Impaired Color Recognition in HCN1 Epilepsy: A Single Case Report.

A Marie Phillips,Ying-Chao Chang,Ming S Soh,Ian C Forster,Chaseley E Mckenzie,Christopher A Reid,Chen-Jui Ho,Meng-Han Tsai,Ingrid E Scheffer

doi:10.3389/fneur.2022.834252

Abstract

Variants in HCN1 are associated with a range of epilepsy syndromes including developmental and epileptic encephalopathies. Here we describe a child harboring a novel de novo HCN1 variant, E246A, in a child with epilepsy and mild developmental delay. By parental report, the child had difficulty in discriminating between colors implicating a visual deficit. This interesting observation may relate to the high expression of HCN1 channels in rod and cone photoreceptors where they play an integral role in shaping the light response. Functional analysis of the HCN1 E246A variant revealed a right shift in the voltage dependence of activation and slowing of the rates of activation and deactivation. The changes in the biophysical properties are consistent with a gain-of-function supporting the role of HCN1 E246A in disease causation. This case suggests that visual function, including color discrimination, should be carefully monitored in patients with diseases due to HCN1 pathogenic variants.

Highlights

Pathogenic hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) variants are strongly associated with genetic epilepsies [1–4]
Epilepsies caused by de novo HCN1 variants tend to be the severe developmental and epileptic encephalopathies (DEEs), while inherited variants cause milder epilepsy syndromes such as genetic epilepsy with febrile seizures plus (GEFS+) [2, 3]
We describe the novel HCN1 E246A pathogenic variant, associated with well controlled focal epilepsy, mild developmental delay and parental report of visual dysfunction, that results in a net gain of channel function

Summary

Introduction

Pathogenic hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) variants are strongly associated with genetic epilepsies [1–4]. Much focus has been on the epileptology and developmental delay of HCN1 disease, there may be pathology in other organs in which HCN1 channels play a role. One such organ is the retina in which HCN1 channels are highly expressed in the inner segment of the photoreceptor of rod and cone cells [5, 6]. We present a patient harboring a novel de novo HCN1 E246A variant with mild epilepsy and developmental delay. We aimed to assess the biophysical properties of the HCN1 E246A variant to see if dysfunction of this gene could underlie both the epilepsy and the unusual clinical finding of poor color discrimination

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