Advances in genetic analysis technology are increasing the opportunities for developmental delay/intellectual disability (DD/ID) cases to reach genetic diagnosis. However, the decision to perform genetic testing depends on the physician's decision; furthermore, the accessibility of genetic testing varies by country or region.
Methods
Japanese certified pediatric neurologists participated in an online survey from February to March 2023 to assess their attitudes toward genetic testing for DD/ID.
Results
The study enrolled 266 pediatric neurologists, including 41 certified clinical geneticists. In Japan, G-banding emerged as the most common first-line genetic testing for DD/ID. For DD/ID without physical and behavioral abnormalities, 30 % of pediatric neurologists indicated that they would not perform genetic testing compared with 15 % of clinical geneticists. 75.6 % of certified clinical geneticists reported experience submitting chromosomal microarray analysis (CMA), while only 39.2 % of pediatric neurologists had experience submitting CMA.
Conclusion
Differences in the decision of indication for genetic testing for DD/ID cases were shown to be influenced by specialized genetic training. Improved education and access to genetic specialists may help standardize genetic diagnosis in Japan. On the other hand, a standardized testing policy, especially for non-genetic specialists, is needed to make genetic testing for DD/ID more widely available.
{"title":"Japanese pediatric neurologist's decision regarding genetic testing for patients with developmental delay/intellectual disability: A nationwide survey","authors":"Tetsuya Okazaki , Chisako Aoki , Kaori Adachi , Takashi Yorifuji , Akira Hirasawa , Eiji Nanba","doi":"10.1016/j.braindev.2025.104361","DOIUrl":"10.1016/j.braindev.2025.104361","url":null,"abstract":"<div><h3>Background</h3><div>Advances in genetic analysis technology are increasing the opportunities for developmental delay/intellectual disability (DD/ID) cases to reach genetic diagnosis. However, the decision to perform genetic testing depends on the physician's decision; furthermore, the accessibility of genetic testing varies by country or region.</div></div><div><h3>Methods</h3><div>Japanese certified pediatric neurologists participated in an online survey from February to March 2023 to assess their attitudes toward genetic testing for DD/ID.</div></div><div><h3>Results</h3><div>The study enrolled 266 pediatric neurologists, including 41 certified clinical geneticists. In Japan, G-banding emerged as the most common first-line genetic testing for DD/ID. For DD/ID without physical and behavioral abnormalities, 30 % of pediatric neurologists indicated that they would not perform genetic testing compared with 15 % of clinical geneticists. 75.6 % of certified clinical geneticists reported experience submitting chromosomal microarray analysis (CMA), while only 39.2 % of pediatric neurologists had experience submitting CMA.</div></div><div><h3>Conclusion</h3><div>Differences in the decision of indication for genetic testing for DD/ID cases were shown to be influenced by specialized genetic training. Improved education and access to genetic specialists may help standardize genetic diagnosis in Japan. On the other hand, a standardized testing policy, especially for non-genetic specialists, is needed to make genetic testing for DD/ID more widely available.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104361"},"PeriodicalIF":1.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869238","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}
Migraine is a common neurological disorder in children, significantly impacting quality of life and academic performance. The kynurenine pathway, a major metabolic route of tryptophan, plays a critical role in neuroinflammation and neurotransmission, yet its involvement in pediatric migraine remains unexplored. This study aims to investigate alterations in kynurenine pathway metabolites in children with migraine and assess their correlation with headache frequency and severity.
Methods
A case-control study was conducted including pediatric patients diagnosed with migraine (n = 45) and healthy controls (n = 48). Serum levels of tryptophan (TRP) and its kynurenine pathway metabolites—including kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3−HK), and 3-hydroxyanthranilic acid (3-HANA)—were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Pediatric Migraine Disability Assessment (PedMIDAS) scores were used to evaluate the functional impact of migraine. Statistical analyses included comparisons between groups and correlation assessments between metabolite levels and clinical parameters.
Results
KYN, KYNA, and the KYN/TRP ratio were significantly higher in the migraine group compared to controls (p < 0.05). KYNA/3-HK ratios showed a negative correlation with headache frequency and PedMIDAS scores, whereas 3-HK levels were positively correlated with PedMIDAS scores. Receiver operating characteristic curve analysis identified KYN as a potential biomarker for distinguishing migraine patients from controls, with a sensitivity of 86.7 % and specificity of 45.8 % at a cutoff value of 1415.
Conclusion
This study is the first to evaluate kynurenine pathway metabolites in pediatric migraine. The findings suggest that alterations in the tryptophan-kynurenine pathway, particularly increased KYN and KYNA levels, may serve as compensatory mechanisms in migraine pathophysiology. Future studies should explore the therapeutic implications of targeting the kynurenine pathway in pediatric migraine treatment.
