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SCN1B-linked early infantile developmental and epileptic encephalopathy.

ABSTRACT: Objective: Patients with Early Infantile Epileptic Encephalopathy (EIEE) 52 have inherited, homozygous variants in the gene SCN1B, encoding the voltage-gated sodium channel (VGSC) ?1 and ?1B non-pore-forming subunits.

Methods: Here, we describe the detailed electroclinical features of a biallelic SCN1B patient with a previously unreported variant, p.Arg85Cys.

Results: The female proband showed hypotonia from birth, multifocal myoclonus at 2.5 months, then focal seizures and myoclonic status epilepticus (SE) at 3 months, triggered by fever. Auditory brainstem response (ABR) showed bilateral hearing loss. Epilepsy was refractory and the patient had virtually no development. Administration of fenfluramine resulted in a significant reduction in seizure frequency and resolution of SE episodes that persisted after a 2-year follow-up. The patient phenotype is more compatible with early infantile developmental and epileptic encephalopathy (DEE) than with typical Dravet syndrome (DS), as previously diagnosed for other patients with homozygous SCN1B variants. Biochemical and electrophysiological analyses of the SCN1B variant expressed in heterologous cells showed cell surface expression of the mutant ?1 subunit, similar to wild-type (WT), but with loss of normal ?1-mediated modification of human Na_v 1.1-generated sodium current, suggesting that SCN1B-p.Arg85Cys is a loss-of-function (LOF) variant.

Interpretation: Importantly, a review of the literature in light of our results suggests that the term, early infantile developmental and epileptic encephalopathy, is more appropriate than either EIEE or DS to describe biallelic SCN1B patients.

SUBMITTER: Aeby A

PROVIDER: S-EPMC6917350 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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SCN1B-linked early infantile developmental and epileptic encephalopathy.

Aeby Alec A Sculier Claudine C Bouza Alexandra A AA Askar Brandon B Lederer Damien D Schoonjans Anne-Sofie AS Vander Ghinst Marc M Ceulemans Berten B Offord James J Lopez-Santiago Luis F LF Isom Lori L LL

Annals of clinical and translational neurology 20191111 12

<h4>Objective</h4>Patients with Early Infantile Epileptic Encephalopathy (EIEE) 52 have inherited, homozygous variants in the gene SCN1B, encoding the voltage-gated sodium channel (VGSC) β1 and β1B non-pore-forming subunits.<h4>Methods</h4>Here, we describe the detailed electroclinical features of a biallelic SCN1B patient with a previously unreported variant, p.Arg85Cys.<h4>Results</h4>The female proband showed hypotonia from birth, multifocal myoclonus at 2.5 months, then focal seizures and my ...[more]

PMID: 31709768

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Project description:Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b-/- mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.

Project description:In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic encephalopathies. We have prospectively studied patients with seizure onset before 3 months of age. Based on the clinical details, neuroimaging, metabolic testing and comprehensive genetic evaluation, patients were classified into different aetiological groups. The phenotypic differences between genetic/unknown groups and remaining aetiologies were compared. Factors that could affect seizure control were also assessed. A total of 80 children (M:F ratio-1.5:1) were recruited. The median seizure onset age was 28 days (range, 1-90 days). The aetiologies were confirmed in 66 patients (83%). The patients were further classified into four aetiological groups: genetic (50%), structural (19%), metabolic (14%; all were vitamin responsive) and unknown (17%). On comparing for the phenotypic differences between the groups, children in the 'genetic/unknown' groups were more frequently observed to have severe developmental delay (Odds Ratio = 57; P < 0.0001), autistic behaviours (Odds Ratio = 37; P < 0.0001), tone abnormalities (Odds Ratio = 9; P = 0.0006) and movement disorder (Odds Ratio = 19; P < 0.0001). Clonic seizures were more common in the vitamin responsive/structural groups (Risk Ratio = 1.36; P = 0.05) as compared to patients with 'genetic/unknown' aetiologies. On the contrary, vitamin responsive/structural aetiology patients were less likely to have tonic seizures (Risk Ratio = 0.66; P = 0.04). Metabolic testing was diagnostic in three out of 41 patients tested (all three had biotinidase deficiency). MRI was abnormal in 35/80 patients (malformation observed in 16/35; 19/35 had non-specific changes that did not contribute to underlying aetiology). A molecular diagnosis was achieved in 53 out of 77 patients tested (69%). Next-generation sequencing had a yield of 51%, while microarray had a yield of 14%. STXBP1 was the most common (five patients) single-gene defect identified. There were 24 novel variants. The mean follow-up period was 30 months (range, 4-72 months). On multivariate logistic regression for the important factors that could affect seizure control (seizure onset age, time lag of first visit to paediatric neurologist and aetiologies), only vitamin responsive aetiology had a statistically significant positive effect on seizure control (P = 0.02). Genetic aetiologies are the most common cause of early-infantile developmental and epileptic encephalopathies. Patients in the genetic/unknown groups had a more severe phenotype. Patients with vitamin responsive epilepsies had the best probability of seizure control.

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SCN1B-linked early infantile developmental and epileptic encephalopathy.

Publications

SCN1B-linked early infantile developmental and epileptic encephalopathy.

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