Hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis (HYPP, HyperKPP) is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.

Hyperkalemic periodic paralysis
Other namesGamstorp episodic adynamy
SpecialtyNeurology

The mutation which causes this disorder is dominant on SCN4A with linkage to the sodium channel expressed in muscle. The mutation causes single amino acid changes in parts of the channel which are important for inactivation. In the presence of high potassium levels, including those induced by diet, sodium channels fail to inactivate properly.

Signs and symptoms

Hyperkalemic periodic paralysis causes episodes of extreme muscle weakness, with attacks often beginning in childhood.[1] Depending on the type and severity of the HyperKPP, it can increase or stabilize until the fourth or fifth decade where attacks may cease, decline, or, depending on the type, continue on into old age. Factors that can trigger attacks include rest after exercise, potassium-rich foods, stress, fatigue, weather changes, certain pollutants (e.g., cigarette smoke) and fasting. Muscle strength often improves between attacks, although many affected people may have increasing bouts of muscle weakness as the disorder progresses (abortive attacks). Sometimes with HyperKPP those affected may experience degrees of muscle stiffness and spasms (myotonia) in the affected muscles. This can be caused by the same things that trigger the paralysis, dependent on the type of myotonia.

Some people with hyperkalemic periodic paralysis have increased levels of potassium in their blood (hyperkalemia) during attacks. In other cases, attacks are associated with normal blood potassium levels (normokalemia). Ingesting potassium can trigger attacks in affected individuals, even if blood potassium levels do not rise in response.

In contrast to HyperKPP, hypokalemic periodic paralysis (noted in humans) refers to loss-of-function mutations in channels that prevent muscle depolarisation and therefore are aggravated by low potassium ion concentrations.

Genetics

In humans, the most common underlying genetic cause is one of several possible point mutations in the gene SCN4A.[2] This gene codes for a voltage-gated sodium channel Nav1.4 found at the neuromuscular junction. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause it.

Action potentials from the central nervous system cause end-plate potentials at the NMJ which causes sodium ions to enter by Nav1.4 and depolarise the muscle cells. This depolarisation triggers the entry of calcium from the sarcoplasmic reticulum to cause contraction (tensing) of the muscle. To prevent the muscle from being perpetually contracted, the channel contains a fast inactivation gate that plugs the sodium pore very quickly after it opens. This prevents further entry of sodium. In time, potassium ions will leave the muscle cells, repolarising the cells and causing the pumping of calcium away from the contractile apparatus to relax the muscle.

Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.[3][4]

In patients with mutations in SCN4A, therefore, the channel is unable to inactivate, sodium conductance is sustained and the muscle remains permanently tense. Since the motor end plate is depolarised, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell to repolarise it to the resting potential. This further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.[5][6]

Treatment
  • Glucose or other carbohydrates can be given during an attack and may reduce the severity.[1]
  • Intravenous calcium decreases activity of sodium channels. It may stop sudden attacks.[1]
  • Diuretics such as furosemide may be needed to stop sudden attacks;[1] acetazolamide and thiazide diuretics such as chlorothiazide are also effective.[1]
  • Intravenous glucose and insulin stimulates potassium uptake into the cell by the Na-K ATPase and may reduce weakness without a loss of total body potassium.[1]
  • A high-carbohydrate diet may be recommended.[1]
  • Avoidance of other known attack triggers.[7]

References
  1. MedlinePlus: Hyperkalemic periodic paralysis Update Date: 7/25/2006. Updated by: David M. Charytan, M.D., M.Sc., Department of Medicine, Division of Nephrology, Brigham and Women's Hospital, Boston, MA.
  2. Online Mendelian Inheritance in Man (OMIM) Hyperkalemic Periodic Paralysis; HYPP -17050
  3. Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH (December 1991). "A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis". Nature. 354 (6352): 387–9. Bibcode:1991Natur.354..387R. doi:10.1038/354387a0. PMID 1659668.
  4. Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ (April 2002). "Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5". Neurology. 58 (8): 1266–72. doi:10.1212/wnl.58.8.1266. PMID 11971097.
  5. Rüdel R, Lehmann-Horn F, Ricker K, Küther G (February 1984). "Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters". Muscle Nerve. 7 (2): 110–20. doi:10.1002/mus.880070205. PMID 6325904.
  6. Jurkat-Rott K, Lehmann-Horn F (August 2005). "Muscle channelopathies and critical points in functional and genetic studies". J. Clin. Invest. 115 (8): 2000–9. doi:10.1172/JCI25525. PMC 1180551. PMID 16075040.
  7. Lee, GM; Kim, JB (June 2011). "Hyperkalemic periodic paralysis and paramyotonia congenita caused by a de novo mutation in the SCN4A gene". Neurology Asia. 16 (2): 163–6.
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