Clinical Research & Therapy 1: NALCN Channel-related Disease
11:00AM - 12:00AM BREAK
Clinical Research & Therapy 2: Clinical Research
12:00PM
1:00PM - 2:00PM
2:00PM - 3:00PM LUNCH Workshop - Translational Science PrioritiesMonterey Oak
3:00PM
3:15PM - 4:30PM
4:30PM - 5:30PM
Keynote: Pangkong Fox “The Power of the Patient Community”
BREAK - Group Photo
Patient Led Science 1: Expert Roundtable
Poster & Exhibit Session - Ballroom Foyer
6:00 PM Dinner - SeaWorld 0 SeaWorld Dr
Keynote Speaker:
Pangkong Fox, PhD Science Engagement Director, CACNA1A Foundation
“The Power of the Patient Community”
Saturday, October 11, 2025
Sunday, October 12, 2025 7:30AM - 12:00PM
7:30AM Breakfast
8:30AM
9:00AM - 9:45AM
9:45AM-10:15AM
10:15AM - 11:30AM 11:30AM
Opening Remarks - Monterey Oak
Keynote: Natasha Ludwig “Patient Engagement in Research”
Patient Led Science 2: Community-Engaged Research & Advocacy
Workshop - Call to Action
Closing
Keynote Speaker:
Natasha Ludwig, PhD
Neuropsychologist, Program Director, Development
Neuropsychology Phenotyping Unit, Kennedy Krieger Institute, Assistant Professor of Psychiatry & Behavioral Science, Johns Hopkins University School of Medicine
“The critical role of patient engagement in the development of novel treatments for rare neurogenetic conditions”
Sunday, October 12, 2025
Speakers & Abstracts
Opening Remarks
Jeremy Tanner, MD MPH
October 10, 2025 8:30AM - 9:00AM
Basic Science 1: NALCN Channelosome Physiology
Session Moderator Arnaud Monteil, PhD October 10, 2025 9:00AM - 10:30AM
The NALCN ion channel in health and disease
Arnaud Monteil, PhD
Senior Researcher at the French National Center for Scientific Research, Adjunct Professor at Mahidol University Siriraj Hospital, Bangkok, Thailand
Neuronal excitability critically depends on ion channel composition, with the leak sodium channel NALCN playing a central role in setting the resting membrane potential and regulating electrical activity: Studies on animal models have shown that NALCN is essential for key physiological processes, including respiration, circadian rhythms, sleep, locomotion, and pain perception: NALCN dysfunctions lead to severe neurodevelopmental disorders marked by a large panel of symptoms that include developmental delay, facial dysmorphisms, seizures, and early mortality: To date, no therapies is available for patients: Our research aims to bridge this therapeutic gap by leveraging innovative in vitro and in vivo models to study NALCN-related diseases: I will present recent insights into patient phenotypes, the functional consequences of pathogenic NALCN variants, and the identification of candidate molecules that modulate NALCN activity: This work is made possible through strong collaborations with scientists, clinicians, and patient families worldwide:
Modulating NALCN Function: The Role of UNC80 and Pathogenic Variations
Dejian Ren, PhD
Professor
of Biology
University of Pennsylvania
The resting membrane potential (RMP) is essential for neuronal function and is largely determined by basal sodium leak currents: We identified NALCN as a sodium-conducting channel responsible for the major Na⁺ leak in neurons: This channel forms a complex with at least three auxiliary subunits: UNC80, UNC79, and FAM155A: While NALCN shares structural and sequence similarities with other 24-transmembrane domain channels, such as voltage-gated Na⁺ and Ca²⁺ channels, its auxiliary subunits are structurally unique and poorly understood: Our findings reveal that UNC80 is critical for NALCN trafficking and regulation: Disease-associated genetic variants in UNC80 impair its ability to modulate NALCN, disrupt interactions with UNC79, and prevent proper dendritic localization, highlighting a mechanistic link between UNC80 dysfunction and severe neurological disorders:
Basic Science 1: NALCN Channelosome Physiology
Session Moderator Arnaud Monteil, PhD October 10, 2025 9:00AM - 10:30AM
Investigating the role of NALCN in modulating uterine activity
Sarah England, PhD
Alan A: and Edith L: Wolff Professor of Medicine, Vice Chair of Research and Professor, Dept: of Obstetrics and Gynecology, Director, Center for Reproductive Health Sciences Washington University School of Medicine
The molecular mechanisms governing the transition of a pregnant uterus from a quiescent state during gestation to a contractile state at delivery are largely unknown, and this deficit has hampered the development of effective therapies to prevent preterm labor: An important feature of uterine contractions is that they occur spontaneously and rhythmically without neuronal or hormonal input: Thus, the uterine muscle (myometrium) must have intrinsic mechanisms to generate and pace contractions: To generate a contraction, the myometrial cell membrane slowly depolarizes (becomes less negative on the inside of the cell relative to the outside) to a threshold level, at which time the cell generates an action potential: My lab has identified the role of Na+ leak currents channels in this slow depolarization, which is vital for myometrial rhythmicity: My talk will focus on ways in which NALCN regulates uterine function:
Early eukaryotic origins of the NALCN channelosome
Adriano Senatore, PhD
Associate Professor & Acting Chair of Biology, University
of Toronto Mississauga
Previous phylogenetic analyses established that NALCN and its subunit FAM155 are also found in fungi, where they are named Cch1 and Mid1, respectively: However, the two cytoplasmic subunits of NALCN, INC79 and UNC80, had not been reported to exist outside of animals: In this study, we sought to re-examine the evolutionary origins of NALCN channelosome subunits, within a broad eukaryotic context: We confirm a phylogenetic link between metazoan NALCN and fungal Cch1 channels and uncover a broader clade of related channels across diverse eukaryotes: Additionally, we identify FAM155/Mid1 homologues in Cryptista algae and UNC79/UNC80 homologues in several non-metazoan eukaryotes, including fungi and microbial taxa: Structural comparisons with the human NALCN complex support the orthology of these subunits across metazoans and nonmetazoans: Together, our analyses reveal unexpected diversity and ancient eukaryotic origins of NALCN/Cch1 channelosome subunits and raise interesting questions about the functional nature of this conserved channel complex within a broad, eukaryotic context:
Basic Science 1: NALCN Channelosome Physiology
Session Moderator Arnaud Monteil, PhD October 10, 2025 9:00AM - 10:30AM
Neural functions of NALCN in neurologic disease
Cheng Zhou, PhD
Professor of Anesthesiology Neuroscience Research Center of Anesthesiology West China Hospital, SCU
Session Moderator Arnaud Monteil, PhD October 10, 2025 11:00AM - 12:30PM
Beyond the brain: The role of NALCN in vascular function and Hypertension
Young Min Bae, DVM, PhD Professor, Department of Physiology Konkuk University School of Medicine
NALCN is best known as a sodium leak channel essential for brain development, with pathogenic mutations linked to disorders such as IHPRF and CLIFAHDD: However, our recent findings suggest that NALCN’s physiological importance goes well beyond the nervous system: In this talk, I will present evidence that NALCN is also expressed in arterial smooth muscle, where it helps regulate blood pressure by controlling the electrical activity of blood vessels: In animal models of hypertension, NALCN expression is increased and contributes to excessive vascular contraction: Blocking NALCN in these models lowers blood pressure and improves vessel function, pointing to a new potential treatment strategy: These findings suggest that NALCN may play a broader role in human health and disease, including in organs like the heart, kidney, and blood vessels: This expanded understanding could open new avenues for diagnosis and therapy not only for patients with known NALCN mutations but also for those with cardiovascular disease:
Uncovering Diverse Roles for NALCN in Cell Behavior, Tissue Homeostasis, and Disease
Eric Rahrmann, PhD
Assistant Professor The Hormel Institute University of Minnesota
