ATP1A3. The ATPases are the “Sisphyean” workhorses of cells, perpetually bound to utilize energy generated by mitochondria to pump ions across cell membranes. This is essential to the maintenance of the intra/extracellular electrochemical gradient. ATP1A3 codes for the α3 subunit of the Na+-K+ ATPase, which utilizes ATP to actively transport sodium out of the cell and potassium into the cell. In the brain, this gradient is critical for cell signaling and for maintaining electrochemical stability, enabling cell excitation and action potential propagation. Both ATP1A3 and one of its counterparts, ATP1A2, are expressed in neurons during embryonal brain development, and ATP1A3 is also thought to contribute to regulation of non-ionic neuronal transporters and receptors. However, whereas ATP1A2 is primarily expressed in glial cells postnatally and into adulthood, ATP1A3 continues to be expressed primarily in neurons, with particular enrichment in excitatory neurons. Here is a brief overview of the clinical spectrum of ATP1A3-related disorders.
Disease spectrum. Pathogenic variants in ATP1A3 cause a spectrum of neurological phenotypes, described previously as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). While it is helpful to consider ATP1A3-related conditions through the lens of these broad classifications, it is likely that most individuals with ATP1A3-related conditions exist along a spectrum of these conditions. Furthermore, there have been hints of variable expressivity within families – both in our own practice and in the literature, and there have been affected children who have inherited the variant from reportedly asymptomatic parents. We are continuing to learn about the functional effect of the different ATP1A3 variants that have been discovered, as well as the genotype-phenotype correlations.
Hemiplegic episodes and epilepsy. Individuals with hemiplegic episodes typically present in infancy or early childhood, usually before the age of 18 months. The classic AHC phenotype has been described as episodic neurologic symptoms that may include hemiplegia, dystonia, seizures, and eye movement abnormalities, affecting either side of the body at different times, and resolving with sleep – though symptoms may return as soon as 10-20 minutes after waking. Up to 50% of patients with AHC may have epilepsy. On the other hand, there have been reports of children with ATP1A3 variants whose phenotypes are not entirely consistent with AHC, but who do have early life epilepsy and episodic apnea, where the latter may be ictal or non-ictal. On the most severe end of the spectrum are neonates with early onset epileptic encephalopathy (EOEE) or epilepsy of infancy with migrating focal seizures. While little is known regarding genotype-phenotype correlation, it has been suggested in the literature that AHC phenotypes tend to cluster before amino acid position 400 or after amino acid position 700, and the majority of AHC-causing variants are transmembrane. Similarly, the individuals with more severe epilepsy have variants either before 400 or after 700. Other disease phenotypes are seen in domains spread throughout the gene.
Dystonia and movement disorders. Dystonia in ATP1A3-related disorders typically involves one limb or one hemibody but may be generalized. Distinguishing features include rostro-caudal pattern, with most prominent bulbar symptoms and upper extremity involvement, and long duration; the episodes may also be painful. There has been a report of 4 children with ATP1A3 variants presenting with paroxysmal dystonia with onset in childhood, without episodes of alternating hemiplegia. These cases were phenotypically variable, where three of the four described cases had progressive movement disorders associated with developmental delay, and one of the four was otherwise neurotypical between episodes. There have also been rare cases reported of recurrent ataxia, particularly associated with febrile illness, with much rarer cases of progressive ataxia, along the spectrum of the CAPOS phenotype.
Other neurological phenotypes. Presumably related to its role in early brain development, ATP1A3 has also been seen in association with structural brain abnormalities, namely polymicrogyria. In addition, some individuals with ATP1A3-related conditions may also have associated neurodevelopmental conditions including developmental delays, intellectual disability, or autism spectrum disorder.
Cardiac phenotype. Importantly, ATP1A3 is also highly expressed in cardiac cells. A recent publication by Balestrini and colleagues showed that EKG abnormalities were seen in over 50% of individuals with the AHC phenotype, with dynamic EKG changes noted in some of these patients; of their cohort of 98 patients with AHC, 3 (3%) required cardiac intervention – one of whom did not carry the ATP1A3 variant. For this reason and echoing the conclusions of this study, screening cardiac evaluation for all patients with ATP1A3-related conditions has been recommended; if patients have had syncopal episodes, implantation of a loop recording device can also be considered.
This is what you need to know. Many of the conditions reported in association with ATP1A3 variants do not fit any previously reported pattern; this again emphasizes the broad spectrum of clinical features associated with this gene. It is likely that these different clinical symptoms are related to different degrees of alteration of function of the Na+-K+ ATPase, including likely dominant negative functional effect in the most severe cases, as well as downstream effects of these functional changes. Unlike some of its compatriots in the channelopathies, including CACNA1A, it is challenging at this point to draw conclusions on clinical phenotype based on the domain inhabited by the variant. At this point, we are in dire need of both harmonization of clinical data to try to better characterize disorders associated with ATP1A3 and functional studies to try to better understand the intricate workings of this complex channel. This may perhaps seem like a Sisyphean task in itself, finding, as we gather more information, that we must renew our efforts continuously without any clear pattern emerging. But, on the contrary, we have seen, as in other genetic conditions, that we continue to make progress as we push forward, our efforts not Sisyphean but productive and hopeful.