RARE DISEASE
Lafora disease
Lafora disease
Lafora disease
Synonyms: EPM2, PME type 2, Progressive myoclonic epilepsy type 2, Progressive myoclonus epilepsy type 2
Synonyms: EPM2, PME type 2, Progressive myoclonic epilepsy type 2, Progressive myoclonus epilepsy type 2
Synonyms: EPM2, PME type 2, Progressive myoclonic epilepsy type 2, Progressive myoclonus epilepsy type 2
Drug discovery
5
drugs
With orphan designations
Overview
Lafora disease is a rare, autosomal recessive progressive myoclonus epilepsy caused by EPM2A or NHLRC1 mutations, leading to toxic glycogen-derived Lafora body accumulation in neurons [1][2][12]. It manifests in adolescence with drug-resistant seizures, myoclonus, cognitive decline, and rapid neurological deterioration, typically resulting in death within 10 years of onset [1][5][15].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
203 drug discovery papers about Lafora disease, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
203 drug discovery papers about Lafora disease, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-12-25 | The biochemical dynamics of the glycogen phosphatase laforin directly impact brain metabolism.
Laforin is the only known glycogen phosphatase. Mutations in the laforin gene lead to the fatal childhood dementia and progressive myoclonic epilepsy known as Lafora disease (LD). A hallmark of LD is aberrant, cytoplasmic, glycogen-like aggregates known as Lafora bodies. Surprisingly, recent reports indicate that overexpression of a phosphatase-deficient laforin mutant, with the catalytic cysteine mutated to serine (LCS), prevented the formation of Lafora bodies in a laforin KO mouse model. This finding led to questions regarding the biological relevance of laforin phosphatase activity and its role in LD etiology. In this study, we defined the in vitro and in vivo effects of the LCS mutation. LCS protein lacks catalytic activity but exhibits significantly higher binding to phosphate and long glucan chains compared with WT laforin. In addition, LCS exhibits altered dynamics via hydrogen-deuterium exchange mass spectrometry and interacts more robustly with its binding partners malin and protein targeting to glycogen. We demonstrate that these altered dynamics result in aberrant retention of the LCS protein in the brain of the LCS knock-in mouse model, compared with laforin levels in WT mice. To examine the metabolic consequences of these biophysical changes, we compared the brain metabolomic phenotypes of LCS mice to WT and laforin KO mice. Furthermore, LCS mice display a distinct and significant global perturbation in metabolism. These results indicate a key signaling role for glycogen phosphorylation in glycogen metabolism, revealing an important biological role for laforin catalytic phosphatase activity.
2025-12-02 | New therapeutic strategies for Lafora disease: Evaluation of the safety, efficacy, pharmacokinetics and metabolomic profile of intravenous VAL-1221 treatment.
Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in EPM2A or NHLRC1, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug - VAL-1221, a glycogen-degrading antibody-enzyme fusion - in LD patients through a 12-month compassionate use program. Five patients (aged 17-24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.
2025-09-21 | Assessment of the potential use of VAL-1221 for Lafora disease: MS-based proteomics for the characterization and quantitation of the biotechnological drug in plasma and cerebrospinal fluid
ABSTRACT Background VAL-1221 is a biotechnological fusion protein that combines the Fab portion of a cell-penetrating antibody with recombinant human acid α-glucosidase. Originally used for the treatment of Pompe disease, it has since attracted interest for possible repurposing in Lafora disease (LD), an ultra-rare, fatal form of progressive myoclonus epilepsy characterized by the accumulation of polyglucosan aggregates (Lafora bodies, LBs) within the central nervous system (CNS). Given its design, which includes a cell-penetrating domain, VAL-1221 has been hypothesized to cross the blood–brain barrier (BBB) and target pathogenic glycogen deposits within the CNS in LD. This study aimed to investigate the presence of VAL-1221 in plasma and cerebrospinal fluid (CSF) of LD patients and assess its potential to cross the BBB, using high-resolution mass spectrometry coupled with micro-liquid chromatography (microLC-HRMS/MS). Methods As part of a compassionate use program, five LD patients received intravenous VAL-1221 (20 mg/kg, every other week). LD untreated patients were included as controls. Plasma samples were collected at multiple time points up to 24 hours post-infusion, and CSF samples were obtained based on concentration profiles. Untargeted-to-targeted bottom-up proteomics were used to detect a unique peptide tag in biological fluids. Method validation included assessments of precision, accuracy, matrix effects, and analyte stability. Results VAL-1221 was consistently detected in plasma up to 4 hours post-infusion, while no VAL-1221 was detected in CSF samples with the method’s limit of detection. The validated method showed high sensitivity, precision (RSD ≤15%), accuracy (RE ≤15%), and acceptable matrix effect. Recovery was optimal for CSF; it was low in plasma (Rec% > ±20). Conclusion VAL-1221 was reliably detected in plasma after infusion, but no measurable levels were observed in CSF based on the validated method’s sensitivity. These findings suggest that the drug, when administered intravenously, may not reach the central nervous system, indicating that this route may not be appropriate for efficacy.
