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5 Burden, S. J., Sargent, P. B. and McMahan, U. J. (1979) J. Cell Biol. 82, 412-425 6 Godfrey, E . W . , Nitkin, R . M . , Wallace, B. G., Rubin, L. L. and McMahan, U. J. (1984) J. Cell Biol. 99, 615--627 7 Fallon, J. R., Nitkin, R. M., Reist, N. E., Wallace, B. G. and McMahan, U. J. (1985) Nature (London) 315, 571-574 8 Wallace, B. G., Nitkin, R. M., Reist, N. E., Fallon, J. R., Moayeri, N. N. and McMahan, U. J. 0985) Nature (London) 315,574-577

9 Slater, C. R. (1985) Nature (London) 315 News and Views, 543 10 Rosa, P., Fumagalli, G., Zanini, A. and Huttner, W. B. (1985) J. Cell Biol. 100, 928937 11 Rosa, P., Hille, A., Lee, R. W. H., Zanini, A., DeCamiUi, P. and Huttner, W. B.J. Cell Biol. (in press) 12 Falkensammer, G., Fischer-Colbrie, R. and Winkler, H. (1985) Neuroscience 14,735-746 13 Settleman, J., Fonseca, R., Nolan, J. and

Angeletti, R. H. (1985) Z Biol. Chem. 260, 1645-1651 14 Cohn, D. V., Elting, J. J., Frick, M. and Elde, R. (1984) Endocrinology 114, 19631974 15 Winkler, H. (1976) Neuroscience l, 65-80 MARY B. KENNEDY

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

The primary periodic paralyses Reinhardt ROdel and Kenneth Ricker Clinical observations on patients and physiological experiments on biopsy muscle specimens have shown that in the periodic paralyses the primary cause o f the paralytic attacks is inexcitability o f the muscle fibers resulting from membrane depolarization. An abnormal dependence o f the excitability on the membrane potential, an abnormal dependence of the membrane potential on extraceUular K + and transient abnormalities o f the serum K + concentration have been described. Several hypotheses have been proposed for these abnormalities; and are currently being tested in several laboratories. The nosological group of primary (i.e. inherited, in contrast to secondarily acquired) periodic paralyses contains the two genetically distinct entities; hypokalemic, i.e. abnormally low K + concentration in the blood, and hyperkalemic periodic paralysis 1,2. A third, very r a r e disorder, normokalemic periodic paralysis has been subject to comparatively little investigation and is probably closely related to, or identical with, the hyperkalemic form and will therefore not be considered further in this review. As the name of the group indicates, patients, who for most of the time have the usual command of their skeletal musculature, suffer periodically (or more correctly episodically) from transient muscle weakness of varying severity and duration. As the respective adjectives indicate, the diseases differ from each other in characteristic patterns of blood electrolyte changes during a paralytic episode. Considering the text-book description of the dependence of the membrane potential and excitability on the extracellular K + concentration, the symptomatic resemblance of two diseases with opposite extremes of this parameter is very surprising. Not only is the course of the attacks strikingly similar in hypo- and hyper-kalemia, also the same drugs, the carboanhydrase inhibitor, acetazolamide and the diuretic, hydrochlorothiazide, are successfully

employed for a symptomatic treatment. In both diseases, but particularly in the hyperkalemic form, an incipient attack may be diminished in severity or even abolished by mild exercise. Both diseases are inherited with autosomal dominance and with a smaller penetrance in females than in males. But there is a clear familial distinction between hypo- and hyperkalemia, as all afflicted members of a family always exhibit the same pattern of electrolyte change throughout their lives. As we want to stress that the two diseases differ basically in the genetic defect and its molecular expression in muscle, we shall describe the trends in their understanding separately. Hypokalemie periodic paralysis Of the two diseases, hypokalemic periodic paralysis is by far the more common. The first extensive report of a typical attack appeared in the eighteenth century 3, but it was not until 1934 that the concomitant fall in serum K + was noted 4. The patients experience the onset of the symptoms in the first or second decade of life with the majority having an attack before they are 16 years old. The attacks are usually infrequent during adolescence, and become more frequent during early adulthood, so that they may occur once a week. They may cease when the patient reaches middle age. The more severe attacks usually begin at night.

