Authors :
Presenting Author: Yu Jia, MD – Xuanwu Hospital, Capital Medical University, Beijing, China
Yuping Wang, MD, PhD – Xuanwu Hospital, Capital Medical University, Beijing, China
Lehong Gao, MD – Xuanwu Hospital, Capital Medical University, Beijing, China
Liankun Ren, MD, PhD – Xuanwu Hospital, Capital Medical University, Beijing, China
Rationale:
Developmental and epileptic encephalopathies (DEEs) are a phenotypically and genetically heterogeneous group of severe epilepsy and intellectual disability. KCNA2 gene encodes the Kv1.2 channel, which is playing a critical role in the initiation and propagation of action potentials. KCNA2 mutations have been identified as a potential cause of DEE. KCNA2-DEE had a broad spectrum of diseases, including drug-resistant seizures, cognitive impairment, and ataxia. Encouragingly, 4-aminopyridine (4-AP), a inhibitor of voltage-gated potassium channels, was reported to be effective in treating KCNA2-DEE. However, further clinical evidence is necessary to determine the generalizability of these effects, particularly in adult patients with the long course beginning in childhood.
Methods:
We reported an adult patient with a 30-year history of epileptic encephalopathy beginning in infancy, carrying the KCNA2 gain-of-function variant p.(Arg297Gln), who benefited from the treatment with 4-AP.
Results:
The patient was a 31-year-old male who had a 30-year history of multiple types of drug-refractory epileptic seizures, including focal seizures secondary to bilateral tonic-clonic seizures, epileptic spasms, atypical absence seizures and myoclonic seizures. He exhibited cognitive regression, unsteady gait, cerebellar speech after the disease. Brain MRI revealed atrophy of the pontine, left hippocampal and cerebellum. EEG showed generalized low-to medium amplitude 4-6 Hz slow-wave activity, along with generalized medium-to-high amplitude 1.5-2.5 Hz spike-and-slow-wave rhythmic discharges. Whole-exome sequencing identified that the patient carried a de novo missense variant in KCNA2 c.890G >A;(p.Arg297Gln), which was confirmed by Sanger sequencing and this variant was categorized as pathogenic (Fig.1). 4-AP was initiated at a dose of 5 mg once daily. Adverse effects were closely monitored, and serial electrocardiograms revealed no QT interval prolongation. After two weeks, the 4-AP dosage was increased to 10 mg. One month after treatment initiation, the patient achieved seizure free. Notable improvements in speech function were observed after three months of treatment. Tolerability of 4-AP was excellent, with no significant adverse effects recorded in our patient. At a 1-year follow-up, the patient remained seizure-free, exhibited improved language fluency, reduced ataxia, and showed absence of falls. The discharges of follow-up EEG were less stereotypical and of shorter duration. Moreover, a 24-hour EEG recorded 96 epileptiform discharges, a substantial reduction from the 1,548 discharges recorded prior to treatment.
Conclusions:
We report the 4-AP treatment for an adult case with KCNA2-DEE. Despite the long duration of DEE, the patient's symptoms improved following a short course of low-