Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Abstract

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine

“…A brain MRI showed cerebellar atrophy predominant in the vermis ( Figure 1 ) Overall, the patient presented with a clinical diagnosis of syndromic Early Infantile Epileptic Encephalopathy (EIEE) with non-progressive ataxia and intellectual disability. Clinical-functional correlations of individuals harboring KCNA2 variants compared to the present case are described in Supplementary Table S1 [ 11 ].…”

“…Inherited and de novo variants in KCNA2 have been associated with a spectrum of symptoms ranging from remittent epilepsy to epileptic encephalopathy, development delay, and ataxia. The functional characterization of mutant Kv1.2 channels and the detailed clinical description of carriers allowed to stratify mutations into three subgroups according to the functional defect and to draw a significant genotype-phenotype correlation [ 11 ]. Here we describe a novel de novo variant in KCNA2 , E236K, identified in a Serbian proband affected by non-progressive ataxia, moderate intellectual disability and generalized epilepsy.…”

“…In mice, the absence of Kv1.2 channels causes a seizure phenotype more severe than Kv1.1 deficiency, possibly due to differences in the function, temporal expression, or localization of the subunits, as well as to the availability of other compensatory subunits [ 5 ]. Recently, de novo and inherited heterozygous variants in KCNA2 gene have been identified in patients presenting with early infantile epileptic encephalopathy, intellectual disability, delayed speech, development delay and ataxia [ 10 , 11 ]. In vitro functional studies provided valuable information to link Kv1.2 variants to the occurrence of ataxia and epilepsy in humans and provide evidence for a significant genotype-phenotype correlation in KCNA2 -encephalopathy.…”

“…They can produce gain-of-function (GoF), loss-of-function (LoF) and even mixed (GoF/LoF) effects [ 10 ]. Less severe phenotypes, with focal seizures occurring in early childhood and with more favorable outcome, are associated with LoF variants (such as I263T, R294H, and P405L); more critical infantile epileptic phenotypes with developmental problems, ataxia and cerebellar atrophy are linked to de novo GoF variants (such as R297Q, L298F, E157K); early onset, often uncontrolled, epilepsies, sometimes beginning at neonatal age and followed by severe intellectual disability and ataxia, are associated with variants leading to both GoF and LoF defects (T374A) [ 10 , 11 , 12 ]…”

“…In some patients, epilepsies only improve with multiple antiepileptic drugs (AEDs) such as lamotrigine, valproic acid, oxcarbazepine and clobazam, whereas in most of them convulsive episodes are severe and pharmacoresistant. Acetazolamide successfully remits ataxia and myoclonic epilepsy caused by KCNA2 variants in some patients [ 11 , 12 ]. The occurrence of both LoF and GoF defects in KCNA2 -associated diseases might support the possibility of deploying a variant-tailored therapy for selected patients.…”