The patient wakes up with weakness of the extremities, or, in a more serious attack, completely helpless and unable to raise the head, move the limbs, or change position. At the same time, consciousness, sensation or coordination are unimpaired. A n attack may last from half an hour to several days, ceasing as muscular force slowly recovers even without any treatment. During an attack, the serum potassium falls, but not always below the normal range. The patients become oliguric, i.e. have a decreased urine secretion in relation to fluid intake, and there is renal retention of K + and Na +. The serum K + returns to normal with recovery of muscle strength. Sinus bradycardia and other electrocardiographic signs of hypokalemia develop when the serum K + drops below the normal range. Common precipitating factors are: a high-carbohydrate meal, rest after exercise, cold, and emotional excitement. Patients usually have normal strength between attacks. However, repeated attacks may result in permanent proximal myopathy. The characteristic histopathological finding is a vacuolar myopathy 5. The vacuoles are located in the center of the fiber, are surrounded with membrane, and contain periodic acid-Schiffs (PAS)reactive material (probably glycogen). These vacuoles may reflect intracellular K + depletion, as experimental K + depletion in animals produCes similar histological changes 6. Myotonic runs, i.e. a series of spontaneously occurring action potentials, often detectable in the electromyogram of patients with hyperkalemic periodic paralysis, are nearly always absent in the hypokalemic form. The diagnosis is suggested by a positive family history, hypokalemia during a paralytic attack,

1985,ElsevierSciencePublishersB.V., Amsterdam 0378- 5912/85/$02.00

468 and a normal serum K + between attacks. The diagnosis can be confirmed by inducing hypokalemic paralysis and restoring strength by replenishing serum K +. The usual provocative test is to administer glucose, as an intravenous infusion, combined with 10-20 units of regular insulin. The clinically well-known K + uptake from the extracellular space by muscle, which is associated with the insulininduced glucose uptake, usually induces hypokalemia and paralysis within three hours. According to the Nernst equation, a fall of the extracellular K + concentration, [K]e, causes hyperpolarization. Therefore, early investigators speculated that paralysis might be caused by a hyperpolarization-induced block of neuromuscular transmission. Soon after the introduction of glass microelectrodes to electrophysiology, Creutzfeldt et al. 7 investigated the resting membrane potential of muscle fibers in hypokalemia patients between and during attacks. In the interictal state, i.e. between attacks, the potential was normal, and during an attack it fell rather than rose, so that depolarization-induced inexcitability was the most likely explanation for the paralysis. In addition, the contractile apparatus of the afflicted muscle fibers was found to be normal 8, and thus the defect was pinpointed to episodic events leading to membrane depolarization. The role of the fall in serum K + was the essential question: what causes it and is it the reason for the depolarization? Is hypokalemia the initiating event of an attack or is it only a consequence of it? Episodical hyperaldosteronism was suggested to cause hypokalemia via renal K + loss. However, aldosterone levels are usually not elevated during a paralytic attack. Measurements of arterial and venous plasma concentrations showed that the hypokalemia during spontaneous or induced attacks is caused by the influx of K + from the extracellular space into the muscle fibers 9. The intracellular space is so much larger than the extracellular space that a K + shift sufficient to lower [K]e to less than 2 mM hardly increases the K + content of skeletal muscle. Since carbohydrate meals and insulin administration precipitate attacks, an impaired carbohydrate metabolism was suggested as a reason for the excessive influx of K + into muscle. Such a defect could increase the number of membrane-impermeant

TINS - No1 e m b e r I q85 anions causing a passive intracellular shift of water and cations. But neither abnormalities in the carbohydrate metabolism 1° nor increased muscle intracellular water content H substantiated experimentally. Another possible line of argument concerns the (Na + + K+)-pump: intracellular K + accumulation could result from intermittent excessive pumping. Although the basal (Na + + K+)-pump activity was reported to be normal 12, episodic acceleration of Na + and K + transport could result from increased response of the pump to insulin or adrenaline. Insulin binding to skeletal muscle was found to be increased in one hypokalemic patient, but it was not clear whether this was due to an increase in the number or in the binding affinity of the insulin receptors. At any rate, the role of the insulin receptor in hypokalemia has continued to be investigated 13. Another possible defect is an abnormality in the ionic permeabilities of the muscle fiber membranes. An increase of the steady-state Na + conductance, gNa 14, or a reduction of the steady-state K + conductance, gK~s, have been proposed as the basic defect resulting in an increase of the gNa/gK ratio. Any further increase of this ratio, for instance caused by lowering of [K],, could then induce the critical shift of the resting potential towards the Na + equilibrium potential. A special consequence of a reduced gK would be an increased contribution of the (Na + + K+)-pump current to the resting potential, caused by the increased membrane resistance. This contribution was guessed to be about 30 mV, opposing depolarization in the interictal state t6. Since the (Na + + K+)-pump is inhibited by low [K]~, the paralysing depolarization was suggested to be the consequence of the elimination of the (Na + + K+)-pump current during a supposed feedback inhibition of the pump 16. This hypothesis is of course in direct contrast to the above-mentioned hypothesis of excessive K + pumping. It is an unlikely one because [K]e hardly ever falls low enough during an attack to turn off the pump. Based on the hypothesis that a reduced gK is the primary defect in muscles of hypokalemia patients, several low gK muscle models, such as K+-depleted 15 or Ba2+-poisoned 17 muscle, were investigated in vivo and in vitro for behavior similar to that of muscles from hypokalemia patients.