2024-05-01 | Treating Lafora Disease with an Antibody-Enzyme Fusion
Abstract Lafora disease (LD) is a horrendous progressive myoclonic epilepsy that strikes healthy teenagers and leads to ever-worsening seizures with no relief from antiepileptic drugs; it then transitions to rapid dementia that ends in death typically after 10 years of onset. LD is the result of mutations in either the EPM2A or EPM2B/NHLRC1 gene that encodes the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, respectively. A hallmark of LD is cytoplasmic, aberrant glycogen-like aggregates called Lafora bodies (LBs); thus, LD is also classified as a glycogen storage disease (GSD). Using LD mouse models, multiple laboratories definitively demonstrated that genetic reduction or elimination of glycogen synthesis decreased LB formation and rescued LD epilepsy, neurodegeneration, and brain inflammation. Thus, LBs are the etiological driver of LD. An antibody-enzyme fusion (AEF) was developed that ablates LBs and normalizes both cell signaling and brain metabolism. This AEF is a promising drug for the treatment of LD and other GSDs as well as a putative therapeutic platform for targeting other neurodegenerative diseases.
2024-02-23 | Effect of intracerebroventricular administration of alglucosidase alfa in two mouse models of Lafora disease: Relevance for clinical practice.
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A, encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a-/- knock-out and Epm2aR240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a-/- and Epm2aR240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a-/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease.
small molecules
2026-06-08 | Polypharmacy's paradox: accelerated decline in a rare case of Lafora body disease.
Lafora body disease (LBD) is a rare autosomal recessive progressive myoclonic epilepsy characterized by neurodegene-ration due to an intracellular accumulation of poorly branched polyglucosan inclusions. Effective pharmacological management remains challenging due to the risk of drug-induced exacerbation of symptoms and adverse interactions. We present the case of an 18-year-old male with intractable seizures, myoclonus, and cognitive regression. Electroencephalogram showed frequent generalized polyspike discharges, and histopathology confirmed Lafora bodies. The patient was initially prescribed a broad polypharmacy regimen including sodium valproate, carbamazepine, phenytoin, and phenobarbitone - leading to detrimental pharmacokinetic and pharmacodynamic interactions, worsening his neurological status. A stepwise revision with withdrawal of contraindicated agents and rational introduction of levetiracetam, clobazam, and perampanel improved seizure control and alertness. This case highlights the hazards of unstructured polypharmacy in LBD and stresses the need for individualized pharmacotherapy. Novel disease-modifying options like metformin, targeting glycogen metabolism, offer future therapeutic potential in altering disease trajectory.
2025-12-18 | Neuronal hyperexcitability: A key to unraveling hippocampal synaptic dysfunction in Lafora disease.
Lafora disease (LD) is a rare progressive disorder caused by mutations in the EPM2A or EPM2B genes, characterized by the accumulation of Lafora bodies, drug-resistant epilepsy, and cognitive decline. To investigate the early molecular mechanisms of LD, we studied electrophysiological changes in the dentate gyrus (DG) of the Epm2aR240X knock-in mouse model at various ages. Electrophysiological recordings measured neuronal membrane properties, epileptic-like activity, epileptic thresholds, and synaptic plasticity in Epm2aR240X mice at 1, 3, and 12 months. We also employed Periodic Acid-Schiff (PAS) diastase staining, immunofluorescence, and Western blotting to detect Lafora bodies, amyloid beta deposition, and the expression of glutamate receptor subunits. Epileptic-like activity began at 1 month and intensified with age. Aberrant long-term potentiation (LTP) appeared at 3 months and worsened by 12 months. Notably, cannabidiol treatment reduced excitability and restored LTP in older mice, suggesting its potential therapeutic value. The reversibility of synaptopathy, even at advanced stages, reinforces the importance of early detection of hyperexcitability and the development of effective therapeutic approaches.
