Brain & Development最新文献

{"title":"Gene therapy for lysosomal storage diseases.","authors":"Hiroshi Kobayashi","doi":"10.1016/j.braindev.2025.104399","DOIUrl":"https://doi.org/10.1016/j.braindev.2025.104399","url":null,"abstract":"<p><p>Lysosomal storage diseases (LSDs) are metabolic disorders caused by the dysfunction of enzymes and other substances localized in lysosomes, known as intracellular organelles. There are many types of LSDs, with a wide range of clinical manifestations. LSDs are highly amenable to gene therapy due to various reasons, including the fact that they are essentially monogenic diseases and existence of cross-correction mechanisms. The only gene therapy product currently approved for lysosomal diseases is one for metachromatic leukodystrophy, but several have progressed to phase III clinical trials such as the products for Mucopolysaccharidosis or Fabry disease. However, serious adverse events have been reported even with gene therapy methods that have been considered safe. Therefore, research on the safety of gene therapy is becoming increasingly important.</p>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"104399"},"PeriodicalIF":1.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-497/PLD regulation contributes to cognitive dysfunction in neonatal rats after repeated sevoflurane exposure","authors":"Yuanyuan Que ,&nbsp;Xingtao Chen ,&nbsp;Dawei Liao ,&nbsp;Duwen Zhang ,&nbsp;Deliang Zeng","doi":"10.1016/j.braindev.2025.104409","DOIUrl":"10.1016/j.braindev.2025.104409","url":null,"abstract":"<div><h3>Background</h3><div>Repeated sevoflurane exposure during early development can induce neurotoxic effects. MicroRNAs (miRNAs) are critical regulators of gene expression, playing essential roles in neural development and function, but their exact mechanisms remain unclear. This study investigates the role of the miR-497/Phospholipase D1(PLD1) axis, which is involved in neuronal differentiation and survival, in mediating the neurotoxic effects of repeated sevoflurane anesthesia.</div></div><div><h3>Methods</h3><div>Neonatal rats were treated with sevoflurane repeatedly. The expression levels of miR-497 in the rat hippocampi were assessed using qRT-PCR, and neuronal apoptosis was detected by TUNEL assay. PLD1 was predicted and confirmed as a target of miR-497. The regulatory relationship between PLD1 and miR-497 in primary neuronal cells was determined using luciferase reporter assays and Western blot. Immunohistochemistry was employed to examine PLD1 expression. A rescue experiment was performed to confirm the involvement of the miR-497/PLD1 pathway in sevoflurane-induced neurotoxicity. Cognitive performance was evaluated using Moris water maze.</div></div><div><h3>Results</h3><div>We identified the miR-497/PLD1 axis as the central mediator of sevoflurane-induced neurotoxicity. Repeated sevoflurane exposure triggered a striking upregulation of hippocampal miR-497, which directly targeted the 3′-UTR of PLD1 to suppress its expression. Functional validation demonstrated that miR-497 inhibition rescued neuronal injury and apoptosis, whereas silencing PLD1 abolished the neuroprotective effects of miR-497 suppression, establishing PLD1 as the indispensable downstream effector of miR-497.</div></div><div><h3>Conclusions</h3><div>Our study provides the first evidence that dysregulation of the miR-497/PLD1 axis drives sevoflurane-related newborn cognitive deficits. This mechanistic insight advances our understanding of anesthetic neurotoxicity, while targeting this newly identified axis may represent a novel therapeutic strategy to counteract anesthesia-associated neurodevelopmental risks.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104409"},"PeriodicalIF":1.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic features of congenital myasthenic syndrome due to the muscle acetylcholine receptor genes","authors":"Jing Guan ,&nbsp;Min Zhang ,&nbsp;Chaoping Hu ,&nbsp;Lei Zhao ,&nbsp;Linmei Zhang ,&nbsp;Xihua Li ,&nbsp;Yi Wang ,&nbsp;Shuizhen Zhou ,&nbsp;Wenhui Li","doi":"10.1016/j.braindev.2025.104412","DOIUrl":"10.1016/j.braindev.2025.104412","url":null,"abstract":"<div><h3>Objective</h3><div>The adult nicotinic acetylcholine receptor in muscle is a pentameric complex composed of four transmembrane subunits, and these are encoded by <em>CHRNA1</em>, <em>CHRNB1</em>, <em>CHRND</em>, and <em>CHRNE</em>, respectively. There were only a few case reports of congenital myasthenic syndromes due to <em>CHRNA1</em>, <em>CHRNB1</em>, and <em>CHRND</em>. We aimed to share phenotypic and genotypic features of the patients.