The NALCN ion channel has traditionally been studied in the context of innervating tissues and heterologous systems, but recent discoveries suggest it plays a much broader role in human biology: Our lab explores how NALCN helps regulate epithelial cell behavior, how cells move, communicate, and respond to their environment across different tissues: We are especially interested in how changes in NALCN activity affect disease processes like cancer spread, tissue injury, and systemic stress: Through a combination of in vivo models and patient-derived systems, we’re uncovering how NALCN influences cellular plasticity and long-distance communication between organs: Our work also suggests that NALCN may hold promise as a potential biomarker for disease progression and a novel target for future therapies: This talk will highlight some of the surprising roles NALCN plays in epithelial cells and tissue microenvironments and how this expanding view of the channel is opening new paths for diagnosis and treatment in a range of conditions:
Basic Science 2: NALCN Channelosome & Disease
Session Moderator Arnaud Monteil, PhD October 10, 2025 11:00AM - 12:30PM
Uncovering REM sleep regulation through NALCN
Hiromasa Funato, MD, PhD
International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba Institute for Advanced Research (TIAR), University of Tsukuba, Japan Department of Anatomy, Graduate School of Medicine, Toho University
Sleep is classified into rapid eye movement (REM) sleep and non-REM sleep: Each state is characterized by distinct brain activity and plays different roles in various physiological functions, including memory consolidation, cognition, endocrine regulation, and autonomic nervous system activity: Recent advances in circuit-level understanding of sleep regulation have identified specific neuronal populations and circuits responsible for the initiation, maintenance, and homeostatic regulation of each sleep state: To elucidate the molecular mechanisms underlying sleep regulation, we have conducted a forward genetic screen in mice, which led to the identification of novel sleepregulating molecules such as NALCN, SIK3, HDAC4/5, and Cacna1a: One mutant mouse line, referred to as Dreamless, carries a single amino acid substitution in NALCN and exhibits both reduced total REM sleep time and unstable maintenance of REM sleep episodes: Additional mutant lines further support the critical role of NALCN in REM sleep regulation: To dissect the sleep phenotypes observed in the Dreamless pedigree and to elucidate the physiological role of NALCN in sleep and wakefulness, we generated two mouse lines: one expressing the mutant form of NALCN in a Credependent manner, and another allowing conditional knockout of NALCN: Although NALCN is broadly expressed throughout the brain, sleep regulation appears to involve specific and combinatorial subsets of neurons: In humans, REM sleep characterized by heart rate variability can be observed during fetal stages, offering the potential for early diagnosis of disorders related to NALCN dysfunction: These findings suggest that NALCN is a key regulator of REM sleep, and that REM sleep phenotyping may, in turn, provide insight into alterations in NALCN-related genes in humans:
Basic Science 2: NALCN Channelosome & Disease
Session Moderator Arnaud Monteil, PhD October 10, 2025 11:00AM - 12:30PM
In vivo BioID of NALCN channel complex protein-protein interactions
Tomoyuki Fujiyama, PhD Assistant
Professor Yanagisawa/Funato Laboratory, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan
Background: Although REM sleep (REMS) is ubiquitous in mammals, the molecular/neural mechanism underlying REMS regulation remains unknown: We previously established the Dreamless mutant pedigree exhibiting abnormal EEG power spectra and around a half reduction in REMS episode duration (Funato et al:, Nature 2016): We identified an SNP specific to Dreamless mutant mice within the Nalcn gene, which leads to a single amino acid substitution (N315K) in the NALCN protein, a voltage-independent, non-selective leak cation channel: Introducing the same point mutation in wild-type mice through genome editing confirmed that the mutation was responsible for the REMS abnormalities, suggesting an important role of NALCN in REMS regulation: Methods: NALCN channel complex proteins such as UNC80, UNC79, and FAM155A have been identified; however, the modulators of the NALCN channel complex in REM sleep regulation remain still unknown: In this study, to elucidate the molecular mechanisms of REM sleep regulation mediated by NALCN, we conducted a comprehensive search for protein-protein interactions within the NALCN channel complex using in vivo BioID (iBioID), a biotin-based proximity labeling technique: We generated two knock-in mice in which NALCN and UNC80 were fused to multipletags consisting of HA-tag, strepⅢ-tag and the promiscuous mutant biotin ligase BirA, enabling parallel analyses of both iBioID and conventional affinity purification-mass spectrometry: Results: Western blot analysis of purified streptavidin-precipitations detected a marked increase in biotinylated proteins and the presence of epitope-tagged bait proteins: LC-MS/MS analysis of these lysates identified more than 142 proteins that were enriched 2:0-fold compared to control mice in both NALCN and UNC80 iBioID: Gene Ontology term analysis classified the identified proteins by subcellular localization, revealing many proteins localized to mitochondria and cytoplasmic vesicles, in addition to the membrane: Notably, the common proximity proteins included molecules known to be involved in sleep regulation, which are predicted to be upstream modulators of the NALCN channel complex: Conclusion: In this study, we identified uncharacterized interacting proteins that may function as NALCN-channel activity regulators: In future studies, we will conduct sleep analysis using genetically modified mice with altered function of candidate genes, to elucidate the relationship between REM sleep regulation and candidate targets:
Basic Science 2: NALCN Channelosome & Disease
Session Moderator Arnaud Monteil, PhD October 10, 2025 11:00AM - 12:30PM
Uncovering the role of NALCN in Cortical Neuronal Excitability and Circuit Integration
The sodium leak channel non-selective (NALCN) provides a background sodium conductance that strongly influences resting membrane potential and neuronal excitability: While its role in maintaining baseline ion flux is well established, much less is known about how NALCN contributes to the functional properties of neurons within the cerebral cortex: In this talk, I will share our work that combined genetic manipulation, patch-clamp electrophysiology, and imaging to probe NALCN function in different types of cortical cell types:
Isabel Del Pino, PhD Institute of Neuroscience CSIC-UMH San Juan de Alicante
Session Moderator Stephan Pless, PhD October 10, 2025 1:00PM - 2:30PM
Regulation of the NALCN channelosome by endogenous and de novo designed proteins
Stephan Pless, PhD Professor, Department of Drug Design and Pharmacology University of Copenhagen
The NALCN channelosome is a multi-protein assembly comprising UNC79, UNC80, FAM155A, and the pore-forming NALCN protein: Despite its physiological significance, our understanding of how this approximately 1 MDa protein complex is regulated by interactions with other proteins remains limited: Additionally, modulating its function using pharmacological tools has proven difficult: We therefore set out to uncover some of the regulatory mechanisms and develop pharmacological tools to specifically modulate channelosome function: In this presentation, I will provide an overview of our recent work aimed at identifying endogenous and de novo designed protein-protein interaction partners of the NALCN channelosome: To this end we have development of a robust bioinformatics pipeline to predict novel partners and used machine learning-assisted protein design to generate artificial miniprotein binders: Our findings offer promising avenues for understanding the broader regulatory landscape of this key protein complex, with potential implications for therapeutic interventions in NALCN-related diseases in the future:
Making sense of missense and nonsense: A functional assay to assess variant pathogenicity
Han Chow Chua, PhD
NHMRC Emerging Leadership Fellow School of Pharmacy/Charles Perkins Centre, The University of Sydney (USyd), Australia Professor, Department of Drug Design & Pharmacology, University of Copenhagen
