Trio rho guanine nucleotide exchange factor (TRIO), 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 TRIO 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.
Case presentation
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 TRIO-related neurodevelopmental disorders caused by gain-of-function variants. However, trio-based exome sequencing identified a de novo missense variant (instead of gain-of-function variant) in the GEF1 domain of TRIO (NM_007118.4:c.4104T>A, p.(Asp1368Glu)).
Conclusions
This case expands the phenotypic spectrum of TRIO-related neurodevelopmental disorders, highlighting macrocephaly associated with a missense variant in the GEF1 domain. Further studies are required to clarify the functional effects of TRIO variants and their phenotypic consequences.
背景：rho鸟嘌呤核苷酸交换因子（TRIO）编码一种鸟嘌呤核苷酸交换因子（GEF），对神经发育至关重要，并调节rho鸟嘌呤三磷酸酶。研究表明，GEF1或GEF2结构域的错义变异或TRIO中的功能缺失变异与小头畸形有关，而spectrin重复结构域的功能获得变异导致大头畸形。已经报道了与GEF1结构域错义变异相关的罕见大头畸形病例；然而，临床细节仍然有限。我们描述了一个日本男孩的情况下，巨大的头畸形，严重的智力障碍，独特的面部特征，脊柱侧凸，生长激素缺乏。脑磁共振显示胼胝体薄，垂体发育不全。他的枕额围大于正常范围+2.5个标准差，而他的身高和体重低于平均水平。他表现出由功能获得变异引起的与trio相关的神经发育障碍的许多特征。然而，基于TRIO的外显子组测序在TRIO的GEF1结构域中发现了一个全新的错义变体（而不是功能获得变体）（NM_007118.4:c.4104T> a, p.(Asp1368Glu)）。结论：该病例扩展了trio相关神经发育障碍的表型谱，突出了与GEF1结构域错义变异相关的大头畸形。需要进一步的研究来阐明TRIO变异的功能影响及其表型后果。
{"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 , Taiju Hayashi , Kaori Yamoto , Yohei Masunaga , Miki Asahina , Tsutomu Ogata , Hirotomo Saitsu , 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>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":"2025-10-01","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}
Pub Date : 2025-10-01Epub Date: 2025-09-06DOI: 10.1016/j.braindev.2025.104426
Hitoshi Osaka , Ken Inoue
Hypomyelinating leukodystrophies (HLDs) are a group of inherited disorders characterized by impaired myelin formation in the central nervous system. Among them, Pelizaeus-Merzbacher disease (PMD) is a well-defined X-linked leukodystrophy caused by mutations in the PLP1 gene, including duplications, missense variants, and null mutations. Recent studies have revealed that different types of PLP1 mutations lead to distinct pathomechanisms: while missense mutations induce endoplasmic reticulum stress and activate the unfolded protein response (UPR), PLP1 duplications cause aberrant intracellular trafficking and cholesterol accumulation without UPR activation. Additionally, mutations in other genes such as GJC2, SOX10, TUBB4A, and POLR3A/B have been implicated in various forms of HLD, each with unique clinical and imaging features. Advances in neuroimaging and next-generation sequencing have enabled more accurate and earlier diagnosis, expanding the clinical spectrum and deepening our understanding of disease mechanisms. This review summarizes the current knowledge on the molecular pathogenesis, genotype–phenotype correlations, and diagnostic approaches in HLDs, with an emphasis on recent biological insights that may inform future therapeutic strategies.
{"title":"Hypomyelinating leukodystrophy: From molecular mechanisms to clinical advances","authors":"Hitoshi Osaka , Ken Inoue","doi":"10.1016/j.braindev.2025.104426","DOIUrl":"10.1016/j.braindev.2025.104426","url":null,"abstract":"<div><div>Hypomyelinating leukodystrophies (HLDs) are a group of inherited disorders characterized by impaired myelin formation in the central nervous system. Among them, Pelizaeus-Merzbacher disease (PMD) is a well-defined X-linked leukodystrophy caused by mutations in the <em>PLP1</em> gene, including duplications, missense variants, and null mutations. Recent studies have revealed that different types of <em>PLP1</em> mutations lead to distinct pathomechanisms: while missense mutations induce endoplasmic reticulum stress and activate the unfolded protein response (UPR), <em>PLP1</em> duplications cause aberrant intracellular trafficking and cholesterol accumulation without UPR activation. Additionally, mutations in other genes such as <em>GJC2</em>, <em>SOX10</em>, <em>TUBB4A</em>, and <em>POLR3A/B</em> have been implicated in various forms of HLD, each with unique clinical and imaging features. Advances in neuroimaging and next-generation sequencing have enabled more accurate and earlier diagnosis, expanding the clinical spectrum and deepening our understanding of disease mechanisms. This review summarizes the current knowledge on the molecular pathogenesis, genotype–phenotype correlations, and diagnostic approaches in HLDs, with an emphasis on recent biological insights that may inform future therapeutic strategies.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104426"},"PeriodicalIF":1.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003691","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}
Small for gestational age (SGA) and developmental coordination disorder (DCD) are receiving increasing attention in pediatric development. Understanding the risk of DCD, particularly in relation to SGA, would support children's health and development. However, the relationship between SGA and DCD remains unveiled beyond single-cohort studies.
