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PHYSICIAN'S INFORMATION SHEET

Hypokalemic Periodic Paralysis

Genetics and Inheritance

Calcium Channel - Voltage-Dependent, L Type, Skeletal Muscle Dihydropyridine-Sensitive, Alpha-1 Subunit; CACNA1S Gene map locus 1q32; Seven Mutations described to Date: ARG1239HIS (1), ARG528HIS (2) ARG528GLY (33), ARG1239GLY (3), ARG1086CYS & ARG1086HIS (19) .

Sodium Channel - Voltage-Gated, Type IV, Alpha Subunit; SCN4A; Gene map locust 17q23.1-q25.3; Six mutations described to date: ARG669HIS (24), ARG672HIS, ARG672GLY (27, 28), ARG672SER (30), DIII-S4 ARG1132Q (32)and alpha subunit, between 4th/5th transmembrane segments, domain III SCN4A, Pro1158Ser. (31, 35, 36)

The disease is inherited as an autosomal dominant trait. Sporadic cases have also been reported (4).

Diagnosis

Diagnosis may be based on patient history and confirmed by appropriate evaluation of serum electrolytes during attacks, with the CMAP amplitude test (Exercise EMG)(30), evaluation of the response to provocative testing or by DNA analysis…(5). It is important that physicians be aware that DNA testing is not conclusive. Knowledge of the gene is incomplete and commercial labs only screen for three of the 14 mutations identified thus far. “It is important to consider that many individuals with HypoKPP will not have one of the identified mutations.” (6)

Clinical Features

Attacks typically begin in the first or second decade. About 60% of patients are affected before the age of 16 years, but HypoKPP attacks may be recognized at any age. Johnsen's 1981 study found a male patient with onset at age 60, and a female with onset at age 70 (7, 8, 17). Attacks initially tend to be infrequent but eventually may occur daily. Diurnal fluctuations in strength may then appear, so that the patient shows the greatest weakness during the night or in the early morning hours and gains strength as the day passes (10, 11).

Attacks may last from less than one hour to days. Weakness can be localized or generalized. Attacks vary in both severity and frequency. The deep tendon reflexes are diminished or lost during paralytic attacks…muscle fibers become unresponsive to either direct or indirect electrical stimulation. The attack of weakness begins with a sensation of heaviness or aching in the legs or back. Generalized attacks usually begin in proximal muscles and then spread to distal ones. Patients may lose sensation in paralyzed limbs. The diagnosis of HypoKPP should not be excluded by abnormal results of sensory nerve conduction studies (25). Oliguria or anuria may develop during attacks. Patients tend to be constipated. Respiratory and cranial muscles tend to be spared but may also be paralyzed…bulbar and respiratory weakness can be fatal. Paralysis may resolve quickly once movement begins to return but there is often residual weakness that is slower to clear. Permanent weakness may ensue (7, 12, 13).

Because the disorder is associated with a shift in potassium, provocative factors include exercise followed by a period of sleep or fast, carbohydrate load, or any other cause of increased insulin secretion, Epinephrine is a well-recognized provocative factor of attacks and should be avoided (7, 12).

Heat and Cold Sensitive Myotonic Form

It has long been believed that hypokalemic PP and myotonia could not occur in the same individual, but a family has been reported as experiencing cold-induced hypokalemic paralysis (serum K+ 2.6) and myotonia, which occurs when serum K+ levels are in the normal range (4.0). The mutation responsible is P1158S in the SCNA4 (Sodium) Channel. (26, 31, 35)

Myopathic form

There is also a myopathic form of HypoKPP which results in progressive fixed muscle weakness that begins as exercise intolerance predominantly in lower limbs. This may begin at any age and may be the only manifestation of the disease in some patients, i.e. these patients may never experience episodic weakness or attacks of paralysis (15, 32).

Laboratory Studies

During an attack, there is usually, but not always, a measurable fall in levels of serum potassium, but in some patients the level may never fall below normal. Johnsen's series of provocative studies recorded an episode of weakness of 11 hours duration provoked by a 0.3 mmol/L fall in the serum K, and an episode of total paralysis of 19½ hours duration provoked by a one point drop. There is urinary retention of sodium, potassium, chloride and water (5, 8, 14).

