Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations

Abstract

Objective: To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.

Methods: Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.

Results: The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.

Conclusions: KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

Figure 1. Representative EEG findings in 3 patients

(A) Ictal videopolygraphic EEG recording of patient 3 (table 2), showing discharges of diffuse polyspike waves concomitant with myoclonic jerks evident on the leads recording from both deltoid muscles. (B) Ictal videopolygraphic EEG recording of patient 3 (table 2), showing generalized paroxysmal activity evoked by eye closure with concomitant eyelid myoclonia (video available as supplementary material). (C) Interictal EEG recording of patient 5, showing bifrontal single complexes of spikes and waves with left predominance. (D) Interictal sleep EEG recording of patient 4, showing very frequent paroxysmal activity over the fronto-centro-temporal regions (continuous spikes and waves during the slow-wave sleep pattern).

Figure 2. Schematic representation of the Kv2.1 protein with mutation distribution

Structure of the human Kv2.1 channel including previously published mutations and those reported here (specified under each mutation). The protein topology was performed using the Protter online tool (29) with the Uniprot accession Q14721 (KCNB1_HUMAN).

Figure 3. Graphic representation of seizure type distribution in patients with KCNB1 mutations

(A) Previously published patients (data from 10 of the 13 patients of previously published KCNB1 mutations and epilepsy) and (B) in our series of 6 patients. AB = absences; CSWS = continuous spikes and waves during slow-wave sleep; FS = febrile seizures; MY = myoclonia; NCSE = nonconvulsive status epilepticus; TCS = tonic-clonic seizures.