RARE DISEASE
Myoclonic-astatic epilepsy
Myoclonic-astatic epilepsy
Myoclonic-astatic epilepsy
Synonyms: Doose syndrome, EMAS, Epilepsy with myoclonic-astatic seizures, Epilepsy with myoclonic-atonic seizures, MAE, Myoclonic atonic epilepsy, Myoclonic-astatic epilepsy in early childhood
Synonyms: Doose syndrome, EMAS, Epilepsy with myoclonic-astatic seizures, Epilepsy with myoclonic-atonic seizures, MAE, Myoclonic atonic epilepsy, Myoclonic-astatic epilepsy in early childhood
Synonyms: Doose syndrome, EMAS, Epilepsy with myoclonic-astatic seizures, Epilepsy with myoclonic-atonic seizures, MAE, Myoclonic atonic epilepsy, Myoclonic-astatic epilepsy in early childhood
Drug discovery
3
drugs
With orphan designations
Overview
Myoclonic-Astatic Epilepsy (MAE), previously termed Doose syndrome, is a rare childhood-onset genetic epilepsy syndrome characterized by myoclonic-atonic seizures, often alongside generalized tonic-clonic, absence, and tonic seizures. Onset occurs between 2–6 years, typically in previously neurotypical children, with a male predominance (2–3:1 ratio) [1][6][11]. While ~66% achieve seizure remission within 3 years, 30–40% develop drug-resistant epilepsy and neurodevelopmental impairment, particularly with tonic seizures or nonconvulsive status epilepticus [1][5][11]. Genetic variants (e.g., STX1B, SLC6A1) and links to GEFS+ are observed [2][5][11].
Burden
Developmental delays (cognitive, motor, or behavioral) in 30–40%, correlating with seizure burden [1][5][14].
High caregiver strain due to injury risks from drop seizures and refractory cases [11][14].
Risk factors for poor outcomes: tonic seizures, recurrent nonconvulsive status, and slow spike-wave EEG [1][5][11].
Therapies
First-line: Valproate (monotherapy or combined with lamotrigine) or levetiracetam [8][12][15].
Dietary: Ketogenic or modified Atkins diet (≥50% seizure reduction in 50–90% of cases) [2][6][12].
Adjuncts: Ethosuximide (absence seizures), topiramate (atonic seizures), clobazam; avoid sodium channel blockers (e.g., carbamazepine) [2][11][12].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
232 drug discovery papers about Myoclonic-astatic epilepsy, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
232 drug discovery papers about Myoclonic-astatic epilepsy, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-27 | 4-Phenylbutyrate Plus Wildtype GAT-1 Augmentation: A Dual Therapy to Rescue SLC6A1 Variant-Associated Developmental and Epileptic Encephalopathy.
Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a novel de novo missense mutation p.Ala305Val in GAT-1 encoding SLC6A1, in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. Ala305Val was compared with the residue-matched comparator p.Ala305Thr (Ala305Thr). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1 p.Ala305Val and GAT-1 p.Ala305Thr. GAT-1 p.Ala305Val reduced 3H GABA uptake across HEK293Ts, astrocytes, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ~80% in GAT-1 p.Ala305Val; PBA reduced ER retention to approximately ~40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved GABA uptake in the heterozygous condition but combined PBA plus wildtype allele augmentation produced rescue greater than either intervention alone in the available dose-response ranges. GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches.
2026-06-22 | 4 Phenylbutyrate Plus Gene augmentation: A Dual Therapy To Rescue of SLC6A1 Variant Associated Developmental And Epileptic Encephalopathy.
Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-Phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a newly identified de novo SLC6A1 missense variant, p.Ala305Val (A305V), in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. A305V was compared with the residue-matched comparator p.Ala305Thr (A305T). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1(A305V) and GAT-1(A305T). A305V reduced 3 H-GABA uptake across HEK293T, astrocyte, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ∼80% in A305V; PBA reduced ER retention to approximately ∼40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved mutant GAT-1 uptake and combined PBA-plus-augmentation produced rescue greater than either intervention alone in the available dose-response ranges. SLC6A1 A305V is a trafficking-impaired, loss-of-function GAT-1 variant whose dysfunction is tractable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter dose. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by increased gene therapy. This work links the patient-derived SLC6A1 A305V variant to a defined molecular mechanism-GAT-1 destabilization, ER retention, and reduced GABA uptake-and demonstrates that the deficit is reversible by two independent interventions that converge at the same downstream endpoint of functional surface transporter. Because PBA is already clinically deployable and GAT-1 cDNA augmentation models a future viral or non-viral gene therapy, the combined-rescue logic provides a falsifiable path for precision medicine in SLC6A1-related DEEs: chemical chaperoning corrects the folding bottleneck while transporter augmentation increases the pool available for rescue.
2026-03-15 | From clinical practice to mechanistic insights in ketogenic diets for epilepsy.
Ketogenic diet therapies, including the classic ketogenic diet, modified Atkins diet, and low glycaemic index treatment, have shown effectiveness in controlling seizures, in part by shifting metabolism from glucose to ketone bodies. They improve mitochondrial function, reduce neuroinflammation, and modulate neurotransmitters. Ketogenic diet therapies also affect the gut microbiome, potentially impacting neurotransmitter balance in ways that contribute to seizure control. A classic ketogenic diet is effective yet restrictive, whereas the modified Atkins diet and low glycaemic index treatment offer greater flexibility, tolerability, and ease of implementation, particularly in resource-limited settings. Cochrane reviews and meta-analyses rank the certainty of randomised controlled trial evidence for ketogenic diet therapies as limited. Early initiation of ketogenic diet therapies, particularly in children or patients with metabolic epilepsies, improves seizure outcomes, potentially preventing further mitochondrial and neuronal damage and reducing the risk of developing resistance to antiseizure medications. Research using rigorous, large-scale comparative effectiveness study designs that accounts for differences in age, epilepsy type, dietary therapy modality, sociodemographic background, care delivery contexts, and that minimises performance and observation bias is needed to resolve remaining uncertainties regarding the efficacy and real-world challenges of ketogenic diet therapies in epilepsy.
2025-12-25 | Doose syndrome (a clinical case)
Epilepsy with myoclonic-atonic seizures, or Doose syndrome, first described by H. Doose in 1970, is a rare form of childhood epileptic encephalopathy. This syndrome is characterized by a triad of features including polymorphic seizures (myoclonic, astatic, absence, and generalized tonic-clonic), a specific EEG pattern (generalized spike-wave activity, with frequency of 2-3 Hz), and the absence of structural brain changes according to neuroimaging data. Diagnosis of Doose syndrome is challenging due to its polymorphism and dynamic clinical presentation, as well as the need for differential diagnosis with other forms of epilepsy, particularly Lennox-Gastaut syndrome, and mandatory confirmation with long-term video-EEG monitoring. The literature presents isolated cases of this syndrome, highlighting the relevance of describing this clinical case.
2025-11-25 | Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights from Drosophila epilepsy models
Arginine 44 (R44) is a highly conserved residue in the human GABA transporter 1 (hGAT-1), a member of the solute carrier 6 (SLC6) family, which plays a critical role in regulating inhibitory neurotransmission in the central nervous system. To elucidate its functional importance, we characterized three epilepsy-associated pathogenic variants - R44Q, R44P and R44W - linked to myoclonic-atonic epilepsy (MAE) and developmental delay. Building on evidence that R44 resides within the N-terminal intracellular gate and is essential for transporter function, we employed biochemical, cellular and organismal models (HEK293 cells and Drosophila melanogaster, respectively) to assess the variants’ functional impairments, subcellular localization and trafficking. Particular emphasis was placed on R44Q, a validated variant with a pronounced clinical phenotype. The mutants trafficked to the plasma membrane, but were non-functional and exhibited reduced protein stability. In vivo , R44Q displayed cell-type–specific degradation: in astrocytes, GAT was rapidly cleared via proteasomal degradation, whereas in neurons, it showed lower expression with presynaptic enrichment. Proteasome inhibitors (MG-132, bortezomib) and the HDAC inhibitor trichostatin A (TSA) partially rescued R44Q function. Moreover, R44Q-expressing flies presented heat-induced seizures, which were mitigated by 4-phenylbutyrate (4-PBA) treatment. These findings elucidate the molecular basis of R44-mediated hGAT-1 dysfunction and highlight potential therapeutic avenues for SLC6A1-related neurodevelopmental disorders.
oligonucleotides
2026-09-19 | Epilepsy with myoclonic-atonic seizures: a comprehensive review with emphasis on current and emerging pharmacotherapies.