The results showed that Ln fact many features of the human disease can be mimicked by low gr, models. For instance, insulin which produces hyperpolarization in normal mammalian muscle, produces depolarization and inexcitability in K+-depleted muscle 1~. However useful the information from such models, decisive results on the human membrane defect are only obtained from the investigation of patients or even better, from experiments on muscle specimens excised from them. Biopsy of external intercostal muscle for an in-vitro preparation with intact fibers was first performed on hypokalemia patients by Hofmann and Smith in 197014. Meanwhile, this preparation has become well established for tests in which extracellular parameters such as ionic concentrations, hormone levels, temperature etc., are rapidly and reversibly varied. The usually determined parameters are the value of the resting potential, the steady-state components of the membrane conductance (slopes of the current-voltage relationships measured under voltage-clamp conditions), excitability characteristics (threshold, rate of rise, and overshoot of the action potential), and the force of contraction. A recent study of biopsies from three unrelated patients 19 showed that in a standard extracellular medium with [K]c = 3.5 raM, the fibers had resting potentials 5-I5 mV lower than the - 8 2 mV found in fibers from healthy controls. Lowering [K]e to 1 mM caused depolarization to - 5 5 mV and paralysis (Fig. 1A), while in controls it caused hyperpolarization without loss of force. The depolarization was not prevented by the application of the sodium channel blocker tetrodotoxin (TFX), was independent of the presence or absence of insulin, and was not reversed by the application of solutions of normal or even increased K + content (Fig. 1A). These results suggest that the episodic fall in serum K + is an essential event in an attack, and that the role of insulin is mainly that of a mediator causing a decrease of [K]e via stimulation of the (Na + + K+)-pump. As an additional effect, insulin reduces gK 13. The relevant physiological effects of lowering [K]~ are a decrease of gK and an increase of gNaDetermination of the membrane conductances in both chloride-containing and chloride-free solutions showed that in [K]~ = 3.5 mM, the steady-state K + conductance was not lower than in

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healthy controls. In [K]~ = 1 n ~ , gK was so low even in the controls that an abnormally low gK would not have been detected in the affected muscles. A n evaluation of the current-voltage relationships in normal and low [K]e favored the hypothesis that in hypokalemic periodic paralysis the primary conductance alteration is an increased gNa rather than a reduced gK. An increased gNa in a resting fiber must be met by an increased activity of the (Na + + K+)-pump to prevent too high a rise of the intracellular Na + concentration. It is, therefore, likely that the fall in [K]e during an attack is caused by an excessive pumping of K + into the muscle ceils in exchange for previously accumulated sodium. A n interesting finding with the muscle bundles in v i t r o was a reduced excitability ~9. In a solution with normal K + content (3.5mM) action potentials could not be elicited by intracellular application of depolarizing current in fibers with resting potentials greater than - 7 0 mV, and when the resting potential was raised with prepulses to - 8 0 mV, the action potentials were without overshoot. This explains why paralysis may occur in patients even during a relatively small fall of [K]~ accompanied by only slight depolarization. It is not known whether the two defects, an increased gNa and a reduced excitability are linked.

electrocardiogram shows T-wave elevation in association with the hyperkalemia. Initially, strength is usually normal between attacks, but a permanent proximal myopathy may develop after repeated attacks. Morphological changes involving vacuolization occur similar to those in the hypokalemic form, but commonly to a lesser degree. In most families patients manifest myotonic signs, i.e. they complain about the sensation of tension in their muscles at the beginning of an attack, spontaneous runs of action potentials are detectable in the electromyogram, and the eyelids do not immediately follow a quick lowering of the glance. In a few families these myotonic signs are always absent. Clinical myotonia, i.e. muscle stiffness is not a typical symptom of the disease. This is one of the features distinguishing hyperkalemic periodic paralysis from paramyotonia con-

genita, another hereditary muscle disease that has sometimes been claimed to be just a variant of episodic adynamia. Having investigated many members of families with either condition, we are convinced that the two diseases are separate entities. A typical difference is the effect of muscular activity: the adynamia which develops during rest after strenuous work in hyperkalemia patients can be worked off at the beginning of an attack, whereas the stiffness and weakness which occur in paramyotonia congenita patients exposed to cold do not develop seriously, unless the muscles are forcefully used ('paradoxical myotonia'). There are paramyotonia patients who never experience paralysis after potassium loading, and hyperkalemia patients who never experience stiffness when exposed to cold. However, the defects responsible for the two symptoms may be located in the same gene or in closely coupled genes

