4Nav 1.4Kir 2.1Kir 6.2

ACZ = acetazolamide

Normo- and hyperkalemic paralysis (normo/hyperPP) differ in several ways from HOKPP:

  • Serum concentration of potassium during the paralytic attacks is normal or elevated.
  • Some triggering factors for HOKPP attacks (e.g., carbohydrate-rich meals) are not found.
  • Age of onset of paralytic attacks is lower.
  • Duration of attacks is assumed to be shorter. However, this is questionable, according to surveys of affected individuals.
  • Electromyography shows myotonic discharges in most individuals between attacks; however, the response patterns for short exercise test (SET) and long exercise test (LET) may be indiscernible; i.e., pattern IV or V defined by Fournier et al [2004] may be caused by both hypokalemic and normo/hyperkalemic periodic paralysis.

HyperPP type 1 is caused by single-nucleotide variants in SCN4A encoding the voltage-gated skeletal muscle sodium channel. Usually, the distinction between HOKPP and normo/hyperPP can be made on the basis of clinical, biologic (i.e., kalemia during an attack), and EMG findings and confirmed by molecular genetic testing [Miller et al 2004, Vicart et al 2004].

Thyrotoxic periodic paralysis (TPP) is most often not familial, but in some instances there may be a familial predisposition. The clinical and biologic picture of TPP is identical to that of the paralytic episodes of HOKPP. Furthermore, the EMG response patterns for SETs and LETs (i.e., patterns IV or V defined by Fournier et al [2004]) for familial genetic HOKPP and TPP are identical when thyrotoxicosis is present. Males of Asian origin, and possibly people of Latin American and African American origin, are assumed to be at greater risk than people of other ethnic/racial origins for developing periodic paralysis as a consequence of thyrotoxicosis.

Although TPP is not usually caused by classic HOKPP-causing pathogenic variants [Dias da Silva et al 2002b, Ng et al 2004], the association of TPP with genetically defined HOKPP and normoPP has been reported [Lane et al 2004, Vicart et al 2004]. An association with CACNA1S 5'UTR and intronic SNPs has been suggested but not confirmed [Kung et al 2004]. Pathogenic variants in KCNJ18 cause 1.5% to 33% of cases of TPP.

Because thyrotoxicosis may be a precipitating factor of genetically defined hypokalemic or normokalemic periodic paralysis [Lane et al 2004, Vicart et al 2004], the following should be measured in anyone with weakness and hypokalemia:

  • Plasma thyroid-stimulating hormone (TSH) (reference range: 0.45-4.5 µU/mL)
  • Free thyroxine (FT4) (reference range: 8.0-20.0 pg/mL)
  • Free triiodothyronine (FT3) (reference range: 1.4-4.0 pg/mL)

Note: (1) Low TSH together with high FT3 and FT4 are diagnostic of hyperthyroidism. Treatment of hyperthyroidism cures TPP. (2) TPP is distinct from hypokalemic periodic paralysis (HOKPP); however, at least two instances of genetically diagnosed familial HOKPP for which hyperthyroidism was an additional trigger for hypokalemic paralytic episodes have been reported [Lane et al 2004, Vicart et al 2004].

Andersen-Tawil syndrome (ATS) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described. Incomplete clinical presentations are possible: Andersen-Tawil syndrome may express itself as pure HOKPP. An electrocardiogram or a Holter-ECG recording between attacks of weakness is necessary to evaluate for the possibility of Andersen-Tawil syndrome. The EMG response patterns for short and long exercise tests may be identical; i.e., patterns IV or V defined by Fournier et al [2004] may be caused by Andersen-Tawil syndrome as well as HOKPP. ECG should be performed again in an interictal period in order to evaluate for a U wave, which is observed in Andersen-Tawil syndrome. Pathogenic variants in KCNJ2 are causative [Plaster et al 2001]. Inheritance is autosomal dominant with reduced penetrance and variable expressivity.

Hypokalemia caused by reduced potassium intake, enhanced renal excretion, or digestive loss. Because the main clinical manifestation of hypokalemia is muscle weakness, it may be difficult in some cases to discriminate between a paralytic attack of HOKPP and an episode of weakness associated with chronic hypokalemia of another cause. In such cases the diagnosis relies on the correct interpretation of findings such as blood pressure, urinary concentration of potassium, and blood concentration of bicarbonate (see Table 6).

See also Testing, Transtubular potassium concentration gradient and potassium-creatinine ratio during paralytic attack.

Table 6.

