Hypokalemic Periodic Paralysis Type 2 (HypoPP2)

Hypokalemic Periodic Paralysis Type 2 (HOKPP2) is a rare, autosomal dominant inheritable congenital genetic disorder, meaning the afflicted person receives a genetic mutation from their parents at birth (Struyk et al, 2007). The disease prevalence is estimated at 1:100,000 with men having a higher incidence of HOKPP2 compared to women and women affected displaying less intense phenotype expression. Symptoms become apparent during the mid to late 20s but decrease in frequency after age 35. Afflicted individuals are struck with unpredictable periods of flaccid muscle weakness or paralysis depending on the severity of the attack (Wang, 2006). The most commonly affected muscles are at the rotator cuff, pelvic girdle, and lower extremities though all muscles can potentially be affected (Goldman, 2007). Attacks of muscle weakness most commonly occur after a period of rest, such as upon waking or after eating a carbohydrate rich meal. Attacks are rare during exercise, but can occur during rest following exercising as well as after glucose or insulin administration (Wang, 2006). Attacks also can be temperature sensitive with cool temperatures potentially increasing severity of attacks. Generally, symptoms last from 3-24 hours before normal muscle functions return (Goldman, 2007). Effects for the individual can vary from difficulty using the affected muscles to complete paralysis of the muscles. The disorder can be life threatening with the possibility of dangerous arrhythmias developing during an attack or paresis of the diaphragm preventing breathing.

While hypokalemic periodic paralysis is not usually fatal, it can have serious complications and long term effects. If an attack should affect muscles involved in breathing or swallowing, the airway can be obstructed or not function normally, leading to an emergency situation (Goldman, 2007). Over time, progressive muscle weakness can occur, leaving the individual weaker between attacks when function would be normal. Treatment includes oral intake of potassium during attacks, which can lessen the severity of the attack, and intake of acetazolamide as a preventative measure (Goldman, 2007).

HOKPP2 disrupts function in the voltage-gated sodium channels of the skeletal muscles (Struyk et al, 2007).  The Na+ channels are composed of four domains, with each domain containing six peptide segments that span the membrane.  The mutation associated with HOKPP2 is found in fourth peptide segment of the second domain; more specifically the mutation occurs on codon 675 (Jurak-Roth et al, 2009).  The missense mutation changes an arginine to a histidine at the voltage sensing segment of the peptide (Jurak-Roth et al, 2009).

This mutation causes a proton leak, as the voltage sensing segment of the Na+ protein is not functioning properly.  The leak allows for an inward current of Na+ ions, which causes instability in the resting potential (Struyk et al, 2007).  With the voltage sensor consistently stuck in the inward configuration, the cell favors hyperpolarization of Na+.  Hyperpolarization and inward current of sodium ions implies the cell is constantly accepting sodium ions into it, which is counterproductive in maintaining an ionic gradient.  This hyperpolarization leads to an overall sustained depolarization of the muscle cell, which can have perilous results (Struyk et al, 2007). When a muscle cells experiences sustained depolarization, the muscle fibers become electrically unexcitable, causing paralysis of the muscles (Struyk et al, 2007). 

As the cell membrane is overall more depolarized than normal with a resting potential varying between -75mV and -87mV compared to -95mV, repolarization and recovery of the action potential is disrupted (Links et al, 1994). Further, there is a decrease in the Na+ channel density which prevents the cell from getting as excited as a cell with no disruption in the action potential (Struyk, 2000). Between a delayed recovery in the action potential and decreased excitatory ability, at the tissue level muscle affected by this disorder displays less contractile force and over time degenerates. A disruption in the action potential shapes the cellular anatomy of the patient resulting in abnormal variation in fiber size, fiber necrosis, and proliferation of connective tissue in the muscles causing muscular atrophy over time (Fontaine et al, 2007). Patients with repeat attacks of paralysis have more fiber anomalies and necrosis which leads to progressively weaker muscle tissue in between attacks.  Post-paresis patients also have delayed recovery of muscular strength compared to baseline even after serum potassium levels have returned to normal. Full strength of the muscle does not return until intra and extracellular ion balances return to normal concentrations. Upon the restoration of potassium concentrations, calcium is able to release in normal concentrations generating the appropriate muscle force (Links et al, 1994).

Changes in the muscle can be visually displayed with electromyography (EMG) testing. During attacks of paresis when there is reduced or absent muscle activity after nerve stimulation, the EMG is electrically silent displaying no significant signal. During initial recovery from paresis there is a very low voltage signal in EMG which prevents accurate readings of the muscle fiber conduction velocity (MFCV). During later recovery there is a reduced MFCV and integrated electromyography (IEMG) signal which returns to baseline measures 22-29 hours post paresis (Links et al, 1994).

Current treatment is twofold: preventative with Acetazolamide and acute treatment with oral Potassium. Acetazolamide is the main treatment for HOKPP2 at the moment, however its mechanism in relation to the disease is largely unknown and its success is variable between cases. Acetazolamide is a carbonic acid inhibitor, meaning it prevents the conversion of carbon dioxide and water into protons and bicarbonate creating systemic acidosis. This acidosis is postulated to minimize the positively charged histadine interactions with the negatively charged channel complex. In HOKPP2 caused by a missense mutation replacing Arg with histadine, Acetzolamide may prove an effective preventative measure against flaccid muscle weakness. However, in cases unresponsive to Acetazolamid or in attacks that have already commenced, oral potassium is still the standard of treatment. Oral Potassium increases the concentration of extracellular potassium ions in the most direct manner possible, ameliorating an attack quickly and effectively.