ATP1A3

Variants (also called mutations) in the ATP1A3 gene are the primary cause of a neurological condition called alternating hemiplegia of childhood. This condition is characterized by recurrent episodes of temporary paralysis that often affects only one side of the body (hemiplegia). During some episodes, the paralysis alternates from one side to the other or affects both sides of the body at the same time.

Most ATP1A3 gene variants associated with alternating hemiplegia of childhood change single protein building blocks (amino acids) in the alpha-3 subunit of Na+/K+ ATPase. These genetic changes appear to impair the pump's ability to transport ions, although it is unclear how the variants lead to the specific features of alternating hemiplegia of childhood.

Multiple variants in the ATP1A3 gene have been found to cause a rare movement disorder called rapid-onset dystonia parkinsonism. This disorder is characterized by the abrupt appearance of signs and symptoms over a period of hours to days. Most of the ATP1A3 gene variants that cause this disorder change single amino acids in the alpha-3 subunit of Na+/K+ ATPase. Changes in the protein's structure can reduce its activity or make it unstable. Studies suggest that the defective Na+/K+ ATPase is unable to transport sodium ions normally, which disrupts the electrical activity of neurons in the brain. However, it is unclear how a malfunctioning Na+/K+ ATPase causes the movement abnormalities seen in people with rapid-onset dystonia parkinsonism.

Variants in the ATP1A3 gene can cause a group of features: cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. This specific presentation is known as CAPOS syndrome (the abbreviation comes from the first letter of each feature). Affected individuals usually develop signs and symptoms of CAPOS syndrome in infancy or early childhood during or following an illness that causes a fever.

To date, all instances of CAPOS syndrome have been caused by the same variant in the ATP1A3 gene. This change replaces the amino acid glutamic acid with the amino acid lysine at position 818 in the alpha-3 subunit of Na+/K+ ATPase (written as Glu818Lys or E818K). This genetic change appears to impair the pump's ability to transport ions, although it is unclear how the variant causes the specific features of CAPOS syndrome.