Ingrid Gamstorp campaigned vigorously for the rejection of the terms "hypo" and "hyper" kalemic, hypopotassemia, and hyperpotassemia. She urged use of the terms "decreasing" and "increasing" serum potassium, as weakness in these disorders occurs in connection with changes in serum potassium level, and is not necessarily related to the serum potassium level. She stated that . . ."It is likely that the severity of symptoms are better related to the quotient between the intra and extracellular potassium than to the extracellular level alone." (13)

Cardiac Signs

Sinus bradycardia and electrocardiographic (ECG) signs of hypokalemia (U waves in leads II, V-2, V-3, and V-4, progressive flattening of T waves and depression of ST segment) may appear when the serum potassium falls below normal. Prolongation of the PR and QT intervals and T-wave flattening are associated with prominent U-waves. Johnsen's study of 106 Danish patients with HypoKPP revealed two patients who developed transient diastolic murmurs during paralysis and another who developed a transient, partial a-v block. He also describes patients who developed bradycardia and unspecified arrhythmias during episodes (7, 8, 14).

Some patients do not exhibit cardiac signs even when serum potassium falls quite low, and others may exhibit profound cardiac signs of hypokalemia with the serum potassium within low normal range (5, 13, 14, 16).

"It has long been recognized as one of the salient features of HypoKPP is that weakness (and hypokalemic cardiac arrhythmias) often commence when the patient's serum potassium is within the limits of normal, 3.5 - 5.0 mmol/L." (5)

In the patient with HypoKPP a patient with low normal serum potassium levels may have an EKG which is markedly abnormal (5, 13, 14, 16).

Serum Creatine Kinase in HypoKPP

It has been recognized since the 1970s that patients with HypoKPP may exhibit higher than normal levels of serum myoglobin and/or serum creatine kinase, either chronically or following episodes, in the absence of myocardial necrosis. The rise in plasma K+ which accompanies recovery from an attack of HypoKPP may be associated with a simultaneous rise in serum Mb, followed by a rise in serum CK. It is postulated that hypokalemia causes muscle ischaemia, resulting in an accumulation of free fatty acids (FFA) within muscle cells. High concentrations of FFA may induce molecular changes and increase the permeability of the sarcolemma. Higher than normal levels of these enzymes have been used to identify non-symptomatic carriers in families where CK is elevated chronically. (39,40,41)

Emergency Management

If the patient presents with total paralysis of the extremities without difficulties in deglutition or respiration, oral sips of KCl solution can be given, for instance 15 to 30 mmol (in children 10 to 15 mmol) in 30 to 60 minute intervals (the release of KCl tablets is too slow in an emergency). In this situation serial measurement of serum K+ and continual electrocardiographic monitoring are necessary. Some HypoKPP patients exhibit serious arrhythmias with only mild hypokalemia.

In patients using K+ sparing diuretics of with renal function disturbance, serum K+ levels may rise rapidly to abnormally high levels after oral administration of KCl. If no improvement is apparent after 4 to 5 oral doses, or if nausea or diarrhea occurs after the oral KCl intake, IV administration of KCl is necessary. This also is preferable in patients with acute attacks of paralysis, difficulties in swallowing and impaired respiration. In severe paralysis swallowing may be compromised and gag reflex lost. Place the patient in coma position due to the possibility of aspiration.

Using a peripheral vein, the preferred dose fro intravenous K+ is 15 mEq (15mmol) over 15 minutes then 10 mEq/hr (10 mmol/hour) diluted in at least 500 mg dilutant. Five percent mannitol is the preferred dilutant: saline (0.9%) may be used, but never glucose. Infusion must be continued until serum K+ is normal and the patient's strength returns. Cardiac function must be continuously monitored during IV administration of potassium. Several hours of observation are necessary during which K+ and muscle strength should be measured, because paralysis may return. Many HypoKPP patients are sodium sensitive. Serum K+ may fall if saline solution is used to administer K+ IV. Mannitol is the solution of choice for IV administration of K+ (15, 16, 17).