Identifying the Cause of Secondary Hypokalemia

If blood pressure is:& Urinary potassium is:& Blood bicarbonate is:Diagnostic Explanations
High
  • Primary or secondary inappropriate (pseudo) hyperaldosteronism
  • Secondary hyperaldosteronism (increased renin blood concentration): renin secreting tumor, renal artery stenosis, malignant hypertension
  • Hyperglucocorticism (normal renin blood concentration)
  • Licorice (normal renin blood concentration)
>25 mmol/LHigh
  • Liddle syndrome (tubulopathy)
Normal<25 mmol/LHigh
  • Past treatment with diuretics
Low or normal
  • Gastrointestinal losses
  • Insufficient potassium intake
>25 mmol/LHigh
  • Vomiting
  • Present treatment with diuretics
  • Bartter syndrome (tubulopathy with normo- or hypercalcuria, normomagnesemia)
  • Gitelman syndrome (tubulopathy with hypocalciuria, hypomagnesemia)
Low
  • Distal tubular acidosis type 1, 2 (but not 4, in which there is hyperkalemia)
  • Diabetic acidosis

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypokalemic periodic paralysis (HOKPP), the following evaluations are recommended:

During an acute paralytic attack:

  • Assessment of respiratory status to detect those individuals who may have early respiratory failure
  • Measurement of serum potassium concentration
  • Cardiac electrophysiologic testing (electrocardiagram) to assess for life-threatening cardiac consequences of hypokalemia
  • Assessment for swallowing difficulty

Between attacks or in a currently asymptomatic individual:

  • Neurologic examination to assess muscle strength in the legs
  • Measurement of the following thyroid functions (see Note):
    • Plasma thyroid-stimulating hormone (TSH)
    • Free thyroxine (FT4)
    • Free triiodothyronine (FT3)
  • In those with fixed muscle weakness, consideration of CT scan of muscles to evaluate the extent of myopathy
  • Clinical genetics consultation

Note: (1) Hyperthyroidism may be a trigger for a hypokalemic episode in individuals with HOKPP; (2) thyroid function tests may help to distinguish between HOKPP and TPP in those who have a pathogenic variant in KCNJ18.

Treatment of Manifestations

For a comprehensive summary of the management of hypokalemic periodic paralysis, see Levitt [2008] (full text). The principles of treatment are summarized in Table 7.

Table 7.

Principles of Treatment for Individuals with HOKPP

GoalMeansPractical Details
To avoid triggering or aggravating factors for paralytic attacksAvoid:
  • Strenuous effort
  • Prolonged immobility
  • Carbohydrate-rich diet
  • Monitor episodes of weakness noting time of day & specific triggers
  • Provide dietary review/counseling
Treatment of paralytic attack:
  • Shorten/prevent aggravation of the weakness episode
  • Normalize kalemia
  • Provide K+ supplementation (oral, or IV if oral impossible or if potassium very low)
  • Avoid glucose intake
  • Do not use slow-release forms of potassium
  • Oral potassium: initially, 1 mEq/kg; add 0.3 mEq/kg after 30 minutes if no improvement
  • IV potassium: 0.3 mEq/kg/h
Preventive treatment for paralytic attacksDaily K+ supplementationSlow-release forms of potassium may be used
Diamox (acetazolamide)
K+-sparing diuretics
Preventive treatment for late-onset myopathyDiamox (acetazolamide)?
Medical precautions
  • Avoid corticosteroids if possible
  • Use alpha- or beta adrenergic drugs w/caution, even in local anesthesia or ophthalmology
Other elements of management
  • Kinesitherapy in case of permanent pelvic deficit
  • Adaptive measures: (1) at school & especially for sports; (2) in the work setting

Paralytic crisis. Treatment of the paralytic crisis is far from perfect, as the only tool is the administration of potassium by mouth or IV, which addresses the hypokalemia directly, but the weakness only indirectly. Resolution of muscle weakness and normalization of the serum concentration of potassium are not strictly parallel. The serum concentration of potassium may normalize before weakness begins to resolve.

During a paralytic attack, there is usually no true potassium depletion in the body (unless digestive or renal losses from another cause are associated), but there is a reversible transfer of potassium from the extracellular to the intracellular space. The global potassium pool (and especially the intracellular pool of the body) is conserved, and the goal of the treatment is to raise the blood potassium level just enough to trigger the shift to repolarization of skeletal muscle membrane, and the liberation of intracellularly sequestered potassium.