Epilepsy with myoclonic-atonic seizures (EMAtS), historically termed Doose syndrome, is a developmental and epileptic encephalopathy characterized by the usually abrupt onset of multiple generalized seizure types, including myoclonic-atonic seizures, in early childhood. Advances in genetic diagnostics, antiseizure treatments, and precision therapies have reshaped understanding and management of EMAtS. This review synthesizes the clinical spectrum of EMAtS, including core clinical features and diagnostic approach based on a literature search of PubMed, Embase, and OVID/MEDLINE. The genetic landscape is discussed to contextualize emerging precision therapies. Treatment is reviewed hierarchically, from valproate, clobazam, levetiracetam and ethosuximide as commonly used first- and second-line agents to the ketogenic diet, cannabidiol, felbamate, and sulthiame for drug-resistant disease. Precision approaches for key genetic etiologies, includingSLC2A1, SLC6A1, SYNGAP1, CHD2, STXBP1,andSCN2A, are also reviewed. Although approximately two-thirds of patients with EMAtS achieve seizure remission, a substantial minority experience drug-resistant seizure, intellectual disability, and behavioral comorbidities, underscoring the importance of timely diagnosis, appropriate pharmacotherapy, and early consideration of the ketogenic diet in drug-resistant cases. As precision therapeutics advance, syndrome-based care will increasingly be complemented by treatments tailored to the specific genetic etiology.
2008-08-08 | Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import.
Mitochondrial genomes generally encode a minimal set of tRNAs necessary for protein synthesis. However, a number of eukaryotes import tRNAs from the cytoplasm into their mitochondria. For instance, Saccharomyces cerevisiae imports cytoplasmic tRNA(Gln) into the mitochondrion without any added protein factors. Here, we examine the existence of a similar active tRNA import system in mammalian mitochondria. We have used subcellular RNA fractions from rat liver and human cells to perform RT-PCR with oligonucleotide primers specific for nucleus-encoded tRNA(CUG)(Gln) and tRNA(UUG)(Gln) species, and we show that these tRNAs are present in rat and human mitochondria in vivo. Import of in vitro transcribed tRNAs, but not of heterologous RNAs, into isolated mitochondria also demonstrates that this process is tRNA-specific and does not require the addition of cytosolic factors. Although this in vitro system requires ATP, it is resistant to inhibitors of the mitochondrial electrochemical gradient, a key component of protein import. tRNA(Gln) import into mammalian mitochondria proceeds by a mechanism distinct from protein import. We also show that both tRNA(Gln) species and a bacterial pre-tRNA(Asp) can be imported in vitro into mitochondria isolated from myoclonic epilepsy with ragged-red fiber cells if provided with sufficient ATP (2 mM). This work suggests that tRNA import is more widespread than previously thought and may be a universal trait of mitochondria. Mutations in mitochondrial tRNA genes have been associated with human disease; the tRNA import system described here could possibly be exploited for the manipulation of defective mitochondria.
proteins
2026-04-23 | Dynamic thalamo-cortical perfusion changes in myoclonic-atonic seizures captured by ictal technetium-99m ethyl cysteinate dimer single-photon emission computed tomography: A case report.