Since the first description of NALCN-associated disorders in 2013, there are now hundreds of variants on ClinVar associated with diseases A robust, well-validated assay is essential for pathogenicity assessment of these variants, but there is currently no consensus on what defines such an assay Here, we present a functional assay benchmarked using both population and pathogenic variants, with the sensitivity to distinguish between benign, loss-, and gain-of-function effects We hope this work contributes to more rigorous classification of NALCN variants and fosters open discussion on standards for variant interpretation
Session Moderator Stephan Pless, PhD October 10, 2025 1:00PM - 2:30PM
Approaches and outcome of repurposed drug screen for CLIFAHDD
Mei Zhen, PhD
Senior Scientist, the LunenfeldTanenbaum Research Institute of the Sinai Health System Professor, Department of Molecular Genetics, University of Toronto
In 2012, we identified and confirmed the first case of CLIFAHDD patient to be caused by a gain-offunction mutation in the sodium leak channels. In 2014, we initiated a collaboration with IBGEN Pharmaceuticals to develop methods and models to screen among FDA-approved drugs that target channels for in hopes to repurpose them for potential therapeutics. We generated two C. elegans models that express two CLIFAHDD-patient mutations from the C. elegans endogenous loci. We developed a C. elegans behavioral assay and a primary mouse hippocampal neuron culture assay to screen for drugs that either exacerbate or alleviate the effect of CLIFADD mutations. In parallel, we developed a mouse CLIFAHDD model and assays to examine the effect of identified compounds from the C. elegans and neuron cultures (see Abstract by Du, et al.) We have identified a potential drug that alleviate the effect of CLIFADD mutations in both C. elegans and mouse neuron cultures. It is being further verified in the mouse model. We believe that our C. elegans, primary neuron culture, as well as the mouse model, and their respective assays can be applied to scale up the screening for treatment of CLIFAHDD. We would like to share our methods, models, and thoughts, look forward to collaborations.
Stem Cell-Based Approaches to Unravel Neurodevelopmental Mechanisms in Epilepsy
Jenny Hsieh, PhD
Professor of Neuroscience, Developmental and Regenerative Biology and Semmes Distinguished Chair in Cell Biology at UTSA
The Hsieh Lab explores how neural stem cells shape brain development and contribute to neurological disorders. We use human iPSC-derived brain organoids to model genetic epilepsies, focusing on mutations in ARX and CHD2 genes associated with epilepsy, autism, and intellectual disability. By analyzing patient-derived cortical and subpallial organoids through molecular and physiological approaches, we aim to uncover the genetic mechanisms underlying these neurodevelopmental disorders and inform future diagnostic and therapeutic strategies.
Session Moderator Stephan Pless, PhD October 10, 2025 1:00PM - 2:30PM
Short Talk
Characterizing a NALCN loss-offunction human disease model
Natasja Jacobsen, PhD
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
The resting membrane potential (RMP) is a fundamental feature of all living cells, essential for ion transport, osmotic balance, and intracellular signaling In excitable cells like neurons, it determines the threshold for action potential generation and modulates synaptic activity The RMP is established through the finely regulated movement of ions across the membrane, involving ion channels, pumps, and transporters Leak channels, which permit the passive flow of ions, particularly potassium and sodium, play a central role in maintaining the membrane potential The sodium leak channel non-selective (NALCN) complex, composed of NALCN and its auxiliary subunits UNC79, UNC80, and FAM155A, is mainly responsible for a constitutive sodium leak into cells and thereby sets the RMP NALCN or subunit variants are the cause of severe neurodevelopmental disorders such as Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies (IHPRF) IHPRF1 results from loss-of-function variants in NALCN, however, the molecular pathology mechanism remains poorly understood, due to the lack of representative human disease modelsTo address this, we used CRISPR/Cas9 to introduce the NALCN variant Q642X into a well-characterized human induced pluripotent stem cell (hiPSC) line We generated two hiPSC lines carrying the NALCN Q642X variant, one homozygous and one heterozygous Edited cell lines along with an isogenic wild-type control were differentiated towards cortical neurons and characterized by patch-clamp electrophysiology to assess passive and active membrane properties, including RMP, input resistance, excitability and firing patterns Additionally, the variants and the control were characterized utilizing immunohistochemistry and molecular profiling to assess the cellular and functional consequences of the variant All hiPSC lines were quality controlled by immunostaining for pluripotency markers (NANOG, OCT3/4, SSEA3, TRA-1-60-R) and markers for all three germ layers, mesoderm, endoderm, ectoderm (SMA, AFP, β-tubulin III, Nestin), confirming pluripotency and capacity to differentiate towards different tissues Copy number variation analysis showed genomic integrity consistent with the parental control line Cortical neuron differentiation of the hiPSCs were successfully achieved We have established a human disease model suitable for investigating NALCN Q642X This model will allow for detailed study of NALCN-related pathophysiology and may contribute to a better understanding of how NALCN contributes to disease
Session Moderator Stephan Pless, PhD October 10, 2025 1:00PM - 2:30PM
Short Talk
Automated high throughput patch clamp studies of voltage gated ion channels in hiPSC-derived neurons
Ion channel studies have long used recombinant human proteins expressed in human cell lines to screen ion channel modulators and to develop potential disease-modifying drug candidates Although recombinant human proteins are powerful tools, they have several limitations such as missing co-expression of appropriate accessory subunits, lack of full excitable cell context and the difficulty of examining complex endogenous channel stoichiometry and gene expression Human induced pluripotent stem cell (hiPSC) derived neurons express native complements of human ion channels and their accessory proteins providing enhanced translatability from early in vitro studies to patient biology. Despite this promise, few studies have examined the suitability of hiPSC neurons for automated patch clamp studies. Here, we establish the feasibility of recording voltage gated channel activity from hiPSC derived excitatory neurons in 384 well format with the Sophion Qube automated patch clamp system. hiPSC derived neurons were generated by overexpression of the transcription factor NGN2 driven from a stably integrated cassette in the AAVS1 locus. We optimized dissociation procedures with 2-3 weeks in vitro NGN2 neurons by assessing the percentage of cells with voltage-gated sodium (NaV) and potassium (KV) currents on the Qube. Recordings following optimized dissociation found that ~30% of single cells had NaV currents >200 pA, leading to recordings of >100 cells in parallel. Minimal reduction of experimental throughput was observed with recordings following culture up to four weeks. Isolation of NaV currents with cesium internal solution showed expected NaV activation and inactivation curves with mean NaV currents >1 nA. Exchange of intracellular solution from cesium to potassium-based reversed block of KV channels did not significantly impact recording success rate. In multi-cell recording configurations we attained success rates of ~80%, sufficient to examine dozens of experimental conditions simultaneously. These results suggest that key hiPSC NGN2 neuronal properties, NaV and Kv activity, are retained in conditions that support high throughput patch clamp studies. Furthermore, we show that the automated patch clamp drastically increases experimental throughput for hiPSC neuron neurophysiology. Future studies will examine properties of other hiPSC derived neuronal types and establish the diversity of ion channels amendable to automated recordings.