Therapy

Preventive therapy consists of relatively low sodium (2 g per day and diet low in simple carbohydrates (85 g per day). (Note: Experience with many patients has taught us that sodium intake is best limited to one gram daily if at all possible.) Patients should avoid exposure to cold and over-exertion, and take supplemental potassium. . . The dosage must be adjusted according to attack frequency and severity. Because severely affected patients may awaken paralyzed, a dose may have to be taken at two a.m. The serum potassium should not exceed 6mmol during therapy. Acetazolamide (Diamox) (125 to 1000 mg/day divided qd to bid) is also highly effective in preventing paralytic attacks. Acetazolamide causes K+ excretion and some patients require K+ supplementation in order to achieve control of episodes (5, 12). Average potassium intake varies from 25nEq to 150mEq daily. The potassium citrate or bicarbonate formulas (K-Lyte and Klor-Con EF) are better tolerated and absorbed than potassium chloride tablets (like Slow-K).

Acetazolamide is most successfully started at a low dose (135 mg daily) then gradually increased over a period of some weeks. Patients should be careful to maintain adequate fluid intake, to avoid renal calculi (5, 8, 12, 19). Patients who respond poorly to Diamox, or who have adapted to the drug after long usage may respond to dichlorphenamide (50-200 mg daily). Unfortunately dichlorphenamide has been discontinued by the manufacturer but patients may respond to another of the carbonic anhydrase inhibitors, methazolamide. Patients who fail to respond to carbonic anhydrase inhibitors, often respond well to the K+ sparing diuretics triamterene (Dyrenium 50-150 mg daily) or spironolactone (Aldactone). Either can be used in addition to acetazolamide or methazolamide. Patients receiving diuretic therapy must be monitored when receiving k+ supplements (7, 18).

Physicians should also be alert to the possibility of Thyrotoxic Hypokalemic Periodic Paralysis, especially in patients with Grave's Disease and Asian mail patients (7, 8). Patients with TPP usually suffer weight loss and very low K+ levels during episodes (below 2.0).

Malignant Hyperthermia (MH)

Malignant Hyperthermia is one of the leading causes of death with anesthetics. It has now been proven to allelic to HypoKPP. All HypoKPP patients must be considered at greatly increased risk to this life-threatening complication of surgery. A persistent elevated creatine kinase could be a hint to a MH predisposition. A prior history of an uneventful anesthetic using does not assure that a subsequent anesthetic will be safe (20, 21, 22).

Andersen's Syndrome (As)

This is a distinct periodic paralysis, occurring in the setting of either hyper- of hypokalemia, with sever cardiac involvement (LQT) and skeletal abnormalities. Every patient with periodic paralysis must be screened for this potentially lethal condition. Partial manifestations are common and the subtle nature of the cardiac and dysmorphic features may delay diagnosis but clinical recognition of this syndrome is vital given the predisposition for dysrhythmias and sudden death. Cardiac evaluations using serial ECGs with measurements of the QTc interval are essential and should be performed on all patients undergoing workup for periodic paralysis if provocative tests are contemplated (23, 24, 25).