2025-11-05 | HIGH-AFFINITY BINDING OF DAPAGLIFLOZIN TO HUMAN GYS1: A STRUCTURE-BASED REPURPOSING STRATEGY FOR LAFORA DISEASE
Lafora disease (LD) is a rare progressive myoclonic epilepsy that begins in adolescence and is characterized by epileptic seizures, psychomotor regression, muscle weakness, progressive dementia, and premature death. In its pathogenesis, Lafora bodies, composed of poorly branched polyglycosan structures, accumulate primarily in neurons, as well as in the liver, muscle, and exocrine glands. Mutations in EPM2A (laforin) or NHLRC1 (malin) disrupt glycogen phosphorylation/branching control, leading to loss of glycogen structural integrity and pathological polyglycosan accumulation. In this context, GYS1, the rate-limiting enzyme of glycogen synthesis, plays a critical role in the pathophysiology of LD. Inhibiting GYS1 is a rational pharmacological strategy for suppressing polyglycosan accumulation and slowing neurodegeneration. In this study, using the high-resolution cryo-EM structure of the human GYS1–GYG1 complex (PDB: 7Q13), which represents the substrate-bound conformation of GYS1, the binding potential of 20 approved drugs to the GYS1 enzyme was evaluated using a drug repurposing approach. Docking simulations were performed with AutoDock Vina. It was determined that compounds with glycosidic skeletons (dapagliflozin, empagliflozin, acarbose), which can deeply dock into the glucose subpocket, tended to have higher affinity, while uridine/pyrimidine analogs, due to their inability to fully mimic the pyrophosphate coordination site, exhibited moderate to low binding. Among the drugs, dapagliflozin achieved the highest binding score. These findings suggested that dapagliflozin could be a prime candidate for therapeutic inhibition of GYS1.
2025-07-21 | Use of cannabidiol in the management of refractory seizures in Lafora disease A case report of two siblings
Disease (LD) is a rare autosomal recessive glycogen storage disorder characterized by Progressive Myoclonic Epilepsy (PME) and neurodegeneration, typically manifesting in adolescence.
2025-05-30 | Case report of Lafora disease: a rare genetic disorder manifesting as progressive myoclonic epilepsy.
Lafora disease (LD) is a rare, autosomal recessive progressive myoclonic epilepsy caused by mutations in EPM2A or EPM2B. It is characterized by abnormal glycogen metabolism leading to poly-glucosan deposits, known as Lafora bodies, in various tissues. LD typically manifests during adolescence with progressive neurological decline, including myoclonic seizures, cognitive impairment, and ataxia. Early diagnosis is critical for symptom management, yet the disease remains challenging to treat due to its refractory nature. We report the case of a 15-year-old male who initially presented with tonic-clonic and myoclonic seizures, bilateral lower limb paralysis, and hand tremors. Despite normal initial imaging findings, subsequent clinical progression raised suspicion for progressive myoclonic epilepsy. Genetic testing identified a homozygous pathogenic variant in EPM2A, confirming the diagnosis of LD. electroencephalogram (EEG) findings evolved over time, showing generalized spikes, poly-spikes, and spike-wave complexes on a slow background, consistent with advanced LD. The patient's seizures proved refractory to standard anti-epileptic drugs, necessitating the addition of phenobarbital, metformin, and zonisamide, which eventually achieved partial seizure control. Family genetic screening identified heterozygous carriers without clinical symptoms, emphasizing the need for genetic counseling. This case highlights the diagnostic challenges of LD, particularly in its early stages when clinical and imaging findings may be nonspecific. The report underscores the importance of genetic testing in confirming the diagnosis and tailoring management strategies. Despite limited treatment options, individualized multi-drug regimens may help achieve partial symptom control. Early recognition and comprehensive management, including family counseling, are essential in improving quality of life for patients and their families.
gene therapies
2026-03-01 | When gene replacement becomes a double-edged sword: Guardrails for precision neurotherapeutics in Lafora disease
Lafora disease (LD) is a paradigmatic progressive myoclonus epilepsy characterized by adolescent onset, refractory seizures, action- and stimulus-sensitive myoclonus, cognitive decline, and premature death. The pathological hallmark of the disease is the slow accumulation of poorly branched, insoluble glycogen aggregates, known as Lafora bodies (LBs), which progressively disrupt neuronal metabolism, trigger neuroinflammation, and ultimately drive neurodegeneration [1,2]. Importantly, the clinical course of LD is typically stereotyped and slowly progressive, unfolding over several years with a relatively predictable trajectory [3].
2025-12-30 | Adeno-Associated Virus-Based Gene Therapy for Lafora Disease in Epm2b-Deficient Mice.
Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in the EPM2A or EPM2B genes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption of Epm2a or Epm2b in mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues. Epm2a-/- and Epm2b-/- mice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carrying EPM2A significantly improved pathology in Epm2a-/- mice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the human EPM2B gene in Epm2b-/- mice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between EPM2A- and EPM2B-based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targeting EPM2B mutations in Lafora disease.
