Hypokalemic Periodic Paralysis

[HOKPP, HypoPP. Includes: Hypokalemic Periodic Paralysis Type 1, Hypokalemic Periodic Paralysis Type 2]

Clinical Diagnosis

The two distinct forms of muscle involvement observed in hypokalemic periodic paralysis (HOKPP), paralytic episodes and fixed myopathy, may occur separately or together. The pure paralytic episodic form occurs most commonly; the combination of paralytic episodes and a slowly progressive myopathy is less common; the pure myopathic form without paralytic episodes is rare:

• Paralytic episodes. The primary symptom consists of attacks of reversible flaccid paralysis with a concomitant hypokalemia that usually leads to paraparesis or tetraparesis but spares the respiratory muscles.

• Myopathic form. The myopathic form results in slowly progressive, fixed muscle weakness that begins as exercise intolerance predominantly of the lower limbs; it usually does not lead to severe disability. This fixed weakness must be distinguished from the reversible weakness that exists between attacks in some affected individuals.

Testing

In individuals who have had one or more paralytic episodes, several tests can be used to differentiate between the other possible causes and primary HOKPP resulting from a genetic skeletal muscle membrane ion channel defect.

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.
  
  * The ratio: [urine potassium/plasma potassium]/[urine osmolality/blood osmolality]

• Note: In the case of associated dysmorphic traits and intercritic-associated cardiac arrhythmia, the diagnosis of Andersen-Tawil syndrome must be considered as a differential diagnosis.

Serum concentration of thyroid-stimulating hormone and free thyroxine and triiodothyronine. Thyrotoxic periodic paralysis (TPP) is a major differential diagnosis of primary genetic HOKPP. Therefore, in case of attacks of weakness with hypokalemia, it is recommended to quantify the following:

• Plasmatic thyroid-stimulating hormone (TSH): Reference range: 0.45-4.5 µU/mL

• Free thyroxine (FT4): Reference range: 8-20 pg/mL

• Free triiodothyronine (FT3): Reference range: 1.4-4 pg/mL

A low level of TSH together with high levels of FT3 and FT4 indicates that hyperthyroidism is present and is the very probable (and treatable) cause of paralytic attacks.

TPP is curable by treatment for hyperthyroidism. TPP is distinct from familial genetic hypokalemic periodic paralysis (FHOKPP); however, at least two cases of genetically defined FHOKPP for which hyperthyroidism was an additional trigger for hypokalemic paralytic episodes have been reported [Lane et al 2004, Vicart et al 2004].

Electromyogram (EMG)

• 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.

• Myotonic discharges are typically absent in HOKPP; however, one family with combined heat-induced myotonia and cold-induced hypokalemic periodic paralysis has been described [Sugiura et al 2000].

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 in 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 disease-causing mutation, especially in asymptomatic individuals or those who have not recently had a paralytic attack [Tengan et al 2004].

Muscle biopsy. In individuals with the myopathic form of HOKPP, muscle biopsy with adequate histochemical and histoenzymologic staining has been the mainstay of diagnosis. Light microscopy shows vacuoles [Pearson 1964, Olivariusbde & Christensen 1965, Martin et al 1984] or sometimes tubular aggregates [Faugere et al 1981]. Although the latter are less specific to HOKPP, they are the only lesions in some cases. Note: Electron microscopy is not necessary.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. Two genes are known to be associated with hypokalemic periodic paralysis (HOKPP):

• CACNA1S, accounting for approximately 55%-70% of HOKPP

• SCN4A, accounting for approximately 8%-10% of HOKPP

Other loci. One study suggested that mutations in another potassium channel gene, KCNE3, cause HOKPP [Abbott et al 2001] and thyrotoxic periodic paralysis [Dias Da Silva et al 2002a]; however, 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].

The nine most common mutations in CACNA1S and SCN4A do not account for about 20%-36% of individuals with clinically diagnosed HOKPP, indicating possible further allelic heterogeneity and/or genetic heterogeneity of the disorder [Sternberg et al 2001, Miller et al 2004]; however, no other loci have been identified.

Clinical testing

• CACNA1S (hypokalemic periodic paralysis type 1)
  
  Targeted mutation analysis. Four mutations (p.Arg528His, p.Arg1239His, p.Arg1239Gly, p.Arg528Gly), clustered in exons 11 and 30, are present in approximately 55%-70% of individuals with HOKPP [Jurkat-Rott et al 1994, Ptacek et al 1994a, Sternberg et al 2001, Miller et al 2004, Wang et al 2005]. Mutations p.Arg528His and p.Arg1239His are far more common than p.Arg1239Gly and p.Arg528Gly. A fifth mutation in exon 21 (p.Arg897Ser) has been described recently [Chabrier et al 2008].
  
