Primary Periodic Paralysis

Introduction:

Periodic paralysis encompasses a diverse group of conditions, including recurrent muscle weakness and episodes of flaccid paralysis. They are categorized into two main types: primary, which are hereditary and result from mutations in genes encoding skeletal muscle membrane channel proteins like sodium, calcium, or potassium channels; secondary, which are acquired and typically occur due to conditions such as thyrotoxic periodic paralysis or various renal, adrenal, or non-renal factors like gastroenteritis. Primary periodic paralysis can be subtyped based on the specific ion channel affected, leading to distinct disorders like hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Anderson’s syndrome.

What Is Primary Periodic Paralysis?

Primary Periodic Paralysis (PPs) is a genetic condition characterized by ion channel abnormalities that result in recurring episodes of muscle weakness due to irregular muscle membrane excitability. These episodes are traditionally categorized as hyperkalemic (HyperPP) or hypokalemic (HypoPP) based on either serum potassium levels or the individual’s response to potassium administration. While PP is typically not life-threatening, it can lead to disability, and many affected individuals experience ongoing weakness between attacks. Additionally, in a specific subset of PP patients, such as those with Anderson-Tawil syndrome (ATS), there is a risk of cardiac arrhythmia-related morbidity and mortality, which has not been fully recognized. Despite advances in understanding the genetic causes of PP in recent years, there are still individuals with this condition for whom the underlying molecular defects remain unidentified.

What Are the Causes of Primary Periodic Paralysis?

Primary periodic paralysis results from gene mutations that encode subunits of skeletal muscle membrane or endoplasmic reticulum ion channels, including sodium, potassium, and calcium channels. These channels play essential roles in muscle function.

Sodium Channels: Sodium channels consist of alpha and beta subunits, with alpha subunits having four domains (DI-DIV) and six transmembrane segments each. These channels are voltage-gated and regulate muscle membrane potential. Mutations in sodium channel genes lead to hyperkalemic periodic paralysis, hypokalemis periodic paralysis, paramyotonia congenita, and congenital myasthenic syndrome.

Calcium Channels: Calcium channels comprise five subunits crucial for excitation-contraction coupling. Mutations in genes encoding these channels can cause hypokalemic periodic paralysis.

Potassium Channels: Potassium channels maintain resting membrane potential and repolarization. Mutations in the potassium channel gene on chromosome 17 result in Anderson-Tawil syndrome, characterized by muscle hyperexcitability followed by inexcitability.

What Are the Types of Primary Periodic Paralysis?

Primary periodic paralysis encompasses various types associated with specific gene mutations and affected channel proteins. These include hypokalemic, hyperkalemic, Anderson’s syndrome, paramyotonia congenita, and CMS.

Hyperkalemic Periodic Paralysis: It is an autosomal dominant condition characterized by recurrent episodes of limb paralysis and elevated serum potassium levels (more than 5 mmol/L). These episodes can last 15 minutes to four hours and may also affect the eyes, throat, and trunk, but they typically spare respiratory and cardiac muscles. Symptoms mostly begin in childhood, with the first attack occurring at age 10, and become frequent and severe until age 50. Triggers for these include potassium-rich foods, post-exercise rest, low temperatures, and emotional stress.

Additionally, most patients experience mild myotonia during each episode, and some may develop chronic progressive myopathy, leading to permanent muscle weakness.

Pathogenesis: Hyperkalemic PP results from various mutations, with the most common occurring in the SCN4A gene located on chromosome 17, which encodes skeletal muscle sodium channels. In individuals with this mutation, the fast inactivation of sodium channels is either incomplete or abnormally slowed, leading to an increased sodium flow and a greater tendency for muscle fibers to depolarize.

Hypokalemic Periodic Paralysis: The most common type of paralysis, it is an autosomal dominant condition characterized by recurring episodes of weak, flaccid muscles that last for several hours to a few days. During these episodes, individuals typically have low serum potassium levels (<3.5 mmol/L). The onset of the first episode usually occurs between the ages of two and 30 years. While it might be a one-time occurrence, it commonly recurs daily, weekly, monthly, or at varying intervals. Factors such as low temperatures, anxiety, excessive salt consumption, lack of exercise, glucocorticoid or alcohol use, and certain anesthetic procedures can exacerbate these paralytic attacks. Some patients may also experience persistent muscle weakness between episodes.

Pathogenesis: Hypokalemic periodic paralysis results from mutations in either the alpha-subunit of the DHP-receptor (CACNA1S) gene on chromosome 1 or the sodium channel (SCN4A) gene on chromosome 17. These genetic mutations disrupt ion channel function and contribute to this condition's characteristic episodes of muscle weakness.

