Self‐limited familial focal epilepsy caused by ANK2 variants: A potentially under‐recognized condition

TL;DR

A genetic variant in ANK2 causes a rare, under-recognized form of epilepsy that is self-limited and responsive to medication.

Contribution

This is the first report of a familial ANK2-related epilepsy, highlighting its underdiagnosis and distinct clinical features.

Findings

ANK2 pathogenic variants can cause self-limited focal epilepsy with no cardiac phenotype in some cases.

Most ANK2-related epilepsies are self-limited and pharmaco-responsive, suggesting underdiagnosis.

Loss-of-function ANK2 variants are associated with central nervous system phenotypes, while missense variants are arrhythmic.

Abstract

The Ankyrin 2 (ANK2) gene encodes the ankyrin‐B protein (ANKB), which is involved in the organization and stability of membrane ion channels, transporters, and receptors in cardiomyocytes and neurons. Variants in ANK2 genes are initially reported in long QT syndrome and autism. Animal models with ANK2 deletion have exhibited seizures and been anecdotally associated with epilepsy in case reports. Hereby, we reported a Taiwanese family with the ANK2 pathogenic variant (chr4:114276707, c.6933del, p.T2312Lfs*2) that affects the giant ankyrin‐B isoform. The family members presented with young‐onset self‐limited focal epilepsy, and achieved seizure‐free in adulthood with antiseizure medications. Interestingly, the electrocardiogram revealed no obvious cardiac phenotype. We further reviewed reported ANK2‐related epilepsies. Most variants are de novo and loss‐of‐function variants. Most patients had young epilepsy or neonatal seizures. Notably, most cases of ANK2‐related epilepsy are self‐limited and pharmaco‐responsive, which suggests that it is likely to be underdiagnosed. With the increased availability of whole exome sequencing, the diagnosis of ANK2‐related epilepsies may increase. The co‐existence of QT prolongation on electrocardiogram, autism, and a positive family history of cardiac arrhythmia or sudden death may provide important clues in the clinical diagnosis of ANK2‐related epilepsy. Furthermore, a correct genetic diagnosis of ANK2‐related epilepsy will initiate close cardiac surveillance to avoid the potential sudden death risk of this disorder.

ANK2 has long been regarded as an arrhythmic gene. This study reported the first familial ANK2‐related epilepsy, highlighting the role of ANK2 in epileptogenesis. Most reported ANK2‐related epilepsies are self‐limited and pharmaco‐responsive, suggesting that they are likely to be underdiagnosed. Literature review of the phenotype and genotype of ANK2 showed that LOF ANK2 variants tend to have CNS phenotypes, whereas missense variants are arrhythmic. Early detection of ANK2 variants in epilepsy patients is worthwhile considering the potential sudden death risk of this disorder.

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