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Published on: January 29, 2018
Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
Edgard Verdura1,2, Carme Fons2,3,4, Agatha Schlüter1,2
1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain.
Insights
A novel recessive KCNA1 mutation caused severe epilepsy and dyskinesia in a patient. This finding highlights the importance of considering recessive inheritance patterns in channelopathies for accurate diagnosis and treatment.
Area of Science:
- Neurogenetics
- Molecular channel physiology
Background:
- Episodic ataxia type 1 (EA1) and related channelopathies are typically linked to dominant KCNA1 mutations.
- Over 50 families with KCNA1 mutations have been identified since 1994, primarily exhibiting autosomal-dominant inheritance or de novo events.
Purpose of the Study:
- To investigate the genetic basis of severe dyskinesia and neonatal epileptic encephalopathy in a patient.
- To characterize a novel KCNA1 variant and its functional consequences.
Main Methods:
- Whole-exome sequencing (WES) was performed on the affected patient.
- Candidate variant validation involved cellular assays and patch-clamp recordings.
- Functional effects of the KCNA1 variant were assessed in homozygous and co-expressed conditions.
Main Results:
- A homozygous KCNA1 variant (p.Val368Leu) was identified in the patient, located in the pore domain.
- The mutant Kv1.1 protein failed to form functional channels in the homozygous state.
- Oxcarbazepine, a sodium channel blocker, effectively controlled seizures in the patient.
Conclusions:
- This study reports the first recessive KCNA1 variant associated with a severe channelopathy phenotype.
- The findings underscore the need to consider varied inheritance modes in diagnosing channelopathies.
- Accurate variant identification is crucial for appropriate therapeutic strategies in neurological disorders.
Background:
Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.
Methods:
A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.
Results:
WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.
Conclusion:
This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.
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