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Hyperkalemic Periodic Paralysis

Synonym: HyperPP

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

Author Information

Initial Posting: ; Last Update: January 28, 2016.

Summary

Clinical characteristics.

Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk), hyperkalemia (serum potassium concentration >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 between attacks, and onset before age 20 years. Although the absence of paramyotonia (muscle stiffness aggravated by cold and exercise) was originally postulated as a means of distinguishing hyperPP from paramyotonia congenita (PMC), approximately 45% of individuals with hyperPP have paramyotonia. In approximately half of affected individuals, attacks of flaccid muscle weakness begin in the first decade of life, with 25% reporting their first attack at age ten years or older. Initially infrequent, the attacks then increase in frequency and severity over time until approximately age 50 years, after which the frequency of attacks declines considerably. Potassium-rich food or rest after exercise may precipitate an attack. A cold environment and emotional stress provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then disappears. Cardiac arrhythmia or respiratory insufficiency usually does not occur during attacks. Between attacks, approximately half of individuals with hyperPP have mild myotonia (muscle stiffness) that does not impede voluntary movements. More than 80% of individuals with hyperPP older than 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.

Diagnosis/testing.

Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in SNC4A. In case of diagnostic uncertainty, one of three provocative tests can be employed.

Management.

Treatment of manifestations: At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, inhalation of salbutamol, or intravenous calcium gluconate.

Prevention of primary manifestations: Hyperkalemic attacks of weakness can be prevented by frequent meals rich in carbohydrates, continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor, and avoidance of potassium-rich medications and foods, fasting, strenuous work, and exposure to cold.

Prevention of secondary complications: During surgery, avoid use of depolarizing anesthetic agents (including potassium, suxamethonium, and anticholinesterases) that aggravate myotonia and can result in masseter spasm and stiffness of respiratory and other skeletal muscles, interfering with intubation and mechanical ventilation.

Surveillance: Periodic assessment of neurologic status; in those with permanent muscle weakness, continuous medication (ie thiazide diuretic) and MRI of proximal leg muscles every one to three years; during prophylactic treatment, determination of serum potassium concentration twice per year to avoid severe diuretic-induced hypokalemia; annual monitoring of thyroid function.

Agents/circumstances to avoid: Potassium-rich medications and foods, fasting, strenuous work, exposure to cold, and use of depolarizing anesthetic agents during general anesthesia.

Evaluation of relatives at risk: It is appropriate to test asymptomatic at-risk family members for the pathogenic variant identified in an affected relative in order to institute preventive measures prior to surgery.

Genetic counseling.

HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent; the proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with hyperPP has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.

Diagnosis

Suggestive Findings

Hyperkalemic periodic paralysis (hyperPP) should be suspected in individuals with the following clinical, family history, electromyogram (EMG), and suggestive laboratory findings:

Clinical findings

  • History of at least two attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, breathing muscles and trunk)
  • Onset or worsening of an attack as a result of oral potassium intake
  • Disease manifestations before age 20 years
  • Absence of cardiac arrhythmia between attacks
  • Normal psychomotor development

Family history

  • Typically, at least one affected first-degree relative
    Note: Absence of a family history suggestive of hyperPP does not preclude the diagnosis.

Electromyogram (EMG)

  • During the attack, EMG demonstrates a reduced number of motor units or may be silent (no insertional or voluntary activity).
  • In the intervals between attacks, EMG may reveal myotonic activity (bursts of muscle fiber action potentials with amplitude and frequency modulation), even though myotonic stiffness may not be clinically present.
  • In some individuals, especially in those with permanent weakness, a myopathic pattern may be visible.
    Note: Approximately 50% of affected individuals have no detectable electrical myotonia.

