Submission Details

ATP1A2 was first reported in relation to autosomal dominant familial hemiplegic migraine in 2003 (De Fusco et al., PMID:12539047). Patients with hemiplegic migraines experience migraine headaches that are accompanied by temporary motor weakness. Since 2003, patients with variants in ATP1A2 have also been reported with autosomal dominant alternating hemiplegia of childhood and autosomal dominant developmental and epileptic encephalopathy (PMIDs: 15174025, 33880529). Individuals with developmental and epileptic encephalopathy often experience seizures that onset in infancy and developmental delays. Alternating hemiplegia of childhood is characterized by episodes of paralysis that typically affect one side of the body, and commonly onsets in infancy or early childhood.

There have been several reports of individuals with the same variant in ATP1A2 and different phenotypes. For example, in one family, a father with an ATP1A2 variant was reported to experience hemiplegic migraines and was noted to have typical cognition. His son with the same variant presented with developmental and epileptic encephalopathy, including seizure onset at six days of life and global developmental delays (PMID: 33493807). Currently, because a patient’s phenotype cannot easily be predicted based on their variant, we have curated cases of “familial hemiplegic migraine” (OMIM:602481), “alternating hemiplegia of childhood” (OMIM:104290), and “developmental and epileptic encephalopathy” (OMIM:619605) under the disease term “hemiplegic migraine-developmental and epileptic encephalopathy spectrum” (MONDO:0100539). Of note, there have also been reports of a relationship between biallelic variants in ATP1A2 and autosomal recessive “fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies.” Due to differences in inheritance pattern and phenotypic variability, these cases have not been included in this curation.

Variants in ATP1A2 (missense, frameshift, nonsense, intronic) have been reported in at least 17 probands in 11 publications (12539047, 15843000, 16088919, 18056581, 21731499, 2313342, 24096472, 24498617, 33880529, 33493807, 33578253). Variants in this gene segregated with disease in at least 20 additional family members. Penetrance has been estimated at 81% for this condition (PMID: 16088919). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. While the disease mechanism is still unclear, Friedrich et al. (2016) state that some variants are “characterized by subtle changes in voltage dependence…In these cases, a shift of the pump current's I-V curve may entail loss-of-function in a particular voltage range, but gain-of-function in another” (PMID: 27445835). This gene-disease relationship is also supported by an animal model and in vitro functional assays. In summary, there is definitive evidence supporting the relationship between ATP1A2 and autosomal dominant hemiplegic migraine-developmental and epileptic encephalopathy spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This gene-disease pair was originally evaluated by the Epilepsy GCEP on January 19, 2021 (SOP Version 8). It was reevaluated and approved on January 16, 2024 (SOP Version 10) to include new case-level data to best capture the spectrum of disease, and to update the disease term from “familial hemiplegic migraine” to “hemiplegic migraine-developmental and epileptic encephalopathy spectrum.” The final classification of definitive did not change.