  Sequence analysis of select exons. Alternately, exons 11 and 30 can be analyzed by direct sequencing, which detects the four common mutations and any additional sequence variants in these exons. Sequencing of exon 21 should also be performed [Chabrier et al 2008].
  
  Sequence analysis of entire coding region is also available on a clinical basis and may be considered when targeted mutation analysis or sequencing of select exons is negative (see Testing Strategy).

• SCN4A (hypokalemic periodic paralysis type 2)
  
  Sequence analysis of select exon(s). Sequence analysis of exon 12 detects five mutations (p.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys) that account for approximately 10% of individuals with HOKPP [Bulman et al 1999, Jurkat-Rott et al 2000b, Sternberg et al 2001, Bendahhou et al 2001, Davies et al 2001, Kim et al 2004]. Sequence analysis of exon 18, in which a sixth mutation (p.Arg1132Gln) has been described, should also be performed [Carle et al 2006].
  
  Sequence analysis / mutation scanning of entire coding region of SCN4A may detect rare or de novo mutations, such as the one reported by Sugiura et al [2000] in a family with a combination of heat-induced myotonia and cold-induced paralysis.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Hypokalemic Periodic Paralysis

Gene Symbol	Test Method	Mutations Detected	Proportion of HOKPP Diagnosed with This Test Method	Test Availability
CACNA1S	Targeted mutation analysis	p.Arg528His, p.Arg1239His, p.Arg1239Gly, p.Arg528Gly p.Arg897Ser 1	55%-70%	Clinical
	Sequence analysis of exons 11, 21 and 30 2	Sequence variants	55%-70%
	Sequence analysis of entire coding region	Sequence variants	Unknown
SCN4A	Targeted mutation analysis	p.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys p.Arg1132Gln 3	8%-10%	Clinical
	Sequence analysis exon 12 and 18	Sequence variants 3	8%-10%
	Sequence analysis of entire coding region	Sequence variants	Unknown

1. Mutations tested may vary among laboratories.

2. Exons sequenced may vary among laboratories.

3. Includes, but not limited to, detection of variants p.Arg669His, p.Arg672Ser, p.Arg672His, p.Arg672Gly, p.Arg672Cys, p.Arg1132Gln. Mutations detected may vary between laboratories.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband. One approach to molecular genetic testing is the following:

• 1

  Test for common mutations in exons 11 and 30 of CACNA1S by targeted mutation analysis or sequencing of select exons.

• 2

  If no mutation is identified, sequence exon 12 and 18 of SCN4A and exon 21 of CACNA1S.

• 3

  If no mutation is identified, sequence all coding regions of SCN4A to search for mutations associated with normokalemic and hyperkalemic periodic paralysis (in case the diagnosis of HOKPP is incorrect).

• 4

  If no mutation is identified, sequence all coding regions of CACNA1S in search of a novel/rare mutation.

• 5

  If no mutation is identified, sequence the coding region of KCNJ2 for a mutation that could cause Andersen-Tawil syndrome, which can mimic HOKPP.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

CACNA1S. While missense mutations in exons 11 and 30 can cause HOKPP type 1, missense mutations in exon 26 (p.Arg1086Cys, p.Arg1086His) have been shown to cause autosomal dominant malignant hyperthermia susceptibility (MHS) without HOKPP in at least two families [Monnier et al 1997, Jurkat-Rott et al 2000a]. One family with combined HOKPP and MHS caused by an unidentified mutation has been reported [Rajabally & El Lahawi 2002]. Mutations in the CACNA1S gene account for 1% of all individuals with MHS [Stewart et al 2001].

MHS is a pharmacogenetic disorder of skeletal muscle calcium regulation. MH-susceptible individuals respond to volatile anesthetics (halothane, sevoflurane, desflurane, enflurane, isoflurane) or depolarizing muscle relaxants (succinylcholine) with uncontrolled skeletal muscle hypermetabolism. The triggering substances release calcium stores from the sarcoplasmic reticulum, causing contracture of skeletal muscles, glycogenolysis, and increased cell metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, hypoxemia, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk of cardiac arrhythmia or even arrest, and myoglobinuria with a risk of renal failure. In almost all cases, the first manifestations of MH occur in the operating room. Death results unless the individual is promptly treated.