Objectives
This study aimed to integrate findings on DCD from different cohorts within the nationwide prospective Japanese Birth Cohort Consortium (JBiCC).
Study design and subjects
DCD was assessed in children aged 4 to 7 years from three birth cohorts participating in the JBiCC: the Hokkaido Study on Environment and Children's Health (Hokkaido Study), the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), and the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study).
Outcome measures
DCD was assessed using either the Developmental Coordination Disorder Questionnaire Japanese Version (DCDQ-J) or the Ages and Stages Questionnaires Third Edition (ASQ-3). Logistic regression was used to assess the association between SGA and DCD in each cohort. Second, meta-analysis of the association between SGA and DCD defined by DCDQ-J, and individual patient data (IPD) meta-analysis of the association between SGA and DCDQ-J scores were conducted with two cohorts.
Results and conclusions
The analysis included 14,233 children in three cohorts. The individual cohort analyses did not explore statistical significance, except for the TMM BirThree Cohort Study. Meta-synthesis of the Hokkaido and HBC studies showed a β-coefficient of −2.63, 95 % CI [−5.22, −0.03]. IPD analysis of linear regression showed a β-coefficient of −2.76, 95 % CI [−5.38, −0.15]. Our results suggest that SGA may be a potential risk factor for DCD.
{"title":"Small for gestational age as a predictor of developmental coordination disorders: Exploring early risk from Japan birth cohort consortium","authors":"Hiroyoshi Iwata , Maki Tojo , Kenji J. Tsuchiya , Mami Ishikuro , Geng Chen , Satoshi Suyama , Akio Nakai , Naomi Tamura , Toshio Yoshikawa , Toyoki Yamagata , Tomoko Nishimura , Takeshi Yamaguchi , Keiko Yamazaki , Taku Obara , Kazue Ishitsuka , Naho Morisaki , Keitaro Makino , Shinichi Kuriyama , Reiko Kishi","doi":"10.1016/j.braindev.2025.104435","DOIUrl":"10.1016/j.braindev.2025.104435","url":null,"abstract":"<div><h3>Background</h3><div>Small for gestational age (SGA) and developmental coordination disorder (DCD) are receiving increasing attention in pediatric development. Understanding the risk of DCD, particularly in relation to SGA, would support children's health and development. However, the relationship between SGA and DCD remains unveiled beyond single-cohort studies.</div></div><div><h3>Objectives</h3><div>This study aimed to integrate findings on DCD from different cohorts within the nationwide prospective Japanese Birth Cohort Consortium (JBiCC).</div></div><div><h3>Study design and subjects</h3><div>DCD was assessed in children aged 4 to 7 years from three birth cohorts participating in the JBiCC: the Hokkaido Study on Environment and Children's Health (Hokkaido Study), the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), and the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study).</div></div><div><h3>Outcome measures</h3><div>DCD was assessed using either the Developmental Coordination Disorder Questionnaire Japanese Version (DCDQ-J) or the Ages and Stages Questionnaires Third Edition (ASQ-3). Logistic regression was used to assess the association between SGA and DCD in each cohort. Second, meta-analysis of the association between SGA and DCD defined by DCDQ-J, and individual patient data (IPD) meta-analysis of the association between SGA and DCDQ-J scores were conducted with two cohorts.</div></div><div><h3>Results and conclusions</h3><div>The analysis included 14,233 children in three cohorts. The individual cohort analyses did not explore statistical significance, except for the TMM BirThree Cohort Study. Meta-synthesis of the Hokkaido and HBC studies showed a β-coefficient of −2.63, 95 % CI [−5.22, −0.03]. IPD analysis of linear regression showed a β-coefficient of −2.76, 95 % CI [−5.38, −0.15]. Our results suggest that SGA may be a potential risk factor for DCD.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104435"},"PeriodicalIF":1.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120899","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}
Pub Date : 2025-10-01Epub Date: 2025-09-18DOI: 10.1016/j.braindev.2025.104451
Christian Messina
{"title":"Decoding the pathophysiological role of fukutin in Fukuyama congenital muscular dystrophy","authors":"Christian Messina","doi":"10.1016/j.braindev.2025.104451","DOIUrl":"10.1016/j.braindev.2025.104451","url":null,"abstract":"","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104451"},"PeriodicalIF":1.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093135","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}
Pub Date : 2025-10-01Epub Date: 2025-10-06DOI: 10.1016/j.braindev.2025.104462
Nihal Akçay
{"title":"Response to the letter to the editor “When details matter: Critical considerations in the study of meningitis”","authors":"Nihal Akçay","doi":"10.1016/j.braindev.2025.104462","DOIUrl":"10.1016/j.braindev.2025.104462","url":null,"abstract":"","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104462"},"PeriodicalIF":1.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246062","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}
Pub Date : 2025-10-01Epub Date: 2025-08-20DOI: 10.1016/j.braindev.2025.104420
Vykuntaraju K. Gowda , Annsmol P. Markose , Varunvenkat M. Srinivasan , Uddhava V. Kinhal , Runa Hamid
Background
Neurotransmitter disorders are a group of heterogeneous conditions that comprise defects in synthesis, transport, receptor binding, and degradation of neurochemical messengers. These rare disorders range from mild intermittent dystonia to lethal encephalopathies. The natural history and clinical presentation remain far from established.