Workshop: Basic Science Priorities
- Identifying key
achievements, gaps, and urgent concern
Facilitators Jeremy Tanner, MD MPH, Emily Durham, PhD
October 10, 2025 2:30PM - 3:30PM
Translational Science Session 2:
NALCN Channelsome Models, Tools, & Disease
Session Moderator Stephan Pless, PhD October 10, 2025 4:00PM - 5:30PM
Developing nanobody-based inhibitors of NALCN by targeting an intracellular domain
Manu Ben-Johny, PhD
Assistant Professor of Physiology & Cellular Biophysics Columbia Vagelos College of Physicians and Surgeons
The sodium-leak channel (NALCN) is a non-selective ion channel that fine-tunes electrical activity in neurons and other excitable cells Human variants in NALCN that increases the leak current is linked to severe congenital neurodevelopmental disorders, characterized by congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD) Here, by panning a yeast display library, we identified synthetic nanobodies that bind to an intracellular region of the NALCN channel Functional analysis showed that these nanobodies partially inhibited NALCN Functionalizing these nanobodies by fusing an E3 ubiquitin ligase that ubiquitinates NALCN to promote internalization and degradation, evoked a further reduction in NALCN current amplitude In all, this work lays the groundwork for developing genetically encoded modulators to inhibit NALCN, and a conceptual framework to develop potential future therapeutic strategies for CLIFAHDD
Recorded Virtual Talk
Channelsome Models, Tools, & Disease
Session Moderator Stephan Pless, PhD October 10, 2025 4:00PM - 5:30PM
The NALCN R1181Q CLIFAHDD variant alters morphology and excitability in patient-derived neurons
Nadine Ritter, PhD
Pless lab, Department of Drug Design and Pharmacology, Copenhagen University
Background: The sodium leak channel (NALCN) is primarily expressed in neuronal tissue, where it mediates the resting membrane potential via a constitutively sodium inward leak current. Inherited or de novo genetic variants can result in severe neurological diseases in humans, namely Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) or Hypotonia, infantile, with psychomotor retardation and characteristic facies (IHPRF). The CLIFAHDD gain-offunction (GOF) variant R1181Q shows an increased sodium inward leak current. But currently there are no human physiological disease model systems to study or rectify NALCN-mediated disease phenotypes. Here, we aim to characterize the NALCN R1181Q variant electrophysiologically, immunohistochemically and quantitatively in human induced pluripotent stem cells (hiPSCs).Methods:We utilized reprogrammed hiPSCs derived from peripheral blood mononuclear cells (PBMCs) from three R1181Q patients and healthy relatives as control. We validated the hiPSCs and differentiated both R1181Q and healthy controls to cortical glutamatergic neurons in order to assess the R1181Q phenotype. Results:Patient and healthy control derived hiPSCs were successfully reprogrammed from PBMCs and stained positive for pluripotency markers Nanog, Octamer-binding transcription factor 4 (OCT4), Stage-Specific Embryonic Antigen 3 (SSEA-3) and TRA-1-60R. Further, all hiPSC lines showed the capacity to spontaneously differentiate into the three germ layers (endoderm, mesoderm and ectoderm). The hiPSC lines were negative for new Copy Number Variations (CNVs) and we validated the NALCN gene sequence in each cell line. Additionally, we confirmed that both R1181Q and healthy controls differentiated into glutamatergic neurons via immunostainings. Preliminary evidence suggests that cells carrying the R1181Q variant show altered morphology and early maturation hyperexcitability. This shifts to a decrease in excitability, action potential peak amplitude, and a depolarized resting membrane potential upon prolonged maturation. Conclusion:We successfully established a human disease model for the NALCN R1181Q variant using hiPSCs. The R1181Q variant changes cell morphology, as well as passive and active membrane properties in patient-derived hiPSC neurons. We aim to further study the underlying disease-causing mechanism in fully differentiated neurons and eventually aim to restore WT-like function through the use of NALCN-specific modulators.
Translational Science Session 2:
NALCN Channelsome Models, Tools, & Disease
Session Moderator Stephan Pless, PhD October 10, 2025 4:00PM - 5:30PM
NALCN (R1181Q) Mutation
Reduces
Cerebellar Purkinje Cell Activity
Tian Du, PhD
of Toronto
Department of Physiology, Faculty of Medicine, University
Background: By conducting background Na+ leak, the NALCN channelosome regulate membrane excitability, which affects neuronal activity Gain-of-function (GOF) mutations in the currentconducting subunit NALCN cause CLIFAHDD, a neurodevelopmental disorder characterized by many symptoms including brain atrophy While the effect of these GOF mutations on exogenously reconstructed channel activity is well characterized, their physiology effect on neurons and neural networks, which are critical for understanding the cause and designing cures, are unclear. Method: We generated a mouse model that expression NACLN(R1181), a recurrent pathological form of the channelosome, in the Cerebellar Purkinje neuron. We targeted Purkinje neurons for following reasons: 1) Our RNA-seq. data identified Cerebellar Purkinje neuron highest and most consistent expression for genes encoding 4 NALCN channel subunits. This is consistent with Purkinje neurons being a tonically active fast-spiking neuron; 2) The cerebellum exhibits the most prominent atrophy in human patients; this is consistent with CLIFADD patients exhibit difficulty in motor balance. We then formed patch-clamp electrophysiology analyses on the Purkinje cells in acute cerebellar slices from 8-week-old mice to examine how R1181Q mutation affects their membrane properties and activity. Result: Consistent with GOF leading to increased Na+ leak of the exogenously reconstituted channel, we observed an increased inward leak currents and depolarized spontaneous membrane potential in R1181Q-expressing Purkinje cells. We found that this leads to strikingly reduced activity, where Purkinje cells cannot sustain spontaneous and evoked firing, likely due to the impaired afterhyperpolarization. Lastly, we showed preliminary data that a repurposed medicine rescues the electrophysiological phenotype in R1181Q-expressing Purkinje cells. Conclusion: Increase sodium leak is commonly assumed to lead to increase neuronal activity. We show that NALCN channel activity in fact differentially regulates neuronal excitability. Similar to what we have observed in C. elegans, this channel has a prominent role in tonically active neurons. CLIFAHDD-mutations impair cerebellar function, at least in part due to reduced Purkinje cell activity.
