Equine Hyperkalemic Periodic Paralysis (HYPP) – NAVLE Study Guide

Overview and Clinical Importance

Hyperkalemic Periodic Paralysis (HYPP) is an inherited autosomal dominant muscular disorder caused by a point mutation in the voltage-gated skeletal muscle sodium channel gene (SCN4A). This condition is virtually exclusive to horses descended from the American Quarter Horse sire Impressive (AQHA #0767246), who was the 1974 World Champion Open Aged halter stallion. The mutation has spread to approximately 4% of Quarter Horses and related breeds including American Paint Horses, Appaloosas, and Quarter Horse crossbreeds.

HYPP is one of the first genetic disorders in horses to be fully characterized at the molecular level. The condition results from a single nucleotide substitution (c.4248C>G) causing a phenylalanine-to-leucine amino acid substitution at position 1416 (p.F1416L) in the alpha subunit of the skeletal muscle sodium channel. This defect leads to intermittent episodes of muscle fasciculations, weakness, and potentially fatal paralysis.

Etiology and Genetics

Molecular Basis

The genetic defect responsible for HYPP involves a missense mutation in the SCN4A gene located on equine chromosome 11. This gene encodes the alpha subunit of the voltage-gated sodium channel (Nav1.4) in skeletal muscle. The specific mutation is a cytosine-to-guanine transversion at nucleotide position 4248, resulting in substitution of leucine for phenylalanine at codon 1416 in transmembrane domain IVS3 of the sodium channel protein.