Rare Disease Report

New Research Finds Cause of Hypokalemic Periodic Paralysis

JUNE 19, 2018
Einav Keet
Researchers from the University of Washington School of Medicine in Seattle have discovered what causes hypokalemic periodic paralysis, a rare genetic disorder that causes attacks of muscle weakness and paralysis.

An estimated 1 in 100,000 individuals have the condition also known as HOKPP, HypoKPP, or HypoPP. Individuals with HOKPP typically experience their first episode of the condition during childhood or adolescence. During an attack, HOKPP can cause a temporary inability to move muscles in the arms and legs, which can last for hours or days. A HOKPP attack can also affect eye muscles, breathing, and swallowing. Triggers of an attack can include high-carbohydrate meals and resting after exercise.

Treatment for moderate to severe HOKPP attacks can include potassium salts or intravenous potassium, to restore low levels in the blood. While the frequency of attacks can vary from daily to once per year, individuals ages 15 to 35 years typically experience the highest frequency of attacks and then see a decrease with age. Over time, repeated attacks can cause more persistent muscle weakness.

Researchers have identified mutations in the CACNA1SSCN4A, or KCNJ18 gene as a cause of HOKPP, but until recently it was unknown how these mutations change the function of certain cell membrane proteins. In a new study published in the journal Nature, researchers have discovered that a hole in the membrane protein disrupts sodium-potassium pumps in muscle cells that move sodium out of cells and maintain potassium levels inside of cells. Higher potassium levels create a negative charge inside a cell, and the charge difference produces a voltage across a cell membrane. This voltage is key to creating the electrical signals that cause muscles to contract.

In individuals with HOPKK, a mutation impacts the voltage sensor or voltage-gated sodium channel. This affects the function of ion channels so that ions don’t flow into muscle cells properly to cause muscle contractions, thereby causing the condition’s telltale weakness and paralysis.  Using X-ray crystallography, the study’s authors determined the structure of both normal and mutated versions of the voltage sensor. In HOPKK, they found that the mutation caused the formation of a small hole at the center of the voltage sensor in the sodium channel protein, allowing for the continuous leak of sodium ions.

“This leak causes sustained membrane depolarization and action potential failure, thereby paralyzing the muscle,” said lead researcher William A. Catterall, PhD, a professor of pharmacology at the University of Washington School of Medicine, in a recent statement. The findings explain why low blood concentrations of potassium lead to muscle weakness and paralysis. “Our results reveal the mechanisms of periodic paralysis at the atomic level and suggest designs for drugs that may prevent this ion leak and provide relief to these patients.”

One possibility for treatment may include the use of compounds containing a chemical group called guanidinium, wrote the authors, who showed that these compounds can essentially block the hole to stop the sodium leak without impacting the function of the voltage sensor.  “Our high-resolution structural models may provide templates for drugs that mimic the effect of guanidinium, block the gating pore current, and could perhaps prevent or treat periodic paralysis,” concluded Dr. Catterall.

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