Mild to moderate paralytic episodes

  • Treatment may occur in a familial or non-medical setting if the diagnosis is well-established and the affected individual is able to manage paralytic episodes.
  • Rapid recovery is typically possible with oral intake of chloride potassium salts, either as capsules or liquid-containing vials. Aqueous potassium contained in vials may act more rapidly.
  • An initial intake of 1mEq/kg potassium chloride is often used (60 mEq; i.e., 4.5 g of potassium chloride for a 60-kg person).
  • A response (at least partial) should be seen after 30 minutes. If no improvement occurs after 30 minutes, an additional 0.3 mEq/kg can be administered (20 mEq; i.e., 1.5 g of potassium chloride for a 60 kg person).

Note: (1) Slow-release forms of potassium should be avoided during a paralytic attack. (2) Potassium ingesting should be followed by oral intake of water (e.g., 100 mL (4 oz) of water for each 20 mEq of potassium). (3) Liquids containing high sugar or sodium content should be avoided.

Severe paralytic episodes. If an affected individual has followed the instructions above for a mild to moderate attack and either no improvement or further aggravation is observed after an additional 30 minutes, medical supervision with measurement of serum potassium level should be considered.

  • The total dose of potassium taken over a 24-hr period for the treatment of an acute attack should not exceed 200 mEq.
  • During severe paralytic episodes or attacks associated with respiratory, swallowing, or speaking difficulties, or with signs of arrythmia, the affected individual must be transferred to hospital.
  • In the case of very low serum potassium and severe symptoms (airway compromise with ictal dysphagia, accessory respiratory muscle paralysis, arrhythmia associated with hypokalemia), intravenous potassium treatment should be initiated. Note the following critical points:
    • The concentration of intravenous potassium chloride solution should not exceed 40 mEq/L because of the risk for thrombophlebitis (the use of a central catheter is rarely necessary).
    • The solution should be given as a continuous infusion that does not exceed 0.3 mEq/kg/h of potassium (i.e., 18 mEq/h for a 60-kg person) because of the high risk for arrhythmia or cardiac arrest associated with faster infusions.
    • The physician should be aware that hyperkalemia may occur, as there is no true potassium depletion; a reverse shift of potassium from the intracellular to the extracellular space occurs during the resolution of paralytic episode.
  • A Y-branched peripheral venous line containing potassium chloride should be branched to a perfusion of mannitol or normal saline (avoid glucose-containing solutions, which may enhance hypokalemia).
  • To prevent cardiac arrhythmias, it is important to monitor the electrocardiogram (ECG) before, during, and after treatment and to perform repeat assessments of blood potassium concentration:
    • A prominent increase in the amplitude of the U wave, triggered by hypokalemia, is associated with a higher susceptibility to the ventricular arrhythmia known as torsades de pointes. Some individuals exhibit serious arrhythmias with only mild hypokalemia.
    • Large and sharp T waves are a marker of hyperkalemia and may occur during and after recovery; they are associated with a risk for cardiac arrest.
  • Monitoring of ECG and blood potassium concentration must be continued some hours after normalization of the serum potassium concentration, in order to detect a relapse of hypokalemia or the development of hyperkalemia secondary to excessive potassium load.
  • Administration of supplemental potassium must be discontinued when the serum potassium concentration is normalized, even if weakness persists.

Attempting to abort paralytic attacks when they begin. Affected individuals are advised to keep a sufficient dose of potassium in various places (at the bedside, in pockets or handbags, in the car) so that when warning symptoms appear, the person can take potassium and possibly avoid a full-blown attack, which would usually occur within minutes [Levitt 2008]. It is also acknowledged that maintaining mild physical activity may abort attacks in some cases.

Myopathy. No curative treatment is known for fixed myopathy in HOKPP. The effects of muscle weakness are managed as in other disorders with similar manifestations.

  • Physiotherapy may help to maintain strength and motor abilities, especially after 40 years of age, when permanent muscle weakness is more often seen.
  • The physiotherapist must be aware of the following peculiarity of periodic paralysis: that sustained effort results in exacerbation of weakness. Therefore, self-managed exercise should be preferred to superimposed physiotherapy [Cavel-Greant et al 2012].

Prevention of Primary Manifestations

Preventive treatment is intended to decrease the frequency and intensity of paralytic attacks. Triggering factors need to be identified and, if possible, avoided (see Table 7).

A diet rather low in sodium and carbohydrate and rich in potassium is recommended.

Potassium supplementation for prevention and treatment of attacks is an empiric but effective treatment for shortening attacks and sometimes preventing their occurrence (see Treatment of Manifestations).

Oral intake of potassium salts (10-20 mmol/dose, 3 doses/day) can prevent attacks, especially if the dose of potassium is taken some hours before the usual time of the attack (i.e., a nocturnal dose if crises occur at awakening).

