Hyperkalemic Periodic Paralysis - Genetics

Genetics

In 1994, researchers at the University of Pittsburgh, with a grant from various horse organizations, isolated the genetic mutation responsible for the problem and developed a blood test for it. Using this test, horses may be identified as:

• H/H, meaning they have the mutation and it is homozygous. These horses always pass on the disease.
• N/H, meaning they have the mutation and it is heterozygous. These horses are affected to a lesser degree, and pass on the disease 50% of the time.
• N/N, meaning they do not have the mutation and cannot pass it on, even if they are descendants of Impressive.

In humans, the most common underlying genetic cause is one of several possible point mutations in the gene SCN4A. This gene codes for a voltage-gated sodium channel Na_v1.4 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 the disorder.

Action potentials from the central nervous system cause end-plate potentials at the NMJ which causes sodium ions to enter via Na_v1.4 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 which 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 Na_v1.4. Mutations have also 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.

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 in order to repolarise it to the resting potential, and 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.

In the case of the horse Impressive, the muscles were always contracting which was equivalent to a constant work-out. Thus the development of an impressive musculature.

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.