How Periodic Paralysis is Hereditary

How Periodic Paralysis is Hereditary: Expanded Overview of Its Forms

Periodic Paralysis (PP) is a group of rare, inherited disorders that cause episodes of muscle weakness or paralysis due to abnormalities in the way ions (such as potassium, sodium, and calcium) move in and out of muscle cells. The episodes are typically triggered by changes in electrolyte levels, physical activity, stress, or even dietary factors. Understanding the hereditary nature of PP and the specific forms it can take is crucial for both diagnosis and management.

Genetic Basis and Inheritance Patterns

Periodic Paralysis is primarily caused by mutations in specific genes that affect ion channels in muscle cells making them ion channelopathies, also known as mineral metabolic disorders. These mutations can be inherited in an autosomal dominant or autosomal recessive manner, meaning that the disorder can be passed down from one or both parents. The specific gene mutations involved determine the type of PP and its associated symptoms.

Key Genes and Ion Channels Involved:

• Sodium Channels (SCN4A on Chromosome 17): Mutations here are associated with both Hypokalemic and Hyperkalemic Periodic Paralysis, as well as Paramyotonia Congenita.
• Potassium Channels (KCNJ2, KCNE3, KCNJ18 on Chromosome 17; KCNJ15 on Chromosome 21; KCNJ5 on Chromosome 11: These are primarily linked to Andersen-Tawil Syndrome and Normokalemic Periodic Paralysis.
• Calcium Channels (CACNA1S on Chromosome 1; CACNA1C on Chromosome 12): Mutations in these channels are mainly associated with Hypokalemic Periodic Paralysis.

Forms of Periodic Paralysis and Their Genetic Underpinnings

1. Hypokalemic Periodic Paralysis (HypoPP or HypoKPP)
• Description: In HypoPP, also known as Westphall Disease, paralysis occurs when potassium moves from the blood into muscle cells in an abnormal way, primarily due to the calcium channel not signaling the appropriate release of calcium. This leads to low potassium levels in the blood (hypokalemia) during episodes.
• Genetic Mutation: Linked to mutations in the CACNA1S gene on Chromosome 1, associated with calcium channels. This type is a Calcium Channelopathy.
2. Hyperkalemic Periodic Paralysis (HyperPP or HyperKPP)
• Description: In HyperPP, also known as Gamstorp Disease, paralysis results from sodium flowing into the cells because the channel remains open inappropriately. This condition is associated with high potassium levels in the blood (hyperkalemia) during episodes.
• Genetic Mutation: Typically involves mutations in the SCN4A gene on Chromosome 17, associated with sodium channels. This type is a Sodium Channelopathy.
3. Andersen-Tawil Syndrome (ATS)
• Description: Also known as Long QT Syndrome 7, ATS is a form of PP where paralysis results from the potassium channel not opening properly, disrupting potassium ion flow in skeletal and cardiac muscles. ATS is associated with low, high, or normal potassium levels during episodes and may include cardiac arrhythmias and distinctive physical features such as webbed toes and dental anomalies.
• Genetic Mutations: Most commonly linked to mutations in the KCNJ2 gene on Chromosome 17, which encodes potassium channels. This type is a Potassium Channelopathy. A more recent mutation has been found on KCNJ5 on Chromosome 11.
4. Normokalemic Periodic Paralysis (NormoPP or NormoKPP)
• Description: NormoPP involves episodes of paralysis when potassium levels remain within normal ranges, but the potassium shifts within the cells, potentially due to rapid and undetectable changes. This shifting itself, rather than high or low potassium levels, is believed to trigger the episodes.
• Genetic Mutation: Often linked to mutations in the CACNA1S gene on Chromosome 1, associated with calcium channels. This type can be classified as a Calcium Channelopathy.
5. Paramyotonia Congenita (PMC)
• Description: PMC, also known as Von Eulenberg’s Disease, is characterized by muscle stiffness and weakness, which occurs when sodium channels close too slowly, allowing continuous flow of sodium, potassium, chloride, and water into the muscles. PMC can manifest as a form of Hyperkalemic Periodic Paralysis, with symptoms arising from shifting potassium levels, whether they are high, low, or normal.
• Genetic Mutation: Linked to mutations in the SCN4A gene on Chromosome 17. This type is a Sodium Channelopathy.
6. Thyrotoxic Periodic Paralysis (TPP)
• Description: TPP, also known as Thyrotoxic Hypokalemic Periodic Paralysis, involves intermittent paralysis due to low potassium levels caused by an overactive thyroid (hyperthyroidism). Unlike other forms of PP, TPP can often be treated and potentially cured by addressing the thyroid condition.
• Genetic Mutation: While not always linked to a specific genetic mutation, TPP is influenced by hyperthyroidism and can be treated by managing the thyroid. This condition is associated with Chloride Channelopathies. Some cases have been linked to mutations in the KCNE3 and KCNJ18 genes, making them Potassium Channelopathies.

Recent research has uncovered additional genetic mutations that may contribute to various forms of Periodic Paralysis:

• ATP1A2 Mutation: This mutation affects the sodium-potassium pump, an essential component of muscle cell function.
• MCM3AP Mutation: Linked to regulation of gene expression in muscle cells.
• RYR1 Mutation: Associated with calcium channels, this mutation can lead to disruptions in muscle contraction and relaxation processes.

Conclusion

Periodic Paralysis is a complex group of hereditary disorders, mineral metabolic disorders also known as ion channelopathies, with each form linked to specific genetic mutations that affect ion channel function. Understanding these genetic underpinnings is crucial for accurate diagnosis, management, and family planning. As research continues, new forms and mutations are being discovered, expanding our knowledge of this challenging condition.

References

1. National Institute of Neurological Disorders and Stroke (NINDS). Periodic Paralysis Information Page. Available at: NINDS
2. National Organization for Rare Disorders (NORD). Periodic Paralysis. Available at: NORD
3. Genetics Home Reference. SCN4A gene. Available at: Genetics Home Reference
4. American Academy of Neurology. Diagnosis and Treatment of Periodic Paralysis. Available at: American Academy of Neurology
5. Harvard Health Publishing. Understanding Genetic Testing. Available at: Harvard Health

Image: Mother and newborn baby, demonstrating heredity.