Last updated:
9/30/2024
Years published: 2024
NORD gratefully acknowledges Michelle Frees, MS, Justin Gomez-Stafford, MS, Kenna Kumnick, MS, Michaela Taylor, MS and Jennefer Kohler, MS, Stanford University MS Program in Human Genetics and Genetic Counseling and Emily Dunn, MD, Stanford University, for the preparation of this report.
Summary
Hypokalemic periodic paralysis (hypoPP) is a variable condition characterized by episodes of an inability to move muscles in arms or legs (paralysis) alongside low potassium levels in the bloodstream (<3.5 mmol/L). Muscles closer to the trunk of the body such as the shoulders and hips are more often affected (proximal weakness) during an episode of muscle weakness than those further from the trunk such as hands and feet (distal weakness). Muscle weakness attacks can last anywhere from several minutes to several days but average about 24 hours. Some people may only experience one attack while others may experience attacks that recur daily, monthly, or yearly. Often, these episodes are triggered after strenuous exercise or consuming carbohydrate-rich meals in the evening. Additional triggers have been noted to be exposure to the cold, strong emotions (stress/excitement/fear), salt intake, prolonged immobility, use of steroid hormones, consumption of alcohol and anesthetic procedures. There is no known cure for hypoPP currently, but symptom-based treatment is available depending on the intensity and duration of muscle weakness episodes.
Introduction
Hypokalemic periodic paralysis is the most common periodic paralysis syndrome associated with low levels of potassium in the blood. Other periodic paralysis syndromes are associated with normal or high levels of potassium in the blood, and some are caused by kidney or hormonal conditions. All periodic paralysis syndromes involve episodes of severe muscle weakness or the inability to move.
Carave and Romberg first described a “periodic palsy” in the 1850s, and Westphal described the condition in detail shortly afterwards. Because of this, the condition was previously called “Carave-Romberg-Westphal syndrome” or other combinations of these three names. Today, hypokalemic periodic paralysis is sometimes abbreviated as hypoPP, HOKPP, or HypoKPP.
There are 2 subtypes of primary hypoPP: type 1 is caused by changes (variants) in the CACNA1S gene and type 2 is caused by variants in the SCN4A gene. These two subtypes do not have different symptoms and are simply divided based on the cause.
Hypokalemic periodic paralysis is characterized by episodes of muscle weakness that coincide with low blood potassium levels (hypokalemia). The first muscle weakness episode can happen in childhood or adulthood, typically between ages two and 30 years. Symptoms of hypoPP typically include:
The episodes of muscle weakness begin quickly, developing over minutes to hours and they may last from several minutes to a few days, with an average of 24 hours. Most episodes resolve on their own without treatment.
The common triggers for these episodes include:
HypoPP can cause long-term muscle weakness, either mild or severe. This may result from muscle breakdown (atrophy), fluid build-up (edema), or both. Some people may experience mild, long-lasting muscle weakness (myopathy) as their only symptom.
People with relatives who have experienced episodes of muscle paralysis are at a higher risk of developing HypoPP themselves.
Hypokalemic periodic paralysis can be caused by a change (pathogenic variant; previously called mutation) in the genes CACNA1S or SCN4A. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic variant in a gene occurs, the protein can no longer work properly. Depending upon the functions of the protein, this can affect different parts of the body, including the muscles.
CACNA1S provides instructions for a calcium channel and SCN4A provides instructions for a sodium channel, both of which are important for muscle function. The appropriate flow of calcium and sodium ions through these channels is necessary for muscles to contract and relax, leading to normal movement. Certain genetic changes in CACNA1S and SCN4A cause the channels to leak ions. This interferes with the muscles ability to contract, causing muscle weakness or paralysis.
A pathogenic variant in the CACNA1S or SCN4A gene has been identified in 60-70% of patients who have a clinical diagnosis of hypoPP. CACNA1S gene variants are the more common genetic cause, making up 60% of patients with a genetic diagnosis. About 20% of patients with an identified genetic cause of hypoPP have a pathogenic variant in the SCN4A gene. For those without an identified pathogenic variant, the cause of the condition is unknown, though it is still thought to be genetic.
HypoPP is inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Not everyone who inherits a variant in the CACNA1S or SCN4A genes will have symptoms of hypoPP. It is estimated that 90% of males with a variant in hypoPP will have symptoms. Females are less likely to have symptoms than males.
