RARE DISEASE
Early-onset Lafora body disease
Early-onset Lafora body disease
Early-onset Lafora body disease
Drug discovery
0
drugs
With orphan designations
Overview
Early-onset Lafora body disease is a rare, genetic progressive myoclonic epilepsy characterized by childhood onset (typically age 5) of dysarthria, myoclonus, ataxia, seizures, and cognitive decline. Unlike classical Lafora disease, symptoms progress more slowly, with survival into the fourth decade. Pathologically, it features Lafora bodies (PAS-positive glycogen aggregates) in tissues. It is linked to PRDM8 mutations, causing nuclear sequestration of laforin/malin, leading to glycogen dysregulation [4][5][13][14].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
53 drug discovery papers about Early-onset Lafora body disease, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
53 drug discovery papers about Early-onset Lafora body disease, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-27 | Drug-Resistant Early-Onset Progressive Myoclonic Epilepsy Revealing Lafora Disease: A Case Report.
Lafora disease is a rare, autosomal recessive progressive myoclonic epilepsy characterized by drug-resistant seizures, myoclonus, and cognitive decline. We present the case of a 25-year-old woman with an unusually early onset of epilepsy at three years of age, progressive neurological deterioration, and a positive family history of progressive myoclonic epilepsy. The patient developed multiple seizure types, including generalized tonic-clonic seizures, atonic seizures, and stimulus-sensitive myoclonus, accompanied by progressive cognitive impairment. Electroencephalography (EEG) demonstrated generalized epileptiform discharges with frontocentral predominance and photosensitivity. Brain magnetic resonance imaging (MRI) revealed periventricular and parietal white matter changes with mild white matter reduction, likely related to a perinatal hypoxic-ischemic insult. Despite extensive antiseizure medication polytherapy and vagus nerve stimulation, seizures remained refractory. Although the skin biopsy was negative, the muscle biopsy showed ultrastructural changes consistent with Lafora disease. Genetic testing confirmed a pathogenic mutation in the EPM2B gene, establishing the diagnosis. This case highlights the diagnostic challenges of Lafora disease and the importance of prioritizing genetic testing in early-onset, drug-resistant epilepsy when standard diagnostic evaluations are nondiagnostic.
2025-12-11 | 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.
2024-02-03 | VAL-1221 FOR THE TREATMENT OF PATIENTS WITH LAFORA DISEASE: STUDY PROTOCOL FOR A SINGLE-ARM, OPEN-LABEL CLINICAL TRIAL
Introduction: Lafora Disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus, and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL1221 is a fusion protein comprised of the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesize that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilize or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL1221 in patients with LD. Methods and analysis: The study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study center in Italy, namely the sponsor IRCCS Istituto delle Scienze Neurologiche di Bologna - Azienda USL di Bologna. The study will enroll 6 genetically-confirmed patients with mid- to late stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months), and follow-up period. VAL1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive. Ethics and dissemination: The study protocol was approved by the local ethics committee (number 232 2023 FARM AUSLBO 23020, 22 Mar 2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals. Trial Registration: European Union Clinical Trials Register (EudraCT number 2023 000185 34).
2023-12-14 | Gene replacement therapy for Lafora disease in the Epm2a -/- mouse model.
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. Common symptoms include seizures, dementia, and a progressive neurological decline leading to death within 5-15 years from onset. The disease results from mutations transmitted with autosomal recessive inheritance in the EPM2A gene, encoding laforin, a dual-specificity phosphatase, or the EPM2B gene, encoding malin, an E3-ubiquitin ligase. Laforin has glucan phosphatase activity, is an adapter of enzymes involved in glycogen metabolism, is involved in endoplasmic reticulum-stress and protein clearance, and acts as a tumor suppressor protein. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein can lead to alterations in this complex, leading to the formation of Lafora bodies that contain abnormal, insoluble, and hyperphosphorylated forms of glycogen called polyglucosans. We used the Epm2a -/- knock-out mouse model of Lafora disease to apply a gene replacement therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment by means of neuropathological studies, behavioral tests, video-electroencephalography recording, and proteomic/phosphoproteomic analysis. Gene therapy with recombinant adeno-associated virus containing the EPM2A gene ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Improvements were observed for up to nine months following a single intracerebroventricular injection. In conclusion, gene replacement therapy with human EPM2A gene in the Epm2a -/- knock-out mice shows promise as a potential treatment for Lafora disease.