Translational Science Session 2:
NALCN Channelsome Models, Tools, & Disease
Session Moderator Stephan Pless, PhD October 10, 2025 4:00PM - 5:30PM
Julia Castro Genetic Counselor, UTHealth San Antonio
Carrie McGovern, Diana Duggan, BA
October 10, 2025 5:30PM - 6:00PM
Opening Remarks
Shayanne Martin, MPH
October 11, 2025 8:30AM - 9:00AM
Clinical Research/Therapy Development 1: NALCN Channel Related Disease
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 9:00AM - 10:30AM
Development of a Cellular Model for Pharmacological Screening of Compounds Targeting the NALCN Channelosome
Nattaya Thongsepee, PhD
Faculty of Medicine, Thammasat University, Thailand Institute of Functional Genomics, University of Montpellier, CNRS, Inserm, France
The sodium leak channel non-selective (NALCN) is a critical regulator of resting membrane potential and cellular excitability in neurons and endocrine cells. Gain-of-function de novo pathogenic variants in NALCN are linked to severe neurodevelopmental disorders characterized by a broad spectrum of symptoms. Partial inhibition of NALCN has been proposed as a potential therapeutic strategy; however, no selective pharmacological modulators have been identified to date. This lack of progress is largely due to the absence of a robust expression system compatible with high-throughput drug screening, as NALCN requires at least three auxiliary subunits for functionality and its constitutive expression is toxic to HEK293 cells. To address this challenge, we developed a multitransposon-based platform to generate HEK293 cell lines both wild-type and mutant that stably express the complete NALCN channelosome under inducible control. Using these novel cell lines, we have initiated the characterization of pharmacological properties of the NALCN channelosome, with several candidate molecules currently under extensive evaluation. Our work provides a foundational tool for the discovery of NALCN-targeting compounds and opens new avenues for therapeutic development not only for NALCN-associated neurodevelopmental disorders, but potentially also for conditions such as psychiatric disorders, chronic pain, and cancer.
Clinical Research/Therapy Development 1:
NALCN Channel Related Disease
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 9:00AM - 10:30AM
Discovering New Therapies for NALCN-Related Disease
Jeremy Tanner MD, MPH
Assistant Professor, UT Health San Antonio Chief Scientific Officer, Founder The Channeling Hope Foundation
Yaxia Yuan, PhD
Assistant Professor Associate Director of the Center for Innovative Drug Discovery Director of the Computer-Aided Drug Discovery Core, UT Health San Antonio
Background: De novo gain-of-function (GOF) mutations in NALCN cause CLIFAHDD, a severe neurodevelopmental disorder Preclinical studies suggest that inhibiting NALCN-GOF can mitigate disease phenotypes However, no treatments for CLIFAHDD or known selective NALCN inhibitors exist Our objective was to establish a drug discovery pipeline including high-throughput screening (HTS) to identify selective NALCN inhibitors as potential CLIFAHDD therapeutic candidates Methods: We established a multidisciplinary collaboration to develop a drug discovery pipeline For hit discovery, we designed a HTS model using a scalable HEK-293T cell line with stable, doxycyclineinducible expression of the NALCN channelosome We designed an assay to measure cell membrane depolarization using the DiBAC4(3) dye and evaluate the inhibitory capacity of compounds on the NALCN channelosome, with extracellular calcium (a non-selective NALCN inhibitor) as a positive control To assess the feasibility of structure-based drug discovery, we performed binding site prediction analyses using CavityPlus on published cryo-electron microscopy structures of the NALCN channelosome Results: We designed a drug discovery pipeline using HTS and virtual screening(VS) for hit discovery, analog screening for hit-to-lead optimization, and in vitro and in vivo characterization to identify lead therapeutic candidates(Figure 1) For HTS, we observed quantifiable cell depolarization after inducing NALCN expression, which was significantly inhibited by extracellular calcium We performed binding site analyses and identified two target binding sites for VS(Figure 2) We piloted this pipeline with a library of 1200 FDA-approved drugs We identified several potential NALCN inhibitors, including NK-1 receptor antagonists (eg, Aprepitant) In structural analyses, we confirmed binding of select hits at target sites Patch-clamp experiments confirmed Aprepitant's inhibition of NALCN currents C elegans models showed Aprepitant reduced phenotypes associated with NALCN-GOF Aprepitant showed a maximum inhibition of 41%, effectively reducing NALCN-GOF while potentially avoiding safety concerns from complete NALCN inhibition Conclusion: We designed a drug discovery pipeline for NALCN GOF inhibitors, including HTS with a scalable and inducible cell membrane depolarization model For initial proof of concept, we performed a drug repurposing screening of FDA-approved compounds and identified potential lead therapeutic candidates We will continue to use this pipeline to screen additional compound libraries to identify potential NALCN inhibitors and/or enhancers
Clinical Research/Therapy Development 1:
NALCN Channel Related Disease
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 9:00AM - 10:30AM
Pharmacological modulation of behavioral phenotypes associated with the NALCN
Donard Dwyer, PhD
Professor
and Vice-Chair
for Research Departments of Psychiatry, and Pharmacology, Toxicology and Neuroscience LSU Health Shreveport
The Na+-leak current channel (NALCN) is crucial for setting the resting membrane potential and controlling the response of excitable cells. Loss-of-function mutations in this channel produce akinesia and freezing reminiscent of Parkinson’s disease, whereas gain-of-function mutations cause hyperkinetic movements and CLIFAHDD – congenital limb and facial contractures, hypotonia and developmental delay. Previously, we identified a selective inhibitor of the NALCN that corrected behavioral phenotypes in Caenorhabditis elegans caused by a gain-of-function mutation. In limited structure-based screens, additional compounds/drugs have been found that likewise correct dystonic phenotypes in C. elegans. We have identified combinations of drugs with different modes of action that restore a normal phenotype to the mutant animals. Shared chemical features of the hits from limited screening may allow structure-based drug discovery to guide selection of compounds for further screening and to direct synthesis of novel NALCN inhibitors. This line of research offers hope of discovering therapeutic agents to address the movement disorders and behavioral features of CLIFAHDD and beyond.