</div></div><div><h3>Methods</h3><div>The clinical features, genetic variants, treatment, and follow-up of congenital myasthenic syndromes patients due to <em>CHRNA1</em>, <em>CHRNB1</em>, <em>CHRND</em> and <em>CHRNE</em> were retrospectively reviewed<strong>.</strong> In addition, a questionnaire-based survey using pediatric quality of life inventory 3.0 neuromuscular module (PedQL™3.0NMM) was conducted on the caregivers.</div></div><div><h3>Results</h3><div>Fourteen patients were enrolled in this study. The variants in <em>CHRNE</em> were the most prevalent (42.9 %), followed by variants in <em>CHRNA1</em>(21.4 %), <em>CHRND</em> (21.4 %), and <em>CHRNB1</em> (14.3 %), respectively. Symptoms presented at birth in 10 patients (71.4 %) and during infancy in the remaining four patients (28.6 %). The patients due to <em>CHRNA1</em>, <em>CHRNB1</em>, and <em>CHRND</em> had an earlier onset(<em>p</em> = 0.01). The initial clinical feature in 6 patients with <em>CHRNE</em> variants was ptosis. In the patients with <em>CHRNA1</em>, <em>CHRNB1</em>, and <em>CHRND</em> variants, the most common initial presentation was feeding difficulties in 6 of 8. Pyridostigmine was beneficial in 12 (92.3 %) patients. Salbutamol was then tried in 10 patients, and only two patients stopped it for no more effects. The mean score of PedQL™3.0 in 10 patients under therapy was 76.50 ± 11.66.</div></div><div><h3>Conclusions</h3><div>All patients had very early onset, and most had ocular, limb, and bulbar symptoms. The patients due to <em>CHRNA1</em>, <em>CHRNB1</em>, and <em>CHRND</em> had an early age at onset and more severe initial symptoms. Most of the patients got some benefit from therapy and had satisfactory results of the life quality survey.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104412"},"PeriodicalIF":1.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of foot intrinsic muscle dynamic stretching intervention on static balance, gait parameters and gross motor ability with hemiplegic cerebral palsy: a randomized controlled pilot study","authors":"YoungHwan Kwag ,&nbsp;DongHwan Park","doi":"10.1016/j.braindev.2025.104414","DOIUrl":"10.1016/j.braindev.2025.104414","url":null,"abstract":"<div><h3>Background</h3><div>The foot intrinsic muscle dynamic stretching (FIMDS) intervention can increase ankle stability, stabilize the foot arch, and induce an increase in gross motor ability.</div></div><div><h3>Objectives</h3><div>The objective of this study is to compare the effects of a 6-week program of FIMDS with those of a slant board (SB) on static balance with open and closed eyes, gait parameters (gait speed, cadence), and gross motor ability in children with cerebral palsy (CP).</div></div><div><h3>Methods</h3><div>Participants were randomized into either the FIMDS (<em>n</em> = 7) or SB (n = 7) group. Patients in both groups underwent standard physiotherapy for 30 min per session. Additionally, FIMDS and SB interventions were performed in 3 sets of 10 repetitions, 3 times a week for 6 weeks. Static balance (with open and closed eyes), gait speed, cadence, and gross motor ability were measured after the 6 weeks of training.</div></div><div><h3>Results</h3><div>After 6 weeks of training, both the FIMDS and SB groups showed significant improvement in all outcome measures compared to baseline (<em>p</em> &lt; .05). Furthermore, the FIMDS group demonstrated greater improvement in open eyes static balance, gait speed, cadence, and gross motor ability while standing compared to the SB group (<em>p</em> &lt; .05).</div></div><div><h3>Conclusions</h3><div>This study demonstrated that FIMDS training, combined with standard physiotherapy, improved open eyes static balance, gait speed, cadence, and gross motor ability while standing in children with hemiplegic CP.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104414"},"PeriodicalIF":1.