KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine

Peter Müller; Danielle S Takacs; Ulrike B S Hedrich; Rohini Coorg; Laura Masters; Kevin E Glinton; Hongzheng Dai; Jon A Cokley; James J Riviello; Holger Lerche; Edward C Cooper

doi:10.1002/acn3.51742

KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine

Ann Clin Transl Neurol. 2023 Apr;10(4):656-663. doi: 10.1002/acn3.51742. Epub 2023 Feb 15.

Authors

Peter Müller^#¹, Danielle S Takacs^#^{2

3}, Ulrike B S Hedrich¹, Rohini Coorg^{2

3}, Laura Masters^{2

3}, Kevin E Glinton^{4

5}, Hongzheng Dai^{5

6}, Jon A Cokley², James J Riviello^{2

3}, Holger Lerche¹, Edward C Cooper^{3

5

7}

Affiliations

¹ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, 72076, Germany.
² Division of Neurology and Developmental Neuroscience, Epilepsy and Neurophysiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
⁴ Division of Genetics, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁶ Baylor Genetics, Houston, Texas, USA.
⁷ Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.

^# Contributed equally.

Abstract

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage-gated K⁺ channel subunit K_V 1.1. So far, loss-of-function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain-of-function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4-aminopyridine. Clinical use of 4-aminopyridine was associated with reduced seizure burden, enabled simplification of co-medication and prevented rehospitalization.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

4-Aminopyridine / pharmacology
4-Aminopyridine / therapeutic use
Epilepsy* / drug therapy
Epilepsy* / genetics
Epilepsy, Generalized*
Gain of Function Mutation
Humans
Kv1.1 Potassium Channel / genetics
Mutation

Substances

4-Aminopyridine
KCNA1 protein, human
Kv1.1 Potassium Channel

Grants and funding

This work was funded by Deutsche Forschungsgemeinschaft grants HE8155/1‐2 and LE1030/16‐2; National Institute of Neurological Disorders and Stroke grant NS108874.