{"title":"Tryptophan metabolism in children with migraine: The role of kynurenine pathway","authors":"Şeyma Sönmez Şahin , Esra Paydaş Hataysal , Elif Yüksel Karatoprak , Fadime Ovalı , Ayşegül Özel , Ferit Durankuş , Hüsamettin Vatansev","doi":"10.1016/j.braindev.2025.104359","DOIUrl":"10.1016/j.braindev.2025.104359","url":null,"abstract":"<div><h3>Background</h3><div>Migraine is a common neurological disorder in children, significantly impacting quality of life and academic performance. The kynurenine pathway, a major metabolic route of tryptophan, plays a critical role in neuroinflammation and neurotransmission, yet its involvement in pediatric migraine remains unexplored. This study aims to investigate alterations in kynurenine pathway metabolites in children with migraine and assess their correlation with headache frequency and severity.</div></div><div><h3>Methods</h3><div>A case-control study was conducted including pediatric patients diagnosed with migraine (<em>n</em> = 45) and healthy controls (<em>n</em> = 48). Serum levels of tryptophan (TRP) and its kynurenine pathway metabolites—including kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3−HK), and 3-hydroxyanthranilic acid (3-HANA)—were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Pediatric Migraine Disability Assessment (PedMIDAS) scores were used to evaluate the functional impact of migraine. Statistical analyses included comparisons between groups and correlation assessments between metabolite levels and clinical parameters.</div></div><div><h3>Results</h3><div>KYN, KYNA, and the KYN/TRP ratio were significantly higher in the migraine group compared to controls (<em>p</em> < 0.05). KYNA/3-HK ratios showed a negative correlation with headache frequency and PedMIDAS scores, whereas 3-HK levels were positively correlated with PedMIDAS scores. Receiver operating characteristic curve analysis identified KYN as a potential biomarker for distinguishing migraine patients from controls, with a sensitivity of 86.7 % and specificity of 45.8 % at a cutoff value of 1415.</div></div><div><h3>Conclusion</h3><div>This study is the first to evaluate kynurenine pathway metabolites in pediatric migraine. The findings suggest that alterations in the tryptophan-kynurenine pathway, particularly increased KYN and KYNA levels, may serve as compensatory mechanisms in migraine pathophysiology. Future studies should explore the therapeutic implications of targeting the kynurenine pathway in pediatric migraine treatment.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104359"},"PeriodicalIF":1.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845028","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 : 2025-04-13DOI: 10.1016/j.braindev.2025.104358
Ruixiang Li , Mai Anzai , Akiko Shibata , Aya Ito-Ishida
Neurodevelopmental disorders (NDDs) are often referred to as “synaptopathies” because many of their behavioral symptoms arise from impaired synaptic development and function. However, the mechanisms that connect synaptic dysfunction to neurological symptoms remain unclear, mainly due to the wide variety of genetic and environmental factors involved in these disorders. Fragile X syndrome and Rett syndrome, two extensively studied monogenic NDDs, provide a unique opportunity to explore these mechanisms at molecular, cellular, and synaptic levels. This review summarizes the current understanding of how synaptic alterations contribute to the neurological symptoms observed in fragile X and Rett syndromes. A comparison of findings from mouse models indicates that an imbalance in local and distal connectivity may serve as a common feature of both disorders.
神经发育障碍（NDDs）通常被称为 "突触病"，因为它们的许多行为症状都源于突触发育和功能受损。然而，将突触功能障碍与神经症状联系起来的机制仍不清楚，这主要是由于这些疾病所涉及的遗传和环境因素多种多样。脆性 X 综合征和雷特综合征是两种被广泛研究的单基因 NDD，它们为从分子、细胞和突触水平探索这些机制提供了一个独特的机会。本综述总结了目前对突触改变如何导致脆性 X 综合征和 Rett 综合征神经症状的认识。对小鼠模型研究结果的比较表明，局部和远端连接失衡可能是这两种疾病的共同特征。
{"title":"Synaptic disturbance in neurodevelopmental disorders: Perspectives from fragile X and Rett syndromes","authors":"Ruixiang Li , Mai Anzai , Akiko Shibata , Aya Ito-Ishida","doi":"10.1016/j.braindev.2025.104358","DOIUrl":"10.1016/j.braindev.2025.104358","url":null,"abstract":"<div><div>Neurodevelopmental disorders (NDDs) are often referred to as “synaptopathies” because many of their behavioral symptoms arise from impaired synaptic development and function. However, the mechanisms that connect synaptic dysfunction to neurological symptoms remain unclear, mainly due to the wide variety of genetic and environmental factors involved in these disorders. Fragile X syndrome and Rett syndrome, two extensively studied monogenic NDDs, provide a unique opportunity to explore these mechanisms at molecular, cellular, and synaptic levels. This review summarizes the current understanding of how synaptic alterations contribute to the neurological symptoms observed in fragile X and Rett syndromes. A comparison of findings from mouse models indicates that an imbalance in local and distal connectivity may serve as a common feature of both disorders.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104358"},"PeriodicalIF":1.4,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824002","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 : 2025-04-10DOI: 10.1016/j.braindev.2025.104360
Turgay Cokyaman , Ulgen Ozcan Erdem
Objective
Childhood migraine is a recurrent neurobiological complex disease and caused by multiple genetic and environmental factors. In this study, the clinical relevance of ICHD-3 diagnostic criteria, familial history of migraine and motion sickness was investigated.