Suggestive laboratory findings during attacks

  • Hyperkalemia (serum potassium concentration >5 mmol/L) or an increase of serum potassium concentration of at least 1.5 mmol/L
    Note: Serum potassium concentration seldom reaches cardiotoxic levels, but changes in the ECG (increased amplitude of T waves) may occur.
  • Elevated serum creatine kinase (CK) concentration (sometimes 5-10x the normal range)

Suggestive laboratory findings between attacks

  • Normal serum potassium concentration and muscle strength between attacks
    Note: At the end of an attack of weakness, elimination of potassium via the kidney and reuptake of potassium by the muscle can cause transient hypokalemia that may lead to the misdiagnosis of hypokalemic periodic paralysis.
  • Elevated serum CK concentration with normal serum sodium concentration

Establishing the Diagnosis

The diagnosis of hyperkalemic periodic paralysis (hyperPP) is established in a proband with the above suggestive findings in whom other hereditary forms of hyperkalemia (see Differential Diagnosis) and acquired forms of hyperkalemia (drug abuse; renal and adrenal dysfunction) have been excluded and/or by the identification of a heterozygous pathogenic variant in SCN4A by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Single-gene testing

1.

Sequence analysis of SCN4A is performed first.

2.

If no pathogenic variant is identified, sequencing of KCNJ2 and CACNA1S may be considered (see Differential Diagnosis).

A multi-gene panel that includes SCN4A and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

More comprehensive genomic testing (when available) including whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq) may be considered if serial single-gene testing (and/or use of a multi-gene panel that contains SCN4A) fails to confirm a diagnosis in an individual with features of hyperPP. For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Hyperkalemic Periodic Paralysis

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
SCN4ASequence analysis 3, 480% 5
Unknown 6NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

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.

Ten common pathogenic variants are listed in Table 3; p.Thr704Met alone accounts for 69% of pathogenic variants [Jurkat-Rott & Lehmann-Horn 2007].

5.

Authors, personal observation

6.

At least one other locus, Xp27.3, has been mapped but the relevant gene has not yet been identified [Ryan et al 1999].

Provocative tests. In case of diagnostic uncertainty (i.e., in the absence of a measurement of ictal (during an attack) serum potassium concentration and normal molecular genetic studies), provocative tests may be employed to ensure the diagnosis. Systemic provocative tests carry the risk of inducing a severe attack; therefore, they must be performed by an experienced physician and a stand-by anesthetist, with close monitoring of the ECG and serum concentration of potassium:

  • The classic provocative test consists of the administration of 2-10 g potassium under clinical surveillance with serum potassium concentration and strength measured at 20-minute intervals. Usually, an attack is induced within an hour and lasts approximately 30 to 60 minutes, accompanied by an increase in serum potassium concentration, similar to spontaneously occurring attacks of weakness. The test is contraindicated in individuals who already have hyperkalemia and in those individuals who do not have adequate renal or adrenal function.
  • An alternative provocative test is exercise on a bicycle ergometer for 30 minutes to increase the heart rate to 120-160 beats/min, followed by absolute rest in bed. An affected individual's serum potassium concentration should rise during exercise, decline after exercise, and rise a second time 20 minutes after the conclusion of exercise.
  • A local provocative test is measurement of evoked compound muscle action potentials (CMAP). They should have a greater-than-normal increase during two to five minutes of exercise followed by a progressive decline in amplitude that is greater than in normal controls and most rapid during the first 20 minutes after exercise. The decline is the more important parameter [Melamed-Frank & Marom 1999, Fournier et al 2004]. In the authors’ experience, the CMAP results are not specific for hyperPP or a given pathogenic variant.

Muscle biopsy. Because no specific findings are observed on muscle biopsy and because the results do not influence therapeutic strategies or prognosis, a muscle biopsy is generally not recommended in individuals suspected of having hyperPP.

Clinical Characteristics

Clinical Description

The attacks of flaccid muscle weakness associated with hyperkalemic periodic paralysis (hyperPP) usually begin in the first decade of life and increase in frequency and severity over time, with 25% experiencing their sentinel attack in the second decade of life. Triggers include cold environment, rest after exercise, stress or fatigue, alcohol, hunger, changes in activity level, potassium in food, specific foods or beverages, changes in humidity, extra sleep, pregnancy, illness of any type, menstruation, medication, and potassium supplements [Charles et al 2013].

