A patient organization perspective: charting the course to a cure for SCN2A-related disorders DOI Creative Commons

Leah F. Schust,

Jennifer Burke,

Christina SanInocencio

et al.

Therapeutic Advances in Rare Disease, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction Nav1.2, often stemming from genetic mutations gene, leads to SCN2A-related disorders. Individuals harboring pathogenic variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement cortical visual impairment, intellectual disabilities. FamilieSCN2A Foundation, 501(c)(3) patient advocacy organization, is dedicated enhancing lives of those affected by Fueled vision world effective treatments cures all patients Foundation has charted course cure based on their core values urgency, integrity, collaboration, inclusion. Their strategic plan centers building comprehensive research-readiness infrastructure that maximizes probability bringing curative therapies patients. Appreciating statistically most drug development initiatives will fail, creating an number drugs turn net success achieving vision. Through dynamic notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 forging partnerships across disorder ecosystem foundation actively executing its plan. With advancing rapidly thriving diverse, engaged stakeholders, believes outlook bright.

Language: Английский

Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associatedScn2a-deficiency DOI Creative Commons
Jingliang Zhang, Muriel Eaton, Xiaoling Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Social behavior is critical for survival and adaptation, which profoundly disrupted in autism spectrum disorders (ASD). withdrawal due to information overload was often described ASD, it suspected that increased basal noise, i.e., excessive background neuronal activities the brain could be a disease mechanism. However, experimental test of this hypothesis limited. Loss-of-function mutations (deficiency) SCN2A , encodes voltage-gated sodium channel Na V 1.2, have been revealed as leading monogenic cause profound ASD. Here, we Scn2a deficiency results robust multifaceted social impairments mice. -deficient neurons displayed an excitation-inhibition (E/I) ratio, contributing elevated noise diminished signal-to-noise ratio (SNR) during interactions. Notably, restoration expression adulthood able rescue both SNR deficits. By balancing E/I reducing firing, FDA-approved GABA A receptor-positive allosteric modulator improves sociability mice normalizes translationally relevant human organoids carrying autism-associated nonsense mutation. Collectively, our findings role 1.2 regulation behaviors, identified molecular, cellular, circuitry mechanisms underlying -associated disorders. leads pronounced deficits overall enhanced activity, impaired ratio. Both are reversible through adulthood. Targeted striatum-projecting rescues impairments. transmission reduced mouse organoid models deficiency, acute systemic administration modulators restores sociability. Graphical abstract: Severe predominate decrease with SNR, adult 1.2-deficient

Language: Английский

Citations

1
Two pores instead of one: Gating pore current and the electrical leak in autism and epilepsy DOI
Ahmed Eltokhi, Tamer M. Gamal El-Din

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2025, Volume and Issue: unknown, P. 111291 - 111291

Published: Feb. 1, 2025

Language: Английский

Citations

0
Gross Motor Function in Individuals With SCN2A-Related Disorders DOI
Anne T. Berg, Aaron J. Kaat, Katherine C. Paltell

et al.

Neurology Clinical Practice, Journal Year: 2025, Volume and Issue: 15(3)

Published: May 2, 2025

SCN2A-related disorders (RDs) are genetic conditions characterized by severe to profound impairments in multiple domains including gross motor function, which could serve as a nonseizure outcome precision medicine therapy trials. This study evaluated specific properties of the Vineland Adaptive Behavior Scales-3 (VABS3) and other assessments for their fitness use trials SCN2A-RDs. Sixty-five families recruited through FamileSCN2A foundation enrolled affected children ("participants," 28 female, median age 6.4 years, interquartile range [IQR] 4.1-10.5) 1-year, longitudinal study. Assessments were administered at 0 (study entry), 6, 12 months. included VABS3, Assessment System 0-5 years (ABAS), modified Functional Mobility Scale (FMS), Activities Questionnaire-Walking Level (FAQ-WL). The VABS3 composite score (34 [IQR 26-46]) indicated overall adaptive function >4 SDs below normative mean. Forty percent participants aged 2 or older required wheelchairs home distances, 28% not take any steps. standardized scores (SSs) domain (20 20-32]) subdomain (1 1-2]) reflected performance floor measures. Standardized discriminated poorly among with different levels mobility (FAQ-WL FMS) markers diseases severity (presence epilepsy, history epileptic spasms, number seizure medications). Cross-sectionally, SSs declined increasing age. By contrast, raw ABAS growth scale values (GSVs) had relatively little effects. They distinguished well between based on FAQ-WL FMS those disease markers. Test-retest inter-rater reliability all excellent. No changed significantly over time analyses. Gross people SCN2A-RDs is so severely impaired that it cannot be adequately measured norm-referenced (standardized) scores. GSVs alternative scoring used out intended have superior promising psychometric features this group, they should considered future similarly severe, rare disorders.

