Introduction[edit | edit source]
KCNA2 epilepsy is an epileptic condition caused by a malfunction in the potassium channels located within the Central nervous System (CNS). KCNQ2-related disorders are rare. However in studies on individuals with presumed genetic epilepsies, KCNQ2 ranks among the most frequently implicated genes.
Clinically Relevant Anatomy[edit | edit source]
KCNA2 is a gene located on chromosome 1p13.3. It encodes the voltage-gated potassium (K+) channels, many of which are located in the CNS. Mutations occurring in K+ channel-coding genes cause different neurological diseases. 
Mechanism of Injury / Pathological Process[edit | edit source]
- A gain of function (GOF) - where the channel does not close properly. This leads to an increased amount of K+ in the brain.
- A loss of function (LOF) - where the channel does not open properly. This leads to a low amount of K+ in the brain.
- A mix of functions - Where the K+ channel does both.
In all three malfunctions, epilepsy may be observed.
Clinical Presentation[edit | edit source]
KCNA2 epilepsy is often linked with encephalopathy in the research literature. Encephalopathy itself can be defined as a "... dysfunction of the level or contents of consciousness due to brain dysfunction and can result from global brain insults or focal lesions." 
LOF is the most common phenotype presented in the literature. It has been reported that epilepsy in this group tends to have an early onset - within infancy or early childhood. Intellectual disability (mild-to-moderate) and motor regression often appear after the onset of seizures. Ataxia has been associated with LOF.
GOF has also been linked to ataxia and intellectual disability, with the severity of these presentations as well as seizures being greater. In addition, hypotonia and myoclonus have also been reported for this phenotype.
The mixed phenotype can present with particularly severe seizures and conditions described in the LOF and GOF phenotypes.
Diagnostic Procedures[edit | edit source]
Genetic testing is ultimately needed to detect mutations in the KCNA2 gene.
Whole Exome Sequencing (WES) is commonly performed in the literature in order to identify KCNA2 mutations. This is a sequencing done of the exome - the coding portion of the genome.
The Promise of Whole-Exome Sequencing in Medical Genetics is an article that discusses this procedure and its development in more detail.
Management / Interventions[edit | edit source]
Medical treatment[edit | edit source]
Medical treatment often involves a team approach and can include:
- Developmental pediatrician
Intervention includes medication to control seizures (anticonvulsants), although there is no real clarity on which anticonvulsants work best with those diagnosed with KCNA2 epilepsy.An article published in 2021 showed promising results of a medication administered to 11 individuals diagnosed with KCNA2 epilepsy. This medication, known as 4-Aminopyridine (4-AP), acts as a K+ channel blocker. 4-AP was able to antagonize the GOF defects observed in this phenotype.
Allied treatment[edit | edit source]
As each individual presents differently, different intervention approaches are needed. Currently, there are no clinical practice guidelines in the literature specifically for KCNA2 epilepsy.
A common theme, however, in all research and information websites is the need for a team approach to the management and care of those with KCNA2 epilepsy. One such approach can be the multidisciplinary approach.
Aspects of development and function to consider when assessing and treating a patient with KCNA2 include:
- Motor development (both fine and gross).
- Cognitive development.
- Feeding and speech development - typically addressed by a speech and language therapist.
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References[edit | edit source]
- KCNA2 Epilepsy Organisation. What is KCNA2 Epilepsy. Available from: https://www.kcna2epilepsy.org/kcna2-epilepsy/what-is-kcna2-epilepsy/ (accessed 26 June 2023).
- Miceli F, Soldovieri MV, Weckhuysen S, Cooper E, Taglialatela M. KCNQ2-related disorders.Available:https://www.ncbi.nlm.nih.gov/books/NBK32534/ (accessed 7.10.2023)
- Wang H, Zhu Y, Cao D, Chen H, Ding X, Zeng Q, Zou H, Liao J. Successful medical treatment of west syndrome with a KCNA2 variant: a case report. Acta Epileptologica. 2022 Mar 2;4(1):6.
- McGinn RJ, Von Stein EL, Stromberg JE, Li Y. Precision medicine in epilepsy. Progress in Molecular Biology and Translational Science. 2022 Jan 1;190(1):147-88.
- Syrbe S, Hedrich U, Riesch E, Djémié T, Müller S, Møller RS, Maher B, Hernandez-Hernandez L, Synofzik M, Caglayan HS, Arslan M. De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature genetics. 2015 Apr;47(4):393-9.
- Masnada S, Hedrich UB, Gardella E, Schubert J, Kaiwar C, Klee EW, Lanpher BC, Gavrilova RH, Synofzik M, Bast T, Gorman K. Clinical spectrum and genotype–phenotype associations of KCNA2-related encephalopathies. Brain. 2017 Sep 1;140(9):2337-54.
- Erkkinen MG, Berkowitz AL. A clinical approach to diagnosing encephalopathy. The American Journal of Medicine. 2019 Oct 1;132(10):1142-7.
- Life with Episodic Ataxia. Dominant KCNA2 gene mutaion causing episodic ataxia with tremor and erratic myoclonic jerks evident. Available from: https://www.youtube.com/watch?v=i572sSLEcN8 [last accessed 5/5/2013]
- Noachtar S, Rémi J. The role of EEG in epilepsy: a critical review. Epilepsy & Behavior. 2009 May 1;15(1):22-33.
- Epilepsy Foundation. Specific Gene Mutation Screening in Infants: Children’s Hosp. PA, Epilepsy Neurogenetics Initiative. Available from: https://www.youtube.com/watch?v=_yV9ovVISes [last accessed 5/5/2013]
- Hedrich UB, Lauxmann S, Wolff M, Synofzik M, Bast T, Binelli A, Serratosa JM, Martínez-Ulloa P, Allen NM, King MD, Gorman KM. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Science translational medicine. 2021 Sep 1;13(609):eaaz4957.