SCN4A. While missense mutations in exon 12 cause HOKPP type 2, a large number of missense mutations in other exons have been shown to cause autosomal dominant disorders characterized by hyperexcitability of the sarcoplasmic membrane [Ptacek et al 1991, Rojas et al 1991, Plassart et al 1994, Ptacek et al 1994b]:

• Hyperkalemic periodic paralysis type 1 (HyperPP1). HyperPP1 is characterized by: attacks of flaccid limb weakness (possibly including muscle weakness of the eyes, throat, and trunk as well); hyperkalemia (>5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L during an attack of weakness and/or provoking/worsening of an attack by oral potassium intake; normal serum potassium and muscle strength between attacks; onset before age 20 years; and absence of paramyotonia (muscle stiffness aggravated by cold and exercise). The attacks of flaccid muscle weakness usually begin in the first decade of life. Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably.
  
  Potassium-rich food or rest after exercise may precipitate an attack. A cold environment, emotional stress, glucocorticoids, and pregnancy provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to an hour, and then disappears. Usually, cardiac arrhythmia and respiratory insufficiency do not occur during the attacks.
  
  Between attacks, HyperPP1 is usually associated with mild myotonia (muscle stiffness) that does not impede voluntary movements. Many older individuals with HyperPP1 develop a chronic progressive myopathy.

• Paramyotonia congenita (PC). PC in general is characterized by myotonic symptoms followed by weakness; symptoms are worsened by repeated movements and triggered or aggravated by exposure to cold [Plassart et al 1994, Ptacek et al 1994b]. It is caused mainly by mutations at codons 1313 and 1448 of SCN4A.

• Potassium-aggravated myotonias (PAM) and related disorders. This group of diseases is characterized by myotonic symptoms that are neither clearly ameliorated by exercise (as in myotonia congenita) nor worsened by exercise and cold (as in paramyotonia congenita). Symptoms may fluctuate (myotonia fluctuans) or be permanent (myotonia permanens) and/or be aggravated by potassium. They may respond to acetazolamide (acetazolamide-responsive myotonias) [Trudell et al 1987]. PAM and related disorders are caused mainly by mutations at codon 1306 of SCN4A. These myotonic syndromes are distinct from myotonic dystrophy type 1 (DM1), caused by a trinucleotide repeat expansion in DMPK, and myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM), caused by a tetranucleotide repeat expansion in ZNF9.
  
  Diseases caused by mutations in SCN4A may also be intermediate or compound forms of HyperPP and PC, or PC and PAM.

• Malignant hyperthermia susceptibility. Moslehi et al [1998] described a large kindred in which affected individuals had hyperkalemic periodic paralysis with or without MHS. None had MHS alone. The causative SCN4A allele was later characterized as having a double mutation, p.[Phe1490Leu + Met1493Ile] [Bendahhou et al 2000]. Vita et al [1995] described a kindred with succinylcholine-induced masseter muscle rigidity, a complication of anesthesia other than malignant hyperthermia susceptibility that was caused by a missense mutation of SCN4A, p.Gly1306Ala.

• Congenital myasthenic syndromes. Congenital myasthenic syndromes (CMS) are characterized by fatigable weakness involving ocular, bulbar, and limb muscles with onset at or shortly after birth. In some types of CMS, myasthenic symptoms may be mild; but sudden severe exacerbations of weakness or even sudden episodes of respiratory insufficiency may occur, precipitated by fever, infections, or excitement. If symptoms start in the neonatal period, the major findings include: feeding difficulties; poor suck and cry; choking spells; eyelid ptosis; and facial, bulbar, and generalized weakness. Respiratory insufficiency with sudden apnea and cyanosis may occur. Individuals with onset later in childhood show abnormal muscle fatigability with difficulty in running or climbing stairs. Motor milestones may be delayed. Affected individuals present with fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Cardiac and smooth muscle are not involved. Tsujino et al [2003] reported a single individual with a particular endplate functioning abnormality caused by a missense mutation of SCN4A that caused markedly enhanced fast inactivation.

Natural History

The two different forms of hypokalemic periodic paralysis (HOKPP) are the paralytic form and the myopathic form. The natural history of the disorder varies among individuals.