A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to an hour, and then passes. In about 20% of affected individuals the attacks last considerably longer, from more than two days to over one week. In some individuals, paresthesias, probably induced by the hyperkalemia, herald the weakness. During an attack of weakness, the muscle stretch reflexes are abnormally diminished or absent.

Sustained mild exercise after a period of strenuous exercise may postpone or prevent the weakness in the muscle groups being exercised and improve the recovery of muscle force, while the resting muscles become weak.

Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. After an attack, affected individuals report clumsiness, weakness, and irritability, and in 62% muscle pain secondary to the attack. Between attacks, the majority report no or mild symptoms. However, 12% report severe symptoms between attacks that impair activities of daily living.

In more than 50% of individuals with hyperPP, mild myotonia (muscle stiffness) that does not impede voluntary movements is present between attacks. Myotonia is most readily observed in the facial, lingual, thenar, and finger extensor muscles; if present, it supports the diagnosis of hyperPP as opposed to other forms of familial periodic paralysis. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals.

Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably. However, more than 80% of the affected individuals older than 40 years report permanent muscle weakness and approximately one third of older affected individuals develop a chronic progressive myopathy [Bradley et al 1990]. The myopathy mainly affects the pelvic girdle and proximal and distal lower-limb muscles.

As shown by a recent observational study, individuals with hyperPP appear to be at higher risk for thyroid dysfunction (relative risk of 3.6) than those in the general population [Charles et al 2013].

Genotype-Phenotype Correlations

Given the clinical variability within a single family (i.e., among individuals with the same pathogenic variant), differences between pathogenic variants can be interpreted as causing a tendency to develop a feature, rather than actually causing a discrete feature (see Table 2).

The most notable tendency is that individuals without interictal myotonia are much more prone to develop progressive myopathy and permanent weakness than individuals with myotonia. This becomes especially obvious in individuals with the pathogenic p.Thr704Met variant, who usually do not have myotonia but in whom permanent myopathy commonly develops (~50% of individuals). Some individuals with "normokalemic periodic paralysis" have also had this common pathogenic variant [Lehmann-Horn et al 1993].

Table 2.

Genotype-Phenotype Correlations in HyperPP

SCN4A Pathogenic VariantSpecial FeaturesFirst Report
p.Asn440LysBoth hyperPP and paramyotonia and potassium aggravated myotoniaLehmann-Horn et al [2011]
p.Arg675GlnBoth hyperPP and normoPP and paramyotoniaLiu et al [2015], Vicart et al [2004]
p.Leu689IlePain resulting from muscle crampingBendahhou et al [2002]
p.Ile693ThrCold-induced weaknessPlassart et al [1996]
p.Thr704MetPermanent weakness, myopathyPtácek et al [1991]
p.Ala1156ThrReduced penetranceMcClatchey et al [1992]
p.Met1360ValReduced penetranceWagner et al [1997]
p.Met1370ValParamyotonia in one family, hyperPP in othersOkuda et al [2001]
p.Ile1495PheCramping pain, muscle atrophyBendahhou et al [1999b]
p.Met1592ValClassic clinical features with EMG myotoniaRojas et al [1991]
p.[Phe1490Leu; Met1493Ile]Malignant hyperthermia susceptibility 2Bendahhou et al [2000]
1.

The anesthesia-related events could have been exaggerated myotonic reactions as in several other individuals with gain-of-function sodium channel variants [Klingler et al 2005].

Penetrance

Usually, the penetrance is high (>90%). A few individuals with rare heterozygous pathogenic variants do not present with clinically detectable symptoms but have signs of myotonia detectable by EMG only [McClatchey et al 1992, Wagner et al 1997].

Nomenclature

Hyperkalemic periodic paralysis was first described in the 1950s. Originally, it was known as "adynamia episodica hereditaria" or Gamstorp disease. Because potassium can provoke an attack of weakness and because a spontaneous attack is usually associated with an increase in serum potassium concentration, the term hyperkalemic periodic paralysis (hyperPP) is recommended [Lehmann-Horn et al 1993].

