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 Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn.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.

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

“…In respect of the missense variant on KCNB1 , it was classified as pathogenic due to recent support on this gene impact on ASD [de Kovel et al, ]. Our patient (F2685‐1) presents ASD and neurodevelopmental delay, adding a new case, to the five published articles in the last 2 years that identified 33 de novo missense and LoF variants in KCBN1 in patients with neurodevelopmental delay, EE, ASD, ID, and epilepsy [Calhoun, Vanoye, Kok, George, & Kearney, ; de Kovel et al, ; Marini et al, ; Parrini et al, ; Yuen et al, ].…”

Spectrum of KV2.1 Dysfunction in KCNB1‐Associated Neurodevelopmental Disorders

“…In addition, 11 KCNB1 variants were obtained from the literature and variant databases. [8][9][10][11][12][13][15][16][17][18][19] No functional studies were available for 17 of 19 variants.…”

“…Phenotypes for novel variants reported in Supplementary Table 1 are consistent with previous reports. [7][8][9][10][11][12][13][14] Supplementary Table 1 also includes variants from previous clinically focused reports, 11,16 summarized here for completeness, with updates when available. In total, there are 17 pathogenic/likely pathogenic variants from 27 individuals, including several recurrent variants…”

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

“…KCNB1 , which encodes voltage‐gated potassium channel subunit K V 2.1, causes various disorders. As for SCN2A , early onset consists of infantile spasms or autism whereas later onset causes the whole range of generalized epilepsy with febrile seizures plus (GEFS+) . No functional study has correlated phenotype with gain‐of‐function versus loss‐of‐function.…”