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, breathing muscles, 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. 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. The major attack trigger is eating potassium-rich foods; other triggers include: cold environment; rest after exercise, stress, or fatigue; alcohol; hunger; and changes in activity level. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to one hour, and then passes. Individuals with hyperPP frequently have myotonia (muscle stiffness), especially around the time of an episode of weakness. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals. More than 80% of individuals with hyperPP older than age 40 years report permanent muscle weakness and about one third develop a chronic progressive myopathy.

Diagnosis/testing.

The diagnosis of hyperPP is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing. In case of diagnostic uncertainty, a provocative test can be employed, although the availability of genetic testing and electrophysiologic studies largely obviates the need for such dangerous tests.

Management.

Treatment of manifestations: At the onset of weakness, attacks may be prevented or aborted with mild exercise and/or oral ingestion of carbohydrates, intravenously injected glucocorticoids, 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.

Surveillance: Yearly neurologic examination with focus on muscle strength in the legs in order to detect permanent weakness; in those with permanent muscle weakness, MRI of 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 or ACE-inhibitor medications.

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, particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events.

Genetic counseling.

HyperPP is inherited in an autosomal dominant manner. Most individuals with hyperPP have an affected parent; the proportion of individuals with hyperPP 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. Once the SCN4A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for hyperPP are possible.

Suggestive Findings

Hyperkalemic periodic paralysis (hyperPP) should be suspected in individuals with the following family history and clinical, electromyogram, 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, firing rate generally between 20 and 150 Hz), 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 electric 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 EKG (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 suggestive findings and a heterozygous pathogenic variant in SCN4A identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous SCN4A variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from other inherited disorders with periodic paralysis are more likely to be diagnosed using genomic testing (see Option 2).

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. Initially infrequent, the attacks increase in frequency and severity over time until approximately age 50 years, after which the frequency declines considerably.

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]. The major attack trigger is eating potassium-rich foods.

Of note, attacks occur more frequently on holidays and weekends when people rest in bed longer than usual.

Pattern of attacks. 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 more than a 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. Dysphagia during an attack of weakness has also been described [Benhammou et al 2017]. The strength of the attacks is not always consistent; sometimes the patient only feels fatigued, but can still move around slowly. Other times the patients are completely paralyzed. Sometimes attacks may come very suddenly.

Individuals most commonly describe their attacks as stiffness followed by weakness, although many have described their attacks as some other permutation of weakness and/or stiffness. The arms and hands are just as frequently affected as the thighs and calves [Charles et al 2013].

Frequency of attacks can vary greatly among individuals. Some have attacks every day, others several times a month; others have them every few months or less often.

Usually, cardiac arrhythmia or respiratory insufficiency does not occur during the attacks. When present, respiratory insufficiency manifests as shortness of breath. In a study by Charles et al [2013], 26% of subjects reported that their breathing musculature was affected and 62% reported that their face was affected during attacks. The mouse model has demonstrated a resistance to weakness triggered by hyperkalemia in diaphragmatic muscle as compared to skeletal muscle [Ammar et al 2015].

Interictal period (i.e., between paralytic attacks) findings. After an attack, affected individuals report clumsiness, weakness, and irritability, and in 62% muscle pain secondary to the attack. One observational study identified fibromyalgia in half of the individuals surveyed who had hyperPP [Giacobbe et al 2021]. Between attacks, the majority report no or mild symptoms. However, 12% report severe symptoms between attacks that impair activities of daily living.

Muscle issues. Individuals with hyperPP frequently (i.e., >50% of the time) have myotonia, especially around the time of an episode of weakness. Mild myotonia (muscle stiffness) that does not impede voluntary movements is often present between attacks. Myotonia is most readily observed in the facial, lingual, thenar, and finger extensor muscles; eyelid myotonia (lid lag myotonia) has been rarely reported. Paramyotonia (muscle stiffness aggravated by cold and exercise) is present in about 45% of affected individuals. Of individuals with myotonia, 37% have experienced progressive myopathy, while of those reporting absence of myotonia, 33% have experienced progressive myopathy [Charles et al 2013].