It has been suggested that the term normokalemic periodic paralysis should be abandoned. The term was originally applied to findings in two reports [Poskanzer & Kerr 1961, Meyers et al 1972]. Normokalemic periodic paralysis resembles hyperPP in many aspects; the only real differences are the lack of serum potassium concentration increase, even during serious attacks, and the lack of a beneficial effect of glucose administration. The existence of normokalemic PP as a nosologic entity has been questioned because of the potassium sensitivity and the identification of SCN4A pathogenic variants in families with normokalemic PP, including the original family described by Poskanzer and Kerr [Lehmann-Horn et al 1993, Chinnery et al 2002].

The name normokalemic periodic paralysis was used to describe a potassium-sensitive type of periodic paralysis with normokalemia and episodes of weakness reminiscent of both hyperPP and hypoPP (also known as HOKPP) caused by heterozygous pathogenic variants in SCN4A at codon 675 [Vicart et al 2004] (see Genetically Related Disorders). However, it has become clear that SCN4A pathogenic variants p.Arg675Gly, p.Arg675Gln, and p.Arg675Trp cause normokalemic PP (see Genetically Related Disorders).

Prevalence

The prevalence of hyperPP is approximately 0.17/100,000 (95% CI 0.13-0.20) [Horga et al 2013].

Differential Diagnosis

In addition to the allelic disorders described in Genetically Related Disorders, hereditary disorders with periodic paralysis or with hyperkalemia to consider when making the diagnosis of hyperkalemic periodic paralysis (hyperPP) are discussed below. Adult onset of clinical manifestations points to other diagnoses such as the Andersen-Tawil syndrome or secondary acquired forms of hyperPP.

Andersen-Tawil syndrome (potassium-sensitive cardiodysrhythmic type of periodic paralysis). Andersen-Tawil syndrome is characterized by the triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and common anomalies such as low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. In the first or second decade, affected individuals present with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or rest after exertion. Heterozygous pathogenic variants in the potassium channel gene KCNJ2 are causative [Plaster et al 2001]. Inheritance is autosomal dominant.

Molecular genetic testing, electrocardiogram, and Holter recording obtained between attacks of weakness are very important for distinguishing between hyperPP and Andersen-Tawil syndrome. In the experience of the author, the cardiologic manifestations precede the neuromuscular ones.

Hyperkalemic periodic paralysis with multiple sleep-onset REM periods. An individual with sporadic hyperPP and excessive daytime sleepiness with multiple sleep-onset REM periods has been reported. Symptoms were improved by a diuretic that decreased serum potassium concentration [Iranzo & Santamaria 1999]. Genetic analysis has not been performed.

Hereditary disorders characterized by hyperkalemia

  • Adrenal insufficiency is characterized by hyperkalemia, hyponatremia, and hypoglycemia. Adrenal insufficiency in infancy may be caused by congenital adrenal hyperplasia (most commonly caused by 21-hydroxylase deficiency) and congenital adrenal hypoplasia including X-linked adrenal hypoplasia congenita. Adrenal cortical hypofunction (Addison disease) can be an autoimmune disorder with familial aggregation or combined with other endocrinopathies, particularly hypoparathyroidism. Addison disease also occurs in X-linked adrenoleukodystrophy.
  • Recessive infantile hypoaldosteronism, another hyperkalemic disorder, leads to a rare form of salt wasting that may be life threatening during the first years of life. Recurrent dehydration and severe failure to thrive, associated with mild hyponatremia and hyperkalemia, are typical features. Laboratory tests reveal elevated plasma renin-to-serum aldosterone ratios and serum 18-hydroxycorticosterone to aldosterone ratios [Picco et al 1992].
  • Pseudohypoaldosteronism type I is characterized by neonatal salt-wasting resistant to mineralocorticoids. The autosomal recessive form (OMIM 264350) with symptoms persisting into adulthood is caused by pathogenic loss-of-function variants in one of the three homologous subunits forming the amiloride-sensitive epithelial sodium channel, ENaC [Chang et al 1996]. The channel is rate limiting for electrogenic sodium reabsorption, particularly in the distal part of the renal tubule. The autosomal dominant or sporadic form (OMIM 177735) shows milder symptoms that remit with age. Truncation of the mineralocorticoid receptor has been identified in one family [Viemann et al 2001].
  • Pseudohypoaldosteronism type II (PHAII), also known as Gordon’s syndrome or familial hyperkalemia and hypertension, is characterized by hypertension, increased renal salt reabsorption, and impaired potassium and hydrogen excretion resulting in hyperkalemia that may be improved by thiazide diuretics. The genes in which mutation is known to cause PHAII are: WNK4 (PHAIIB), WNK1 (PHAIIC), KLHL3 (PHAIID), and CUL3 (PHAIIE) All types of PHAII are inherited in an autosomal dominant manner; PHAIID may also be inherited in an autosomal recessive manner.