2025-11-12 | Lafora disease ( NHLRC1 ) associated with multiple malformations of cortical development: A clinical vignette
The authors declare no conflicts of interest related to this work. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-05-12 | [Progressive Myoclonus Epilepsy: Diversity of Disorders and Key Points in Clinical Practice].
Progressive myoclonic epilepsies (PMEs) are a group of disorders characterized by progressive (1)myoclonus, (2)myoclonic and generalized tonic-clonic seizures, (3)cerebellar symptoms, and (4)cognitive decline. PMEs encompass various genetic disorders, including dentatorubral-pallidoluysian atrophy, benign adult familial myoclonus epilepsy, myoclonic epilepsy with ragged-red fibers, Unverricht-Lundborg disease, and Lafora disease. The diagnosis is based on clinical symptoms, inheritance patterns, electrophysiological findings, and genetic or pathological tests. Treatment for PMEs remains primarily symptomatic for seizures and myoclonus, although perampanel has reportedly improved epileptic symptoms with rational pharmacological properties. This review highlights the clinical features, genetic bases, and diagnostic and therapeutic advancements in PMEs, offering a comprehensive overview of this challenging and diverse group of disorders.
2025-02-02 | Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.
Because children have little temporal exposure to environment and aging, most pediatric neurological diseases are inherent, i.e. genetic. Since postnatal neurons and astrocytes are mostly non-replicating, gene therapy and genome editing present enormous promise in child neurology. Unlike in other organs, which are highly permissive to adeno-associated viruses (AAV), the mature blood-brain barrier (BBB) greatly limits circulating AAV distribution to the brain. Intrathecal administration improves distribution but to no more than 20% of brain cells. Focused ultrasound (FUS) opens the BBB transiently and safely. In the present work we opened the hippocampal BBB and delivered a Cas9 gene via AAV9 intrathecally. This allowed brain first-pass, and subsequent vascular circulation and re-entry through the opened BBB. The mouse model used was of Lafora disease, a neuroinflammatory disease due to accumulations of misshapen overlong-branched glycogen. Cas9 was targeted to the gene of the glycogen branch-elongating enzyme glycogen synthase. We show that FUS dramatically (2000-fold) improved hippocampal Cas9 distribution and greatly reduced the pathogenic glycogen accumulations and hippocampal inflammation. FUS is in regular clinical use for other indications. Our work shows that it has the potential to vastly broaden gene delivery or editing along with clearance of corresponding pathologic basis of brain disease.
oligonucleotides
2023-09-12 | Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model
Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.
2021-11-01 | Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity.
Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition. The hallmark of LD is the accumulation of aberrant glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Impeding glycogen synthesis from early embryonic stages by genetic suppression of glycogen synthase (MGS) in an animal model of LD prevents LB formation and ultimately the pathological manifestations of LD thereby indicating that LBs are responsible for the pathophysiology of the disease. However, it is not clear whether eliminating glycogen synthesis in an adult animal after LBs have already formed would halt or reverse the progression of LD. Herein we generated a mouse model of LD with inducible MGS suppression. We evaluated the effect of MGS suppression at different time points on LB accumulation as well as on the appearance of neuroinflammation, a pathologic trait of LD models. In the skeletal muscle, MGS suppression in adult LD mice blocked the formation of new LBs and reduced the number of glycogen aggregates. In the brain, early but not late MGS suppression halted the accumulation of LBs. However, the neuroinflammatory response was still present, as shown by the levels of reactive astrocytes, microglia and inflammatory cytokines. Our results confirm that MGS as a promising therapeutic target for LD and highlight the importance of an early diagnosis for effective treatment of the disease.
2021-02-11 | Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease
Abstract Lafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in the disease’s mouse models. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene ( Gys1 ). We administered Gys1-ASO by intracerebroventricular injection and analyzed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.
proteins
2025-12-25 | The biochemical dynamics of the glycogen phosphatase laforin directly impact brain metabolism.