Acetazolamide is generally considered the additive treatment of choice for prevention of paralytic attacks and myopathy in HOKPP. However, there is no standardized treatment regimen and no consensus as to when to start treatment with acetazolamide.

  • Typical dosage for acetazolamide in adults is between 125 mg/day and 1000 mg/day (usually 250-500 mg/day), divided into three doses and taken with meals; in children a dose of 5-10 mg/kg/day, divided into three doses and taken with meals, is used.
  • Acetazolamide treatment:
    • Is beneficial in approximately 50% of individuals with HOKPP;
    • Has no effect in 30% of affected individuals;
    • Exacerbates symptoms in approximately 20% (this deleterious effect may be predicted by genotype, see Genotype-Phenotype Correlations).
  • In some affected persons, permanent weakness may be partly reversed and muscle strength may be improved by acetazolamide treatment [Links et al 1988].
    • Whether acetazolamide treatment prevents or treats myopathy and the resulting fixed weakness that occurs with age is unknown.
    • Further studies are needed to evaluate the effect of preventive acetazolamide treatment on attack rate, severity-weighted attack rate, permanent weakness, and myopathy.

Alternatives to acetazolamide. If acetazolamide is not tolerated or if it is not effective after prolonged use, alternatives include dichlorphenamide (50-200 mg/day), triamterene (50-150 mg/day), and spironolactone (25-100 mg/day).

Other drugs have been used with limited success: lithium gluconate [Confavreux et al 1991] (though Ottosson & Persson [1971] earlier demonstrated lack of efficacy); pinacidil [Ligtenberg et al 1996]; and bumetanide [Wu et al 2013].

Prevention of Secondary Complications

Creating a safe environment, getting help in case of paralytic attack, and preventing falls and accidents are critical [Levitt 2008].

  • An affected person experiencing a paralytic attack must have access to potassium as well as physical assistance. Thus, those with HOKPP should inform their companions or acquaintances of their risk for paralytic attack, especially in a sports or school context, so that they can access appropriate help rapidly in case of an attack.
  • Falls and injuries from falls are frequent in those with HOKPP (67% of affected individuals age >40 years report such falls and injuries) [Cavel-Greant et al 2012].

Pre- or postoperative paralysis. Because of the risk for paralysis preceding or following anesthesia, precautions should be taken during administration of anesthesia to individuals with HOKPP. Individuals with HOKPP should be considered susceptible to malignant hyperthermia and managed with a non-triggering anesthetic technique – although general anesthesia using volatile anesthetics and succinylcholine has been reported as safe in a small number of individuals with HOKPP.

General guidelines for perioperative care include the following:

  • Strict control of serum potassium concentration
  • Avoidance of large glucose and salt loads
  • Low-carbohydrate diet
  • Maintenance of body temperature and acid-base balance
  • Careful use of neuromuscular blocking agents with continuous monitoring of neuromuscular function [Hofer et al 2001]

Late-onset myopathy with fixed muscle weakness. It is not known whether the prevention of paralytic attacks also prevents the development of myopathy. Individuals with known pathogenic variants who developed myopathy without having experienced episodes of weakness have been reported.

Surveillance

The frequency of consultations needs to be adapted to the individual's signs and symptoms and response to preventive treatment. Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect permanent weakness associated with myopathy.

Questionnaires completed by the affected individual may be used to evaluate disease severity without treatment and with treatment.

For those individuals who take acetazolamide the following parameters should be evaluated every three months: complete blood count, electrolytes, glucose, uric acid, and liver enzyme levels. Renal ultrasound should be performed annually.

Agents/Circumstances to Avoid

Factors such as the following can trigger paralytic attacks and thus should be avoided when possible:

  • Unusually strenuous effort
  • Excess of carbohydrate-rich meals
  • Sweets
  • Alcohol
  • Prolonged immobility
  • Oral or intravenous corticosteroids, which may induce paralytic attacks and thus should be used with care in individuals with HOKPP
  • Glucose infusionm, which may induce paralytic attacks and thus should be replaced by another type of infusion

Evaluation of Relatives at Risk

When a pathogenic variant is identified in a proband, molecular genetic testing of at-risk, asymptomatic family members is appropriate because of the risk for unexpected acute paralysis and/or malignant hyperthermia.

