Hypokalemic Periodic Paralysis

Last updated Tuesday, June 28th, 2011

Printer-friendly version Hypokalemic periodic paralysis (HypoKPP) is one of the primary forms of periodic paralysis, caused by one or more mutations in the calcium, sodium or potassium ion channels in muscle membrane. Features of Hypokalemic Periodic Paralysis There are two forms of HypoKPP, a paralytic form and a myopathic form. The paralytic form is more common, causing randomly spaced attacks (or episodes) of weakness which range from mild (which feels like fatigue) to flaccid (rag-doll-type) paralysis triggered by a fall in serum potassium. Attacks usually last at least several hours but sometimes can last for several days. Some patients have only one episode in a lifetime; but more often attacks occur repeatedly; daily, weekly, or once or twice a year. The major triggering factors are sweets, starchy or salty foods, sleep and rest after exercise or an unusual level of exertion. Patients also report that attacks can be triggered by becoming chilled or overheated, or by strong emotion. Attacks usually begin between one and 20 years of age. Paralytic attacks are more common during the ages of 15-40 in most patients, then begin to decrease, and may be replaced by what are called abortive attacks. Abortive attacks are longlasting attacks of fluctuating weakness which never progress to paralysis. These attacks can be more disruptive than paralytic attacks, which are over and done with in hours when you are young. A few patients continue to have paralytic attacks into their 60s. About 25% of patients with the paralytic form go on to develop myopathy, or permanent muscle weakness (PMW), which is weakness which never varies. It can begin as exercise intolerance of the legs at any age (even in childhood) and results in permanent muscle weakness by middle age. In some patients it may be the only symptom of HypoKPP, i.e. these patients may never experience episodic weakness or attacks of paralysis.15, 32. Patients who have only myopathy can find getting a diagnosis extremely difficult, even when they have family members who have been diagnosed with HypoKPP. All these varying patterns of weakness can produce an extremely complex clinical picture. A patient of 60 years, who has lost perhaps 40% of their muscle function, may have paralytic attacks during which their muscles function at perhaps 10-15% of their remaining 60% capacity. And/or they may have abortive attacks which reduce their strength to from 20-70% of the 60%, varying from hour to hour and day to day. Many a physician looks at a pattern like this and does

not know what to think - which puts them in the same position as the patient. Answers are not always easy to come by. Genetics and Inheritance The disease is inherited as an autosomal dominant trait. About 1/3 of cases are sporadic or occur in those without any known family history. The most common mutations are found in the Calcium channel on chromosome 1. ---- Calcium Channel: Voltage-Dependent, L Type, Skeletal Muscle Dihydropyridine-Sensitive, Alpha-1 Subunit; CACNA1S Gene map locus 1q32; Mutations described to Date: ARG1239HIS 1, ARG528HIS 2 ARG528GLY 33, ARG1239GLY 3, ARG1086CYS & ARG1086HIS19, ARG897SER50, Arg900Gly52, His916Gln (which appears to cause symptoms only in males)53 . Sodium Channel: Voltage-Gated, Type IV, Alpha Subunit; SCN4A; Gene map locus 17q23.1-q25.3; Six mutations described to date: ARG669HIS 24, ARG672HIS, ARG672GLY 27,28, ARG672SER 30, DIII-S4 ARG1132Q 32 Heat and Cold Sensitive Myotonic Form: It was believed that HypoKPP and myotonia could not occur in the same individual, but a family has been reported which experiences cold-induced hypokalemic paralysis (serum K+ 2.6) and myotonia, occurring when serum K+ levels are in the normal range (4.0). The mutation responsible is in alpha subunit, between 4th/5th transmembrane segments, domain III SCN4A, Pro1158Ser.26, 31, 34, 35, 36 Potassium Channel: In 2010-2011 research teams identified a previously unreported gene which they called KCNJ18 in which were located mutations responsible for the susceptibility to Thyrotoxic HypoKPP in Kir2.6 a skeletal muscle specific-inwardly rectifying K+ channel; 47, 48 Building on this knowledge mutations R43C, V168M and A200P were identified in HypoKPP patients with no recognized family history of the disorder and normal thyroid function. All three mutations exert dominant-negative inhibition on wild type Kir2.6 and Kir2.1. It is now theorized malfunctions of inwardly rectifying K+ channel decrease outward K+ current and predispose the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na+ channel inactivation and inexcitability of muscles.48