Gene therapy primeropportunities & challenges
Deepa Rajan, MD, FAAP, FAAN
Associate Professor of Pediatrics Director, UPMC Children's Center for NeuroGenomics Director of Neurogenetics, UPMC Children's Hospital of Pittsburgh Director, Program for the Study of Neurodevelopment in Rare Disorders (NDRD)
Recorded Virtual Talk
Clinical Research/Therapy Development 2: Clinical Research
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 11:00AM - 12:00PM
Antonio Gil-Nagel Rein, MD, PhD
Co-Head of Neurology Department and Chief of the Epilepsy Program Ruber International Hospital
Recorded Virtual Talk
Clinical Research/Therapy Development 2: Clinical Research
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 11:00AM - 12:00PM
Congenital Contractures of the Limbs and Face,
Hypotonia,
and Developmental Delay (CLIFAHDD) syndrome: case series and systematic review
Background: Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the NALCN gene. While hallmark neurologic and musculoskeletal features are well described, the broader multisystem clinical spectrum, including gastrointestinal, respiratory, autonomic, and sleep-related involvement, remains incompletely characterized. Methods:Four individuals with CLIFAHDD were clinically characterized. A systematic review of molecularly confirmed CLIFAHDD cases was performed using PubMed, Scopus, and CINAHL databases, with additional screening of references and grey literature. Inclusion criteria were unique individuals with confirmed CLIFAHDD diagnosis due to NALCN mutation. Data from 102 total unique individuals were extracted using a standardized form. Features reported in ≥10% of cases and assessed in ≥15 patients were analyzed. Results:Clinical evaluations of four unique patients revealed key features of CLIFAHDD: global neurodevelopmental delay, hyperkinetic movement disorders, ataxia, autism spectrum disorders, irregular breathing, disrupted sleep, recurrent vomiting (possibly migraine-related), and clinical regression with progressive ataxia. In the systematic review, hallmark findings included hypotonia (85%, n=44/52), global neurodevelopmental delay (100%, n=69/69), distinct craniofacial features nasal abnormalities (98%, n=41/42), long philtrum (86%, n=24/28), micrognathia (87%, n=27/31), full cheeks (92%, n=22/24); and musculoskeletal contractures such as distal arthrogryposis (79%, n=37/47), camptodactyly (100%, n=36/36), ulnar deviation (100%, n=34/34), and clubfoot (67%, n=47/70). Neonatal complications included ventilatory support (42%, n=14/33), ICU care (53%, n=19/36), and feeding difficulties (81%, n=30/31). Neurologic features included movement disorders (75%, n=46/61), strabismus (65%, n=28/43), seizures (43%, n=23/53), autonomic dysfunction (90%, n=43/48), and ASD (34%, n=17/50). Gastrointestinal symptoms included feeding difficulties (92%, n=24/26), GERD (76%, n=41/54), constipation (76%, n=48/63), and recurrent vomiting (75%, n=27/36). Respiratory findings included irregular breathing (63%, n=24/38), respiratory insufficiency (47%, n=27/58), ventilatory support (24%, n=8/34), and central (38%, n=16/42) and obstructive (41%, n=17/42) apneas. Sleep disturbances included nocturnal arousals (54%, n=19/35) and other sleep issues (46%, n=26/56). Brain MRI was abnormal in 60% (n=30/50), with >90% showing cerebellar and cerebral atrophy. Conclusion:CLIFAHDD is a complex multisystem disorder. Broader recognition of nonneurologic manifestations is essential for comprehensive care and highlights the need for longitudinal, standardized phenotyping to guide future management and interventions.
Sandra Azareli Garcia Velazquez
UT Health San Antonio
Clinical Research/Therapy Development 2: Clinical Research
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 11:00AM - 12:00PM
A Comprehensive Overview of Drug Development: How to Plan for a Successful Program Execution Towards a Clinical Trial in an Ever-Evolving Landscape.
In this presentation, I will go over a brief but comprehensive overview of the drug development process, from modality selection to clinical trial initiation
UNC79-related disorders
Ismail A. Ibrahim, PT Department of Pediatrics, Danish Epilepsy Center, Dianalund, Denmark, Faculty of Health Science, Fenerbahce University, Istanbul, Turkey
Keynote Speaker:
Pangkong Fox, PhD Science Engagement Director, CACNA1A Foundation
“The Power of the Patient Community”
Saturday, October 11, 2025
Workshop: Translational Science Priorities
Facilitators Shayanne Martin MPH, Emily Durham, PhD October 11, 2025 2:00PM - 3:00PM
Progress on NALCN Channelosomopathies
Patient Led Science 1: Expert Roundtable
Daniel Calame, MD PhD Pediatrics Pediatric Neurology and Developmental Neurosciences Baylor College of Medicine Houston, TX
Session Moderator Jeremy Tanner, MD MPH October 11, 2025 3:15PM - 4:30PM
Daniel Calame, MD PhD Pediatrics Pediatric Neurology and Developmental Neurosciences Baylor College of Medicine Houston, TX
Julia Castro, Genetic Counselor UT Health San Antonio
Shayanne Martin, MPH Executive Director, The Channeling Hope Foundation Pangkonk Pox, PhD Science Engagement Director, CACNA1A Foundation
Poster Presentations
October 11, 2025 4:30PM - 5:30PM
Modeling hippocampus development in a dish
Sophia Carlson
Department
of Neuroscience, Developmental
Biology,
and Regenerative
The University of Texas at San Antonio, San Antonio, TX, USA
Background: The ability to mimic the development of distinct brain regions in a dish is crucial for studying how gene mutations impact early neuronal differentiation and circuit formation. Patientderived induced pluripotent stem cell (iPSC) organoids provide a unique platform to investigate how neural networks emerge differently in mutation backgrounds compared to controls. While several studies have focused on cortical and other brain regions, there are limited studies specifically addressing hippocampal development in vitro. Given the hippocampus’s central role in memory and cognition, establishing reliable hippocampal organoids is critical for modeling neurodevelopmental and neuropsychiatric disorders and for understanding how disease-linked mutations alter early circuit formation.
Methods: Using immunohistochemistry (IHC), we characterized three-dimensional hippocampal organoids generated from human iPSC lines. Fluorescent microscopy was employed to visualize and identify presumptive regions within the developing organoids.
Results: We observed robust expression of markers corresponding to the medial pallium and hippocampal primordium beginning at days 35 and 42, respectively. Expression of hippocampal precursor cells and dentate gyrus (DG) neurons was not detected within this timeframe, which aligns with reports that these populations typically emerge around day 60. As our cultures were analyzed up to day 42, this absence is consistent with expected developmental timing.
