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Seizure Disorders

KCNA2-Related Epileptic Encephalopathy


Jennifer A Kearney

Northwestern University Feinberg School of Medicine
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Investigators from the University Leipzig and University of Tübingen report mutations of KCNA2 as a novel cause of epileptic encephalopathy.
How to Cite: Kearney, J.A., 2015. KCNA2-Related Epileptic Encephalopathy. Pediatric Neurology Briefs, 29(4), p.27. DOI:
  Published on 29 Apr 2015
 Accepted on 10 Apr 2015            Submitted on 28 Mar 2015

Investigators from the University Leipzig and University of Tübingen report mutations of KCNA2 as a novel cause of epileptic encephalopathy. They identified four de novo mutations in KCNA2 in six unrelated patients using next generation sequencing.

Four individuals had KCNA2 mutations that resulted in dominant-negative loss of protein function. Seizure onset was at 8-17 months. EEG became abnormal with multifocal epileptiform discharges. All had delayed speech development and mild to moderate intellectual disability. All became seizure free between 4-15 years of age. Two additional individuals presented with a more severe epileptic encephalopathy phenotype. They had an earlier age of onset, pharmacoresistant seizures, generalized epileptiform discharges with background slowing on EEG, moderate to severe intellectual disability, and moderate to severe ataxia. KCNA2 mutations associated with the more severe phenotype resulted in pronounced gain-of-function effects. [1]

COMMENTARY. KCNA2 joins a growing list of voltage-gated potassium channel genes associated with epileptic encephalopathy, including KCNQ2, KCNQ3, KCNT1 and KCNB1 [14]. KCNA2 encodes KV1.2, a voltage-gated potassium channel subunit that contributes to repolarization of the neuronal membrane following an action potential. Mutations in KCNA2 that interfere with normal Kv1.2 function result in impaired electrical signaling and altered membrane excitability. Loss-of-function mutations are predicted to impair membrane repolarization, resulting in neuronal hyperexcitability and a propensity for repetitive firing. Consistent with this, complete absence of KV1.2 in homozygous mice resulted in spontaneous seizures and premature death, and heterozygous deletion resulted in increased seizure susceptibility [5]. Mutations were also identified that exhibited gain-of-function effects [1]. At the level of a single neuron, the observed effects predict KV1.2 channels that are open at resting membrane potentials, resulting in neuronal hypoexcitability. However, based on the more severe phenotype of the patients, the net effect within neuronal networks is hyperexcitability. Additional studies will be required to determine the effect of KCNA2 mutations at the level of the network.

Thus far, the phenotypes associated with KCNA2 mutations comprise two distinct groups based on age of onset, seizure semiology, and electroclinical features. These distinctive clinical phenotypes appear to correlate with differential effects of the mutations on protein function [1]. Patients with gain-of-function mutations have a more severe phenotype and do not achieve seizure freedom. In contrast, patients with loss-of-function mutations have later seizure onset, and achieve seizure freedom in childhood. This nascent genotype-phenotype correlation is reminiscent of KCNQ2-associated epileptic encephalopathy, where loss-of-function mutations are associated with neonatal onset, while gain-of-function mutations are associated with infantile onset [3, 6]. Studies with KCNA2 mutations from additional patients will be required to confirm the genotype-phenotype relationship. If the relationship holds, it will be useful for predicting disease progression and guiding management.


The author(s) have declared that no competing interests exist.


  1. Syrbe, S Hedrich, UB Riesch, E Djemie, T Muller, S Moller, RS et al. (2015). De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 9(10)DOI: [PubMed]  

  2. Torkamani, A Bersell, K Jorge, BS Bjork, RL Friedman, JR Jr Bloss, CS et al. (2014). De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol 76(4): 529–40, DOI: [PubMed]  

  3. Miceli, F, Soldovieri, MV, Ambrosino, P, De Maria, M, Migliore, M and Migliore, R (2015). Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 35(9): 3782–93, DOI: [PubMed]  

  4. Pena, SD and Coimbra, RL (2015). Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genetics 87(2): e1–3, DOI: [PubMed]  

  5. Brew, HM Gittelman, JX Silverstein, RS Hanks, TD Demas, VP Robinson, LC et al. (2007). Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol 98(3): 1501–25, DOI: [PubMed]  

  6. Miceli, F Soldovieri, MV Ambrosino, P Barrese, V Migliore, M Cilio, MR et al. (2013). Genotype-phenotype correlations in neonatal epilepsies caused by mutations in the voltage sensor of K(v)7.2 potassium channel subunits. Proc Natl Acad Sci U S A 110(11): 4386–91, DOI: [PubMed]  

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