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 Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn.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

SUBMITTER: Marini C

PROVIDER: S-EPMC5733250 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Clinical features and outcome of 6 new patients carrying de novo <i>KCNB1</i> gene mutations.

Marini Carla C Romoli Michele M Parrini Elena E Costa Cinzia C Mei Davide D Mari Francesco F Parmeggiani Lucio L Procopio Elena E Metitieri Tiziana T Cellini Elena E Virdò Simona S De Vita Dalila D Gentile Mattia M Prontera Paolo P Calabresi Paolo P Guerrini Renzo R

Neurology. Genetics 20171211 6

<h4>Objective</h4>To describe electroclinical features and outcome of 6 patients harboring <i>KCNB1</i> mutations.<h4>Methods</h4>Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.<h4>Results</h4>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. Epi ...[more]

PMID: 29264397

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Project description:Importance:Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives:To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants:This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures:The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results:Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance:De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Dataset Information

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

Publications

Clinical features and outcome of 6 new patients carrying de novo <i>KCNB1</i> gene mutations.

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