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Case Reports
. 2019 Dec;6(12):2354-2367.
doi: 10.1002/acn3.50921. Epub 2019 Nov 11.

SCN1B-linked early infantile developmental and epileptic encephalopathy

Alec Aeby  1 , Claudine Sculier  2 , Alexandra A Bouza  3 , Brandon Askar  3 , Damien Lederer  4 , Anne-Sofie Schoonjans  5 , Marc Vander Ghinst  6   7 , Berten Ceulemans  5 , James Offord  3 , Luis F Lopez-Santiago  3 , Lori L Isom  3
Affiliations
Case Reports

SCN1B-linked early infantile developmental and epileptic encephalopathy

Alec Aeby et al. Ann Clin Transl Neurol. 2019 Dec.

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) β1 and β1B 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 β1 subunit, similar to wild-type (WT), but with loss of normal β1-mediated modification of human Nav 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pedigree of the family.
Figure 2
Figure 2
Electroencephalogram of the patient at 2.5 months in awake state showing a normal background with isolated, bilateral slow amplitude central spikes without clinical manifestations (arrows). Time constant: 10 sec. Amplitude: 100 µV/cm. High band filter: 0.3 Hz. Low band filter: 70 Hz.
Figure 3
Figure 3
Electroencephalogram of the patient at 2.5 months in awake state showing clusters of bilateral high‐amplitude central spikes followed by high‐amplitude slow waves and erratic focal right myoclonus (arrows). Time constant: 10 sec. Amplitude: 100 µV/cm. High band filter: 0.3 Hz. Low band filter: 70 Hz.
Figure 4
Figure 4
Electroencephalogram of the patient at 2.5 months in awake state showing rhythmic bilateral central high‐voltage spikes accompanied by a cluster of high‐voltage myoclonus (n = 10, arrow to arrow) followed by a focal to bilateral clonic seizure with alteration of consciousness lasting 80 sec. Time constant: 10 sec. Amplitude: 300 µV/cm. High band filter: 0.3 Hz. Low band filter: 70 Hz.
Figure 5
Figure 5
Number of seizures lasting more than 1 minute before and after fenfluramine (FFA) add‐on.
Figure 6
Figure 6
Auditory brainstem response obtained at various intensities decreasing from 90 to 20 dB alternatively in condensation and rarefaction polarity. ABR show, when stimulation intensity decreases, an early loss of the wave V, while wave I/III remains, and a prolonged I–V interpeak latencies. (For illustration purpose, only the right side is shown).
Figure 7
Figure 7
β1‐p.Arg85Cys localizes to the plasma membrane. (A) Cartoon diagram of β1‐p.Arg85Cys. (B) Crystal structure of WTβ1 (PDB: 6AGF).23 The residue, Arg85, is shown in cyan. Right: 20 angstrom area showing detail of the Ig domain. (C) Cell surface biotinylation shows that β1‐p.Arg85Cys can localize to the plasma membrane, similar to WT (representative of four independent experiments). (D) β1 WT and β1‐p.Arg85Cys colocalize with the plasma membrane marker, WGA (representative of five independent experiments). (E) Orthogonal views of a single z‐stack (YZ plane to right, XZ plane below) from immunofluorescence microscopy indicating colocalization between V5 and WGA signals.
Figure 8
Figure 8
β1‐p.Arg85Cys does not modulate INa density or τ of inactivation. (A) Representative INa density traces; currents were evoked with a 50‐msec test pulse to 0 mv following a prepulse to − 120 mV. Top: Cells expressing hNav1.1 alone (eGFP only). Middle: Cells expressing hNav1.1 plus WT β1 subunits. Lower: Cells expressing hNav1.1 plus β1‐p.Arg85Cys subunits. All traces are shown at the same scale. (B) Mean transient INa density measured at the peak from currents represented in (A). (C) Mean persistent INa density measured as the average current of the last 2 msec of the current to 0 mV represented in (A). (D and E) INa inactivation was fit to a double exponential equation and the mean τ for the fast and slow components were plotted. n = 13 cells per condition; *P < 0.05. Error bars indicate mean ± standard error of the mean. *P < 0.05. [Correction added on 06 December 2019 after first online publication: Figure 8 has been updated.]
Figure 9
Figure 9
WT β1 subunit co‐expression increases hNav1.1 INa density but neither WT β1 nor β1‐p.Arg85Cys affect the voltage dependence of hNav1.1‐generated INa. (A) Mean current‐voltage relationships of transient INa: hNav1.1 alone, tranfected with eGFP only, (open circles, n = 12 cells), hNav1.1 plus WT β1 (closed circles, n = 11 cells), hNav1.1 plus β1‐p.Arg85Cys (triangles, n = 13 cells). (B) Activation curves from the data shown in (A). (C). Steady‐state inactivation curves recorded using a standard two‐pulse protocol (hNav1.1, n = 12 cells; hNav1.1 plus WT β1, n = 13 cells; hNav1.1 plus β1‐p.Arg85Cys, n = 13 cells). [Correction added on 06 December 2019 after first online publication: Figure 9 has been updated.]
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