Authors :
Presenting Author: Rebecca John, MD – The University of Alabama at Birmingham
Lawrence Ver Hoef, MD – The University of Alabama at Birmingham
Rationale:
The KCNA2 gene encodes the voltage-gated potassium channel Kv1.2, which is expressed in the central nervous system¹.Variants in this gene include loss of function, gain of function (GOF), or both, can present as generalized seizures, cognitive decline, and cerebellar ataxia². 4-Aminopyridine (4-AP), a potassium channel blocker, has shown efficacy in conditions like multiple sclerosis, downbeat nystagmus, and episodic ataxia². This case illustrates the clinical course of an epilepsy patient with a KCNA2 GOF variant and highlights the symptomatic improvement observed with 4-AP.Methods:
We present a case of a 17-year-old male with subacute cognitive decline, ataxia, and increased seizure frequency. His birth was complicated by intrauterine growth restriction and hypoglycemia. Early development was normal until a febrile seizure following the MMR vaccine. Subsequently, exhibited global developmental delay, autism, and approximately two generalized tonic-clonic seizures annually. EEGs from infancy to adolescence showed multifocal 3Hz bioccipital spike-and-wave discharges (right greater than left), bitemporal polyspike waves, and occasional generalized polyspikes. Brain MRI revealed progressive cerebellar atrophy and periatrial hyperintensities. Initial genetic analysis using CGH microarray was unremarkable. Seizure burden increased with addition of absence type, despite optimal therapy. By age 13, he gradually regressed from walking and running to being bedridden with decreased alertness. At the time of presentation, he was on oxcarbazepine, clobazam, and brivaracetam, with seizures occurring every two weeks.Results:
Whole genome sequencing identified a de novo pathogenic variant in KCNA2 (c.890G >A, p.(Arg297Gln), CGG >CAG in exon 3, NM_004974.3), consistent with a GOF mutation associated with KCNA2-related epilepsy and neurodevelopmental disorder type 32. Following the initiation of Dalfampridine (4-AP) at 20 mg daily, the patient remained seizure-free for six weeks, followed by two subsequent breakthrough seizures. Currently, he has been seizure-free for five months, with significant improvements in ambulation, cognition, interaction, and speech.Conclusions:
A total of 15 patients with an identical genomic variant to our patient have been reported³. This case emphasizes the importance of molecular studies as an early investigation of epilepsy with associated autism or psychomotor delay. It also contributes to the growing literature on the therapeutic value of 4-AP in drug-resistant KCNA2 epileptic encephalopathies.
1.Syrbe S, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet. 2015;47:393-399. PMID: 25751627.
2.Hedrich UBS, et al. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Sci Transl Med. 2021;13:4957. PMID: 34516822.
3.Döring JH, et al. Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders. Int J Mol Sci. 2021;22:2824. PMID: 33802230.Funding: None