When the results of presymptomatic testing are not known, the at-risk family members must be considered at risk for complications and precautions must be taken, particularly in the administration of anesthesia and avoidance of risk factors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

While in utero acetazolamide exposure is reported to cause limb defects in rodents, acetazolamide therapy during human pregnancy does not appear to increase the risk for fetal malformations [Heinonen et al 1977].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Functional magnetic resonance imaging (fMRI) has been used in research protocols to evaluate abnormalities in ionic muscle content in periodic paralyses of different types. It represents a possible research tool to evaluate the effect of treatment on skeletal muscles and to assess clinical outcomes in individuals with HOKPP.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hypokalemic periodic paralysis (HOKPP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with HOKPP have an affected parent. The autosomal dominant inheritance pattern may be masked by incomplete penetrance in the preceding generations.
  • However, a proband with HOKPP may have the disorder as the result of a de novo pathogenic variant.The CACNA1S pathogenic variants c.1583G>A and c.3716G>A have been shown to occur de novo [Ptácek et al 1994a, Elbaz et al 1995, Kim et al 2001]. The proportion of cases caused by a de novo pathogenic variant is unknown.
  • Recommendations for the evaluation of parents of an individual with no known family history of HOKPP include: a search for a history of full or incomplete paralytic crises in the past; a search for history of adverse response to glucose infusion, surgery, or general anesthesia in the past; results of evaluation of muscle strength; and results of molecular genetic testing.
  • In cases in which it is not possible to establish a definite clinical or molecular diagnosis of HOKPP in one of the parents, both parents may need to be considered at risk for complications, including unexpected acute paralysis and hypokalemia, and possibly malignant hyperthermia associated with anesthesia.

Note: Although most individuals diagnosed with HOKPP have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or incomplete penetrance in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents of the proband.
  • If a parent is affected and/or has the family-specific pathogenic variant, the risk to each sib of inheriting the SCN4A, CACNA1S, or KCNJ18 variant is 50%.
  • When neither parent has the pathogenic variant present in the proband, the risk to the sibs of a proband appears to be low.
  • If the SCN4A, CACNA1S, or KCNJ18 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Offspring of a proband are at a 50% risk of inheriting the SCN4A, CACNA1S, or KCNJ18 pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected and/or has a pathogenic variant in SCN4A, CACNA1S, or KCNJ18, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Testing of at-risk asymptomatic family members. When a pathogenic variant in SCN4A, CACNA1S, or KCNJ18 is identified in an individual, testing of at-risk, asymptomatic family members is appropriate because of the risk for unexpected acute paralysis and/or malignant hyperthermia. When the results of presymptomatic testing are not known, the at-risk family members must be considered at risk for complications and precautions must be taken, particularly in the administration of anesthesia.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of an individual with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SCN4A, CACNA1S, or KCNJ18 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for HOKPP are possible.

Requests for prenatal testing for conditions which (like HOKPP) do not affect intellect, are compatible with a nearly normal life, and have available treatment possibilities are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Periodic Paralysis Association (PPA)
    155 West 68th Street
    Suite 1732
    New York NY 10023
    Phone: 407-339-9499
    Email: lfeld@cfl.rr.com
  • Periodic Paralysis News Desk
    3919 Landry Crescent
    E-23
    Summerland British Columbia V0H 1Z9
    Canada
    Phone: 403-244-7213
    Email: calexeditor@nucleus.com
  • Malignant Hyperthermia Association of the United States (MHAUS)
    11 East State Street
    PO Box 1069
    Sherburne NY 13460
    Phone: 800-644-9737 (Toll-free Emergency Hotline); 607-674-7901; 315-464-7079
    Fax: 607-674-7910
    Email: info@mhaus.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hypokalemic Periodic Paralysis: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Hypokalemic Periodic Paralysis (View All in OMIM)

114208CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1S SUBUNIT; CACNA1S
170400HYPOKALEMIC PERIODIC PARALYSIS, TYPE 1; HOKPP1
603967SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4A
613236POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 18; KCNJ18

Molecular Genetic Pathogenesis

Putting together the pieces of a puzzle, from the observation of potassium imbalance to the discovery of omega pore currents

The first observations on potassium imbalance in HOKPP. The observation of a decline in serum potassium concentration during paralytic attacks of HOKPP – combined with the relief of symptoms following administration of potassium salts – indicated clearly that HOKPP involved a defect in potassium metabolism [Biemond & Daniels 1934, Aitken et al 1937]. It was later ascertained that the reduction in potassium in plasma was not due to urine loss – as the potassium urine loss was rather reduced before, during, and after the attack – but rather to the transfer of potassium into intracellular space. It was later shown that the shift of potassium was into skeletal muscle [Zierler & Andres 1957].