Periodic paralysis secondary to acquired sustained hyperkalemia. This type of periodic paralysis can occur in any individual when the serum potassium concentration exceeds 7 mmol/L. Weakness can be accompanied by glove-and-stocking paresthesias. Hyperkalemia can cause cardiac arrhythmia, usually tachycardia, and typical ECG abnormalities (i.e., T-wave elevation, disappearance of P waves). Rest after exercise provokes weakness as in hyperPP. The diagnosis is suggested by very high serum potassium concentration during the attack, persistent hyperkalemia between attacks, and the underlying disorder. Serum potassium concentrations are far higher than those in hyperPP. The usual cause is chronic use of medications such as spironolactone, ACE inhibitors, trimethoprim, nonsteroidal anti-inflammatory drugs, and heparin. Myopathies associated with paroxysmal myoglobinuria (e.g., McArdle disease, carnitine palmitoyltransferase II deficiency) can damage the kidneys and thus also lead to potassium retention. Therapy of acquired sustained hyperkalemia involves restriction of dietary potassium intake and treating the underlying cause of the hyperkalemia.

Management

Evaluations Following Initial Diagnosis

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

  • Determine neurologic status
  • Perform 1H MRI (STIR) of proximal leg muscles to identify muscular water accumulation and fatty muscle degeneration [Weber et al 2006]. Edema should be extruded with long-term diuretics; evaluate by muscle strength measurement and MRI four weeks after start of treatment.
  • Consult with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment for hyperPP is symptomatic and not curative.

  • Attacks can often be prevented or aborted by continuing mild exercise and/or oral ingestion of carbohydrates at the onset of weakness (e.g., 2 g glucose per kg body weight).
    • Attacks occur more frequently on holidays and weekends when people rest in bed longer than usual
    • Individuals are advised to rise early and have a full breakfast.
  • In some individuals attacks can be aborted or attenuated by intravenously injected glucocorticoids or the inhalation of two puffs of 0.1 mg salbutamol.
    • Both mild exercise and treatment with β2-stimulating agents appear to work by stimulating the Na+K+-pumps [Clausen et al 2011].
  • Calcium gluconate (0.5-2 g taken intravenously) may terminate attacks in some individuals [Lehmann-Horn et al 2004].

Prevention of Primary Manifestations

Diet/environment. Preventive therapy for individuals with hyperPP consists of frequent meals rich in carbohydrates and avoidance of the following:

  • Potassium-rich medications and foods (e.g., fruits, fruit juices)
  • Fasting
  • Strenuous work
  • Exposure to cold

Diuretics. It is often advisable to prevent hyperkalemic attacks of weakness by the continuous use of a thiazide diuretic or a carbonic anhydrase inhibitor, such as acetazolamide or the recently approved medication dichlorphenamide. Diuretics are used in modest dosages at intervals from twice daily to twice weekly.