Conclusion: Our findings validate that iPSC-derived hippocampal organoids recapitulate early developmental hallmarks of hippocampal tissue, including medial pallium and hippocampal primordium marker expression. Although later-born populations such as hippocampal precursors and DG neurons were not yet observed, this is consistent with their known developmental timeline. Beyond validation, this system provides a foundation to assess the impact of gene mutations, including ARX and NALCN, on hippocampal development from its earliest stages. Furthermore, by fusing hippocampal organoids with ganglionic eminence organoids containing interneurons, this approach can be extended to model network formation and reveal how neural circuitry develops differently in patient-derived mutation models
Poster Presentations
October 11, 2025 4:30PM - 5:30PM
Recapitulating CLIFAHDD syndrome phenotypes in a mouse model of NALCN gain-of-function during cortical circuit development
The sodium (Na⁺)-leak channel (NALCN) is a non-selective ion channel essential for maintaining the neuronal resting membrane potential by conducting a background sodium leak current Pathogenic mutations in the NALCN channelosome complex (comprising NALCN, UNC80, and UNC79) are associated with rare developmental and epileptic encephalopathies Despite the frequent occurrence of developmental delay in NALCN-related disorders, the specific role of NALCN in brain development remains unclear We aimed to generate a mouse model of the CLIFAHDD syndrome with which we could investigate the role of Nalcn in cortical neural circuit formation To address this, we generated a conditional mouse model expressing a gain-of-function mutation of NALCN in forebrain GABAergic interneurons, using a Cre-loxP system We first determined whether gain-of-function of NALCN in GABAergic interneurons resulted in alterations of the neurogenesis and neuronal migration Ex vivo whole-cell patch-clamp recordings from distinct hippocampal interneuron subtypes revealed no significant changes in intrinsic excitability within CA1, despite the presence of the gain-of-function mutation However, behavioral assays demonstrated robust deficits across multiple tasks, indicating circuit-level dysfunction Finally, we explored the therapeutic potential of recently identified NALCN inhibitors to rescue behavioral phenotypes in this model Our findings reveal a previously unappreciated role for NALCN in GABAergic circuit maturation and function and provide mechanistic insights into NALCN-related channelopathies associated with gain-of-function such as CLIFAHDD syndrome In addition, these results underscore the potential of NALCN as a therapeutic target during critical periods of cortical development
Candela Barettino Instituto de Neurociencias CSICUMH, Alicante, Spain
Poster Presentations
October 11, 2025 4:30PM - 5:30PM
What Matters Most: Patient and Caregiver Priorities in NALCN-Related Diseases
Kezia Elizabeth Philip MD Candidate, Long School of Medicine
Background: NALCN-channel related diseases are ultra-rare neurodevelopmental conditions characterized by motor, cognitive, and physiological impairments Despite growing awareness of the genetic basis, there remains a critical gap in understanding the lived experiences, treatment priorities, and support needs of patients and their caregivers This project aims to develop and implement a comprehensive, patient-oriented outcomes survey to capture these perspectives We hypothesize that individuals affected by NALCN-channel related diseases and their caregivers will identify unmet needs in symptom management, communication support, and access to coordinated care; and treatment priorities will include neurodevelopmental delay, regression (ataxia), disrupted sleep, and respiratory related symptoms
Methods: A detailed, mixed method survey has been developed as a patient-centered needs assessment The assessment will collect data on quality of life, daily functioning, emotional wellbeing, symptom prioritization for treatment, and unmet needs The survey will be distributed to families and individuals affected by NALCN disorders
Results: Results are expected to highlight key quality-of-life impacts and reveal trends in caregiver priorities, including those not currently addressed in clinical care guidelines or research endpoints The results will be used to develop patient-centered outcomes for clinical trials
Conclusion: This project will provide the first structured dataset capturing the lived experiences and priorities of families affected by NALCN-channel related diseases Findings from this project will inform patient-centered research and therapeutic development for NALCN disorders and serve as an example for outcomes research in other ultra-rare neurogenetic conditions
Summary for the Community: This proposal aims to better understand the lived experiences and symptoms that are most impactful to individuals and families living with NALCN-channel related diseases To do so, we created a patient-oriented outcomes survey that is designed to identify critical patient and caregiver perspectives The results will guide the selection of meaningful outcomes for future clinical trials that reflect real-world needs of patients and caregivers Everyone’s voice will shape the future of
Poster Presentations
October 11, 2025 4:30PM - 5:30PM
Uncovering Mechanisms of Hyperexcitability in ARX Mutant Brain Organoids During Neurodevelopment
Sara Mirsadeghi Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX,
Background: Mutations in the ARX gene are associated with epilepsy and neurodevelopmental disorders, often leading to disrupted neural development and network dysfunction. Brain organoids, derived from human stem cells, provide a physiologically relevant three-dimensional model to study these mechanisms. Methods: We used three-dimensional multi-electrode array (3D-MEA) technology to assess neuronal activity in fused brain organoids composed of cortical (CO) and ganglionic eminence (GEO) regions. Organoids were generated from ARXPA2 mutant and isogenic control induced pluripotent stem cell (iPSC) lines and were either matched-fused (CO and GEO from the same genotype) or mixed-fused (mutant fused with isogenic control). This design enabled us to test whether the electrophysiological phenotype is cell autonomous. Results: ARXPA2 matched-fused organoids exhibited hallmark features of epileptiform activity, including increased burst rate, prolonged burst duration, and abnormal synchronization, reflecting a hyperexcitable network state Interestingly, mixed-fused organoids containing ARXPA2 COs reproduced the hyperactive phenotype, whereas those containing ARXPA2 GEOs showed reduced activity, suggesting impaired interneuron integration or synaptic connectivity Conclusion: While previous mouse studies have largely attributed ARX-related epilepsy to interneuron dysfunction, our findings suggest a complementary mechanism Specifically, pyramidal neuron–containing COs carrying the ARXPA2 mutation were sufficient to drive hyperexcitability, hypersynchrony, and prolonged burst activity, indicating that pyramidal neurons may play a more prominent role in driving the epileptic phenotype than previously recognized
Poster Presentations
October 11, 2025 4:30PM - 5:30PM
Uncovering Mechanisms of Hyperexcitability in ARX Mutant Brain Organoids During Neurodevelopment
Sara
Mirsadeghi
Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX,
Background: Mutations in the ARX gene are associated with epilepsy and neurodevelopmental disorders, often leading to disrupted neural development and network dysfunction. Brain organoids, derived from human stem cells, provide a physiologically relevant three-dimensional model to study these mechanisms. Methods: We used three-dimensional multi-electrode array (3D-MEA) technology to assess neuronal activity in fused brain organoids composed of cortical (CO) and ganglionic eminence (GEO) regions. Organoids were generated from ARXPA2 mutant and isogenic control induced pluripotent stem cell (iPSC) lines and were either matched-fused (CO and GEO from the same genotype) or mixed-fused (mutant fused with isogenic control). This design enabled us to test whether the electrophysiological phenotype is cell autonomous. Results: ARXPA2 matchedfused organoids exhibited hallmark features of epileptiform activity, including increased burst rate, prolonged burst duration, and abnormal synchronization, reflecting a hyperexcitable network state. Interestingly, mixed-fused organoids containing ARXPA2 COs reproduced the hyperactive phenotype, whereas those containing ARXPA2 GEOs showed reduced activity, suggesting impaired interneuron integration or synaptic connectivity. Conclusion: While previous mouse studies have largely attributed ARX-related epilepsy to interneuron dysfunction, our findings suggest a complementary mechanism. Specifically, pyramidal neuron–containing COs carrying the ARXPA2 mutation were sufficient to drive hyperexcitability, hypersynchrony, and prolonged burst activity, indicating that pyramidal neurons may play a more prominent role in driving the epileptic phenotype than previously recognized.