Ictal and interictal single-photon emission computed tomography (SPECT) has not been used to characterize myoclonic-atonic seizures. However, monitoring changes in cerebral blood flow (CBF) may help determine the pathogenetic mechanisms of this condition. We evaluated myoclonic-atonic seizures using technetium-99m ethylene cysteinate dimer (ECD)-SPECT and ictal SPECT subtraction co-registered with magnetic resonance imaging (SISCOM). A 3-year-old boy with normal development presented with truncal ataxia caused by acute cerebellitis at 1 year and 10 months, followed by atonic seizures at 2 years and 1 month and myoclonic-atonic seizures at 2 years and 6 months. Seizures could not be controlled by valproate, lamotrigine, or clonazepam. By 3 years of age, he experienced up to 40 myoclonic-atonic seizures per day, confirmed using ictal electroencephalography. Interictal electroencephalography showed diffuse spike-and-wave complexes. Ictal ECD-SPECT demonstrated increased CBF in the right precentral gyrus and temporal lobe and decreased CBF in both thalami. The patient was diagnosed with epilepsy with myoclonic-atonic seizures. Seizure control was achieved after adrenocorticotropic hormone therapy. Following treatment, interictal ECD-SPECT images demonstrated no difference in CBF between the left and right precentral gyri and temporal lobes, and resolution of hypoperfusion in both thalami. SISCOM revealed hyperperfusion in the right centroparietal region. Adrenocorticotropic hormone therapy successfully treated myoclonic-atonic seizures and resolved bilateral thalamic hypoperfusion. Thalamic dysfunction may also be involved in myoclonic-atonic seizures. This case uniquely demonstrates CBF changes in the motor cortex and thalamus and provides insight into the mechanisms underlying myoclonic-atonic seizures.
2017-03-01 | Epilepsy with myoclonic atonic seizures and chronic cerebellar symptoms associated with antibodies against glutamate receptors N2B and D2 in serum and cerebrospinal fluid
A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell-based assay revealed the presence of anti-NMDA-type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti-C-terminal GluN2B and anti-N-terminal GluD2 antibodies, and CSF anti-N-terminal GluN2B and anti-C-terminal anti-GluD2 antibodies. Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.
gene therapies
2025-03-23 | Epilepsy with myoclonic-atonic seizures: an update on genetic causes, nosological limits, and treatment strategies.
Epilepsy with myoclonic-atonic seizures is a childhood-onset epilepsy syndrome characterised by a range of seizure types, including myoclonic-atonic, atonic, myoclonic, absence, and generalised tonic-clonic seizures. The causes and outcomes of this syndrome are highly variable, with many uncertainties surrounding its classification and prognosis. Traditional antiseizure medications and the ketogenic diet remain the main treatment options. Although two-thirds of children attain remission from seizures without cognitive or behavioural sequelae, some continue to have drug-resistant seizures, intellectual disability, and behavioural problems. The identification of single-gene causes in a substantial subset of patients highlights the importance of genetic testing for development of personalised treatment strategies. However, diagnostic complexities have hindered the development of trials for new therapies. Better recognition of the distinct features of epilepsy with myoclonic-atonic seizures, combined with advances in molecular genetic testing, will pave the way for more focused clinical research and drug development. Future studies should aim to identify genetic causes and tailor treatment options, offering hope for improved long-term outcomes.
small molecules
2026-08-27 | 4-Phenylbutyrate Plus Wildtype GAT-1 Augmentation: A Dual Therapy to Rescue SLC6A1 Variant-Associated Developmental and Epileptic Encephalopathy.
Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a novel de novo missense mutation p.Ala305Val in GAT-1 encoding SLC6A1, in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. Ala305Val was compared with the residue-matched comparator p.Ala305Thr (Ala305Thr). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1 p.Ala305Val and GAT-1 p.Ala305Thr. GAT-1 p.Ala305Val reduced 3H GABA uptake across HEK293Ts, astrocytes, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ~80% in GAT-1 p.Ala305Val; PBA reduced ER retention to approximately ~40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved GABA uptake in the heterozygous condition but combined PBA plus wildtype allele augmentation produced rescue greater than either intervention alone in the available dose-response ranges. GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches.
2026-06-22 | 4 Phenylbutyrate Plus Gene augmentation: A Dual Therapy To Rescue of SLC6A1 Variant Associated Developmental And Epileptic Encephalopathy.
Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-Phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a newly identified de novo SLC6A1 missense variant, p.Ala305Val (A305V), in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. A305V was compared with the residue-matched comparator p.Ala305Thr (A305T). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1(A305V) and GAT-1(A305T). A305V reduced 3 H-GABA uptake across HEK293T, astrocyte, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ∼80% in A305V; PBA reduced ER retention to approximately ∼40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved mutant GAT-1 uptake and combined PBA-plus-augmentation produced rescue greater than either intervention alone in the available dose-response ranges. SLC6A1 A305V is a trafficking-impaired, loss-of-function GAT-1 variant whose dysfunction is tractable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter dose. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by increased gene therapy. This work links the patient-derived SLC6A1 A305V variant to a defined molecular mechanism-GAT-1 destabilization, ER retention, and reduced GABA uptake-and demonstrates that the deficit is reversible by two independent interventions that converge at the same downstream endpoint of functional surface transporter. Because PBA is already clinically deployable and GAT-1 cDNA augmentation models a future viral or non-viral gene therapy, the combined-rescue logic provides a falsifiable path for precision medicine in SLC6A1-related DEEs: chemical chaperoning corrects the folding bottleneck while transporter augmentation increases the pool available for rescue.
2026-03-15 | From clinical practice to mechanistic insights in ketogenic diets for epilepsy.
Ketogenic diet therapies, including the classic ketogenic diet, modified Atkins diet, and low glycaemic index treatment, have shown effectiveness in controlling seizures, in part by shifting metabolism from glucose to ketone bodies. They improve mitochondrial function, reduce neuroinflammation, and modulate neurotransmitters. Ketogenic diet therapies also affect the gut microbiome, potentially impacting neurotransmitter balance in ways that contribute to seizure control. A classic ketogenic diet is effective yet restrictive, whereas the modified Atkins diet and low glycaemic index treatment offer greater flexibility, tolerability, and ease of implementation, particularly in resource-limited settings. Cochrane reviews and meta-analyses rank the certainty of randomised controlled trial evidence for ketogenic diet therapies as limited. Early initiation of ketogenic diet therapies, particularly in children or patients with metabolic epilepsies, improves seizure outcomes, potentially preventing further mitochondrial and neuronal damage and reducing the risk of developing resistance to antiseizure medications. Research using rigorous, large-scale comparative effectiveness study designs that accounts for differences in age, epilepsy type, dietary therapy modality, sociodemographic background, care delivery contexts, and that minimises performance and observation bias is needed to resolve remaining uncertainties regarding the efficacy and real-world challenges of ketogenic diet therapies in epilepsy.
2025-12-25 | Doose syndrome (a clinical case)
Epilepsy with myoclonic-atonic seizures, or Doose syndrome, first described by H. Doose in 1970, is a rare form of childhood epileptic encephalopathy. This syndrome is characterized by a triad of features including polymorphic seizures (myoclonic, astatic, absence, and generalized tonic-clonic), a specific EEG pattern (generalized spike-wave activity, with frequency of 2-3 Hz), and the absence of structural brain changes according to neuroimaging data. Diagnosis of Doose syndrome is challenging due to its polymorphism and dynamic clinical presentation, as well as the need for differential diagnosis with other forms of epilepsy, particularly Lennox-Gastaut syndrome, and mandatory confirmation with long-term video-EEG monitoring. The literature presents isolated cases of this syndrome, highlighting the relevance of describing this clinical case.