Objectives
The study was conducted between October 2015 and September 2024. This study aims to describe the spectrum of clinical presentation, laboratory, imaging features, and genetic profiles of children diagnosed with neurotransmitter disorders and to assess the treatment modalities and clinical outcomes in these children.
Results
Among 29 patients, the median age was 12 months, with a male predominance. Positive family history was noted in 9 cases. The most frequent presentation was global developmental delay (GDD), dystonia, and seizures with autonomic disturbances, with diurnal variation. Various subcategories of neurotransmitter disorders are aromatic L amino acid decarboxylase deficiency-7 cases, tyrosine hydroxylase deficiency-3 cases, dopamine transporter deficiency syndrome-1 case, vesicular monoamine transporter 2 deficiency (VMAT2)-2 cases, GTP cyclohydrolase type deficiency-1 case, 6-pyruvoyl-tetrahydropterin synthase deficiency-1 case, dihydropteridine reductase deficiency-3, sepiapterin reductase deficiency-1 case, glycine encephalopathy-1 case, FOLR1-related cerebral folate transport deficiency-3 cases, and succinic semialdehyde dehydrogenase deficiency-5 cases. Metabolic workups were normal in all cases, with elevated phenylalanine levels in tandem mass spectrometry (TMS) in 5 children. Neuroimaging and electroencephalogram (EEG) were abnormal in 7 and 5 children, respectively. Multi-pronged and early treatment ensured better outcomes in these children.
Conclusion
The most common type of neurotransmitter disorder in our series was aromatic L-amino acid decarboxylase deficiency, with the most common presentation being global developmental delay and dystonia.
{"title":"Treatable and preventable causes of inborn errors of metabolism: Cohort of neurotransmitter disorders in children from India","authors":"Vykuntaraju K. Gowda , Annsmol P. Markose , Varunvenkat M. Srinivasan , Uddhava V. Kinhal , Runa Hamid","doi":"10.1016/j.braindev.2025.104420","DOIUrl":"10.1016/j.braindev.2025.104420","url":null,"abstract":"<div><h3>Background</h3><div>Neurotransmitter disorders are a group of heterogeneous conditions that comprise defects in synthesis, transport, receptor binding, and degradation of neurochemical messengers. These rare disorders range from mild intermittent dystonia to lethal encephalopathies. The natural history and clinical presentation remain far from established.</div></div><div><h3>Objectives</h3><div>The study was conducted between October 2015 and September 2024. This study aims to describe the spectrum of clinical presentation, laboratory, imaging features, and genetic profiles of children diagnosed with neurotransmitter disorders and to assess the treatment modalities and clinical outcomes in these children.</div></div><div><h3>Results</h3><div>Among 29 patients, the median age was 12 months, with a male predominance. Positive family history was noted in 9 cases. The most frequent presentation was global developmental delay (GDD), dystonia, and seizures with autonomic disturbances, with diurnal variation. Various subcategories of neurotransmitter disorders are aromatic L amino acid decarboxylase deficiency-7 cases, tyrosine hydroxylase deficiency-3 cases, dopamine transporter deficiency syndrome-1 case, vesicular monoamine transporter 2 deficiency (VMAT2)-2 cases, GTP cyclohydrolase type deficiency-1 case, 6-pyruvoyl-tetrahydropterin synthase deficiency-1 case, dihydropteridine reductase deficiency-3, sepiapterin reductase deficiency-1 case, glycine encephalopathy-1 case, <em>FOLR1-</em>related cerebral folate transport deficiency-3 cases, and succinic semialdehyde dehydrogenase deficiency-5 cases. Metabolic workups were normal in all cases, with elevated phenylalanine levels in tandem mass spectrometry (TMS) in 5 children. Neuroimaging and electroencephalogram (EEG) were abnormal in 7 and 5 children, respectively. Multi-pronged and early treatment ensured better outcomes in these children.</div></div><div><h3>Conclusion</h3><div>The most common type of neurotransmitter disorder in our series was aromatic L-amino acid decarboxylase deficiency, with the most common presentation being global developmental delay and dystonia.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 5","pages":"Article 104420"},"PeriodicalIF":1.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879432","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}
Pub Date : 2025-10-01Epub Date: 2025-07-29DOI: 10.1016/j.braindev.2025.104404
Masayuki Sasaki
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 CLCN2-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.
{"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":"2025-10-01","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}
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