Background: Central nervous system (CNS) infection in childhood can lead to neurological sequelae, including epilepsy, and neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This study investigated the association of etiologically diagnosed childhood brain infections with the subsequent risks of epilepsy and neurodevelopmental disorders. Objectives: We retrospectively analyzed the data of children aged <18 years who had definite brain infections with positive cerebrospinal fluid cultures from January 1, 2005, to December 31, 2017. These patients were followed to evaluate the risks of epilepsy and neurodevelopmental disease (ADHD and ASD) after brain infections (group 1) in comparison with the risks in those without brain infections (group 2). Results: A total of 145 patients with an average age of 41.2 months were included in group 1. Enterovirus accounted for the majority of infections, followed by group B Streptococcus, S. pneumoniae, and herpes simplex virus. A total of 292 patients with an average age of 44.8 months were included in group 2. The 12-year risk of epilepsy in group 1 was 10.7 (95% confidence interval [CI], 2.30–49; p < 0.01). Compared with group 2 (reference), the risk of ASD in the age interval of 2–5 years in group 1 was 21.3 (95% CI, 1.33–341.4; p = 0.03). The incidence of ADHD in group 1 was not significantly higher than that in group 2. Conclusions: This study identified the common etiological causes of brain infections in Taiwanese children. The highest-risk neurodevelopmental sequelae associated with brain infections was epilepsy. Children who had a diagnosis of brain infection (specially Enterovirus) should be followed since they are at greater risk of developing epilepsy and ASD.

Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes is currently accessible and has resulted in higher rates of diagnosis and better comprehension of the disease mechanisms underlying the condition. Children with developmental disabilities have a higher risk of developing epilepsy. As our understanding of the mechanisms underlying encephalopathies and epilepsies improves, there may be greater potential to develop innovative therapies tailored to an individual’s genotype. This article provides an overview of the significant progress in epilepsy genomics in recent years, with a focus on developmental and epileptic encephalopathies in children. The aim of this review is to enhance comprehension of the clinical utilization of genetic testing in this particular patient population. The development of effective and precise therapeutic strategies for epileptic encephalopathies may be facilitated by a comprehensive understanding of their molecular pathogenesis.

Rationale: Progressive encephalopathy with brain edema and/or leukoencephalopathy-1 is an infantile, lethal neurometabolic disorder caused by a NAD(P)HX epimerase (NAXE) gene mutation. It is characterized by a fluctuating disease course with repeated episodes of improvement and regression. In this report, we present a rare case of NAXE gene mutation-related encephalopathy with unexpected neurological recovery and long survival time. Patient concerns: A 20-month-old girl presented with progressively unsteady gait and bilateral hand tremors after a trivial febrile illness. Her disease rapidly progressed to consciousness disturbance, 4-limb weakness (muscle power: 1/5 on the Medical Research Council scale), and respiratory failure. The patient gradually recovered 2 months later. However, another episode of severe fever-induced encephalopathy developed 2 years after the initial presentation. Diagnoses: Results of laboratory investigations, including complete blood count, blood chemistry, inflammatory markers, and cerebral spinal fluid analysis were unremarkable. Electroencephalography and nerve conduction velocity studies yielded normal results. Brain magnetic resonance imaging on diffusion-weighted imaging revealed abnormal sysmmetric hyperintensity in the bilateral middle cerebellar peduncles. A genetic study using whole exome sequencing confirmed the diagnosis of NAXE gene mutation-related encephalopathy. Interventions: Pulse therapy with methylprednisolone, intravenous immunoglobulin, coenzyme Q10, and carnitine were initially introduced. After a NAXE gene defect was detected, the vitamin B complex and coenzyme Q10 were administered. A continuous rehabilitation program was also implemented. Outcomes: NAXE gene mutation-related encephalopathy is usually regarded as a lethal neurometabolic disorder. However, the outcome in this case is better than that in the previous cases. She showed progressive neurological recovery and a longer survival time. The muscle power of the 4 limbs recovered to grade 4. At present (age of 5.5 years old), she can walk with an unsteady gait and go to school. Lessons: Although NAXE gene mutation-related encephalopathy is rare, it should be considered as a differential diagnosis of early onset progressive encephalopathy.

Defective autophagy is one of the cellular hallmarks of Parkinson’s disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of Acanthopanax senticosus. It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in C. elegans, degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome–lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting SIRT1. The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.

Background: Kawasaki disease (KD) is a common vasculitis of childhood in East Asia. The complications of KD ascribed to long-term cardiovascular sequelae are considerably diverse. Although studies have investigated neurodevelopmental problems following KD in the past few decades, they have reported inconsistent conclusions. This study investigated potential epilepsy and associated neurodevelopmental disorders (NDDs) following KD in Taiwanese children. Methods: We retrospectively analyzed the data of children aged < 18 years with clinically diagnosed KD from January 1, 2005, to December 31, 2015. These patients were followed up to estimate the prevalence of epilepsy and associated NDDs in comparison with the prevalence in general pediatric population in Taiwan and worldwide. Results: A total of 612 patients with an average age of 1.6 years were included. The prevalence of associated NDDs was 16.8% (n = 103/612) in the study group, which consisted of epilepsy, intellectual disability (ID), autism spectrum disorders, Tourette syndrome (TS), attention deficit hyperactivity disorder, (ADHD), and others. Moreover, children with KD had a higher prevalence of epilepsy and TS in both Taiwan and worldwide (epilepsy: 2.61% in the KD group vs 0.33% in Taiwan and 0.05–0.8% in worldwide, p < 0.05; TS: 2.77% in the KD group vs 0.56% in Taiwan and 0.3–1% in worldwide, p < 0.05). The prevalence of ID, ADHD, and developmental language disorders was not significantly different between our study patients and those in Taiwan or worldwide. Conclusions: Results revealed a higher prevalence rate of NDDs, especially epilepsy and TS, in Taiwanese children with KD than in the general pediatric population in Taiwan. However, these NDDs could be heterogeneous. Children diagnosed with KD were followed up because they had a higher risk of heterogeneous NDDs.

Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA₅₀) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA₅₀ interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA₅₀, thus inhibiting NLRP3 inflammasome activity in GA₅₀-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.