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:
2026-04-10 | Lafora Disease
Abstract Alois Alzheimer’s Spanish trainee Gonzalo Lafora described a neurodegenerative disease, now known as Lafora disease, resembling his mentor’s (Alzheimer’s disease) but with early (teenage) onset, a rapid ten-year course, and a severe, incessant, and intractable epilepsy. Although in Alzheimer’s disease, neuroinflammation and neurodegeneration are driven by protein accumulations (misfolded amyloid), in Lafora’s they are spurred by glucan (amylose-like) accumulations. Lafora disease is caused by autosomal recessive inheritance of inactivating mutations in the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Laforin and malin form a tight complex that regulates glycogen branches, preventing their overlengthening by the enzyme glycogen synthase. In their absences, glycogen acquires overlong branches, precipitates, and accumulates into disease-driving Lafora bodies. The extreme severity of Lafora disease has stimulated extensive therapeutic research, including gene therapy, antisense oligonucleotide (ASO), and small molecule approaches. One therapy approach, an ASO targeting the brain-expressed isoform of glycogen synthase, is being tested in a clinical trial. More than 100 years after Lafora accepted Alzheimer’s and Ramón y Cajal’s suggestion that he take a position as a neuropathologist at what was then known as the Government Hospital for the Insane, near Washington, DC, where he came to describe the disease, his research will hopefully bear therapeutic fruit.
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.
2026-04-10 | Lafora Disease
Abstract Alois Alzheimer’s Spanish trainee Gonzalo Lafora described a neurodegenerative disease, now known as Lafora disease, resembling his mentor’s (Alzheimer’s disease) but with early (teenage) onset, a rapid ten-year course, and a severe, incessant, and intractable epilepsy. Although in Alzheimer’s disease, neuroinflammation and neurodegeneration are driven by protein accumulations (misfolded amyloid), in Lafora’s they are spurred by glucan (amylose-like) accumulations. Lafora disease is caused by autosomal recessive inheritance of inactivating mutations in the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Laforin and malin form a tight complex that regulates glycogen branches, preventing their overlengthening by the enzyme glycogen synthase. In their absences, glycogen acquires overlong branches, precipitates, and accumulates into disease-driving Lafora bodies. The extreme severity of Lafora disease has stimulated extensive therapeutic research, including gene therapy, antisense oligonucleotide (ASO), and small molecule approaches. One therapy approach, an ASO targeting the brain-expressed isoform of glycogen synthase, is being tested in a clinical trial. More than 100 years after Lafora accepted Alzheimer’s and Ramón y Cajal’s suggestion that he take a position as a neuropathologist at what was then known as the Government Hospital for the Insane, near Washington, DC, where he came to describe the disease, his research will hopefully bear therapeutic fruit.
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.
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0 orphan drug designations.
0 orphan drug designations.
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