Language: Английский

Citations

0
The Need for Speed; Investigating Channelopathy-Associated Epilepsy Using High Throughput Electrophysiological Approaches DOI Open Access
Alfred L. George, Evangelos Kiskinis

Epiliepsy currents/Epilepsy currents, Journal Year: 2024, Volume and Issue: 24(5), P. 345 - 349

Published: Oct. 1, 2024

Pathogenic variants in genes encoding ion channels are frequently discovered monogenic disorders associated with epilepsy and neurodevelopmental disorders. This review covers advances the use of automated patch clamp recording for determining functional consequences epilepsy-associated channel induced pluripotent stem cell (iPSC) derived neurons in-depth investigations physiological such variants. The combination these advanced technologies was a focus recently completed NINDS-funded Channelopathy-associated Epilepsy Research Center without Walls.

Language: Английский

Citations

1
Rare dysfunctional SCN2A variants are associated with malformation of cortical development DOI Creative Commons
Jérôme Clatot, Christopher H. Thompson, Susan Sotardi

et al.

Epilepsia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

Abstract Objective SCN2A encodes the voltage‐gated sodium (Na+) channel α subunit Na V 1.2, which is important for generation and forward back propagation of action potentials in neurons. Genetic variants are associated with a spectrum neurodevelopmental disorders. However, mechanisms whereby variation leads to disease remains incompletely understood, full ‐related disorders may not be fully delineated. Methods Here, we identified seven de novo heterozygous eight individuals developmental epileptic encephalopathy (DEE) accompanied by prominent malformation cortical development (MCD). We characterized electrophysiological properties + currents human embryonic kidney (HEK) cells transfected adult (A) or neonatal (N) isoform wild‐type (WT) variant 1.2 using manual automated whole‐cell voltage clamp recording. Results The isoforms all studied exhibit gain function (GoF) large depolarized shift steady‐state inactivation, creating markedly enhanced window current common across four tested. Computational modeling demonstrated that expression 1.2‐p.Met1770Leu‐N developing neocortical pyramidal neuron results hyperexcitability. Significance These support expansion clinical association genetic MCD, suggests previously undescribed roles fetal brain development.

Language: Английский

Citations

1
Assessing Communication Impairments in a Rare Neurodevelopmental Disorder DOI
Anne T. Berg, Amanda N. Nili, Lindsey Evans

et al.

Neurology Clinical Practice, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 18, 2024

-related disorders (

Language: Английский

Citations

0
Brain Gene Registry; neurite density; income disparities in autism diagnoses DOI

Jill Adams

The Transmitter, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Citations

0
The Spectrum of Self-Limited Infantile Epilepsy Syndromes DOI
Imad Yassin Saadeldin,

Hussein Naseer Matlik,

Hiba Mohammed

et al.

Journal of Pediatric Epilepsy, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 5, 2024

Abstract Infantile epilepsy syndromes' nomenclature has changed over time. The International League Against Epilepsy (ILAE) revised its 2021 classification and definition of syndromes in neonates infants, replacing the term “benign” with “self-limited,” now identifies them as “self-limited infantile epilepsy” (SeLIE). SeLIE is characterized by seizures that begin during infancy resolve spontaneously normal developmental progress. recognition favorable outcomes dates back more than 60 years, noted Fukuyama Japan. Thirty years later, Watanabe et al reported benign focal infancy, majority cases being nonfamilial. These seizures' self-limited nature since been acknowledged various countries, spanning diverse ethnic populations beyond Infants who undergo such are recognized having nonfamilial (SeLNFIE). Initially, Vigevano detailed familial variant five coining “benign seizures” to characterize this condition, known (SeLFIE). SeLNFIE SeLFIE may present similarly exception a positive family history. After initial description these (familial nonfamilial) ILAE's 1989 Classification Epilepsies Epileptic Syndromes, several less frequently encountered related have recognized. conditions comprise spectrum including choreoathetosis paroxysmal dyskinesia, termed convulsions syndrome (ICCA); midline spikes waves sleep (SeLIMSE); mild gastroenteritis (SeLISwG); associated hemiplegic migraine (FHM); neonatal-infantile (SeLFNIE). This review aims document prevalence SeLIEs, elucidate their unique characteristics, underscore nature.

Language: Английский

Citations

0
A patient organization perspective: charting the course to a cure for SCN2A-related disorders DOI Creative Commons

Leah F. Schust,

Jennifer Burke,

Christina SanInocencio

et al.

Therapeutic Advances in Rare Disease, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction Nav1.2, often stemming from genetic mutations gene, leads to SCN2A-related disorders. Individuals harboring pathogenic variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement cortical visual impairment, intellectual disabilities. FamilieSCN2A Foundation, 501(c)(3) patient advocacy organization, is dedicated enhancing lives of those affected by Fueled vision world effective treatments cures all patients Foundation has charted course cure based on their core values urgency, integrity, collaboration, inclusion. Their strategic plan centers building comprehensive research-readiness infrastructure that maximizes probability bringing curative therapies patients. Appreciating statistically most drug development initiatives will fail, creating an number drugs turn net success achieving vision. Through dynamic notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 forging partnerships across disorder ecosystem foundation actively executing its plan. With advancing rapidly thriving diverse, engaged stakeholders, believes outlook bright.

Language: Английский

Citations

0