Methods
This study was conducted on children aged 10–18 years, who were randomly selected from 22 middle and 26 high schools. The survey, prepared in Turkish, asked about headache characteristics (ICHD-3 diagnostic criteria: 7 items), familial history of migraine, and presence of motion sickness (2 items).
Results
According to data from the survey, 4 main factors emerged in the exploratory factor analysis. Photophobia, pain attack duration ≥1 h, headache attacks more than 4 times, familial history of migraine in factor-1, vomiting and nausea in factor-2, pulsatile pain and forehead and bitemporal localization in factor-3, avoidance routine physical activities and motion sickness in factor-4 are collected.
Conclusion
Migraine, in which strong genetic pieces of evidence have been uncovered is a multifactorial brain disease. Moreover, the intense connections between the trigeminal system and vestibular nuclei demonstrated in the current literature reveal that the relationship between motion sickness and migraine cannot be ignored. Therefore, a positive familial history and motion sickness in childhood migraine are important additional diagnostic clues in addition to ICHD-3.
{"title":"Can a familial history of migraine and motion sickness be used in the diagnosis of childhood migraine?","authors":"Turgay Cokyaman , Ulgen Ozcan Erdem","doi":"10.1016/j.braindev.2025.104360","DOIUrl":"10.1016/j.braindev.2025.104360","url":null,"abstract":"<div><h3>Objective</h3><div>Childhood migraine is a recurrent neurobiological complex disease and caused by multiple genetic and environmental factors. In this study, the clinical relevance of ICHD-3 diagnostic criteria, familial history of migraine and motion sickness was investigated.</div></div><div><h3>Methods</h3><div>This study was conducted on children aged 10–18 years, who were randomly selected from 22 middle and 26 high schools. The survey, prepared in Turkish, asked about headache characteristics (ICHD-3 diagnostic criteria: 7 items), familial history of migraine, and presence of motion sickness (2 items).</div></div><div><h3>Results</h3><div>According to data from the survey, 4 main factors emerged in the exploratory factor analysis. Photophobia, pain attack duration ≥1 h, headache attacks more than 4 times, familial history of migraine in factor-1, vomiting and nausea in factor-2, pulsatile pain and forehead and bitemporal localization in factor-3, avoidance routine physical activities and motion sickness in factor-4 are collected.</div></div><div><h3>Conclusion</h3><div>Migraine, in which strong genetic pieces of evidence have been uncovered is a multifactorial brain disease. Moreover, the intense connections between the trigeminal system and vestibular nuclei demonstrated in the current literature reveal that the relationship between motion sickness and migraine cannot be ignored. Therefore, a positive familial history and motion sickness in childhood migraine are important additional diagnostic clues in addition to ICHD-3.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104360"},"PeriodicalIF":1.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143807008","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 : 2025-04-03DOI: 10.1016/j.braindev.2025.104357
Yating Yang , Jing Kang , Yiyan Zhang , Yuehao Cai , Qiong Fang , Yukun Huang , Chengyong Huang , Qiaobin Chen , Ying He , Fan Lin
Objective
This study explored the potential of miRNA-134-3p and miRNA-155-5p as biomarkers for assessing seizure severity in children.
Methods
Healthy children and children with epilepsy from Fujian Provincial Hospital (Sept 2022 to July 2023) were grouped into the control group (n = 20), the well-controlled group (n = 22), and the poorly-controlled group (n = 18). Clinical data and serum samples were analyzed using quantitative real-time polymerase chain reaction to detect miRNA levels. Receiver operating characteristic curve analysis evaluated diagnostic potential.