  • Thiazide diuretics are preferable because they have fewer side effects than either acetazolamide or dichlorphenamide therapy.
  • The dosage should be kept as low as possible (e.g., 25 mg hydrochlorothiazide daily or every other day). In severe cases, 50 mg or 75 mg of hydrochlorothiazide should be taken daily very early in the morning.
  • Individuals should be monitored so that the serum potassium concentration does not fall below 3.3 mmol/L or the serum sodium concentration below 135 mmol/L [Lehmann-Horn et al 2004].

Prevention of Secondary Complications

General anesthesia. Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles. Intubation and mechanical ventilation may be impaired. Also, alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli can exacerbate the myotonic reaction.

An induction sequence incorporating inhalation of oxygen, cricoid pressure, thiamyal or thiopental, and two times the ED95 dose of an intermediate or short-action non-depolarizing muscle relaxant, followed by intubation, is a reasonable approach to securing the airway in persons with myotonia. Alternatively, inhalational induction may be a possibility for hyperkalemic paralysis and is well tolerated in those undergoing elective surgery.

Following administration of general anesthesia, the affected individual may develop respiratory distress in the recovery room resulting from weakness of respiratory muscles in addition to generalized weakness lasting for hours. The weakness is aggravated by drugs that depress respiration and by the hypothermia induced by anesthesia.

To prevent such attacks, glucose should be infused, a normal body temperature maintained, and serum potassium kept at low level [Klingler et al 2005, Mackenzie et al 2006, Jurkat-Rott & Lehmann-Horn 2007, Barker 2010].

Note: Because the generalized muscle spasms associated with such attacks may lead to an increase in body temperature, individuals with hyperPP have been considered to be susceptible to malignant hyperthermia. Most likely, anesthesia-related complications suggestive of a malignant hyperthermia crisis result from severe myotonic reactions [Lehmann-Horn et al 2004, Klingler et al 2005].

Surveillance

The frequency of consultations needs to be adapted to the individual's clinical features and the response to preventive treatment.

During prophylactic treatment, measure serum potassium concentration twice per year to avoid severe diuretic-induced hypokalemia.

Neurologic examination with attention to muscle strength in the legs should be performed, in order to detect permanent weakness.

Permanent weakness requires continuous medication, eg. with a thiazide diuretic, and MRI of the leg muscles once every one to three years. During treatment, serum potassium concentration should be measured twice per year to avoid severe diuretic-induced hypokalemia. The value should be between 3.0 and 3.5 mmol/L.

Annual monitoring of thyroid function is appropriate.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of preventive measures, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events.

  • Molecular genetic testing can be pursued if the pathogenic variant in the family is known.
  • When the results of genetic testing or presymptomatic testing are not known, the related family members must be considered at risk for complications and precautions are indicated, particularly during anesthesia.

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

Pregnancy Management

More than 90% of affected women report an increase in attack frequency during pregnancy. While approximately 80% reported improved muscle weakness during attacks, 75% also reported worse muscle stiffness during attacks [Charles et al 2013].

Women who are chronically treated with a diuretic may continue treatment in pregnancy. Human data on prenatal exposure to acetazolamide have not demonstrated an increased risk of fetal malformations. Human data on the use of oral dichlorphenamide therapy during pregnancy – and whether it leads to an increased risk of malformations in exposed fetuses – are limited.

Therapies Under Investigation

A study that compared treatment with dichlorphenamide to treatment with placebo for prevention of episodes and for improvement of strength in individuals with hyperPP and hypoPP has recently been completed; for results, see ClinicalTrials.gov.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Whether the spontaneous attacks of weakness usually associated with hyperPP are influenced by mexiletine (the drug of choice for several allelic disorders) is unknown.

No data concerning the influence of therapeutic drugs on the development of the myopathy are available.

Cation exchangers are less beneficial than diuretics in treating hyperPP because they result in more severe side effects.

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

Hyperkalemic periodic paralysis (hyperPP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with hyperPP have an affected parent.
  • A proband with hyperPP may have the disorder as the result of a de novo SCN4A pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of both parents for the pathogenic variant identified in the proband.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (although no instances of germline mosaicism have been reported, it remains a possibility).
  • The family history of some individuals diagnosed with hyperPP may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for hyperPP because of the possibility of reduced penetrance in a parent.
  • If the SCN4A 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.

