ACADEMIC RESEARCH IN MODERN SCIENCE
International scientific-online conference
121
A CASE REPORT ON SCN2A-RELATED DEVELOPMENTAL AND
EPILEPTIC ENCEPHALOPATHY WITH APPARENT GAIN-OF-
FUNCTION EFFECTS
Samadov Furkatjon Nosibjanovich
Vagizova Madina Bahtiyarovna
Sattorov Salohiddin Shuhratjon o'g'li
National Children’s Medical Center, Tashkent, Uzbekistan
E-mail: furkat.samadov@gmail.com
https://doi.org/10.5281/zenodo.13789098
Introduction:
SCN2A has emerged in recent years as a key causative gene
for pediatric epilepsy (1). In addition to epilepsy, SCN2A is also a well-
established disease gene associated with other neurological and
neurodevelopmental disorders including dystonia and ataxia, autism spectrum
disorder, and intellectual disability (ID).
The function of Na
V
1.2 has been well characterized. Along with other
sodium channel paralogs, Na
V
1.2 is involved in the generation and propagation
of action potentials in predominantly excitatory neurons. Alterations of single
amino acid residues in the protein sequence of Na
V
1.2 are known to induce
significant alterations in channel function, contributing to disease phenotypes.
Although pathogenic
SCN2A
variants are most often present in the germline
state, mosaicism has been reported at a rate of 6.4% in a cohort of
SCN2A
-
related epilepsy cases.
Genotype-phenotype correlations have been observed recently for
pathogenic
SCN2A
variants. Loss-of-function (LoF) variants are typically
associated with later-onset seizures, and gain-of-function (GoF) variants are
more closely associated with early-onset epilepsy in the neonatal or infantile
period.
SCN2A
GoF potentiates Na
V
1.2 activity and is most closely associated
with early infantile epileptic encephalopathy (EIEE) and self-limited familial and
nonfamilial infantile epilepsy (formerly benign familial infantile seizures).
Published data indicates that SCN2A is being more widely acknowledged as
a cause of epileptic encephalopathy. Loss-of-function variants are generally
linked to neurodevelopmental delay and later-onset seizures, while gain-of-
function variants tend to lead to early infantile-onset epilepsy. These
correlations indicate genotype-phenotype relationships.
Objective:
We report an infant who presented with migrating focal seizures
in the neonatal period. She was found to have a mosaic c.4534C>Gp.Pro1512Ala
variant in SCN2A. Functional studies on this variant revealed a mixture of gain-
ACADEMIC RESEARCH IN MODERN SCIENCE
International scientific-online conference
122
and loss-of-function effects. This was unexpected in the context of her severe
infantile-onset epilepsy, as previous reports on genotype-phenotype
correlations and EIMFS would have suggested a pure GoF effect. This study
demonstrates that our current understanding of genotype-phenotype
correlations for SCN2A-related epilepsy and neurodevelopmental disorders is
still evolving.
Materials and Methods:
Genetic Testing.
A Whole Exome Sequencing was performed through a
commercial diagnostic laboratory (SmartGene, Tashkent, Uzbekistan). Whole
exome sequencing (WES) as a trio was also performed by SmartGene.
Clinical Description.
The proband was delivered at term after an
uncomplicated pregnancy to a 23-yr-old mother. Parents were
nonconsanguineous with no family history of epilepsy. The patient presented
with hypotonia and tonic seizures (bilateral independent focal and sequential)
on day 5 of life. Her head circumference (HC) at birth was at the 25th percentile.
Continuous video electroencephalography (EEG) monitoring confirmed multiple
electroclinical tonic seizures of asymmetric clinical semiology but likely
symmetric EEG onset, in addition to frequent multifocal epileptiform potentials.
Background activity was seemingly normal during the awake state, with trace
alternant during quiet sleep with up to 9 s of interburst intervals. By 10 days of
life, focal seizures with rapid contralateral hemispheric involvement were
observed, suggesting EIMFS
A 6-week-old girl was hospitalized in our department due to experiencing
daily seizures in multiple areas, which started on the 5th day after birth. She had
no notable personal history. Prior to her admission to our clinic, she had been
given levetiracetam within the recommended therapeutic levels but it did not
effectively control her seizures. Upon undergoing electroencephalography,
bilateral and multifocal epileptiform discharges were observed. Prompt seizure
management was achieved using phenytoin, in accordance with recent literature
suggesting the use of sodium channel blockers for SCN2A-related epileptic
encephalopathies. Following treatment, the child remained free from seizures
but experienced delayed development in motor and cognitive skills. She is now 8
months old and has a DQ of ~ 55. No other family members are known to have
similar issues.