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inherited white matter disorders in Japan: focusing on demyelinating leukodystrophy","authors":"Masayuki Sasaki","doi":"10.1016/j.braindev.2025.104404","DOIUrl":"10.1016/j.braindev.2025.104404","url":null,"abstract":"<div><div>We reviewed published articles on representative inherited cerebral white matter disorders that develop in childhood. In this paper, we described demyelinating disorders (adrenoleukodystrophy, globoid cell leukodystrophy or Krabbe disease, and metachromatic leukodystrophy), astrocytic disorders (Alexander disease and vanishing white matter disease), and disorders of water homeostasis in the myelin sheath (megalencephalic leukoencephalopathy with subcortical cysts and <em>CLCN2</em>-related leukoencephalopathy). The causes, symptoms, diagnostic imaging, and forefront of treatment for these disorders are discussed. Each disease is rare and progressive. Although the number of analyzed cases is very small, establishing a radical treatment is still necessary. We do hope that the patients with these disorders could be treated completely in the near future.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104404"},"PeriodicalIF":1.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor: A case of spinal muscular atrophy type 0 treated with nusinersen without progression of early-onset scoliosis","authors":"Meghan Moore Burk ,&nbsp;Carolyn Kelley ,&nbsp;Kelli Browning ,&nbsp;Anne Stratton ,&nbsp;Susan Apkon ,&nbsp;Melissa Wright ,&nbsp;Michele L. Yang","doi":"10.1016/j.braindev.2025.104411","DOIUrl":"10.1016/j.braindev.2025.104411","url":null,"abstract":"","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104411"},"PeriodicalIF":1.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-COVID-19 trends in pediatric meningitis in the PICU: A multicenter study","authors":"Nihal Akçay ,&nbsp;İlyas Bingöl ,&nbsp;Demet Tosun ,&nbsp;Muhterem Duyu ,&nbsp;Abdulrahman Özel ,&nbsp;Servet Yüce ,&nbsp;Burcu Bursal ,&nbsp;Meningitis Study Group","doi":"10.1016/j.braindev.2025.104408","DOIUrl":"10.1016/j.braindev.2025.104408","url":null,"abstract":"<div><h3>Background</h3><div>Meningitis is a severe and potentially life-threatening infection characterized by inflammation of the leptomeningeal membranes that protect the brain and spinal cord. This study aimed to evaluate the epidemiological and clinical features of pediatric patients with laboratory-confirmed meningitis admitted to pediatric intensive care units (PICUs).</div></div><div><h3>Methods</h3><div>This multicenter retrospective study included patients with laboratory-confirmed meningitis who were admitted to eight tertiary PICUs in Istanbul, Turkey, between January 1, 2023, and December 31, 2024.</div></div><div><h3>Results</h3><div>A total of 66 pediatric patients with laboratory-confirmed meningitis requiring intensive care were included. Of these, 39 (59 %) were diagnosed with bacterial meningitis and 27 (41 %) with viral meningitis. Among the bacterial meningitis cases, the most frequently identified pathogens were <em>Streptococcus pneumoniae</em> (41.0 %), <em>Neisseria meningitidis</em> (15.4 %), and <em>Haemophilus influenzae</em> (10.2 %). In the viral group, the most common pathogens were herpes simplex virus type 1 (25.9 %), enterovirus (22.2 %), and human herpesvirus 6 (22.2 %). The bacterial meningitis group had significantly higher white blood cell counts and C-reactive protein levels, and lower cerebrospinal fluid glucose levels compared with the viral meningitis group (<em>p</em> &lt; 0.05). Signs of meningeal irritation and Pediatric Logistic Organ Dysfunction (PELOD) scores were also significantly higher in the bacterial meningitis group (p &lt; 0.05). Age, sex distribution, PICU length of stay, presenting symptoms, rates of sequelae, and mortality did not differ significantly between the two groups. Intravenous immunoglobulin use was significantly more common in the viral meningitis group (p &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>Bacterial meningitis remains the leading cause of meningitis cases requiring pediatric intensive care. Continued public health efforts are essential to reduce mortality and prevent long-term sequelae associated with this serious condition.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104408"},"PeriodicalIF":1.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic clarification and exclusion of differential diagnoses in pediatric acute encephalopathy","authors":"Josef Finsterer","doi":"10.1016/j.braindev.2025.104407","DOIUrl":"10.1016/j.braindev.2025.104407","url":null,"abstract":"","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104407"},"PeriodicalIF":1.