Bradley et al [1990] reported more than 80% of the affected individuals older than 40 years to have permanent muscle weakness and approximately one third of older affected individuals developed a chronic progressive myopathy. The myopathy mainly affects the pelvic girdle and proximal and distal lower-limb muscles. A more recent study using MRI reveals an even earlier onset of progressive myopathy: progressive myopathy was observed even in individuals at the second and third decades of life with myopathic findings prominent in the gastrocnemius muscle. Muscle atrophy, edematous change, and fatty change were prominent in the superficial posterior compartment of the lower leg [Jeong et al 2018].

Thyroid dysfunction. As shown by an 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

No genotype-phenotype correlations have been identified.

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

Names for hyperPP no longer in use include adynamia episodica hereditaria and Gamstorp disease.

Prevalence

The prevalence of hyperPP is approximately 0.17/100,000 (95% CI 0.13-0.20) [Horga et al 2013]. In the Netherlands, a prevalence of 0.06/100,000 (95% CI 0.03–0.12) has been reported [Stunnenberg et al 2018]. In a large cohort of Italian patients with periodic paralysis and SCN4A pathogenic variants, the hyperPP/normo-PP phenotype accounted for seven of 80 (8.7%) individuals [Maggi et al 2020]. In a German observational study of nondystrophic myotonia, 20% of the patients with SCN4A pathogenic variants showed periodic paralysis [Vereb et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hyperkalemic periodic paralysis (hyperPP), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment for hyperPP is symptomatic and not curative.

Prevention of Primary Manifestations

Diet/environment. Preventive measures for individuals with hyperPP consist 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

Early start to the day. As 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.

Lifestyle. Individuals should prioritize avoidance or minimization of triggers whenever possible by keeping stress levels low and avoiding exercise that is overly intense (as rest after such exercise is a trigger).

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 dichlorphenamide. (Note: In a trial of dichlorphenamide, the median attack rate was lower in participants with hyperPP on dichlorphenamide than in participants with hyperPP on placebo (0.9 vs 4.8), but the difference in median attack rate was not significant (p = 0.10) [Sansone et al 2016]). 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]. Thiazides may be helpful even if the serum potassium concentration is in the normal range [Akaba et al 2018].

Four weeks after start of diuretic treatment, effects should be evaluated by muscle strength measurement and MRI of proximal leg muscles.

Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• Opioids or depolarizing agents such as potassium, anticholinesterases, and succinylcholine as part of general anesthesia. These can aggravate a myotonic reaction and induce masseter spasms and stiffness of respiratory muscles, which may impair intubation; mechanical ventilation may also be impaired.
• Drugs known as ACE-inhibitors for the treatment of arterial hypertension. These may lead to hyperkalemia as a side effect, especially if they are combined with potassium-sparing diuretics (e.g., spironolactone) and/or renal function is impaired.
• Alterations of serum osmolarity, pH, and hypothermia-induced muscle shivering and mechanical stimuli during general anesthesia. These can exacerbate the myotonic reaction in individuals with hyperPP.

See also Prevention of Primary Manifestations.

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. Evaluations include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• Full neurologic examination to rule out muscular weakness and EMG to rule out myotonia if the pathogenic variant in the family is not known.

At-risk relatives who have not undergone molecular genetic testing or clinical evaluation (i.e., neurologic examination and EMG) must be considered at risk for hyperPP-related 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, Yong et al 2018]. In contrast, however, are case reports describing improvement during pregnancy [Finsterer et al 2017, Huang et al 2019].

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.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 individuals with hyperPP caused by a de novo pathogenic variant is unknown.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in 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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• Substantial intrafamilial clinical variability may be observed among sibs who inherit the same SCN4A pathogenic variant: a heterozygous sib may have manifestations of hyperPP identical to those of the proband, subclinical findings only, or very few and minor symptoms during adolescence that may not be recognized as abnormal. (Note: Significant intrafamilial variability can make it difficult to establish a dominant mode of inheritance based on the clinical features of family members.)
• If the proband has a known SCN4A pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental 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 and/or is known to have the SCN4A pathogenic variant identified in the proband, 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 in order to identify family members who would benefit from initiation of preventive measures (particularly those that would decrease the risk of unexpected acute paralysis or anesthetic events).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SCN4A encodes the muscular voltage gated sodium channel Na_v1.4. Missense variants that cause gain-of-function defects for Na_V1.4 lead to hyperPP symptoms.