Understanding of membrane excitability and ion channels, the first electrophysiologic observations, and the first pieces of the puzzle. From the 1940s and 1950s, the bases of membrane excitability and the existence of ion channels, as well as new tools to study them, became available. It was then recognized that HOKPP attacks arise from phases of depolarization in an inexcitable state affecting skeletal muscle membrane.

It was then progressively noted from ex vivo experiments on excised muscle fibers that skeletal muscle membrane in patients with HOKPP has abnormal properties that could explain the occurrence of such depolarization and inexcitability phases. Increased membrane permeability to sodium was proposed as a common mechanism for all types of periodic paralysis.

Discovery of the HOKPP-causing missense variants in Cav 1.1 and Nav 1.4. In 1994, genetic linkage studies in large families made it possible to locate the gene responsible for hypokalemic paralysis on chromosome 1, and then to identify it as the gene coding for the alpha subunit of skeletal muscle voltage-gated calcium channel. Pathogenic variants were characterized as arginine-to-histidine substitutions in S4 segments (see Figure 1, Figure 2). However, in vitro functional expression studies of pathogenic variants did not provide a straightforward pathophysiologic explanation for the periodic paralysis phenotype. It was in 2001 that mutated arginines in the S4 segment of the alpha subunit of skeletal muscle voltage-gated sodium channel were identified in other cases of HOKPP, raising questions about the role of the S4 pathogenic variants.

Figure 2. . Localization of pathogenic missense variants of the S4 segments of Cav 1.

Figure 2.

Localization of pathogenic missense variants of the S4 segments of Cav 1.1 and Nav 1.4 that have been reported. Most are associated with HOKPP (blue), and account for nearly all genetically characterized cases of HOKPP. Some particular pathogenic variants (more...)

Pathogenic variants in CACNA1S and SCN4A proven to cause HOKPP are almost exclusively nucleotide substitutions causing an amino acid change that turns positively charged arginines of voltage sensor S4 segments into other amino acids (most often histidine; sometimes glutamine, serine, glycine, cysteine) (see Figure 1, Figure 2).

The electrical properties of skeletal muscle membranes in individuals with HOKPP. Ruff and his coauthors have studied the electrical properties of skeletal muscle fibers excised from individuals with HOKPP as a result of pathogenic variants in CACNA1S and SCN4A.

Their observations and conclusions about the electrical properties of skeletal muscle fibers in individuals with HOKPP are the following: (1) excitability is impaired, as fibers are very susceptible to depolarization-induced inexcitability; (2) conduction velocity is lowered ; (3) inward rectifying potassium currents (IKir) are lower than normal; (4) sodium currents (INa) and sodium conductance (GNa) are lower than normal (and this is more likely to be due to a reduced number of channels, than to a reduction of single channel conductance); (5) fibers demonstrate a depolarizing cationic current that is not sensitive to drugs that block the normal current pathways of sodium current (blocker: tetrodotoxin) and calcium channels (blocker:nitrendipine); (6) intracellular calcium is elevated.

The action of insulin on skeletal muscle of individuals with HOKPP. In normokalemic or hypokalemic bathing solutions, insulin hyperpolarizes normal muscle fibers, but depolarizes muscle fibers of persons with HOKPP.

Data suggest that the depolarization of fibers of persons with HOKPP in normokalemic solutions and insulin-induced depolarization are associated with reduced membrane K conductance [Puwanant & Ruff 2010]. Clinical experiments and studies of the K-depleted rat model of HypoPP suggest that the KATP channel is abnormal in HypoPP.

The enhancement of K1 conductance improved the performance of muscle fibers of persons with HOKPP. Specifically, agents that activated ATP-sensitive K1 channels decreased the severity of paralytic attacks, reversed muscle fiber depolarization, and increased twitch force in persons with HOKPP.

Omega pore currents and their role in HOKPP pathophysiology. Voltage-gated ion channels are transmembrane proteins that share a common structure and are highly conserved [Catterall 1988, Ackerman & Clapham 1997, Greenberg 1997, Celesia 2001]. Sodium and calcium channels consist of (1) a major alpha subunit responsible for most of the channel properties and (2) accessory subunits that have regulatory roles (Figure 1). Alpha subunits are made of four domains (DI to DIV), each of them comprising six transmembrane segments (S1 to S6). The four domains cooperate in forming the ion pore. On depolarization, modification of the channel protein conformation allows ion fluxes through the plasma membrane by opening the ion pore (activation). Activation of the channel is promptly followed by closure of the pore (inactivation). Inactivation of voltage-gated ion channels may occur on the time scale of milliseconds (fast inactivation) or seconds (slow inactivation).