Opening Remarks
Suzanne Engel, Psy.D O t b 12 2025 8 30AM 9 00AM
Keynote Speaker:
Natasha Ludwig, PhD
Neuropsychologist, Program Director, Development
Neuropsychology Phenotyping Unit, Kennedy Krieger Institute, Assistant Professor of Psychiatry & Behavioral Science, Johns Hopkins University School of Medicine
“The critical role of patient engagement in the development of novel treatments for rare neurogenetic conditions”
Sunday, October 12, 2025
Patient Led Science 2: Community-Engaged Research & Advocacy
Jeremy Tanner MD, MPH Assistant Professor, UT Health San Antonio Chief Scientific Officer, Founder The Channeling Hope Foundation
Emily Durham, PhD The Channeling Hope Foundation
Shayanne Martin, MPH The Channeling Hope Foundation
Session Moderator Jeremy Tanner, MD MPH October 12, 2025 9:45AM - 10:15AM Jill Wahl The Channeling Hope Foundation
Workshop: Call to Action
Facilitators Shayanne Martin MPH, Jill Wahl, Emily Durham PhD
October 11, 2025 10:15AM - 11:30AM
Closing Remarks Jill Wahl, The Channeling Hope Foundation
October 12, 2025 11:30AM - 12:00PM
Sponsors
RARE WORDS TO KNOW
Glossary
CONFERENCE
Ataxia - Lack of coordination An inability to coordinate voluntary muscular movements that is symptomatic of some nervous disorders
Biomarkers - A measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure
Biorepository - stores de-identified samples for scientific research These samples can be easily shared throughout our science community reducing barriers to research and accelerating NALCN science
CLIFAHDD - a rare genetic disorder characterized by congenital contractures (stiff, bent joints) of the limbs and face, muscle weakness (hypotonia), and developmental delays, all caused by a de novo mutation in the NALCN gene Symptoms include a short neck, scoliosis, respiratory issues, poor speech, seizures, and distinct facial features, with brain abnormalities like atrophy seen in some patients
COMBINEDBrain - Non-profit organization devoted to speeding the path to clinical treatments for people with rare genetic neurological disorders
Comorbidity - The occurrence of two or more medical conditions simultaneously in one individual
Diagnostic odyssey - the significant diagnostic delay and misdiagnosis that is commonly faced by people when trying to achieve a diagnosis for a medical condition4
DNA (deoxyribonucleic acid) - contains the information for making and maintaining all living things, including people5
Etiology -The cause or origin of a disease or disorder
Gain of function variant - a genetic mutation that alters a gene product, leading to an enhanced or entirely new molecular function or a different pattern of gene expression, ultimately affecting disease phenotypes
Gene - Often referred to as the “unit of heredity.” A gene is composed of a sequence of DNA required to produce a functional protein.
Gene Therapy - a medical technique that involves introducing genetic material (DNA or RNA) into a person's cells to treat or prevent diseases. The goal of gene therapy is to modify or replace a defective gene or to introduce a new gene that can provide a therapeutic benefit.
RARE WORDS TO KNOW
Glossary
Genetic counselling - talking about a genetic condition with a health professional who has qualifications in both genetics and counsellingGenetic counselling can help you understand more about an inherited condition (a condition passed down from one or both parents) and what causes it
Genetic Variant - a naturally occurring difference in a DNA sequence compared to a population's common reference sequence, making each person unique
Genetic variant of uncertain significance - is a genetic variant identified in the DNA of an individual with a health condition but it is not yet known if the variant causes or contributes to that health condition
Genetics - ‘the study of how genes work and transmit information from parents to offspring It can help us understand the risk of inheriting a genetic disease’
Genomic testing - allows the investigation of vast amounts of the genetic sequence (testing of many genes or the entire genome) at once This is used when there are several genes associated with a condition, or when the causal gene is unknown
Genomics - ‘the study and mapping of genomes – the full set of genetic instructions for an organism It includes both human and other genomes and how these interact with the environment Genomics can help doctors identify and diagnose genetic disorders and rare diseases, develop prevention strategies and tailor a patient’s treatment’
Genotype - the specific set of alleles (versions of a gene) an individual carries, determining its specific genetic makeup for a given trait, such as the alleles for eye color In simpler terms, it's the inherited genetic instructions from parents that influence an organism's observable characteristics, known as its phenotype
Global Genes - Non-profit organization working to eliminate the daily challenges for 1 in 10people affected by rare disease
Homeostasis - the tendency toward a relatively stable equilibrium
Idiopathic - A condition where the underlying cause is unknown.
Incidence/Prevalence - Measures of how many new cases of a disease occur (incidence) or how many people have the disease at a given time (prevalence).
RARE WORDS TO KNOW
Glossary
Inhibitors - a substance which slows down or prevents a particular chemical reaction or other process or which reduces the activity of a particular reactant, catalyst, or enzyme
iPSC - induced pluripotent stem cells - which are adult cells artificially reprogrammed to a "stem cell-like" state, allowing them to differentiate into virtually any other cell type in the body
Loss of function variant - the reduced or completely abolished activity of a gene, protein, or body part, often due to a genetic mutation or cellular damage
Missense variants - a type of DNA substitution that changes a single amino acid in a protein, potentially altering the protein's function
NALCN - Sodium leak channel playing a central role in setting the resting membrane potential and regulating electrical activity
Natural History Study - Tracks the progression of a disease over time to understand how NALCNrelated conditions affect patients This information is important for developing treatments
Neurodevelopmental Disorder - conditions that affect the development and function of the brain, leading to impairments in various areas of cognitive, motor, and social functioning
Nonsense variants - a type of genetic change that results in a DNA sequence being prematurely read as a stop codon, causing protein synthesis to terminate early
NORD - National Organization for Rare Disease
Once Upon a Gene podcast - Podcast for families living with rare disease There are personal stories and resources shared to help connect us with our community
ORPHAcodes are the Orphanet nomenclature of rare diseases – a unique, time-stable and nonreusable numerical identifier for a rare diseaseThey are recognised as the most appropriate nomenclature for clinical coding of rare diseases in Europe.
Orphan Drug - A medication developed for treating rare diseases.
RARE WORDS TO KNOW
Glossary
Patient Registry - a systematic collection of data on individuals with a specific disease, condition, or treatment
Phenotype - observable traits, including its physical appearance, behavior, and biochemical properties, that result from the interaction between its genetic makeup (genotype) and environmental factors
Prognosis - The predicted course or outcome of a disease
Rare diseases – A disease is considered rare if it affects fewer than, or equal to, 5 in 10, 000 people
Registry - A collection of standardized information about a group of patients with a shared condition or health experience
Stem Cell - undifferentiated cells that can divide to create more stem cells (self-renew) and can differentiate into specialized cells, like muscle or nerve cells, to form all the different tissues and organs in the body
Syndrome - A group of symptoms that consistently appear together, or a condition characterized by a cluster of associated symptoms