All forms of periodic paralysis, regardless of pathogenic variant, share a common final mechanism, a long-lasting partial depolarization of the sarcolemma leading to inactivation of Na_v1.4 channels, thereby inhibiting action potentials and rendering the muscle fibers inexcitable. This phenomenon of partial depolarization – which was initially only shown in physiologic studies of biopsies of intact muscle fibers [Lehmann-Horn et al 1987] and in cellular physiologic experiments – has recently been shown in vivo via muscle velocity recovery cycles [Tan et al 2020].

Normal Na_v1.4 channels have only a very small persistent current, about 0.2% of the transient peak elicited by a step depolarization. Pathogenic variants associated with hyperPP lead to incomplete fast inactivation, which results in persistent Na⁺ currents of 1% to 4% of the transient peak. Although the absolute amplitude of the anomalous persistent current is small, the relative increase of five- to 20-fold has a large effect on the membrane voltage. Normally, the resting membrane potential is -85 mV, and all channels are closed. In response to a stimulus, the inactivation defect is revealed and the fiber may respond with a myotonic burst. The repetitive firing produces a cumulative increase of T-tubular K⁺ within the muscle fiber, which together with the inactivation defect results in a steady inward Na⁺ current that keeps the fiber depolarized at about -45 mV. From this depolarized potential the normal Na_v1.4 channels and most of the abnormal ones are inactivated, rendering the fiber inexcitable, as occurs in periodic paralysis. The requirement for elevated extracellular K⁺, either interstitial or T-tubular, to mildly depolarize the fiber and reveal the inactivation defect explains why attacks may be triggered or aggravated by potassium ingestion in hyperPP [Cannon 2018].

Data from mouse models suggest that the lag in onset of clinical features of hyperPP during the first decade and the progression of symptoms during adolescence are a function of Na_v1.4 channel content [Khogali et al 2015]. The clinical phenotype can also be affected by polymorphisms, as described for the Na_v1.4. pathogenic variant p.Ile692Met, where a concomitant p.Ser906Thr polymorphism results in longer weakness episodes, more affected muscles, CK elevation, and presence of permanent weakness [Fan et al 2017].

Mechanism of disease causation. The pathogenic variants associated with hyperPP all produce gain-of-function changes for Nav1.4. Most often, this gain of function is produced by defects of channel inactivation [Cannon 2018].

Notable SCN4A variants. See Table 3 (pdf) for an author-curated list of associated SCN4A pathogenic variants.

Author Notes

Frank Weber is a clinical neurologist and, as a military physician, is a certified flight surgeon. After many years in hospital-based neurology, he is currently head of the department of research of the German Air Force Center of Aerospace Medicine. He was trained in clinical neurology at the University of Ulm and at the Technical University in Munich, where he met Frank Lehmann-Horn. He has a special interest in neuromuscular disorders and in clinical neurophysiology. His scientific interests include disorders of nerve and muscle and channelopathies of the peripheral nervous system and the muscle system, particularly sodium channels.

Contact: frankweber@bundeswehr.org

Voltage-Gated Ion Channels and Hereditary Disease

Acknowledgments

Thanks 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.

Author History

Karin Jurkat-Rott, MD, PhD; Ulm University (2003-2021)
Frank Lehmann-Horn, MD, PhD; Ulm University (2003-2021 *)
Frank Weber, MD, PhD (2016-present)

* Dr Lehmann-Horn died in 2018 after a long illness.

Revision History

• 1 July 2021 (ha) Comprehensive update posted live
• 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 live
• 23 September 2005 (me) Comprehensive update posted live
• 2 March 2005 (cd) Revision: sequencing of select exons clinically available
• 18 July 2003 (me) Review posted live
• 27 January 2003 (kjr) Original submission

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