Paralytic form. The primary symptom of the paralytic form is an attack of reversible flaccid paralysis with concomitant hypokalemia usually leading to paraparesis or tetraparesis but sparing the respiratory muscles and heart. No correlation between serum potassium concentration and severity of weakness exists. Some individuals have only one episode in a lifetime; more commonly, attacks repeat daily, weekly, monthly, or less often. 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 mean age of onset of the first paralytic episode in symptomatic individuals depends on the mutation (see Genotype-Phenotype Correlations) and gender; on average, onset is earlier by two to three years in females than in males. Generally, the frequency of attacks is highest between ages 15 and 35 years and then decreases with age.

The major factors triggering attacks are carbohydrate-rich meals and rest after exercise. The triggering threshold appears to differ from one individual to another, some having a small number of attacks in their lifetime, triggered by a very unusual effort, a significant stress, a long trip, or a medical intervention (such as glucose perfusion or surgery); and others having frequent crises, triggered by ordinary nocturnal rest (crises often begin during the night or at awakening), rest following participation in sports, digestion of a carbohydrate meal, or menstruation.

Acute paralytic crises usually last at least several hours and sometimes several days. In some affected individuals, abortive or full attacks in close succession may lead to permanent muscle weakness and severe handicap, including inability to play sports or even to perform routine daily activities [Links et al 1990].

Between paralytic attacks, some individuals experience subacute weakness that may be reversed by treatment with potassium salts and acetazolamide or may resolve spontaneously. It may be difficult to differentiate this subacute weakness from the permanent muscle weakness of the myopathic form. By contrast, some individuals have no limitation of activity or exercise between attacks. Severity of disability in HOKPP thus varies both over the individual's lifetime and between individuals.

Myopathic form. The myopathic form of HOKPP, which develops in approximately 25% of individuals with HOKPP, results in a progressive, fixed muscle weakness that begins at extremely variable ages as exercise intolerance predominantly in the lower limbs. Muscle weakness occurs independent of paralytic symptoms and may be the sole manifestation of HOKPP [Buruma & Bots 1978].

Increased risk for malignant hyperthermia (MH). Individuals with HOKPP have an 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. Results of in vitro contracture tests performed on muscle obtained from individuals with HOKPP are not abnormal but are often equivocal [Lehmann-Horn & Iaizzo 1990, Lambert et al 1994], and 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 mutation 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 may depend on the specific mutation. In individuals with the p.Arg528His CACNA1S mutation, it usually consists of vacuoles. Two male members of a family with the p.Arg672Gly SCNA4 mutation presented only with tubular aggregates [Sternberg et al 2001].

Genotype-Phenotype Correlations

Age of onset of paralytic attacks. Retrospective analysis of a significant number of probands with the p.Arg528His or p.Arg1239His mutation in CACNA1S or the p.Arg672His mutation in SCN4A allows definition of trends for the age of onset for each mutation:

• Age of onset is lower for individuals with the p.Arg1239His mutation (age 10±5 years [Sternberg et al 2001]; age 7±4 years [Miller et al 2004]) than for individuals with the p.Arg528His mutation (age 14±3 years [Sternberg et al 2001]; age 14±5 years [Miller et al 2004]).

• Mean age of onset is higher for individuals with SCN4A mutations (age 16±5 years [Sternberg et al 2001, Miller et al 2004]).

• A case of de novo p.Arg897Ser mutation in CACNA1S was associated with an unusually young age of onset [Chabrier et al 2008]

Serum concentration of potassium during paralytic attacks. In the series of Miller et al [2004], the serum concentration of potassium noted during paralytic attacks is the lowest for the p.Arg1239His mutation in CACNA1S (1.9±0.4 mmol/L), higher for the SCN4A mutations (2.2±0.8 mmol/L), and still higher for the p.Arg528His mutation in CACNA1S (2.9±0.7 mmol/L). Conversely, Sternberg et al [2001] found that percritic serum concentration of potassium was lower for individuals with the p.Arg528His mutation (1.69±0.49 mmol/L) than for individuals with the p.Arg1239His mutation (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 p.Arg528His or p.Arg1239His mutation in CACNA1S or with SCN4A mutations.

• Duration of attacks was shorter in individuals with SCN4A mutations (average: 1 hour) than in individuals with either CACNA1S mutation (average: 10 hours).

• The most frequent precipitant of attacks was:

  • Rest after exercise for individuals with the p.Arg1239His mutation or an SCN4A mutation

  • High carbohydrate meal or sweets for individuals with the p.Arg528His mutation.

