ATP1A2

At least one mutation in the ATP1A2 gene can cause alternating hemiplegia of childhood. The primary feature of this condition is recurrent episodes of temporary paralysis, often affecting 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. The known ATP1A2 gene mutation associated with this condition replaces a single protein building block (amino acid) in Na+/K+ ATPase: the amino acid threonine is replaced with the amino acid asparagine at protein position 378 (written as Thr378Asn or T378N). This genetic change probably impairs the protein's ability to transport ions, although it is unclear how the mutation leads to the specific features of alternating hemiplegia of childhood.

More than 30 mutations in the ATP1A2 gene have been identified in people with familial hemiplegic migraine type 2 (FHM2). This condition is characterized by migraine headaches with a pattern of neurological symptoms known as aura. In FHM2, the aura includes temporary numbness or weakness on one side of the body (hemiparesis). Most of the mutations involved in FHM2 change single amino acids in the Na+/K+ ATPase protein. Some mutations impair the protein's ability to transport ions. Others prevent the production of any protein from one copy of the ATP1A2 gene in each cell. As a result, less potassium is pumped into neurons, less sodium is pumped out of these cells, and neurotransmitters spend more time in the spaces between neurons. The resulting changes in signaling in the brain lead people with FHM2 to develop these severe headaches.

ATP1A2 gene mutations can also cause sporadic hemiplegic migraine. The signs and symptoms of this condition are identical to those of FHM2 (described above); however, sporadic hemiplegic migraine occurs in people with no family history of the condition. As in FHM2, most of the mutations associated with sporadic hemiplegic migraine change single amino acids in the Na+/K+ ATPase protein. These changes impair the function of the protein. Although the mutations that cause sporadic hemiplegic migraine are not as well-studied as those in familial hemiplegic migraine, it is thought that they have similar effects: impairing the transport of sodium and potassium ions and prolonging the presence of neurotransmitters between neurons. The abnormal signaling resulting from these changes leads to the headaches and auras characteristic of the condition.