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Hyperkalemie periodic paralysis Hyperkalemic periodic paralysis, detected only 30 years ago in Scandinavia2°, was originally named adynamia episodica hereditaria, but the former designation is now preferred in English-speaking countries because it stresses the puzzling discovery that in adynamia patients the change in serum K + during an attack goes in the direction opposite to that in hypokalemia patients. In the interictal periods, hyperkalemia patients often have serum K + concentrations above the normal range, and the postprandial change, (i.e. occurring after a meal) in K + relative to insulin release exceeds normal2L The attacks usually commence in childhood or adolescence. On the average, the attacks are shorter in duration, and more frequent than in the hypokalemic form. At the onset of an attack, the patients may develop myalgia, i.e. muscle pain, and/or myotonia, and characteristically the serum K + rises though not always beyond the normal range. The

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Fig. 1. Resting membrane potentials recorded in excised external intercostal muscles from a patient with hypokalemic periodic paralysis (A) and from a patient with hyperkalemic periodic paralysis (B). In either case, measurements began shortly before mid-day, 3 h after the surgical removal of the small muscle specimens containing intact fibers. The variation of the extracellular K + concentration ([K],) o f the synthetic interstitial fluid is indicated, in raM, at the top o f each panel. In the fibers of the hypokalemia patient, lowering o f [K]e to l mM and the addition o f 100 IU 1-1 insulin produced depolarization even though the Na + channel blocker tetrodotoxin (TTX) was present. A subsequent gradual increase of [K]~ to 7 mM did not restore high resting potentials. In the fibers of the hyperkalemia patient, lowering o f [K]~ to 1 mM and the addition of 1(30 IU 1-I insulin produced hyperpolarization (i. e. no paralysis, similar as in controls), but the increase of [K]~ to 6 mM caused an abnormal depolarization in most of the fibers, making them inexcitable. This depolarization was reversed by the addition o f TTX, indicating that it was caused by an increased Na + conductance. RMP

= resting membrane potential. (Taken, with permission,from Refs 19 and 24.)

470 as there are a few families in which affected members show both symptoms. Nevertheless, the individuality of the two disorders is preserved in these patients, as the symptoms may be selectively and exclusively treated by the respective drugs known to be effective for either condition 22. Paralysis may be precipitated in hyperkalemia patients by rest after exercise, oral ingestion of potassium, cold exposure, pregnancy, or administration of mineralocorticoids. The usual provocative test is administration of 1-2.5 g potassium in tablet form. More instructive is to have a patient work for 30 min on a bicycle ergometer under 125 W load and then keep him lying absolutely still. The serum K + rises to 5--6 mM during the work, as it does in controls. Within the first 10 min after the termination of the work, the serum K ÷ drops to almost the initial normal value as it does in controls, however, 20-30 min later it begins to rise again. The level reaches a maximum of up to 7 mM after about an hour and falls within the next hour, quite often to a level which is below normal. It is during this abnormal secondary rise that the patients become paralysed. The secondary rise and paralysis do not appear when a patient has been pretreated with hydrochlorothiazide or when he moves about instead of lying still. If the patient moves just one arm during the rest period, this arm will be excepted from the paralysis. Measurement of arterial and venous plasma concentrations showed that the secondary rise results from an efflux of potassium from muscle, causing a decrease of muscle potassium content 23. Part of the extra plasma potassium is excreted by the kidneys, which explains the hypokalemia after an attack which occurs when the muscles retake up the K + that they have previously lost. The reason for the abnormal K + efflux during the rest period is not known. It is not caused by diminished secretion of insulin, catecholamins, or glucagon, or by elevated mineralo- or gluco-corticoid levels. In-vitro investigation of external intercostal muscle from a hyper-