Laforin is the only known glycogen phosphatase. Mutations in the laforin gene lead to the fatal childhood dementia and progressive myoclonic epilepsy known as Lafora disease (LD). A hallmark of LD is aberrant, cytoplasmic, glycogen-like aggregates known as Lafora bodies. Surprisingly, recent reports indicate that overexpression of a phosphatase-deficient laforin mutant, with the catalytic cysteine mutated to serine (LCS), prevented the formation of Lafora bodies in a laforin KO mouse model. This finding led to questions regarding the biological relevance of laforin phosphatase activity and its role in LD etiology. In this study, we defined the in vitro and in vivo effects of the LCS mutation. LCS protein lacks catalytic activity but exhibits significantly higher binding to phosphate and long glucan chains compared with WT laforin. In addition, LCS exhibits altered dynamics via hydrogen-deuterium exchange mass spectrometry and interacts more robustly with its binding partners malin and protein targeting to glycogen. We demonstrate that these altered dynamics result in aberrant retention of the LCS protein in the brain of the LCS knock-in mouse model, compared with laforin levels in WT mice. To examine the metabolic consequences of these biophysical changes, we compared the brain metabolomic phenotypes of LCS mice to WT and laforin KO mice. Furthermore, LCS mice display a distinct and significant global perturbation in metabolism. These results indicate a key signaling role for glycogen phosphorylation in glycogen metabolism, revealing an important biological role for laforin catalytic phosphatase activity.
2025-12-02 | New therapeutic strategies for Lafora disease: Evaluation of the safety, efficacy, pharmacokinetics and metabolomic profile of intravenous VAL-1221 treatment.
Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in EPM2A or NHLRC1, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug - VAL-1221, a glycogen-degrading antibody-enzyme fusion - in LD patients through a 12-month compassionate use program. Five patients (aged 17-24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.
2025-09-21 | Assessment of the potential use of VAL-1221 for Lafora disease: MS-based proteomics for the characterization and quantitation of the biotechnological drug in plasma and cerebrospinal fluid
ABSTRACT Background VAL-1221 is a biotechnological fusion protein that combines the Fab portion of a cell-penetrating antibody with recombinant human acid α-glucosidase. Originally used for the treatment of Pompe disease, it has since attracted interest for possible repurposing in Lafora disease (LD), an ultra-rare, fatal form of progressive myoclonus epilepsy characterized by the accumulation of polyglucosan aggregates (Lafora bodies, LBs) within the central nervous system (CNS). Given its design, which includes a cell-penetrating domain, VAL-1221 has been hypothesized to cross the blood–brain barrier (BBB) and target pathogenic glycogen deposits within the CNS in LD. This study aimed to investigate the presence of VAL-1221 in plasma and cerebrospinal fluid (CSF) of LD patients and assess its potential to cross the BBB, using high-resolution mass spectrometry coupled with micro-liquid chromatography (microLC-HRMS/MS). Methods As part of a compassionate use program, five LD patients received intravenous VAL-1221 (20 mg/kg, every other week). LD untreated patients were included as controls. Plasma samples were collected at multiple time points up to 24 hours post-infusion, and CSF samples were obtained based on concentration profiles. Untargeted-to-targeted bottom-up proteomics were used to detect a unique peptide tag in biological fluids. Method validation included assessments of precision, accuracy, matrix effects, and analyte stability. Results VAL-1221 was consistently detected in plasma up to 4 hours post-infusion, while no VAL-1221 was detected in CSF samples with the method’s limit of detection. The validated method showed high sensitivity, precision (RSD ≤15%), accuracy (RE ≤15%), and acceptable matrix effect. Recovery was optimal for CSF; it was low in plasma (Rec% > ±20). Conclusion VAL-1221 was reliably detected in plasma after infusion, but no measurable levels were observed in CSF based on the validated method’s sensitivity. These findings suggest that the drug, when administered intravenously, may not reach the central nervous system, indicating that this route may not be appropriate for efficacy.
2024-05-01 | Treating Lafora Disease with an Antibody-Enzyme Fusion
Abstract Lafora disease (LD) is a horrendous progressive myoclonic epilepsy that strikes healthy teenagers and leads to ever-worsening seizures with no relief from antiepileptic drugs; it then transitions to rapid dementia that ends in death typically after 10 years of onset. LD is the result of mutations in either the EPM2A or EPM2B/NHLRC1 gene that encodes the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, respectively. A hallmark of LD is cytoplasmic, aberrant glycogen-like aggregates called Lafora bodies (LBs); thus, LD is also classified as a glycogen storage disease (GSD). Using LD mouse models, multiple laboratories definitively demonstrated that genetic reduction or elimination of glycogen synthesis decreased LB formation and rescued LD epilepsy, neurodegeneration, and brain inflammation. Thus, LBs are the etiological driver of LD. An antibody-enzyme fusion (AEF) was developed that ablates LBs and normalizes both cell signaling and brain metabolism. This AEF is a promising drug for the treatment of LD and other GSDs as well as a putative therapeutic platform for targeting other neurodegenerative diseases.