References

  1. Sillen, A. et al: Identification of mutations in the CACNL1A3 gene in 13 families of Scandinavian origin having hypokalemic periodic paralysis and evidence of a founder effect in Danish families. Am. J. Med Genet.69; 102-106, 1997.
  2. Jurkat-Rott, k. et al: A calcium channel mutation causing hypokalemic periodic paralysis. Hum. Molec. Genet.3: 1415-1419, 1994.
  3. Ptacek, L.J. et al: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77: 863-868, 1994,
  4. Lapie, P. et al: Hypokalemic Periodic Paralysis: an autosomal dominant muscle disorder caused by mutations in a voltage-gated calcium channel. Neuromuscular Disorders 7(1997) 234-240.
  5. Ptacek L.J. et al: Periodic paralysis, In: Fauci A.S., et al, Eds. Harrison's Principles of Internal Medicine. 14th Ed NYC McGraw Hill, 1998.
  6. Scacheri C.: Personal correspondence, 1999,
  7. Brooke M. H.: Disorders of Skeletal Muscle. Neurology in Clinical Practice. Third Ed., 2000: Bradley, W.G. et al. Eds. Boston, MA: Butterworth/Heinemann.
  8. Johnsen, Torsten: Family Periodic Paralysis with Hypokalaemia, Danish Medical Bulletin, March 1981 Vol. 28 No. 1
  9. Sagild, U.: Hereditary Transient Paralysis, Copenhagen: Munksgaard, 1959.
  10. Talbott, J.J.: Periodic paralysis: a clinical syndrome. Medicine 20: 85-143, 1941.
  11. Engel, A.G.: Disorders of Voluntary Muscle, 5th ed. Edinburgh: Churchill Livingstone, 1988, Chapter 25 "Metabolic and Endocrine Myopias".
  12. Links, T. et al: Permanent Muscle Weakness in Familial Hypokalemic Periodic Paralysis, Brain 1990.
  13. Gamstorp, I.: Disorders Characterised by Spontaneous Attacks of Weakness Connected with Changes of Serum Potassium: Genetics of Neuromuscular Disorders, pp 175-195 1989: Alan R. Liss Inc.
  14. Schlichtmann, J, Graber, M.: University of Iowa Family Practice Handbook, 3rd Edition, Chapter 5, 1999 Hematologic, Electrolyte, and Metabolic Disorders: Potassium,
  15. Links, L. P. et al: Familial Hypokalemic Periodic Paralysis: Cip-Cegevens Kononklijke Bibliotheek, Den Haag 1992 ISBN 90-9005053-1.
  16. Swash, Michael, Schwartz, Martin S: Neuromuscular Diseases: A practical approach to diagnosis and management: 2nd ed. London: Springer-Verlagg 1988, The Periodic Paralyses, pp 344-348.
  17. Riggs, Jack E.: Review of the Periodic Paralysis; Clinical Neuropharmacology 1989.
  18. Links, T. et al: Improvement of Muscle Strength in Familial Hypokalemic Periodic Paralysis with Acetazolamide; Journal of Neurology, Neurosurgery and Psychiatry, 1988.
  19. Monnier, N. et al. Malignant-Hyperthermia susceptibility is associated with a mutation of the alpha1-subunit of the human dihydropyridine sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle: Am J Hum Genet, 60:1316-1325: 1997.
  20. Manning, B.M. et al: Novel mutations at CpG dinucleotide in the ryanodine receptor in malignant hyperthermia. Hum. Mutat. 11: 45-50, 1998.
  21. Manning, B. M. et al: Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Am. J. Hum. Genet. 62: 599-609, 1998.
  22. Levitt, L. P., Rose, L.I, Dawson, D.M.: Hypokalemic periodic paralysis with arrhythmia. New Eng. J. Med 286: 253-254, 1972.
  23. Sansone, V. et al: Andersen's syndrome: a distinct periodic paralysis. Ann. Neurol. 42: 305-312, 1997.
  24. Bulman, D.E. et al: A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurol. 53: 1932-36 1999.
  25. Inshasi, J.S. et al: Dysfunction of sensory nerves during attacks of HypoKPP, Neuromuscular Disorders: June 1999.
  26. Aoki, T. et al: A family with Heat sensitive Myotonia Alternating with Hypokalemic Periodic Paralysis; Rinsho Shinkeigaku 2000 Apr; 40(4): 358-63.
  27. Jurkat-Rott, K. et al: Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc. Nat. Acad. Sci. 97: 9549-9554, 2000 Pub Med MD: 10944223.
  28. Sternberg, D. et al: Hypokalemic Periodic Paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain (2001), 124, 1091-1099.
  29. Gennari F.J.: Hypokalemia. N Engle J Med 339:451, 1998.
  30. Kuzmenkin, A., Muncan, V., Jurkat-Rott, K. et al: Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II. Brain 2002 Apr; 125(pt 4):835-43.
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  34. Carle T, Lhuillier L, Luce S, et al.;Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun. 2006 Sep 22;348(2):653-61. Epub 2006 Jul 28.
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The information on this site is based on current medical knowledge but should never at any time be substituted for the advice and care of a properly qualified medical consultant.