2025-11-25 | Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights from Drosophila epilepsy models
Arginine 44 (R44) is a highly conserved residue in the human GABA transporter 1 (hGAT-1), a member of the solute carrier 6 (SLC6) family, which plays a critical role in regulating inhibitory neurotransmission in the central nervous system. To elucidate its functional importance, we characterized three epilepsy-associated pathogenic variants - R44Q, R44P and R44W - linked to myoclonic-atonic epilepsy (MAE) and developmental delay. Building on evidence that R44 resides within the N-terminal intracellular gate and is essential for transporter function, we employed biochemical, cellular and organismal models (HEK293 cells and Drosophila melanogaster, respectively) to assess the variants’ functional impairments, subcellular localization and trafficking. Particular emphasis was placed on R44Q, a validated variant with a pronounced clinical phenotype. The mutants trafficked to the plasma membrane, but were non-functional and exhibited reduced protein stability. In vivo , R44Q displayed cell-type–specific degradation: in astrocytes, GAT was rapidly cleared via proteasomal degradation, whereas in neurons, it showed lower expression with presynaptic enrichment. Proteasome inhibitors (MG-132, bortezomib) and the HDAC inhibitor trichostatin A (TSA) partially rescued R44Q function. Moreover, R44Q-expressing flies presented heat-induced seizures, which were mitigated by 4-phenylbutyrate (4-PBA) treatment. These findings elucidate the molecular basis of R44-mediated hGAT-1 dysfunction and highlight potential therapeutic avenues for SLC6A1-related neurodevelopmental disorders.
oligonucleotides
2026-09-19 | Epilepsy with myoclonic-atonic seizures: a comprehensive review with emphasis on current and emerging pharmacotherapies.
Epilepsy with myoclonic-atonic seizures (EMAtS), historically termed Doose syndrome, is a developmental and epileptic encephalopathy characterized by the usually abrupt onset of multiple generalized seizure types, including myoclonic-atonic seizures, in early childhood. Advances in genetic diagnostics, antiseizure treatments, and precision therapies have reshaped understanding and management of EMAtS. This review synthesizes the clinical spectrum of EMAtS, including core clinical features and diagnostic approach based on a literature search of PubMed, Embase, and OVID/MEDLINE. The genetic landscape is discussed to contextualize emerging precision therapies. Treatment is reviewed hierarchically, from valproate, clobazam, levetiracetam and ethosuximide as commonly used first- and second-line agents to the ketogenic diet, cannabidiol, felbamate, and sulthiame for drug-resistant disease. Precision approaches for key genetic etiologies, includingSLC2A1, SLC6A1, SYNGAP1, CHD2, STXBP1,andSCN2A, are also reviewed. Although approximately two-thirds of patients with EMAtS achieve seizure remission, a substantial minority experience drug-resistant seizure, intellectual disability, and behavioral comorbidities, underscoring the importance of timely diagnosis, appropriate pharmacotherapy, and early consideration of the ketogenic diet in drug-resistant cases. As precision therapeutics advance, syndrome-based care will increasingly be complemented by treatments tailored to the specific genetic etiology.
2008-08-08 | Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import.
Mitochondrial genomes generally encode a minimal set of tRNAs necessary for protein synthesis. However, a number of eukaryotes import tRNAs from the cytoplasm into their mitochondria. For instance, Saccharomyces cerevisiae imports cytoplasmic tRNA(Gln) into the mitochondrion without any added protein factors. Here, we examine the existence of a similar active tRNA import system in mammalian mitochondria. We have used subcellular RNA fractions from rat liver and human cells to perform RT-PCR with oligonucleotide primers specific for nucleus-encoded tRNA(CUG)(Gln) and tRNA(UUG)(Gln) species, and we show that these tRNAs are present in rat and human mitochondria in vivo. Import of in vitro transcribed tRNAs, but not of heterologous RNAs, into isolated mitochondria also demonstrates that this process is tRNA-specific and does not require the addition of cytosolic factors. Although this in vitro system requires ATP, it is resistant to inhibitors of the mitochondrial electrochemical gradient, a key component of protein import. tRNA(Gln) import into mammalian mitochondria proceeds by a mechanism distinct from protein import. We also show that both tRNA(Gln) species and a bacterial pre-tRNA(Asp) can be imported in vitro into mitochondria isolated from myoclonic epilepsy with ragged-red fiber cells if provided with sufficient ATP (2 mM). This work suggests that tRNA import is more widespread than previously thought and may be a universal trait of mitochondria. Mutations in mitochondrial tRNA genes have been associated with human disease; the tRNA import system described here could possibly be exploited for the manipulation of defective mitochondria.
proteins
2026-04-23 | Dynamic thalamo-cortical perfusion changes in myoclonic-atonic seizures captured by ictal technetium-99m ethyl cysteinate dimer single-photon emission computed tomography: A case report.