Response to treatment. Response to acetazolamide may also be mutation dependent:

• SCN4A. Treatment with acetazolamide resulted in exacerbation of symptoms in several individuals in a family with the p.Arg672Gly mutation [Sternberg et al 2001] and one individual with the p.Arg672Ser mutation [Bendahhou et al 2001]. However, Venance et al [2004] showed that exacerbation of symptoms by acetazolamide was not predictable in individuals with SCN4A mutations, as symptoms improved in at least four individuals with either the p.Arg669His or p.Arg672Ser mutation.
  
  Treatment was not effective in a Chinese individual with the p.Arg672His mutation [Ke et al 2006].

• CACNA1S. Acetazolamide treatment is frequently beneficial in individuals with the p.Arg528His or p.Arg1239His mutations.

Muscle histology

• CACNA1S. Vacuoles (or less frequently, nonspecific myopathic changes), but not tubular aggregates, were the histologic lesions seen in individuals with the p.Arg528His or p.Arg1239His mutation.

• SCN4A. Tubular aggregates seem to be the main histologic lesion in individuals with the p.Arg672Gly mutation [Sternberg et al 2001]; however, vacuoles may be the main lesion in those with other SCN4A mutations [Miller et al 2004].

Penetrance

Among individuals with disease-causing mutations, females have fewer symptoms than males:

• CACNA1S. Approximately one-half of women with the p.Arg528His mutation and one-third of those women with the p.Arg1239His mutation are asymptomatic. In contrast, more than 90% of males with a disease-causing mutation have symptoms [Elbaz et al 1995, Fouad et al 1997, Sternberg et al 2001, Kawamura et al 2004].

• SCN4A. The p.Arg672His mutation seems to have a low penetrance in women, as all individuals diagnosed to date in the authors' laboratory are men [Author, personal observation]. In Chinese pedigrees, Ke et al [2006] noted non-penetrance in women for p.Arg672His.

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.

Prevalence

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

Evaluations Following Initial Diagnosis

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

• Neurologic examination to assess muscle strength in the legs

• Measurement of the following thyroid functions:

  • Plasma thyroid-stimulating hormone (TSH)

  • Free thyroxine (FT4)

  • Free triiodothyronine (FT3)

Treatment of Manifestations

Paralytic crisis. The treatment of a paralytic crisis in an individual with HOKPP has two aims: (1) to normalize the serum concentration of potassium; and, (2) to shorten the paralytic episode. Normalization of the serum concentration of potassium and resolution of muscle weakness are not strictly parallel. The serum concentration of potassium may normalize several hours before weakness begins to resolve.

Treatment of the paralytic crisis is thus far from perfect, as the only tool is the administration of potassium by mouth or IV, which treats the hypokalemia directly but the weakness only indirectly:

• Potassium in doses of 0.2 to 0.4 mmol/kg is administered orally every 15 to 30 minutes over one to three hours.

• If the individual is unable to swallow or does not tolerate potassium by mouth, potassium may be administered intravenously. In that case, it must be diluted in 5% mannitol rather than in glucose or sodium chloride, which trigger crises in individuals with HOKPP. The concentration of potassium administered intravenously must not exceed 40 mmol/L, and the flow must not exceed 20 mmol/hour or 200-250 mmol/day; administration must be stopped when the serum potassium concentration is normalized, even if weakness persists.

Because the hypokalemia and subsequent changes in potassium concentration induced by treatment may result in cardiac arrhythmias, it is important to monitor the electrocardiogram (ECG) before, during, and after treatment and to have repeated assessment of blood potassium concentration. In particular, a prominent increase in the amplitude of the U wave on ECG, 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.

Monitoring of the 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 development of hyperkalemia secondary to an excessive potassium load.

Myopathy. No preventive or curative treatment is known for fixed myopathy in HOKPP. The prevention of paralytic attacks does not seem to prevent the development of myopathy. The effects of muscle weakness are managed as in other disorders with similar manifestations.

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.

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

Oral intake of potassium salts (10-20 mmol/dose, three 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 highly effective in individuals with the CACN1AS mutations p.Arg528His and p.Arg1239His. However, the role of acetazolamide in treating individuals with SCN4A mutations is less clear; although it may aggravate crises in individuals with the p.Arg672Gly and p.Arg672Ser mutations, it may be effective in individuals with other SCN4A mutations [Venance et al 2004].