Hypokalemic periodic paralysis affects both males and females, although studies have shown symptoms are more likely to occur in males. It can affect individuals of any ethnic or racial background. The prevalence of hypoPP is not precisely known but thought to be approximately 1:100,000.
A diagnosis of hypokalemic periodic paralysis may be considered after someone has a paralytic attack and when other potential causes of hypokalemia (low blood potassium levels) have been ruled out. Someone may be given a diagnosis of hypoPP if they have at least two muscle weakness attacks during which they were found to have low blood potassium levels. If a family member has experienced a hypokalemic paralytic attack, a diagnosis may be made after only one paralytic attack. In the absence of documented low blood potassium levels, a diagnosis is most likely to be made if symptoms began before age 30, the muscle weakness affected at least one limb and lasted longer than two hours, and symptoms improved with potassium intake. Healthcare providers might suspect a diagnosis of hypoPP if symptoms began after eating a carbohydrate-rich meal, after exercising, or while stressed. A long exercise test may clarify a diagnosis of hypoPP by measuring changes in the electrical activity of the muscle after exercise. Genetic testing for variants in the two genes associated with hypoPP (CACNA1S and SCN4A) may confirm a diagnosis.
Clinical Testing and Work-Up
During a paralytic attack, the initial evaluation should include checking for breathing problems (respiratory status assessment), measurement of blood potassium level, EKG (testing the heart rhythm and electrical activity) and a swallowing assessment.
When an individual is asymptomatic or between attacks, an initial evaluation should include a neurologic examination, thyroid function studies, muscle sonography or MRI in those with long-lasting weakness beyond an attack and consultation with a clinical geneticist and/or genetic counselor.
Once diagnosed, affected individuals should be seen regularly by a neurology team to monitor muscle strength in the legs to detect possible long-lasting weakness. If treating hypoPP with acetazolamide, blood tests every three months and annual kidney ultrasounds are recommended.
Treatment
The treatment of hypokalemic periodic paralysis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including pediatricians, neurologists and geneticists experienced in the treatment of periodic paralysis.
Specific drugs known as carbonic anhydrase inhibitors, such as acetazolamide and dichlorphenamide, are used to treat periodic paralysis in individuals with hypoPP. Clinical trials have shown that dichlorphenamide reduces the frequency and severity of attacks of periodic paralysis and is now approved by the U.S. Food and Drug Administration (FDA) for the treatment of periodic paralysis.
Individuals with hypoPP are encouraged to avoid potential triggers of a paralytic attack, including high-carbohydrate and high-salt meals, alcohol and stress.
Patients with hypoPP commonly have low potassium which can be treated with daily oral potassium supplementation as a preventative measure. Potassium may also be given orally or through an IV during a hypokalemic paralysis attack.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Sansone VA. Episodic muscle disorders. Continuum (Minneap Minn). 2019;25(6):1696-1711. doi:10.1212/CON.0000000000000802
Latorre R, Purroy F. [Hypokalemic periodic paralysis: a systematic review of published case reports]. Rev Neurol. 2020;71(9):317-325. doi:10.33588/rn.7109.2020377
Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008;(1):CD005045. doi:10.1002/14651858.CD005045.pub2
INTERNET
Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis. 2002 Apr 30 [Updated 2018 Jul 26]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1338/ Accessed Sept 30, 2024.
Phuyal P, Bhutta BS, Nagalli S. Hypokalemic Periodic Paralysis. [Updated 2024 Mar 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559178/ Accessed Sept 30, 2024.
Siddamreddy S, Dandu VH. Thyrotoxic Periodic Paralysis. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560670/ Accessed Sept 30, 2024.
Hypokalemic periodic paralysis: MedlinePlus Genetics. Last updated March 1, 2020. https://medlineplus.gov/genetics/condition/hypokalemic-periodic-paralysis/ Accessed Sept 30, 2024.
Hypokalemisk periodisk paralys. Socialstyrelsen. Last reviewed 4/10/2018. https://www.socialstyrelsen.se/kunskapsstod-och-regler/omraden/sallsynta-halsotillstand/om-kunskapsdatabasen/sok-bland-sallsynta-halsotillstand/hypokalemisk-periodisk-paralys/ Accessed Sept 30, 2024.
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