Frizzle (FRRS1L) Research
ASGCT 2026 Abstracts and Posters
Title: Understanding the lived experience of FRRS1L disorder: A qualitative study from the caregiver and clinician perspective
Introduction: Ferric Chelate Reductase 1 Like (FRRS1L) disorder is a rare genetic neurodevelopmental disease caused by loss-of-function mutations in the FRRS1L gene, characterized by global developmental delay, hyperkinetic movements, refractory seizures, and developmental regression with gross loss of function and abilities. FRRS1L disorder involves a rapid loss of abilities (typically referred to as regression) around two years of age and leads to severe lifelong disability. Treatment options are ineffective and limited to symptom management and supportive care. There is limited published research into the lived experience of the condition. This qualitative study aimed to characterize the patient experience of FRRS1L disorder from the perspective of caregivers and clinicians, and to summarize key signs/symptoms, and health-related quality of life (HRQoL) and functional impacts in a patient-centric conceptual model.
Parent-Led Therapeutic Development: A Patient-Driven Model for Faster, More Collaborative Rare Disease Treatment Progress
Introduction: The voice of the rare disease community is growing louder, more unified, and increasingly urgent in its call for change. The public is taking notice, the news is now covering it, patients are emboldened, and some venders are helping, but it’s the institutions and scientists that need to hear and respond with change. This collective voice is clear: the current approach to treatment development must evolve in order to move the field forward. Chrissy Green, Co-Founder and Co-President of Finding Hope for FRRS1L, a parent-led patient advocacy foundation, is among the leaders driving this shift. She has guided her small, parent-led rare disease organization to take ownership of its therapeutic program—comprehensively restructuring the development strategy to accelerate timelines and reduce costs, all with the goal of delivering treatment to patients more efficiently. Green advocates for a model in which parent leaders remain firmly in the driver’s seat of treatment development, supported by the right scientific, clinical, and industry partners who provide expertise and guidance along the way. She has spoken to targeted audiences of researchers and scientists on this approach and is helping to pioneer a more collaborative and effective framework for engagement between parent advocacy groups, researchers, and industry partners. Her message is specifically tailored to scientists, researchers, and industry stakeholders, emphasizing the need for partnership models that are both patient-driven and scientifically rigorous. Change is underway, but meaningful progress will only occur if the path forward empowers patients and caregivers to lead. It is time for industry to listen, learn, and adapt so that science and treatment development can move forward more effectively.
Establishing scalable TfR1 CapX manufacturing platform to accelerate multiple CNS gene therapy programs
Introduction: The clinical translation of novel AAV capsids is frequently constrained not by biological performance, but by Chemistry, Manufacturing, and Controls (CMC) readiness, including scalability, comparability, and access to clinical-grade starting materials. These factors can become rate-limiting for IND submission when nonclinical and clinical manufacturing approaches diverge, when scale-up introduces unplanned changes to process or control strategy, or when critical starting materials are not available in forms suitable for clinical manufacturing.
Poster here.
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FRRS1L Mouse Model and Gene Replacement Therapy Research
Note: Finding Hope for Frizzle (FRRS1L) funded pre-clinical research for FRRS1L mouse modeling and gene replacement therapy at the University of Texas Southwestern (UTSW). At this time data from that study is under manuscript review and pending publication.
