進行性ミオクローヌスてんかん

Lafora disease (LD) is a fatal neurodegenerative disorder caused by mutations in the EPM2A or EPM2B/NHLRC1 genes, encoding Laforin and Malin, respectively. While the Laforin/Malin E3-ubiquitin ligase complex is a known regulator of canonical autophagy and glycogen metabolism, its role in non-canonical autophagy pathways remains unexplored. Given that neuroinflammation is a hallmark of LD, we investigated the relationship between the Laforin/Malin complex and Rubicon, a critical regulator of LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO). In this work, we identify Rubicon as a novel substrate and binding partner of the Laforin/Malin complex. Co-immunoprecipitation and confocal microscopy assays in HEK293 and U2OS cells demonstrated that Malin physically interacts with Rubicon, promoting its K63-linked polyubiquitination. This post-translational modification adds another layer of control to the regulation of Rubicon in specific cellular contexts. To determine the functional relevance of this interaction in LD, we assessed LAP and LANDO in primary astrocytes from Malin-deficient mice. Using flow cytometry, we quantified the engulfment and degradation of Zymosan particles and microglial debris (LAP), as well as EGF receptor internalization (LANDO). Surprisingly, no significant functional impairments were observed in Malin-deficient astrocytes compared to WT controls. These findings suggest that while the Laforin/Malin complex regulates Rubicon via K63-linked ubiquitination, redundant signaling nodes may preserve non-canonical autophagy output in Malin-deficient astrocytes.

ObjectiveWe aimed to characterize the clinical, magnetic resonance imaging, and genetic features of Chinese patients with dentatorubral-pallidoluysian atrophy.MethodsIn this retrospective case-series and literature-review study, we analyzed three affected members belonging to the same family diagnosed at our institution. We also reviewed genetically confirmed Chinese dentatorubral-pallidoluysian atrophy cases reported in the China National Knowledge Infrastructure, Wanfang, and PubMed databases up to 31 May 2025 and included additional 42 patients from separate families. Cases with available age at onset, initial symptoms, and CAG repeat size were included; cases without magnetic resonance imaging data were excluded only from imaging-specific analyses. Thus, the final cohort included 45 Chinese dentatorubral-pallidoluysian atrophy patients.ResultsForty-five patients were analyzed. The median ATN1 CAG repeat count was 62 (range, 53-79), and mean age at onset was 28.22 ± 17.48 (range, 2-69) years. Seizures (46.7%) and gait instability (42.2%) were the most common initial manifestations. Multiple clinical manifestations frequently co-occurred, including gait instability (88.9%), cognitive impairment (73.3%), speech impairment (66.7%), seizures (64.4%), and involuntary movements (48.9%). Patients with seizure onset had larger CAG expansions and younger age at onset than those with gait-instability onset. Age at onset negatively correlated with CAG repeat count in the overall cohort and seizure-onset subgroup, but not in the gait-instability subgroup.ConclusionsLarger ATN1 CAG repeat expansions may be associated with earlier onset, especially in seizure-predominant dentatorubral-pallidoluysian atrophy. Magnetic resonance imaging commonly shows cerebellar atrophy and white-matter or brainstem involvement. After excluding common causes, dentatorubral-pallidoluysian atrophy should be considered in patients presenting with unexplained combinations of seizures, ataxia, cognitive impairment, and a compatible family history.

PURPOSE: 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. CASE DESCRIPTION: 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. COMMENT: 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.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an ultra-rare, fatal autosomal-recessive disorder caused by ASAH1 mutations, with no curative treatment. We report the first-in-human intravenous administration of an AAV9 vector carrying the human ASAH1 coding sequence in a 15-year-old female with advanced SMA-PME (heterozygous ASAH1 c.456A>C and c.918-2A>G mutations). The patient presented with severe neuromuscular impairment, deafness, and recurrent myoclonic status epilepticus, without detectable anti-AAV9 neutralizing antibodies. A marked clinical deterioration warranted compassionate use (GNT-017-ASAH-CU). A dose of 2.2 × 1014 vector genomes per kilogram of body weight was administered under prophylactic prednisolone and sirolimus. The patient experienced rapid onset of complement activation leading to cytokine-mediated capillary leak syndrome, culminating in refractory shock, multiorgan failure, and death on day 8. A postmortem examination revealed acute circulatory failure as the cause of death without myocarditis or thrombotic microangiopathy. Some endothelial injury was suggested by a rise in von Willebrand factor from days 4 to 8, paralleled by increased hyaluronic acid on days 7 and 8. These findings underscore the potential for life-threatening innate immune activation in patients with advanced SMA-PME receiving high-dose systemic AAV9 gene therapy, highlighting the need to identify high-risk patients and proactively monitor biomarkers of endothelial injury.

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.