2024-02-23 | Effect of intracerebroventricular administration of alglucosidase alfa in two mouse models of Lafora disease: Relevance for clinical practice.
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A, encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a-/- knock-out and Epm2aR240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a-/- and Epm2aR240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a-/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease.
small molecules
2026-06-08 | Polypharmacy's paradox: accelerated decline in a rare case of Lafora body disease.
Lafora body disease (LBD) is a rare autosomal recessive progressive myoclonic epilepsy characterized by neurodegene-ration due to an intracellular accumulation of poorly branched polyglucosan inclusions. Effective pharmacological management remains challenging due to the risk of drug-induced exacerbation of symptoms and adverse interactions. We present the case of an 18-year-old male with intractable seizures, myoclonus, and cognitive regression. Electroencephalogram showed frequent generalized polyspike discharges, and histopathology confirmed Lafora bodies. The patient was initially prescribed a broad polypharmacy regimen including sodium valproate, carbamazepine, phenytoin, and phenobarbitone - leading to detrimental pharmacokinetic and pharmacodynamic interactions, worsening his neurological status. A stepwise revision with withdrawal of contraindicated agents and rational introduction of levetiracetam, clobazam, and perampanel improved seizure control and alertness. This case highlights the hazards of unstructured polypharmacy in LBD and stresses the need for individualized pharmacotherapy. Novel disease-modifying options like metformin, targeting glycogen metabolism, offer future therapeutic potential in altering disease trajectory.
2025-12-18 | Neuronal hyperexcitability: A key to unraveling hippocampal synaptic dysfunction in Lafora disease.
Lafora disease (LD) is a rare progressive disorder caused by mutations in the EPM2A or EPM2B genes, characterized by the accumulation of Lafora bodies, drug-resistant epilepsy, and cognitive decline. To investigate the early molecular mechanisms of LD, we studied electrophysiological changes in the dentate gyrus (DG) of the Epm2aR240X knock-in mouse model at various ages. Electrophysiological recordings measured neuronal membrane properties, epileptic-like activity, epileptic thresholds, and synaptic plasticity in Epm2aR240X mice at 1, 3, and 12 months. We also employed Periodic Acid-Schiff (PAS) diastase staining, immunofluorescence, and Western blotting to detect Lafora bodies, amyloid beta deposition, and the expression of glutamate receptor subunits. Epileptic-like activity began at 1 month and intensified with age. Aberrant long-term potentiation (LTP) appeared at 3 months and worsened by 12 months. Notably, cannabidiol treatment reduced excitability and restored LTP in older mice, suggesting its potential therapeutic value. The reversibility of synaptopathy, even at advanced stages, reinforces the importance of early detection of hyperexcitability and the development of effective therapeutic approaches.
2025-11-05 | HIGH-AFFINITY BINDING OF DAPAGLIFLOZIN TO HUMAN GYS1: A STRUCTURE-BASED REPURPOSING STRATEGY FOR LAFORA DISEASE
Lafora disease (LD) is a rare progressive myoclonic epilepsy that begins in adolescence and is characterized by epileptic seizures, psychomotor regression, muscle weakness, progressive dementia, and premature death. In its pathogenesis, Lafora bodies, composed of poorly branched polyglycosan structures, accumulate primarily in neurons, as well as in the liver, muscle, and exocrine glands. Mutations in EPM2A (laforin) or NHLRC1 (malin) disrupt glycogen phosphorylation/branching control, leading to loss of glycogen structural integrity and pathological polyglycosan accumulation. In this context, GYS1, the rate-limiting enzyme of glycogen synthesis, plays a critical role in the pathophysiology of LD. Inhibiting GYS1 is a rational pharmacological strategy for suppressing polyglycosan accumulation and slowing neurodegeneration. In this study, using the high-resolution cryo-EM structure of the human GYS1–GYG1 complex (PDB: 7Q13), which represents the substrate-bound conformation of GYS1, the binding potential of 20 approved drugs to the GYS1 enzyme was evaluated using a drug repurposing approach. Docking simulations were performed with AutoDock Vina. It was determined that compounds with glycosidic skeletons (dapagliflozin, empagliflozin, acarbose), which can deeply dock into the glucose subpocket, tended to have higher affinity, while uridine/pyrimidine analogs, due to their inability to fully mimic the pyrophosphate coordination site, exhibited moderate to low binding. Among the drugs, dapagliflozin achieved the highest binding score. These findings suggested that dapagliflozin could be a prime candidate for therapeutic inhibition of GYS1.
