大田原症候群

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

INTRODUCTION: Ohtahara syndrome (OS) features neonatal-onset tonic spasms with suppression-burst EEG, high early mortality, and evolution to other epileptic encephalopathies. Respiratory complications are frequent yet underdescribed longitudinally. CASE: We followed a female with neonatal-onset OS and suppression-burst EEG to the age of seven. Despite combination antiseizure therapy (phenobarbital, levetiracetam, vigabatrin, and clonazepam), she had breakthrough events and severe developmental impairment. Between the ages 1 and 7 years, she experienced ≥ 15 documented hospitalizations for recurrent bronchopneumonia, frequently with hypoxemia requiring supplemental oxygen; several episodes were accompanied by seizure exacerbations and clinical aspiration or choking events. MANAGEMENT AND OUTCOMES: Admissions were managed with supportive respiratory care (oxygen, bronchodilators, and corticosteroids when indicated) and broad-spectrum antimicrobials alongside ongoing seizure management, enabling survival to school age in a resource-limited context. CONCLUSIONS: In OS, respiratory complications, often driven by aspiration risk and impaired airway clearance, can become a dominant source of morbidity and should be addressed with the same priority as antiseizure therapy. We highlight practical pillars for long-term care: proactive infection prevention and early treatment pathways; aspiration-risk assessment with feeding/swallow support when feasible; airway-clearance planning with bronchodilator trials during illnesses; judicious corticosteroid use; and caregiver education with explicit thresholds for escalation.

PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.

To systematically summarize the clinical phenotypes, treatment responses, prognosis, and genetic characteristics of STXBP1-encephalopathy in Chinese pediatric patients, and to explore the clinical value of genetic testing in this disease. We retrospectively analyzed the clinical data, gene variant information, and treatment outcomes of 19 children with STXBP1-encephalopathy admitted to the Department of Pediatrics, Second Affiliated Hospital of Zhejiang University, between January 2020 and January 2024. Whole-exome sequencing was performed for genetic diagnosis, and Sanger sequencing was used to verify variants and confirm their parental origin. Pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics guidelines. STXBP1-encephalopathy showed early onset, with 15 cases (78.9%) occurring within the 1st month of life. Five patients were diagnosed with Ohtahara syndrome, 5 with West syndrome, and 9 with unclassifiable early-onset epileptic encephalopathy. All patients had abnormal electro-encephalogram findings, mainly burst suppression (68.4%) and hypsarrhythmia (63.2%). Among the 19 patients, 1 achieved seizure freedom and discontinued antiepileptic drugs, and 4 achieved seizure control with levetiracetam. A total of 18 de novo pathogenic/likely pathogenic variants in STXBP1 were identified, including 7 novel variants: c.326-3(IVS5)delC, c.656del(p.Met219Argfs*13), c.746-747del(p.F249fs*6), c.798T > G(p.Y266*), c.1155delC(p.D385fs), c.1249G > A(p.G417S), and c.1250-2A > G. STXBP1 pathogenic variants are an important cause of early-onset developmental epileptic encephalopathy in Chinese children. Genetic testing is crucial for early diagnosis of STXBP1-encephalopathy. Levetiracetam shows good efficacy in controlling seizures in these patients, and early use is recommended. The 7 novel variants identified in this study expand the STXBP1 mutation spectrum.

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.