Results:
Genetic testing revealed a new
de
novo
, missense mutation in the
SCN2A gene, c.4534C>A, in a heterozygote state, not previously reported by our
knowledge, in both, patient and his mother. This variant was confirmed with
ACADEMIC RESEARCH IN MODERN SCIENCE
International scientific-online conference
123
Sanger sequencing. This variant is absent in gnomAD (date of access
02/12/2023) and has only been reported once in the literature in an individual
with early infantile epileptic encephalopathy but otherwise limited available
phenotypic information. Trio-based exome sequencing was subsequently
performed to rule out other potential contributing variants and was negative for
other rare variants in epilepsy-associated genes and for other de novo coding
variants.
Conclusion:
This case illustrates that our understanding of genotype-
phenotype correlations is still limited and highlights the complexity of the
underlying electrophysiological effects of SCN2A variants. Also of note in our
patient is her favorable response to phenytoin, a known sodium channel blocker.
Additional studies will be extremely important in helping to further clarify
genotype-phenotype correlations, as well as in identifying reasons behind
exceptions and nuances. With an improved understanding of the functional and
clinical consequences of various disease-related
SCN2A
variants, the possibility
for the development of specific, individualized therapies for different variant
types will become increasingly tangible.
References:
1.
Sands TT, Choi H. Genetic testing in pediatric epilepsy. Curr Neurol
Neurosci Rep 17: 45, 2017. doi: 10.1007/s11910-017-0753-y.
2.
Sanders SJ, Campbell AJ, Cottrell JR, Moller RS, Wagner FF, Auldridge AL,
Bernier RA, Catterall WA, Chung WK et all. Progress in understanding and
treating SCN2A-mediated disorders. Trends Neurosci 41: 442–456, 2018. doi:
10.1016/j.tins.2018.03.011
3.
Leach EL, van Karnebeek CD, Townsend KN, Tarailo-Graovac M, Hukin J,
Gibson WT. Episodic ataxia associated with a de novo SCN2A mutation. Eur J
Paediatr Neurol 20: 772–776, 2016. doi: 10.1016/j.ejpn.2016.05.020.
4.
Wang J, Ou SW, Wang YJ. Distribution and function of voltage-gated
sodium channels in the nervous system. Channels (Austin) 11: 534–554, 2017.
doi: 10.1080/19336950.2017.1380758
5.
de Lera Ruiz M, Kraus RL. Voltage-gated sodium channels: structure,
function, pharmacology, and clinical indications. J Med Chem 58: 7093–7118,
2015. doi: 10.1021/jm501981g.
6.
Stosser MB, Lindy AS, Butler E, Retterer K, Piccirillo-Stosser CM, Richard G,
McKnight DA. High frequency of mosaic pathogenic variants in genes causing
epilepsy-related neurodevelopmental disorders. Genet Med 20: 403–410, 2018.
doi: 10.1038/gim.2017.114.
ACADEMIC RESEARCH IN MODERN SCIENCE
International scientific-online conference
124
7.
Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ.
Opposing effects on NaV1.2 function underlie differences between SCN2A
Variants observed in individuals with autism spectrum disorder or infantile
seizures.
Biol
Psychiatry
82:
224–232,
2017.
doi:
10.1016/j.biopsych.2017.01.009.
8.
Wolff M, Johannesen KM, Hedrich UB, Masnada S, Rubboli G, Gardella E, et
al.. Genetic and phenotypic heterogeneity suggest therapeutic implications in
SCN2A-related
disorders.
Brain
140:
1316–1336,
2017.
doi:
10.1093/brain/awx054.
9.
Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-
Casero V, Webster R, Clark D, Freeman JL, Calvert S, Olson HE, Mandelstam S,
Poduri A, Mefford HC, Harvey AS, Scheffer IE. SCN2A encephalopathy: a major
cause of epilepsy of infancy with migrating focal seizures. Neurology 85: 958–
966, 2015. doi: 10.1212/WNL.0000000000001926.
10.
Su DJ, Lu JF, Lin LJ, Liang JS, Hung KL. SCN2A mutation in an infant
presenting with migrating focal seizures and infantile spasm responsive to a
ketogenic
diet.
Brain
Dev
40:
724–727,
2018.
doi:
10.1016/j.braindev.2018.03.005.
