Structure reveals mechanism behind periodic paralysis

Three states of the voltage-sensing domain (VSD) of a membrane-channel protein. In the normal state, the water-accessible space (magenta) does not extend through the channel, preventing sodium (gray spheres) from passing through. In the disease state, a clear passage allows sodium to leakthrough, resulting in muscle paralysis. In the “rescued” state, the binding of guanidinium (blue and yellow spheres) effectively closes the channel and blocks sodium leakage. The red sphere represents the location of the disease-causing mutation. The side-chain sticks represent the voltage sensors of the sodium channel.

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Myopathy of Hypokalemic Periodic Paralysis

EREDITARY intermittent flaccid paralysis of skeletal muscle is at present classified into three types on the basis of the changes in the serum potassium during the paralytic attack. The hypokalemic form was the first to be clinically recognized, and is the most common of the three variants, more than 600 cases having been described in the literature by 1959.¹ The clinical manifestations of this disease will not be detailed here as many reviews are available.^2-5 Worthy of emphasis, however, is that permanent proximal muscle weakness may occur. This feature was first noted by Oppenheim⁶ in 1891 and was later thought to be a variant of spinal muscular atrophy occurring in conjunction with periodic paralysis.⁷ However, it has now become apparent that permanent myopathic weakness is not uncommon, and not dependent upon severe or repeated paralytic attacks.^8-10

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What is hypokalemic periodic paralysis?

What is hypokalemic periodic paralysis?

Hypokalemic periodic paralysis is an inherited condition characterized by transient episodes of extreme muscle weakness and/or paralysis of the muscles in the arms and legs, along with a decreased serum potassium concentration during an attack. These episodes may last from a few hours to one day.

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Hyper- and Hypokalemic Periodic Paralysis Study

Hyper- and Hypokalemic Periodic Paralysis Study 

Periodic paralysis is a relatively rare, life-long disorder characterized by intermittent bouts of paralysis, progressive weakness, and diminished quality of life. Two drugs, acetazolamide (ACZ) and dichlorphenamide, have been prescribed to treat the disorder, however, dichlorphenamide is no longer available. In this multi-center, parallel, randomized trial researchers will compare the effects of dichlorphenamide vs. placebo in patients with hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. The trial consists of two 9-week studies—one study will enroll persons with hyperkalemic periodic paralysis and the other study will enroll persons with hypokalemic periodic paralysis. Participants will be randomly assigned to one of two treatment groups: dichlorphenamide or placebo (an inactive substance). During the studies, participants will be asked to keep a daily diary to record the time, length, and severity of each episode of weakness (attack). The study coordinator will contact participants weekly to review the diary information. The 9-week phase will be followed by a 1-year open-label dichlorphenamide extension without placebo to determine the long-term effects of dichlorphenamide on the course of the disease and on inter-attack weakness. Duration of the trial for participants is approximately 65 weeks, including a screening phase to determine eligibility, the first 9-week treatment phase, and the one-year open-label extension phase. 

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HYPERKALEMIC PP VS HYPOKALEMIC PERODIC PARALYSIS

1. HYPERKALEMIC PERIODIC PARALYSIS MUTATED GENE SCN4A CHROMOSOME 17q DEFECTIVE CHANNEL SODIUM MODE OF INHERITENCE AUTOSOMAL DOMINANT 
2.  Hyperkalemic Periodic Paralysis • term hyperkalemic is misleading since patients are often normokalemic during attacks. • Onset first decade • M : F 1:1 • Attacks are brief and mild, usually lasting 30 minutes to 4 hours. • Weakness affects proximal muscles, sparing bulbar muscles. • Attacks are precipitated by rest following exercise and fasting. 
3.  In a variant of this disorder, the predominant symptom is myotonia without weakness (potassium-aggravated myotonia). • The symptoms are aggravated by cold, and myotonia makes the muscles stiff and painful. • Clinically apparent myotonia is seen less than 20% of patients, but electrical myotonia may be found in 50-75%. 
4. Pathophysiology  In hyperKPP, Na+ channels fail to inactivate and prolonged openings and depolarization result.  Increased extracellular K+ levels worsen the inactivation of Na+ channels.

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