Offspring of a proband. Each child of an individual with hyperPP has a 50% chance of inheriting the SCN4A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents; if a parent is affected, his or her family members may be 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.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the SCN4A pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with hyperPP has the pathogenic variant or clinical evidence of the disorder, the SCN4A pathogenic variant is likely de novo. However, 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 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for hyperPP may be possible options.

Differences in perspective may exist among medical professionals and within 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.

Hyperkalemic Periodic Paralysis: Genes and Databases

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

Table B.

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

170500HYPERKALEMIC PERIODIC PARALYSIS; HYPP
603967SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, ALPHA SUBUNIT; SCN4A

Molecular Genetic Pathogenesis

Hyperkalemic periodic paralysis (hyperPP)-causing pathogenic variants are situated at several disseminated, intracellularly faced positions potentially involved in the formation of the inactivation apparatus [Lehmann-Horn & Jurkat-Rott 1999]. Therefore, they lead to incomplete or slowed fast inactivation and a pathologically increased sodium current; the result is an increased tendency of the muscle fibers to depolarize.

The degree of depolarization determines the clinical symptoms: slight depolarizations near the sodium channel threshold result in repetitive muscle action potentials (→ hyperexcitability = myotonic bursts in the EMG or clinically obvious myotonia); stronger depolarizations beyond the threshold lead to sodium channel inactivation and abolition of action potentials (→ reduced excitability resulting in muscle weakness) [Lehmann-Horn et al 1987]. The myotonia and the paralysis are thus caused by the same mechanism. The dominance of the pathogenic variant results from the fact that it is decisive for excitability; i.e., it produces a so-called dominant gain of function. Potassium has no direct effect on the mutant channel but triggers an attack as a result of membrane depolarization that opens the sodium channels [Wagner et al 1997]. Whereas the normal channels properly inactivate, the mutant channels do not.

Usually, a sodium current caused by incomplete fast inactivation should be terminated by slow channel inactivation. However, several hyperPP-causing pathogenic variants also impair slow inactivation [Cummins & Sigworth 1996]. Although not essential for the occurrence of a paralytic attack, this incomplete slow inactivation presumably stabilizes the persistence of the sodium current, making the depolarization of the muscle fibers long enough to be clinically obvious. Several hyperPP-causing variants are situated in the intracellular S4-S5 loops of the channel that act in a cooperative manner for proper fast inactivation and, depending on the domain, are important for activation and deactivation [Popa et al 2004], whereas voltage sensor variants mainly affect channel deactivation [Groome et al 2007].

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

Benign allelic variants. See Table 3, Benign variants.

Pathogenic allelic variants. See Establishing the Diagnosis and Table 3, Pathogenic variants.

Table 3.

SCN4A Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesReference
Benignc.737C>Tp.Ser246LeuNM_000334​.4
NP_000325​.4
Tsujino et al [2003]
c.968C>Tp.Thr323MetWu et al [2005]
c.2341G>Ap.Val781IleGreen et al [1997]
c.2717G>Cp.Ser906ThrKuzmenkin et al [2003]
Pathogenicc.1320T>Gp.Asn440Lys 1, 2Lehmann-Horn et al [2011]
c.2006G>Ap.Arg669His 1Bulman et al [1999]
c.2014C>Ap.Arg672Ser 1Davies et al [2001]
c.2014C>Gp.Arg672Gly 1Jurkat-Rott et al [2000]
c.2014C>Tp.Arg672Cys 1Kim et al [2007]
c.2015G>Ap.Arg672His 1Jurkat-Rott et al [2000]
c.2023C>Gp.Arg675GlyVicart et al 2004
c.2023C>Tp.Arg675Trp
c.2024G>Ap.Arg675Gln 2
c.2065C>Ap.Leu689Ile 2, 3Bendahhou et al [2002]
c.2078T>Cp.Ile693Thr 2, 3Plassart et al [1996]
c.2111C>Tp.Thr704Met 1, 2, 3Ptácek et al [1991]
c.3466G>Ap.Ala1156Thr 2, 3McClatchey et al [1992]
c.4078A>Gp.Met1360Val 2, 3Wagner et al [1997]
c.4108A>Gp.Met1370Val 1, 2, 3Okuda et al [2001]
c.4342C>Ap.Arg1448Ser 1Bendahhou et al [1999a]
c.4342C>Tp.Arg1448Cys 1Ptácek et al [1992]
c.4343G>Ap.Arg1448His 1, 3
c.4343G>Cp.Arg1448Pro 1Lerche et al [1996]
c.4483A>Tp.Ile1495Phe 2, 3Bendahhou et al [1999b]
c.4774A>Gp.Met1592Val 1, 2, 3Rojas et al [1991]
c.[4468T>C; 4479G>A]p.[Phe1490Leu; Met1493Ile] 2, 3, 4Bendahhou et al [2000]