2025-07-21 | Use of cannabidiol in the management of refractory seizures in Lafora disease A case report of two siblings
Disease (LD) is a rare autosomal recessive glycogen storage disorder characterized by Progressive Myoclonic Epilepsy (PME) and neurodegeneration, typically manifesting in adolescence.
2025-05-30 | Case report of Lafora disease: a rare genetic disorder manifesting as progressive myoclonic epilepsy.
Lafora disease (LD) is a rare, autosomal recessive progressive myoclonic epilepsy caused by mutations in EPM2A or EPM2B. It is characterized by abnormal glycogen metabolism leading to poly-glucosan deposits, known as Lafora bodies, in various tissues. LD typically manifests during adolescence with progressive neurological decline, including myoclonic seizures, cognitive impairment, and ataxia. Early diagnosis is critical for symptom management, yet the disease remains challenging to treat due to its refractory nature. We report the case of a 15-year-old male who initially presented with tonic-clonic and myoclonic seizures, bilateral lower limb paralysis, and hand tremors. Despite normal initial imaging findings, subsequent clinical progression raised suspicion for progressive myoclonic epilepsy. Genetic testing identified a homozygous pathogenic variant in EPM2A, confirming the diagnosis of LD. electroencephalogram (EEG) findings evolved over time, showing generalized spikes, poly-spikes, and spike-wave complexes on a slow background, consistent with advanced LD. The patient's seizures proved refractory to standard anti-epileptic drugs, necessitating the addition of phenobarbital, metformin, and zonisamide, which eventually achieved partial seizure control. Family genetic screening identified heterozygous carriers without clinical symptoms, emphasizing the need for genetic counseling. This case highlights the diagnostic challenges of LD, particularly in its early stages when clinical and imaging findings may be nonspecific. The report underscores the importance of genetic testing in confirming the diagnosis and tailoring management strategies. Despite limited treatment options, individualized multi-drug regimens may help achieve partial symptom control. Early recognition and comprehensive management, including family counseling, are essential in improving quality of life for patients and their families.
gene therapies
2026-03-01 | When gene replacement becomes a double-edged sword: Guardrails for precision neurotherapeutics in Lafora disease
Lafora disease (LD) is a paradigmatic progressive myoclonus epilepsy characterized by adolescent onset, refractory seizures, action- and stimulus-sensitive myoclonus, cognitive decline, and premature death. The pathological hallmark of the disease is the slow accumulation of poorly branched, insoluble glycogen aggregates, known as Lafora bodies (LBs), which progressively disrupt neuronal metabolism, trigger neuroinflammation, and ultimately drive neurodegeneration [1,2]. Importantly, the clinical course of LD is typically stereotyped and slowly progressive, unfolding over several years with a relatively predictable trajectory [3].
2025-12-30 | Adeno-Associated Virus-Based Gene Therapy for Lafora Disease in Epm2b-Deficient Mice.
Lafora disease is a fatal neurodegenerative disorder caused by loss-of-function mutations in the EPM2A or EPM2B genes, which encode laforin and malin, respectively. These mutations lead to the accumulation of intracellular inclusions of abnormal glycogen, known as Lafora bodies, the hallmark of the disease. Symptoms typically begin in early adolescence with seizures and rapidly progress to cognitive and motor decline, ultimately resulting in dementia and death within a decade of onset. Disruption of Epm2a or Epm2b in mice causes neuronal degeneration and Lafora body accumulation in the brain and other tissues. Epm2a-/- and Epm2b-/- mice exhibit motor and memory impairments, epileptic activity, and molecular and histological abnormalities. We previously demonstrated that intracerebroventricular delivery of a recombinant adeno-associated virus carrying EPM2A significantly improved pathology in Epm2a-/- mice. In this study, we tested recombinant adeno-associated virus-mediated delivery of the human EPM2B gene in Epm2b-/- mice. The treatment partially improved neurological, molecular, and histopathological outcomes, although some pathological features persisted. Importantly, our findings reveal differences between EPM2A- and EPM2B-based gene therapies, highlighting the need to better understand their distinct mechanisms. Despite limitations, our study provides new insights into the complexity of targeting EPM2B mutations in Lafora disease.
2025-11-12 | Lafora disease ( NHLRC1 ) associated with multiple malformations of cortical development: A clinical vignette
The authors declare no conflicts of interest related to this work. The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-05-12 | [Progressive Myoclonus Epilepsy: Diversity of Disorders and Key Points in Clinical Practice].