Acetazolamide is started at 125 mg/day and may be increased over some weeks to as much as 1000 mg/day. Sufficient fluid intake must be maintained during treatment in order to prevent the development of renal calculi.

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).

Prevention of Secondary Complications

Pre- or postoperative paralysis. Because of the risk of paralysis preceding or following anesthesia, precautions should be taken during administration of anesthesia to individuals with HOKPP. Individuals with HOKPP should be considered as 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 close control of serum potassium concentration, avoidance of large glucose and salt loads, carbohydrate-poor diet, maintenance of body temperature and acid-base balance, and careful use of neuromuscular blocking agents with continuous monitoring of neuromuscular function [Hofer et al 2001].

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/or response to medication.

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

Oral or intravenous corticosteroids may induce paralytic attacks and should be used with care in individuals with HOKPP.

Glucose infusion may induce paralytic attacks and should be replaced by another type of infusion.

Testing of Relatives at Risk

When a disease-causing mutation 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.

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

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 non-penetrance in the preceding generations.

• However, a proband with HOKPP may have the disorder as the result of a de novo gene mutation. De novo mutations have been demonstrated for the p.Arg528His and p.Arg1239His mutations in CACNA1S [Ptacek et al 1994a, Elbaz et al 1995, Kim et al 2001]. The proportion of cases caused by de novo gene mutations is unknown.

• Recommendations for the evaluation of parents of an individual with no known family history of HOKPP include: a careful search for a history of full or incomplete paralytic crises in the past; a careful history of response to glucose infusion, surgery, or general anesthesia in the past; an evaluation of muscle strength; and 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 mutation, the risk to each sib of inheriting the mutation is 50%.

• When neither parent has the disease-causing mutation present in the proband, the risk to the sibs of a proband appears to be low.

• If neither parent has a HOKPP-causing mutation detectable in DNA extracted from leukocytes, it is presumed that the proband has a de novo gene mutation; and the risk to the sibs of the proband depends on the spontaneous mutation rate and the probability of germline mosaicism.

• Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Offspring of a proband have a 50% risk of inheriting the mutation.

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 found to have a disease-causing mutation, his or her family members are at-risk.

Related Genetic Counseling Issues

See the Management section for information on testing at-risk relatives for the purpose of early diagnosis and treatment

Testing of at-risk asymptomatic family members. When a disease-causing mutation is identified in a proband, testing of at-risk, asymptomatic family members is appropriate because of the risk of 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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 availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk, asymptomatic family members are best made 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as HOKPP that do not affect intellect and have some treatment available 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Voltage-gated ion channels are transmembrane proteins that share a common structure and were highly conserved throughout evolution [Catterall 1988, Ackerman & Clapham 1997, Greenberg 1997, Celesia 2001]. Sodium and calcium channels consist of a major alpha subunit responsible for most of the channel properties and of accessory subunits that have regulatory roles. 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. Upon 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 timescale 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 mutations are found in the S4 segment of both domain II (p.Arg528His) and domain IV (p.Arg1239Gly and p.Arg1239His). Segment S4 consists of a ring of positive charges every three amino acids and is thought to be the voltage sensor of the channel. Both mutations in segment 4 of domains II and IV replace a positively charged amino acid by a lesser charged amino acid. So far, segments 4 of domains II and IV are the only sites in the voltage-gated calcium channel in which mutations causing HOKPP have been described. Possible biophysical defects specific to CACNA1S mutations have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing mutations 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 mutations of the cardiac rabbit channel confirmed those 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. Mutations 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. Possible biophysical defects specific to SCN4A mutations have been investigated by in vitro patch-clamp-based electrophysiologic studies of transiently or persistently transfected cells expressing mutated channels. HOKPP-causing mutations in SCN4A enhance fast [Jurkat-Rott et al 2000b, Kuzmenkin et al 2002] and/or slow [Struyk et al 2000, Kuzmenkin et al 2002] inactivation and reduce current density [Jurkat-Rott et al 2000b]. Altogether, those defects reduce the fraction of available noninactivated 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 paradoxical 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 2000b]. This paradoxical 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].

Recent progress has been made in understanding the pathophysiology of HOKPP, by showing that HOKPP-causing mutations 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]. This current is a low-amplitude inward current at the resting potential, and varies in its amplitude and selectivity according to the precise mutation and to the physiologic or pathologic conditions, thus contributing to membrane depolarization in pathologic circumstances [Struyk et al 2008]

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Revision History

• 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