RARE DISEASE
Progressive myoclonic epilepsy type 8
Progressive myoclonic epilepsy type 8
Progressive myoclonic epilepsy type 8
Synonyms: EPM8, PME type 8, Progressive myoclonic epilepsy due to CERS1 deficiency, Progressive myoclonus epilepsy type 8
Synonyms: EPM8, PME type 8, Progressive myoclonic epilepsy due to CERS1 deficiency, Progressive myoclonus epilepsy type 8
Synonyms: EPM8, PME type 8, Progressive myoclonic epilepsy due to CERS1 deficiency, Progressive myoclonus epilepsy type 8
Drug discovery
0
drugs
With orphan designations
Overview
Progressive Myoclonic Epilepsy Type 8 (EPM8) is a rare autosomal recessive disorder caused by CERS1 mutations, characterized by childhood/adolescent-onset action myoclonus, generalized tonic-clonic seizures, and progressive cognitive decline. Patients develop cerebellar/brainstem atrophy on MRI and EEG abnormalities. Diagnosis relies on genetic testing, and management focuses on symptom control due to the absence of disease-modifying therapies [2][6][12][16].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
7 drug discovery papers about Progressive myoclonic epilepsy type 8, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
7 drug discovery papers about Progressive myoclonic epilepsy type 8, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-26 | Topiramate-Responsive Myoclonic Status Epilepticus in a Child with Progressive Myoclonus Epilepsy Due to Neuronal Ceroid Lipofuscinosis Type 8: A Case Report.
Progressive myoclonus epilepsy (PME) is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures and progressive neurological regression. In the late stage, patients often develop myoclonic status epilepticus (MSE), for which an optimal treatment has not been established. Neuronal ceroid lipofuscinosis type 8 (NCL8), caused by pathogenic variants in the CLN8 gene, is a rare lysosomal disorder that can present with PME. However, published clinical experience is limited. We report the case of a boy with PME due to NCL8 who developed recurrent MSE with respiratory compromise and showed clinical improvement following the introduction of oral topiramate. He had developmental delays from late infancy, onset of epilepsy at three years of age, and multiple seizure types, including myoclonic seizures, generalized tonic-clonic seizures, and atypical absence seizures. Neurological regression progressed, and the patient became bedridden by 6 years of age. NCL8 was diagnosed based on the presence of a known pathogenic CLN8 variant and autofluorescent storage material in lysosomes identified on skin biopsy. At nine years of age, frequent and prolonged myoclonic seizures, confirmed by long-term video electroencephalography (EEG), occurred repeatedly with oxygen desaturation, requiring intensive care with continuous midazolam infusion. Despite escalation of antiseizure medication therapy, MSE persisted. After the initiation and titration of oral topiramate, the duration and frequency of myoclonic events decreased, allowing successful withdrawal of the continuous midazolam infusion. No further MSE occurred during an 8-month follow-up period, although occasional isolated myoclonic events persisted. Therefore, topiramate may be a useful therapeutic option for MSE in children with PME due to NCL8.
2025-09-25 | Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.
The brain is highly susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by early onset of neurodegenerative traits. The function of CerS is embedded in a complex, conserved metabolic pathway, making it difficult to identify the specific disease-relevant alterations. Here, we show that the expression of an enzymatically inactive cerS allele in Drosophila sensory neurons yielded developmental and early onset dendrite loss. Combining lipidomics and refined genetics with quantitative analysis of neuronal morphology in cerS mutants, we identified which lipids species are dysregulated and how they affect neuronal morphology. In cerS mutants, long and very-long acyl-chain C18-C24-ceramides were missing and necessary for dendrite elaboration. In addition, the substrate of CerS, (dh)S, and its metabolite (dh)S1P, increased. Especially increasing (dh)S1P strongly reduces dendritic complexity in cerS mutant neurons. Finally, we performed in vivo experiments to cell-autonomously rescue the morphological defects of cerS mutant neurons and report that a complete rescue can only be achieved if the toxic CerS substrate is converted to produce specific (C18-C24) ceramides. Thus, despite the complex metabolic alterations, our data provides essential information about the metabolic origin of PME8 and delineates a potential therapeutic avenue.
2024-10-31 | Lipid Disbalance Affects Neuronal Dendrite Growth and Maintenance in a Human Ceramide Synthase Disease Model
Summary The brain is susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by neurodegenerative traits. We show that expression of a disease-causing c erS allele in Drosophila sensory neurons yielded developmental and degenerative dendrite loss. In cerS mutants, C18-C24 ceramides and membrane-forming complex sphingolipids, into which ceramides are converted, were reduced. At the same time bioactive signaling lipids including (dh)Sphingosine-1-P, deriving from the CerS substrate, were increased. To clarifying the etiology of PME8, we thus performed in vivo experiments to cell-autonomously rescue the individual metabolic alterations. We report that restoring specific long-chain ceramides while in parallel decreasing (dh)Sphingosine-1-P fully rescues the cerS mutant phenotype. Thus, despite the complex metabolic alterations, our data provide essential information about the metabolic origin of PME8 and delineate a potential therapy.