Progressive myoclonic epilepsies (PMEs) are a group of disorders characterized by progressive (1)myoclonus, (2)myoclonic and generalized tonic-clonic seizures, (3)cerebellar symptoms, and (4)cognitive decline. PMEs encompass various genetic disorders, including dentatorubral-pallidoluysian atrophy, benign adult familial myoclonus epilepsy, myoclonic epilepsy with ragged-red fibers, Unverricht-Lundborg disease, and Lafora disease. The diagnosis is based on clinical symptoms, inheritance patterns, electrophysiological findings, and genetic or pathological tests. Treatment for PMEs remains primarily symptomatic for seizures and myoclonus, although perampanel has reportedly improved epileptic symptoms with rational pharmacological properties. This review highlights the clinical features, genetic bases, and diagnostic and therapeutic advancements in PMEs, offering a comprehensive overview of this challenging and diverse group of disorders.
2025-02-02 | Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.
Because children have little temporal exposure to environment and aging, most pediatric neurological diseases are inherent, i.e. genetic. Since postnatal neurons and astrocytes are mostly non-replicating, gene therapy and genome editing present enormous promise in child neurology. Unlike in other organs, which are highly permissive to adeno-associated viruses (AAV), the mature blood-brain barrier (BBB) greatly limits circulating AAV distribution to the brain. Intrathecal administration improves distribution but to no more than 20% of brain cells. Focused ultrasound (FUS) opens the BBB transiently and safely. In the present work we opened the hippocampal BBB and delivered a Cas9 gene via AAV9 intrathecally. This allowed brain first-pass, and subsequent vascular circulation and re-entry through the opened BBB. The mouse model used was of Lafora disease, a neuroinflammatory disease due to accumulations of misshapen overlong-branched glycogen. Cas9 was targeted to the gene of the glycogen branch-elongating enzyme glycogen synthase. We show that FUS dramatically (2000-fold) improved hippocampal Cas9 distribution and greatly reduced the pathogenic glycogen accumulations and hippocampal inflammation. FUS is in regular clinical use for other indications. Our work shows that it has the potential to vastly broaden gene delivery or editing along with clearance of corresponding pathologic basis of brain disease.
oligonucleotides
2023-09-12 | Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model
Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.
2021-11-01 | Suppression of glycogen synthesis as a treatment for Lafora disease: Establishing the window of opportunity.
Lafora disease (LD) is a fatal adolescence-onset neurodegenerative condition. The hallmark of LD is the accumulation of aberrant glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Impeding glycogen synthesis from early embryonic stages by genetic suppression of glycogen synthase (MGS) in an animal model of LD prevents LB formation and ultimately the pathological manifestations of LD thereby indicating that LBs are responsible for the pathophysiology of the disease. However, it is not clear whether eliminating glycogen synthesis in an adult animal after LBs have already formed would halt or reverse the progression of LD. Herein we generated a mouse model of LD with inducible MGS suppression. We evaluated the effect of MGS suppression at different time points on LB accumulation as well as on the appearance of neuroinflammation, a pathologic trait of LD models. In the skeletal muscle, MGS suppression in adult LD mice blocked the formation of new LBs and reduced the number of glycogen aggregates. In the brain, early but not late MGS suppression halted the accumulation of LBs. However, the neuroinflammatory response was still present, as shown by the levels of reactive astrocytes, microglia and inflammatory cytokines. Our results confirm that MGS as a promising therapeutic target for LD and highlight the importance of an early diagnosis for effective treatment of the disease.
2021-02-11 | Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease
Abstract Lafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in the disease’s mouse models. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene ( Gys1 ). We administered Gys1-ASO by intracerebroventricular injection and analyzed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.
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Drug Discovery Landscape
5 orphan drug designations for Lafora disease.
5 orphan drug designations for Lafora disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a therapeutic transgene cassette with an adeno-associated viral (AAV)-9 vector expressing a functional human codon optimized complimentary deoxyribonucleic acid (cDNA) encoding hEPM2A, under control of a CAG promoter | gene therapies | FDA | 2024-06-24 | — | Genixcure Inc. |
2’-O-(2-methoxyethyl) modified antisense oligonucleotide targeting glycogen synthase 1 pre-mRNA | oligonucleotides | EMA | 2020-12-09 | — | Ionis Development (Ireland) Limited |
2¿-O-(2-methoxyethyl) modified antisense oligonucleotide targeting glycogen synthase 1 (GYS1) pre mRNA | oligonucleotides | FDA | 2020-10-08 | — | Ionis Pharmaceuticals, Inc. |
metformin | small molecules | FDA | 2017-12-14 | — | Consorcio Centro de Investigación Biomédica en Red, M.P. (CIBER) |
Metformin | small molecules | EMA | 2016-12-12 | — | Consorcio Centro de Investigación Biomédica en Red |
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