Abstract Details

Title Relationship Between Genetic Variants and Disease Characteristics in Patients with SCN8A Developmental and Epileptic Encephalopathy (SCN8A-DEE) or SCN8A-Related Epilepsy

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) Epilepsy/Clinical Neurophysiology (EEG) Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 067

Objective A caregiver survey, solicited by an advocacy group (The Cute Syndrome Foundation) via an online questionnaire, was conducted to better understand variability in the clinical presentation of SCN8A-DEE and SCN8A-related epilepsy.

Background SCN8A encodes the NaV1.6 channel, which is highly expressed in the central nervous system with a major role in regulating excitatory networks in the brain. SCN8A-DEE is a rare and severe genetic epilepsy syndrome characterized by early onset cognitive impairment, developmental delay, and intractable seizures. Variants in the SCN8A gene have also been reported in patients with a broader phenotypic spectrum with varying degrees of severity.

Design/Methods A 36-question online survey was developed to obtain de-identified data from caregivers of children. Patterns of association were investigated between SCN8A genetic variants and disease characteristics, including seizure type, frequency, and progression.

Results Of 70 SCN8A reported variants, G1475R (n=6), R850Q (n=6), and R1872W (n=4) were the most common. These variants were significantly correlated with absence seizures and infantile/epileptic spasms at onset, current seizures and seizure clusters, and seizure-free periods (Fisher’s exact p-value <0.05). Among the 16 patients with these 3 variants, the most common current seizure types were generalized tonic-clonic (n=8) and absence (n=8). Among the 6 patients with R850Q variant, myoclonic and partial/focal seizures were also common (both, n=4). Seizure frequency of 1 to >10x per day was reported for R850Q (n=5) and R1862W (n=1). Since seizure onset, 67% (4/6) of G1475R patients worsened over time, 83% (5/6) of R850Q patients had variable progression (periods of worsening and improvement), and 50% (2/4) of R1872W patients improved over time.

Conclusions

SCN8A-related epilepsy is a disorder in which phenotypes may differ across the spectrum of genotypes. Effective anti-seizure medications are still needed for this severely impacted patient population.

Authors/Disclosures
Dietrich Haubenberger, MD, F�鶹��ýӳ�� (Neurocrine Biosciences) PRESENTER	Dr. Haubenberger has received personal compensation for serving as an employee of Neurocrine Biosciences, Inc. Dr. Haubenberger has stock in Neurocrine Biosciences. Dr. Haubenberger has a non-compensated relationship as a Member of the Board with American Society for Experimental Neurotherapeutics that is relevant to �鶹��ýӳ�� interests or activities.
Celene Grayson, PhD (Xenon Pharmaceuticals Inc)	Dr. Grayson has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc.. Dr. Grayson has stock in Xenon Pharmaceuticals Inc..
Alison Cutts	Alison Cutts has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Alison Cutts has or had stock in Xenon Pharmaceuticals.Alison Cutts has received intellectual property interests from a discovery or technology relating to health care.
Constanza Luzon	Constanza Luzon has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc.. Constanza Luzon has stock in Xenon Pharmaceuticals.
Noam Butterfield, PhD (Xenon Pharmaceuticals)	Dr. Butterfield has received personal compensation for serving as an employee of Xenon Pharmaceuticals.
	No disclosure on file
	No disclosure on file
John M. Schreiber, MD (Children'S National Medical Center)	Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xenon. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zogenix. The institution of Dr. Schreiber has received research support from Dravet Syndrome Foundation.
	No disclosure on file
Ernesto Aycardi, MD (Kyowa Kirin)	Dr. Aycardi has received personal compensation for serving as an employee of XENON. Dr. Aycardi has received stock or an ownership interest from XENON.
Cynthia L. Harden, MD (Xenon Pharmaceuticals Inc)	Dr. Harden has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc.. Dr. Harden has stock in Xenon Pharmaceuticals Inc.. Dr. Harden has received intellectual property interests from a discovery or technology relating to health care.
Eric Jen (Neurocrine Biosciences, Inc.)	Eric Jen has received personal compensation for serving as an employee of Neurocrine Biosciences, Inc.
	No disclosure on file

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