2022-07-01 | A systematic review of the efficacy of perampanel as treatment for myoclonic seizures and symptomatic myoclonus.
Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.
2022-02-03 | Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures.
The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs). We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication. Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564). Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type. The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.
small molecules
2026-05-26 | Topiramate-Responsive Myoclonic Status Epilepticus in a Child with Progressive Myoclonus Epilepsy Due to Neuronal Ceroid Lipofuscinosis Type 8: A Case Report.
Progressive myoclonus epilepsy (PME) is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures and progressive neurological regression. In the late stage, patients often develop myoclonic status epilepticus (MSE), for which an optimal treatment has not been established. Neuronal ceroid lipofuscinosis type 8 (NCL8), caused by pathogenic variants in the CLN8 gene, is a rare lysosomal disorder that can present with PME. However, published clinical experience is limited. We report the case of a boy with PME due to NCL8 who developed recurrent MSE with respiratory compromise and showed clinical improvement following the introduction of oral topiramate. He had developmental delays from late infancy, onset of epilepsy at three years of age, and multiple seizure types, including myoclonic seizures, generalized tonic-clonic seizures, and atypical absence seizures. Neurological regression progressed, and the patient became bedridden by 6 years of age. NCL8 was diagnosed based on the presence of a known pathogenic CLN8 variant and autofluorescent storage material in lysosomes identified on skin biopsy. At nine years of age, frequent and prolonged myoclonic seizures, confirmed by long-term video electroencephalography (EEG), occurred repeatedly with oxygen desaturation, requiring intensive care with continuous midazolam infusion. Despite escalation of antiseizure medication therapy, MSE persisted. After the initiation and titration of oral topiramate, the duration and frequency of myoclonic events decreased, allowing successful withdrawal of the continuous midazolam infusion. No further MSE occurred during an 8-month follow-up period, although occasional isolated myoclonic events persisted. Therefore, topiramate may be a useful therapeutic option for MSE in children with PME due to NCL8.
2025-09-25 | Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.
The brain is highly susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by early onset of neurodegenerative traits. The function of CerS is embedded in a complex, conserved metabolic pathway, making it difficult to identify the specific disease-relevant alterations. Here, we show that the expression of an enzymatically inactive cerS allele in Drosophila sensory neurons yielded developmental and early onset dendrite loss. Combining lipidomics and refined genetics with quantitative analysis of neuronal morphology in cerS mutants, we identified which lipids species are dysregulated and how they affect neuronal morphology. In cerS mutants, long and very-long acyl-chain C18-C24-ceramides were missing and necessary for dendrite elaboration. In addition, the substrate of CerS, (dh)S, and its metabolite (dh)S1P, increased. Especially increasing (dh)S1P strongly reduces dendritic complexity in cerS mutant neurons. Finally, we performed in vivo experiments to cell-autonomously rescue the morphological defects of cerS mutant neurons and report that a complete rescue can only be achieved if the toxic CerS substrate is converted to produce specific (C18-C24) ceramides. Thus, despite the complex metabolic alterations, our data provides essential information about the metabolic origin of PME8 and delineates a potential therapeutic avenue.
2024-10-31 | Lipid Disbalance Affects Neuronal Dendrite Growth and Maintenance in a Human Ceramide Synthase Disease Model
Summary The brain is susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by neurodegenerative traits. We show that expression of a disease-causing c erS allele in Drosophila sensory neurons yielded developmental and degenerative dendrite loss. In cerS mutants, C18-C24 ceramides and membrane-forming complex sphingolipids, into which ceramides are converted, were reduced. At the same time bioactive signaling lipids including (dh)Sphingosine-1-P, deriving from the CerS substrate, were increased. To clarifying the etiology of PME8, we thus performed in vivo experiments to cell-autonomously rescue the individual metabolic alterations. We report that restoring specific long-chain ceramides while in parallel decreasing (dh)Sphingosine-1-P fully rescues the cerS mutant phenotype. Thus, despite the complex metabolic alterations, our data provide essential information about the metabolic origin of PME8 and delineate a potential therapy.
2022-07-01 | A systematic review of the efficacy of perampanel as treatment for myoclonic seizures and symptomatic myoclonus.
Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.
2022-02-03 | Exploring the Evidence for Broad-Spectrum Effectiveness of Perampanel: A Systematic Review of Clinical Data in Generalised Seizures.
The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs). We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication. Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564). Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type. The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.
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