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.
2026-02-27 | Drug-Resistant Early-Onset Progressive Myoclonic Epilepsy Revealing Lafora Disease: A Case Report.
Lafora disease is a rare, autosomal recessive progressive myoclonic epilepsy characterized by drug-resistant seizures, myoclonus, and cognitive decline. We present the case of a 25-year-old woman with an unusually early onset of epilepsy at three years of age, progressive neurological deterioration, and a positive family history of progressive myoclonic epilepsy. The patient developed multiple seizure types, including generalized tonic-clonic seizures, atonic seizures, and stimulus-sensitive myoclonus, accompanied by progressive cognitive impairment. Electroencephalography (EEG) demonstrated generalized epileptiform discharges with frontocentral predominance and photosensitivity. Brain magnetic resonance imaging (MRI) revealed periventricular and parietal white matter changes with mild white matter reduction, likely related to a perinatal hypoxic-ischemic insult. Despite extensive antiseizure medication polytherapy and vagus nerve stimulation, seizures remained refractory. Although the skin biopsy was negative, the muscle biopsy showed ultrastructural changes consistent with Lafora disease. Genetic testing confirmed a pathogenic mutation in the EPM2B gene, establishing the diagnosis. This case highlights the diagnostic challenges of Lafora disease and the importance of prioritizing genetic testing in early-onset, drug-resistant epilepsy when standard diagnostic evaluations are nondiagnostic.
2025-12-11 | 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.
2024-02-03 | VAL-1221 FOR THE TREATMENT OF PATIENTS WITH LAFORA DISEASE: STUDY PROTOCOL FOR A SINGLE-ARM, OPEN-LABEL CLINICAL TRIAL
Introduction: Lafora Disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus, and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL1221 is a fusion protein comprised of the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesize that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilize or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL1221 in patients with LD. Methods and analysis: The study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study center in Italy, namely the sponsor IRCCS Istituto delle Scienze Neurologiche di Bologna - Azienda USL di Bologna. The study will enroll 6 genetically-confirmed patients with mid- to late stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months), and follow-up period. VAL1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive. Ethics and dissemination: The study protocol was approved by the local ethics committee (number 232 2023 FARM AUSLBO 23020, 22 Mar 2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals. Trial Registration: European Union Clinical Trials Register (EudraCT number 2023 000185 34).
2023-12-14 | Gene replacement therapy for Lafora disease in the Epm2a -/- mouse model.
Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. Common symptoms include seizures, dementia, and a progressive neurological decline leading to death within 5-15 years from onset. The disease results from mutations transmitted with autosomal recessive inheritance in the EPM2A gene, encoding laforin, a dual-specificity phosphatase, or the EPM2B gene, encoding malin, an E3-ubiquitin ligase. Laforin has glucan phosphatase activity, is an adapter of enzymes involved in glycogen metabolism, is involved in endoplasmic reticulum-stress and protein clearance, and acts as a tumor suppressor protein. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein can lead to alterations in this complex, leading to the formation of Lafora bodies that contain abnormal, insoluble, and hyperphosphorylated forms of glycogen called polyglucosans. We used the Epm2a -/- knock-out mouse model of Lafora disease to apply a gene replacement therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment by means of neuropathological studies, behavioral tests, video-electroencephalography recording, and proteomic/phosphoproteomic analysis. Gene therapy with recombinant adeno-associated virus containing the EPM2A gene ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Improvements were observed for up to nine months following a single intracerebroventricular injection. In conclusion, gene replacement therapy with human EPM2A gene in the Epm2a -/- knock-out mice shows promise as a potential treatment for Lafora disease.
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.
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