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An atypical case of macrocephaly and severe intellectual disability associated with a missense variant in the guanine nucleotide exchange factor-1 domain of TRIO","authors":"Takuya Hiraide ,&nbsp;Taiju Hayashi ,&nbsp;Kaori Yamoto ,&nbsp;Yohei Masunaga ,&nbsp;Miki Asahina ,&nbsp;Tsutomu Ogata ,&nbsp;Hirotomo Saitsu ,&nbsp;Tokiko Fukuda","doi":"10.1016/j.braindev.2025.104405","DOIUrl":"10.1016/j.braindev.2025.104405","url":null,"abstract":"<div><h3>Background</h3><div>Trio rho guanine nucleotide exchange factor (<em>TRIO</em>)<em>,</em> encodes a guanine nucleotide exchange factor (GEF) that is critical for neurodevelopment and regulates Rho guanosine triphosphatase. It has been shown that missense variants in the GEF1 or GEF2 domains or loss-of-function variants in <em>TRIO</em> are associated with microcephaly while gain-of-function variants in the spectrin repeat domain result in macrocephaly. Rare cases of macrocephaly linked to missense variants in the GEF1 domain have been reported; however, clinical details remain limited.</div></div><div><h3>Case presentation</h3><div>We describe the case of a Japanese boy with macrocephaly, severe intellectual disability, distinctive facial features, scoliosis, and growth hormone deficiency. Brain magnetic resonance imaging revealed a thin corpus callosum and pituitary hypoplasia. His occipitofrontal circumference was +2.5 standard deviations above the normal range, while his height and weight were below the average. He displayed many features characteristic of <em>TRIO</em>-related neurodevelopmental disorders caused by gain-of-function variants. However, trio-based exome sequencing identified a <em>de novo</em> missense variant (instead of gain-of-function variant) in the GEF1 domain of <em>TRIO</em> (NM_007118.4:c.4104T&gt;A, p.(Asp1368Glu)).</div></div><div><h3>Conclusions</h3><div>This case expands the phenotypic spectrum of <em>TRIO</em>-related neurodevelopmental disorders, highlighting macrocephaly associated with a missense variant in the GEF1 domain. Further studies are required to clarify the functional effects of <em>TRIO</em> variants and their phenotypic consequences.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104405"},"PeriodicalIF":1.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duchenne muscular dystrophy: Evolving therapeutic strategies and multidimensional evaluation approaches","authors":"Hirofumi Komaki","doi":"10.1016/j.braindev.2025.104397","DOIUrl":"10.1016/j.braindev.2025.104397","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disorder caused by the absence of dystrophin. Standard therapies prolong survival; however, there is an increasing need for disease-modifying approaches and sensitive evaluation tools. This review presents a summary of the recent advances in DMD therapeutic strategies and multidimensional evaluation approaches, emphasizing their clinical applicability and future perspectives. In this study, a comprehensive review of the current literature was conducted focusing on mutation-specific therapies (exon skipping and gene therapy), non-mutation-specific pharmacological interventions (steroids, vamorolone, and histone deacetylase inhibitors), and emerging modalities such as cell-based therapy. The clinical outcome measures used across the disease stages were also examined, ranging from functional motor tests and imaging biomarkers to digital endpoints and quality of life (QOL) indices. Exon skipping and microdystrophin gene therapies have shown promising results in restoring partial dystrophin expression. Vamorolones and givinostat are alternative drugs with improved safety profiles. Time-based motor tests (such as time to sand, 10 m run) and digital biomarkers (Stride Velocity 95th Centile) enable the earlier detection of disease progression. Natural history data, including large registry-based datasets, enhance the interpretation of clinical trials. Patient-reported outcomes and disease-specific QOL measures, such as the DMD-QoL, are increasingly being incorporated to assess meaningful treatment benefits. The therapeutic landscape of DMD is evolving toward combination and personalized approaches. Multidimensional stage-specific evaluations are essential to capture functional changes and their therapeutic effects. Ongoing research on gene-, pharmacological-, and cell-based therapies, coupled with robust outcome assessments, may further improve patient care and QOL.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104397"},"PeriodicalIF":1.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}