ATP1A3. We recently posted about ATP1A3, a gene implicated in alternation hemiplegic of childhood, epilepsy, and other phenotypes. Today, we have added a new gene page going into more depth on this fascinating gene. Below are the five highlights to know about ATP1A3.
ATP1A3. The gray figure represents an axon terminal and demonstrates the function of ATP1A3, which uses ATP to shuttle Na+ out of and K+ into the axon terminal, thereby maintaining an electrochemical gradient that allows the propagation of action potentials and ultimately the influx of Ca++ to result in neurotransmitter release into the synapse. The purple figure represents an astrocyte, with another Na+/K+ ATPase (encoded by ATP1A2) embedded in the membrane. This channel also plays a role in maintaining the electrochemical gradient, as well as serving other downstream functions. Figure created with BioRender.com.
1 – Alternating hemiplegic of childhood (AHC). AHC involves episodes of hemiplegia that can affect either side of the body at different times. Episodes can also involve dystonia, seizures, and eye movement abnormalities and resolve during sleep. The side affected with hemiplegic can alternate even during the same episode. Unlike hemiplegic migraines, these events typically present in infancy or early childhood, usually before 18 months.
2 – Other neurological phenotypes. Individuals may also have seizures, dystonia (typically hemibody or one limb), structural brain abnormalities such as polymicrogyria. There can also be developmental phenotypes such as developmental delays, intellectual disability, and autism spectrum disorder. One important associated clinical syndrome is cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). This syndrome is characterized by paroxysmal, recurrent events that can become progressive, with symptom onset between 1 and 5 years.
3 – Cardiac phenotype. Individuals with AHC may have cardiac abnormalities, with a minority requiring cardiac intervention. Cardiac screening is recommended for all patients with ATP1A3-related disorders.
4 – Mechanism. ATP1A3 is a Na+-K+ ATPase that works to maintain the electrochemical gradient across neuronal cell membranes. Both loss of function and gain of function (typically dominant negative effects) are known to be mechanisms of disease. Recurrent variants associated with developmental and epileptic encephalopathy and/or severe brain abnormalities are likely dominant negative, and may affect binding of sodium and potassium ions. There is wide spectrum of phenotypes, even among individuals with the same variant.
Here is what you need to know. ATP1A3-related disorders involve a spectrum of phenotypes, generally caused by loss of function or dominant negative effects. Classic phenotypes include AHC, CAPOS, seizures, developmental differences, movement disorders, and structural brain abnormalities. Cardiac phenotypes are rare but warrant screening. Some associated features can be progressive, and onset is usually during infancy or early childhood. Overall, ATP1A3-related disorders are somewhat mysterious and incompletely understood, but have distinct, recognizable features that require early detection and intervention.