T I N S - N o v e m b e r 198.5

kalemia patient with myotonia and from a patient without myotonia showed that in a standard extracellular medium with [K]e = 3.5 mM the fibers had normal resting potentials 24. Increasing [K]¢ to 7 mM had different effects in the two muscles. While the fibers from the patient with myotonia depolarized, they had increased excitability so that they developed repetitive activity which later gave way to paralysis because depolarization did not end before the membrane potential had reached a level at which even normal fibers would be inexcitable. This depolarization was not prevented by curare, indicating that it was not due to nervous influence, but it was reversed by TTX, indicating that it was caused by an increased Na + conductance (Fig. 1B). The fibers from the patient without myotonia depolarized without repetitive activity and were inexcitable when the potential had reached a level at the low side of the control range, at which normal fibers are still excitable. Excitability was generally reduced in this muscle. Conclusion In conclusion, the paralysis in both types of disorder results from sarcolemmal depolarization producing inactivation of the excitatory Na + current. In the hypokalemic form, a critical increase of the ratio gr~a/gK seems to exist already in the interictal state so that any further increase of this ratio e.g. by a lowering of [K]e, results in depolarization and paralysis. The properties of the Na ÷ channels seem to be altered so that a reduced excitability results. Therefore, inexcitability and paralysis occur already with small membrane depolarization. In the hyperkalemic form with myotonia, the excessive depolarization could be explained by an abnormality in the inactivation of the sodium channels; in the hyperkalemic form without myotonia, the pathomechanism is least understood. Many of the features reported in this review await explanation, for example the beneficial effects of exercise in laying off an attack and the therapeutic effects of acetazolamide; why are they present in either form? Perhaps the general mechanism

is via metabolic acidosis shifting the Na + channel inactivation to less negative membrane potentials 2 Selected references 1 Buruma, O~ J. S. and Schippcrheyn, J. J. (1979) in Handbook of Clinical Neurology Vol. 4L pp. 147-173, Elsevier/North Holland, New York 2 Ruff, R. L. and Gordon, A. M. in Physiol. ogy of Membrane Disorders, 2nd edn

Plenum, New York, (in press) 3 Musgrave,W. (1727). Philos. Trans. R. Soc. London Ser. B 3, 33-34 4 Biemond, A. and Daniels, A.P. (1934) Brain 57.91-108 5 Engel, A. G. (1970} Proc, Mayo Clin. 45. 774-814 6 Kao, L. I. and Gordon. A.M. (1977) Neurology 27. 855--860 7 Creutzfeldt, O. D.. Abbott. P. C.. Fowler. W. M. and Pearson. C. M. (1963) Electcoencephalogr. Clin. Neurophysiol. 15. 508515 8 Engel, A. G. and Lambert, E. H. (1969) Neurology 19. 851-858 9 Zierler, K. I. and Andres, R. (1957) J. Clin. Invest. 36. 730-737 10 Engel, A. G.. Potter, C. S. and Rosevear, J. W. (1967) Neurology 17, 329-338 11 Gordon, A. M.. Green. J. R. and Lagonoff, D. (1970) Am. J. Med. 48, 185-195 12 Samaha, E. J. (1969) Neurology 19,551-552 13 Hofmann. W. W., Adornator, B.T. and Reieh, H. (1983) MuscleNerv. 6. 48-51 14 Hofmann. W. W. and Smith. R. A. (1970) Brain 93. 445--474 15 Kao, I. and Gordon. A, M. (1975) Science 188,740-741 16 Layzer, R. B. (19821 Ann. Neurol. 11,547552 17 Gallant, E. M. (1983)J. Physiol. (London) 335, 577-590 18 Dengler, R., Hofmann, W. W. and Riidel, R. (1980) J. Neurol. Neurosurg. Psychiatry 42, 818-826 19 Riidel, R., Lehmann-Horn, F., Rieker, K. and Kiither, G. (1984~ Muscle Nerv. 7. 110-120 20 Gamstorp, 1. (1956) Acta Paediatr Scand. 45 (Suppl 108), 1-126 21 Lewis, E. D.. Griggs, R. C. and Mo~ey, R. T. (1979) Neurology 29, 1131-1137 22 Ricker, K. B6hlen, R. and Rohkamm. R. (1983) Neurology 33. 1615-1618 23 MeArdle, B. (1962) Brain 85, 121-148 24 Lehmann-Horn, F., Riidel. R., Rieker, K.. Lorkovi6. H.. Dengler, R. and Hopf, H. C. (19831 Mu,vcle Nerv. 6. 113-121

Reinhardt RiJdel is at the Department of General Physiology, University of Ulm. 1)-7900 Ulm, FRG. Kenneth Ricker is at the Neurological Clinic, University of W~rzburg, Wiirzburg, FRG.