An ER Assembly Line of AMPA-Receptors Controls Excitatory Neurotransmission and Its Plasticity
Jochen Schwenk1,6 ∙ Sami Boudkkazi1,6 ∙ Maciej K. Kocylowski1,6 ∙ Aline Brechet1 ∙ Gerd Zolles1 ∙ Thorsten Bus3 ∙ Kaue Costa4 ∙ Astrid Kollewe1 ∙ Johannes Jordan1 ∙ Julia Bank1 ∙ Wolfgang Bildl1 ∙ Rolf Sprengel3 ∙ Akos Kulik1,2 ∙ Jochen Roeper4 ∙ Uwe Schulte1,2,5 ∙ Bernd Fakler1,2,7
Summary:
Excitatory neurotransmission and its activity-dependent plasticity are largely determined by AMPA-receptors (AMPARs), ion channel complexes whose cell physiology is encoded by their interactome. Here, we delineate the assembly of AMPARs in the endoplasmic reticulum (ER) of native neurons as multi-state production line controlled by distinct interactome constituents: ABHD6 together with porcupine stabilizes pore-forming GluA monomers, and the intellectual-disability-related FRRS1l-CPT1c complexes promote GluA oligomerization and co-assembly of GluA tetramers with cornichon and transmembrane AMPA-regulatory proteins (TARP) to render receptor channels ready for ER exit. Disruption of the assembly line by FRRS1l deletion largely reduces AMPARs in the plasma membrane, impairs synapse formation, and abolishes activity-dependent synaptic plasticity, while FRRS1l overexpression has the opposite effect. As a consequence, FRSS1l knockout mice display severe deficits in learning tasks and behavior. Our results provide mechanistic insight into the stepwise biogenesis of AMPARs in native ER membranes and establish FRRS1l as a powerful regulator of synaptic signaling and plasticity.
Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy
Madeo M., Stewart M., Sun Y., Sahir N., Wiethoff S., Chandrasekar I., Yarrow A., Rosenfeld J. A., Yang Y., Cordeiro D. et al. (2016). Loss-of-function mutations in FRRS1L lead to an epileptic-dyskinetic encephalopathy. Am. J. Hum. Genet. 98, 1249-1255. 10.1016/j.ajhg.2016.04.008
Abstract:
Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
Shaheen R., Al Tala S., Ewida N., Abouelhoda M. and Alkuraya F. S. (2016). Epileptic encephalopathy with continuous spike-and-wave during sleep maps to a homozygous truncating mutation in AMPA receptor component FRRS1L. Clin. Genet. 90, 282-283. 10.1111/cge.12796
AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability
Aline Brechet 1, Rebecca Buchert 2, Jochen Schwenk 1 3, Sami Boudkkazi 1, Gerd Zolles 1, Karine Siquier-Pernet 4, Irene Schaber 1, Wolfgang Bildl 1, Abdelkrim Saadi 5, Christine Bole-Feysot 4, Patrick Nitschke 4, Andre Reis 2, Heinrich Sticht 6, Nouriya Al-Sanna'a 7, Arndt Rolfs 3 8, Akos Kulik 1 3, Uwe Schulte 1 3 9, Laurence Colleaux 4, Rami Abou Jamra 2 10, Bernd Fakler 1 3
Abstract:
AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.
Emerging Monogenic Complex Hyperkinetic Disorders
Miryam Carecchio 1 2 3, Niccolò E Mencacci 4 5
Abstract
Purpose of review: Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.
Recent findings: Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,. Thanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.
Michelle Stewart 1, Petrina Lau 1, Gareth Banks 1, Rasneer Sonia Bains 1, Enrico Castroflorio 1, Peter L Oliver 1, Christine L Dixon 2, Michael C Kruer 3, Dimitri M Kullmann 2, Abraham Acevedo-Arozena 4 5 6, Sara E Wells 1, Silvia Corrochano 7, Patrick M Nolan 7
Abstract
Loss-of-function mutations in a human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies has implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive, irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic (EEG) recordings also revealed abnormal EEG results in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged, with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 (also known as GRIA2) and GLUA4 (also known as GRIA4) AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling, and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.This article has an associated First Person interview with the first author of the paper.
Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements
Imane Abdelmoumen, Sandra Jimenez, Ignacio Valencia, Joseph Melvin, Agustin Legido, Mayela M. Diaz-Diaz, Christopher Griffith, Lauren J. Massingham, Melissa Yelton, Janice Rodríguez-Hernández, Rhonda E. Schnur, Laurence E. Walsh, Ana G. Cristancho, Christina A. Bergqvist, Kirsty McWalter, Iain Mathieson, Gillian M. Belbin, Eimear E. Kenny, Xilma R. Ortiz-Gonzalez, Michael C. Schneider
Abstract
Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
Abstract
Loss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l -/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l -/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l -/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in an increased proportion of immature AMPA receptors, indicated by incomplete glycosylation of GLUA2 and GLUA4 AMPA receptor proteins. This incomplete maturation leads to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.