Ictal and interictal single-photon emission computed tomography (SPECT) has not been used to characterize myoclonic-atonic seizures. However, monitoring changes in cerebral blood flow (CBF) may help determine the pathogenetic mechanisms of this condition. We evaluated myoclonic-atonic seizures using technetium-99m ethylene cysteinate dimer (ECD)-SPECT and ictal SPECT subtraction co-registered with magnetic resonance imaging (SISCOM). A 3-year-old boy with normal development presented with truncal ataxia caused by acute cerebellitis at 1 year and 10 months, followed by atonic seizures at 2 years and 1 month and myoclonic-atonic seizures at 2 years and 6 months. Seizures could not be controlled by valproate, lamotrigine, or clonazepam. By 3 years of age, he experienced up to 40 myoclonic-atonic seizures per day, confirmed using ictal electroencephalography. Interictal electroencephalography showed diffuse spike-and-wave complexes. Ictal ECD-SPECT demonstrated increased CBF in the right precentral gyrus and temporal lobe and decreased CBF in both thalami. The patient was diagnosed with epilepsy with myoclonic-atonic seizures. Seizure control was achieved after adrenocorticotropic hormone therapy. Following treatment, interictal ECD-SPECT images demonstrated no difference in CBF between the left and right precentral gyri and temporal lobes, and resolution of hypoperfusion in both thalami. SISCOM revealed hyperperfusion in the right centroparietal region. Adrenocorticotropic hormone therapy successfully treated myoclonic-atonic seizures and resolved bilateral thalamic hypoperfusion. Thalamic dysfunction may also be involved in myoclonic-atonic seizures. This case uniquely demonstrates CBF changes in the motor cortex and thalamus and provides insight into the mechanisms underlying myoclonic-atonic seizures.
2017-03-01 | Epilepsy with myoclonic atonic seizures and chronic cerebellar symptoms associated with antibodies against glutamate receptors N2B and D2 in serum and cerebrospinal fluid
A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell-based assay revealed the presence of anti-NMDA-type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti-C-terminal GluN2B and anti-N-terminal GluD2 antibodies, and CSF anti-N-terminal GluN2B and anti-C-terminal anti-GluD2 antibodies. Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.
gene therapies
2025-03-23 | Epilepsy with myoclonic-atonic seizures: an update on genetic causes, nosological limits, and treatment strategies.
Epilepsy with myoclonic-atonic seizures is a childhood-onset epilepsy syndrome characterised by a range of seizure types, including myoclonic-atonic, atonic, myoclonic, absence, and generalised tonic-clonic seizures. The causes and outcomes of this syndrome are highly variable, with many uncertainties surrounding its classification and prognosis. Traditional antiseizure medications and the ketogenic diet remain the main treatment options. Although two-thirds of children attain remission from seizures without cognitive or behavioural sequelae, some continue to have drug-resistant seizures, intellectual disability, and behavioural problems. The identification of single-gene causes in a substantial subset of patients highlights the importance of genetic testing for development of personalised treatment strategies. However, diagnostic complexities have hindered the development of trials for new therapies. Better recognition of the distinct features of epilepsy with myoclonic-atonic seizures, combined with advances in molecular genetic testing, will pave the way for more focused clinical research and drug development. Future studies should aim to identify genetic causes and tailor treatment options, offering hope for improved long-term outcomes.
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Drug Discovery Landscape
3 orphan drug designations for Myoclonic-astatic epilepsy.
3 orphan drug designations for Myoclonic-astatic epilepsy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Cannabidiol | small molecules | EMA | Jazz Pharmaceuticals Ireland Limited | |
cannabidiol oral solution (CBD-OS) | small molecules | FDA | Jazz Pharmaceuticals Research UK Limited | |
adeno-associated viral vector serotype 9 encoding a codon-optimized human SLC6A1 transgene | gene therapies | FDA | — | University of Texas Southwestern Medical Center |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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