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:
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.
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.
2025-12-25 | 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.
2025-12-18 | 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.
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.
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.
2025-12-25 | 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.
2025-12-18 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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