The voltage-gated calcium channel of the skeletal muscle (Cav 1.1) is located in the T-tubule of the muscle fibers and is responsible for L-type calcium currents. It has the double function of regulating calcium entry into the muscle fiber and coupling (via voltage detection) muscle excitation and contraction. HOKPP-causing variants are found in the S4 segment of both domain II (c.1583G>A) and domain IV (c.3715C>G and c.3716G>A) (Figure 1). Segment S4 consists of a ring of positive charges every three amino acids and is the voltage sensor of the channel. Both pathogenic variants in segment 4 of domains II and IV replace a positively charged amino acid by a lesser-charged amino acid. So far, segment 4 in domain II and in domain IV are the nearly exclusive sites in the voltage-gated calcium channel in which pathogenic variants causing HOKPP have been described. Possible biophysical defects specific to CACNA1S pathogenic variants have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing variants in CACNA1S result in a half-reduced calcium current density and a slowing in the rate of activation [Morrill & Cannon 1999]. A more recent investigation on homologous pathogenic variants of the cardiac rabbit channel confirmed these loss-of-function features [Kuzmenkin et al 2007].

The voltage-dependent sodium channel of the skeletal muscle (Nav 1.4) is activated by membrane depolarization and is responsible for the upstroke of the action potential. It therefore plays a key role in muscle contraction, allowing a proper propagation of the action potential along the muscle membrane. Pathogenic variants causing HOKPP concern only the voltage-sensitive segment S4 of domain II of the sodium channel alpha subunit and change positively charged arginines to non-charged amino acid residues (Figure 1). Possible biophysical defects specific to SCN4A pathogenic variants have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing variants in SCN4A enhance fast [Jurkat-Rott et al 2000, Kuzmenkin et al 2002] and/or slow [Struyk et al 2000, Kuzmenkin et al 2002] inactivation and reduce current density [Jurkat-Rott et al 2000]. Altogether, those defects reduce the fraction of available non-inactivated sodium channels at the resting potential.

Flaccid weakness in both types of HOKPP, as well as in hyperPP (see Hyperkalemic Periodic Paralysis), is caused by a paradoxic sustained membrane depolarization [Cannon 2002]. Paroxystic membrane depolarization in HOKPP is partially or totally coupled with paroxystic hypokalemia resulting from the transfer of potassium from the extracellular to the intracellular compartment of skeletal muscle cells, and with subtle hormonal changes. In HOKPP type 1 as well as in HOKPP type 2, muscle paradoxically depolarizes in response to hypokalemia, whereas normal muscle hyperpolarizes [Ruff 1999, Jurkat-Rott et al 2000]. This paradoxic depolarization may be made possible by a reduction of inward rectifier potassium currents [Ruff 1999] and especially ATP-sensitive potassium channels [Tricarico et al 1999].

Progress has been made in understanding the pathophysiology of HOKPP, by showing that HOKPP-causing variants in Nav 1.4 S4 segments create an abnormal gating pore current; i. e., an accessory ionic transmembrane permeation pathway through the aqueous environment of S4 segment [Sokolov et al 2005, Sokolov et al 2007, Struyk & Cannon 2007, Sokolov et al 2008, Struyk et al 2008, Francis et al 2011, Jurkat-Rott et al 2012]. This current is a low-amplitude inward current at the resting potential, and varies in its amplitude and selectivity according to the precise pathogenic variant and to the physiologic or pathologic conditions, thus contributing to membrane depolarization in pathologic circumstances [Struyk et al 2008].

Molecular and pathophysiologic correlates of phenotypic variation. The location of substituted S4 arginine influences the nature and properties of gating-pore current responsible for HOKPP phenotype.

Biophysical studies have shown that the effects of the substitution of the different arginines of S4 helixes of Cav 1.1 and Nav 1.4 (Figure 1) – the most frequent genetic causes of HOKPP –differ depending on the localization of the substituted arginines.

Substitution of outermost arginine at codon 1448 in Nav 1.4 IVS4 does not result in HOKPP but rather in paramyotonia congenita, because it does not result in a gating pore current [Francis et al 2011].

The nature of the amino acid that replaces arginine influences the nature and properties of gating-pore current responsible for the HOKPP phenotype.

Genetically engineered animal models of HOKPP. Mouse models have been generated for the SCN4A c.2006G>A pathogenic variant [Wu et al 2011] and the CACNA1S c.1583G>A pathogenic variant [Wu et al 2012].

Observations in a model of potassium-depleted rats showed that acetazolamide prevented the development of vacuolar myopathy [Tricarico et al 2008].