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.
3.

A common pathogenic variant (see Table 1, footnote 4)

4.

Designates two variants in one allele

Normal gene product. The α subunit of the voltage-gated sodium channel of skeletal muscle comprises 1836 amino acids. The sodium channel of skeletal muscle is decisive for generating the so-called action potential, the signal by which excitation spreads over the muscle fiber in order to initiate a uniform contraction response [Lehmann-Horn & Jurkat-Rott 1999]. The main sodium channel subunit (the so-called α subunit) is mutated in hyperPP. It is arranged as four homologous domains around a central ion-conducting pore. The α subunit determines the main characteristics of the sodium channel, conveying the properties of ion selectivity, voltage sensitivity, pharmacology, and binding characteristics for endogenous and exogenous ligands. The accessory β subunit has one transmembrane segment and binds to the α subunit with an extracellular immunoglobulin-like fold with a stoichiometry of 1:1. It influences channel expression, trafficking, and gating characteristics.

The voltage-sensitive sodium channel has one open and at least two closed states: one from which the channel can be directly activated (the resting state) and one from which it cannot (the inactivated state) [Lehmann-Horn & Jurkat-Rott 1999]. This implies that at least two gates regulate the opening of the pore, an activation and an inactivation gate, both of which are usually mediated by the α subunit. In addition to the inactivated state produced by depolarizations of short duration, another inactivated state, the so-called slow inactivated state, has been described. It is elicited by long-lasting depolarizations [Ruff 1996]. Recovery from this state requires several seconds, in contrast to recovery from the fast inactivated state, which takes only a few milliseconds.

Abnormal gene product. It is not known which parts of the channel protein are involved in generating the slow inactivated state, but functional studies of the pathogenic variants suggest that regions mutated in hyperPP are of importance. Because no long-lasting depolarizations physiologically exist (except in the diseased state), changes in the slow inactivated state may be associated with frequency modulation of the early postsynaptic potential of the neuromuscular endplate. Research has therefore included studies of high frequency-induced changes of inactivation [Richmond et al 1997].

References

Literature Cited

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Chapter Notes

Acknowledgments

We are grateful to the many patients who gave their consent to the publication of their data and to the Periodic Paralysis Association. This work was supported by the German Research Foundation (DFG) (JU470/1), the network on Excitation-contraction coupling and calcium signaling in health and disease of the IHP Program funded by the European Community, the non-profit Hertie Foundation, the IonNeurONet of German Ministry of Research (BMBF), The German Muscle Society (DGM), and the Else-Kröner-Fresenius Foundation.

Revision History

  • 28 January 2016 (me) Comprehensive update posted live
  • 31 May 2011 (me) Comprehensive update posted live
  • 11 August 2009 (cd) Revision: sequence analysis available clinically
  • 25 April 2008 (me) Comprehensive update posted to live Web site
  • 23 September 2005 (me) Comprehensive update posted to live Web site
  • 2 March 2005 (cd) Revision: sequencing of select exons clinically available
  • 18 July 2003 (me) Review posted to live Web site
  • 27 January 2003 (kjr) Original submission
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