Anderson-Tawil Syndrome: Also known as cardio-dysrhythmic periodic paralysis or potassium-sensitive periodic paralysis, is a relatively rare hereditary autosomal dominant disorder characterized by recurrent episodes of flaccid paralysis. These episodes can occur with intervals ranging from an hour to several days. This syndrome is associated with various complications, including cardiac arrhythmias such as bigeminy, long QT syndrome, prolonged QUc interval, ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Additionally, individuals with Anderson’s-Tawail syndrome may exhibit various physical abnormalities, including:

• Short stature, a broad forehead, hypertelorism (widely-spaced eyes), low-set ears, a broad-based nose, micrognathia (a small jaw), cleft palate, molar hypoplasia, enamel discoloration, tapered and curved fingers, clinodactyly (curvature of the fingers), syndactyly (fusion of fingers or toes), or scoliosis (spinal curvature).

Less common associations may include:

• Short palpebral fissures, retained primary dentition, oligodontia (few teeth), a thin upper lip, unilateral kidney hypoplasia or dysplasia, dilated cardiomyopathy, heart block, abnormalities in semilunar valves, bicuspid aortic valve, coarctation of the aorta, valvular pulmonary stenosis, small hands or feet, or joint laxity.

Andersen’s syndrome is caused by mutations in the KCNJ2 gene located on chromosome 17, which encodes the potassium channel Kir2.1. These mutations can disrupt the function of Kir2.1 channels by blocking or hindering the flow of potassium ions, leading to prolonged terminal-phase muscle action potentials. Additionally, the mutations may interfere with the transport of Kir2.1 channels to the muscle membrane. Prolonged depolarization can trigger cardiac arrhythmias, especially in hypokalemia (low blood potassium levels). Other complications of Andersen’s syndrome result from the interaction of mutant Kir2.1 alleles with wild-type channels, forming tetramers that affect ion channel function.

Paramyotonia Congenita: It is an autosomal dominant disorder characterized by persistent, non-progressive myotonia and muscle weakness, primarily affecting the eyelids, neck, and upper limb muscles. Symptoms are triggered by exposure to cold temperatures and aggravated by physical exercise. These episodes of muscle weakness can persist for minutes to several hours, even after the triggering factors are removed. Importantly, the severity and frequency of symptoms are not influenced by potassium intake; they are specifically triggered by cold temperatures and voluntary muscle activity.

Pathogenesis: Paramyotonia congenita is primarily caused by mutations in the SCN4A gene located on chromosome 17. This gene encodes for skeletal muscle sodium channels. The most affected region is the voltage-sensitive part of domain IV, although other areas, such as the cytoplasmic surface of transmembrane segments S2, S3, and S4 can also be involved. A common cause of paramyotonia congenita is a mutation in segment S4, where arginine is replaced by other amino acids, resulting in the loss of its positive charge.

Congenital Myasthenic Syndrome (CMS): CMS is a diverse inherited disorder characterized by episodes of respiratory or bulbar paralysis and generalized muscle weakness. Additional symptoms may involve facial weakness, ptosis (drooping eyelids), feeding difficulties, poor sucking reflex, and in some cases, arthrogryposis. Notably, CMS does not affect cardiac or smooth muscles, and symptoms typically manifest at birth or shortly after that, varying in severity.

Pathogenesis: CMS arises from mutations in several genes responsible for encoding proteins involved in the myoneural junction, the point of communication between nerves and muscles. These genes include various subunits of the acetylcholine receptor (CHNRE, CHRNA1, CHRNB1, and CHRND), the collagenic tail subunit of acetylcholinesterase (COLQ), choline acetyltransferase (CHAT), rapsyn (RAPSN), or the sodium channel. Mutations in these genes disrupt the normal functioning of the neuromuscular junction, leading to the symptoms in CMS.

What Is the Treatment of Primary Periodic Paralysis?

Treatment and management of periodic paralysis include:

Acute Management:

• Normalize serum potassium levels during attacks.

• Administer oral potassium chloride in incremental doses.

• Close monitoring of serum potassium when using large oral doses.

• Intravenous potassium with mannitol may be used for severe cases.

• Exercise may help in milder attacks.

Preventive Treatment:

• Lifestyle modifications to avoid triggers.

• Medications like Acetazolamide, a Carbonic Anhydrase Inhibitor (CAI), can reduce attack frequency.

• Dichlorphenamide is an FDA-approved alternative.

• Potassium-sparing diuretics may be added to CAIs.

• Regular electrolyte monitoring is important.

• Response to treatment can vary based on gene mutations.

• Topiramate may be considered in some cases.

Special Considerations:

• Malignant hyperthermia risk during surgery for patients with CACNA1S mutations.

• Caution with medications during pregnancy, as they are pregnancy category C.

Conclusion:

Primary periodic paralysis comprises a group of rare genetic disorders characterized by recurrent episodes of muscle weakness or paralysis. These conditions are typically triggered by potassium levels, cold temperatures, and exercise. The subtypes result from specific genetic mutations affecting ion channels or neuromuscular junction proteins. while there is no definitive cure, tailored treatment approaches can improve well-being.