CACNA1S

Gene structure. CACNA1S has 44 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 8. All CACNA1S pathogenic variants associated with HOKPP identified to this day are missense single-nucleotide variants. No splice variants, stop variants, or sequence duplications or deletions of CACNA1S are known to be associated with HOKPP.

Table 8.

Selected CACNA1S Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1583G>Ap.Arg528HisNM_000069​.2
NP_000060​.2
c.1582C>Gp.Arg528Gly
c.2627T>Ap.Val876Glu
c.2691G>Tp.Arg897Ser
c.3716G>Ap.Arg1239His
c.3715C>Gp.Arg1239Gly

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CACNA1S codes for the voltage-dependent L-type calcium channel alpha-1S subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

SCN4A

Gene structure. SCN4A has 24 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 2 (pdf), Table 8, and Table 9. All SCN4A pathogenic variants associated with HOKPP identified to date are missense single-nucleotide variants. No splice variants, stop variants, or sequence duplications or deletions of SCN4A are known to be associated with HOKPP.

Table 9.

SCN4A Pathogenic Variants Causing Hypokalemic Periodic Paralysis Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.664C>Tp.Arg222TrpNM_000334​.4
NP_000325​.4
c.2006G>Ap.Arg669His
c.2014C>Ap.Arg672Ser
c.2014C>Gp.Arg672Gly
c.2014C>Tp.Arg672Cys
c.2015G>Ap.Arg672His
c.3386G>Ap.Arg1129Gln
c.3395G>Ap.Arg1132Gln
c.3404G>Ap.Arg1135His

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SCN4A codes for the sodium channel protein type 4 subunit alpha.

Abnormal gene product. See Molecular Genetic Pathogenesis.

KCNJ18

Gene structure. The transcript NM_001194958.2 has three exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 10.

Table 10.

KCNJ18 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.127C>Tp.Arg43CysNM_001194958​.2
NP_001181887​.2
c.419C>Tp.Thr140Met
c.429del
(428delC)
p.Ile144SerfsTer8
c.502G>Ap.Val168Met
c.598G>Cp.Ala200Pro
c.1195C>Tp.Arg399Ter
c.1219C>Tp.Gln407Ter
c.1061C>Tp.Thr354Met
c.1097A>Gp.Lys366Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The inward rectifier potassium channel 18 has 433 amino acids and two transmembrane helix domains. It tetramerizes, possibly as homotetramers, or as heterotetramers with other types of inward rectifier potassium channel.

Abnormal gene product. Pathogenic variants reported to date in KCNJ18 appear to affect (Kir 6.2) by different mechanisms. Nonsense (stop) variants apparently result in complete loss of gene function (amorphic alleles), exerting their effect by haploinsufficiency. Some missense variants may lead to channels with reduced function (hypomorphic alleles) and cause decreased K+ currents leading to depolarization. Some other missense variants (hypermorphic alleles) appear to cause hyperactivity and possibly hyperpolarization and difficulty reaching excitability threshold. These effects coupled with a trigger circumstance (e.g., hyperthyroidism in TPP) would lead to the weakness and paralysis observed in TPP or s-HOKPP. It remains to be elucidated how the genomic and non-genomic effects of thyrotoxicosis on this ion channel and other ion channels lead to paralytic attacks.

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Suggested Reading

  • Jen J, Ptáček L. Skin cancer (including nevoid basal cell carcinoma syndrome). In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 204. New York, NY: McGraw-Hill. Available online.

Chapter Notes

Author History

Marianne Arzel-Hézode, MD (2014-present)
Saïd Bendahhou, PhD (2014-present)
Bertrand Fontaine, MD, PhD (2002-present)
Emmanuel Fournier, MD, PhD (2014-present)
Jérôme Franques, MD (2014-present)
Bernard Hainque, PharmD, PhD (2002-present)
Philippe Lory, PhD (2014-present)
Sophie Nicole, PhD (2014-present)
Damien Sternberg, MD, PhD (2002-present)
Nacira Tabti, MD, PhD; Assistance Publique - Hôpitaux de Paris (2002-2014)
Savine Vicart, MD (2014-present)

Revision History

  • 31 July 2014 (me) Comprehensive update posted live
  • 28 April 2009 (me) Comprehensive updated posted live
  • 4 March 2008 (cd) Revision: mutation scanning for CACNA1S no longer available on a clinical basis
  • 4 August 2006 (me) Comprehensive update posted to live Web site
  • 19 May 2004 (me) Comprehensive update posted to live Web site
  • 30 April 2002 (me) Review posted to live Web site
  • 20 November 2001 (bf) Original submission
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