Results
The poorly-controlled group showed increased seizure frequency (P < 0.001), medication dosage (P < 0.001), and intellectual disabilities (P = 0.041). MiRNA-134-3p and miRNA-155-5p levels were higher in epilepsy patients, especially in the poorly-controlled group (P < 0.001). When the critical value of miRNA-134-3p for diagnosing seizure control was 4.336, the specificity was 90.9 % and the sensitivity was 88.9 %. When the diagnostic threshold of miRNA-155-5p was 2.870, the specificity was 63.6 % and the sensitivity was 100 %. The sensitivity, specificity, and accuracy of the combined diagnosis of serum miRNA-134-3p and miRNA-155-5p for seizure control were 88.9 %, 100 %, and 94.45 %, respectively.
Conclusion
The expressions of miRNA-134-3p and miRNA-155-5p were elevated in the serum of children with epilepsy, and were positively correlated with the severity of seizures. The serum miRNA-134-3p has high specificity in diagnosing the degree of seizure control in children, while miRNA-155-5p has high sensitivity. Their combination of the two can improve the specificity of predicting the degree of seizure control in children.
{"title":"Diagnostic value of serum miRNA-134-3p and miRNA-155-5p for monitoring seizure control in pediatric epilepsy","authors":"Yating Yang , Jing Kang , Yiyan Zhang , Yuehao Cai , Qiong Fang , Yukun Huang , Chengyong Huang , Qiaobin Chen , Ying He , Fan Lin","doi":"10.1016/j.braindev.2025.104357","DOIUrl":"10.1016/j.braindev.2025.104357","url":null,"abstract":"<div><h3>Objective</h3><div>This study explored the potential of miRNA-134-3p and miRNA-155-5p as biomarkers for assessing seizure severity in children.</div></div><div><h3>Methods</h3><div>Healthy children and children with epilepsy from Fujian Provincial Hospital (Sept 2022 to July 2023) were grouped into the control group (<em>n</em> = 20), the well-controlled group (<em>n</em> = 22), and the poorly-controlled group (<em>n</em> = 18). Clinical data and serum samples were analyzed using quantitative real-time polymerase chain reaction to detect miRNA levels. Receiver operating characteristic curve analysis evaluated diagnostic potential.</div></div><div><h3>Results</h3><div>The poorly-controlled group showed increased seizure frequency (<em>P</em> < 0.001), medication dosage (<em>P</em> < 0.001), and intellectual disabilities (<em>P</em> = 0.041). MiRNA-134-3p and miRNA-155-5p levels were higher in epilepsy patients, especially in the poorly-controlled group (P < 0.001). When the critical value of miRNA-134-3p for diagnosing seizure control was 4.336, the specificity was 90.9 % and the sensitivity was 88.9 %. When the diagnostic threshold of miRNA-155-5p was 2.870, the specificity was 63.6 % and the sensitivity was 100 %. The sensitivity, specificity, and accuracy of the combined diagnosis of serum miRNA-134-3p and miRNA-155-5p for seizure control were 88.9 %, 100 %, and 94.45 %, respectively.</div></div><div><h3>Conclusion</h3><div>The expressions of miRNA-134-3p and miRNA-155-5p were elevated in the serum of children with epilepsy, and were positively correlated with the severity of seizures. The serum miRNA-134-3p has high specificity in diagnosing the degree of seizure control in children, while miRNA-155-5p has high sensitivity. Their combination of the two can improve the specificity of predicting the degree of seizure control in children.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104357"},"PeriodicalIF":1.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760938","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}
Tubulin plays an important role in cell morphogenesis and chromosomal segregation. Tubulinopathies are caused by pathogenic TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB, and TUBG1 variants. Although radiological features and genotype–phenotype correlations of tubulinopathy have been described, clinical severity by genotype has not been described in detail. Herein, we discuss the correlations between the clinical and radiological features of head MRI of patients with tubulinopathy and its clinical severity by genotype.
Methods
We retrospectively reviewed medical records of patients diagnosed as having tubulinopathy at our hospital between January 2000 and May 2022.
Results
Twelve (5 male, 7 female) patients were diagnosed with tubulinopathy: four with the TUBA1A variant, one with the TUBB2B variant, three with the TUBB3 variant, one with the TUBB variant, and three with the TUBB4A variant. All patients exhibited psychomotor delay; patients with perisylvian polymicrogyria-like cortical dysplasia had milder symptoms than those with generalized cortical dysplasia. Eight patients with epilepsy had good response to anti-seizure medications. Head MRI of all patients with TUBA1A, TUBB2B, TUBB3, and TUBB variants revealed basal ganglia dysplasia. All patients with the TUBB4A variant had cerebral white matter atrophy and delayed myelination, which were not found in patients with other variants.
Conclusions
The severity of psychomotor delay in patients with tubulinopathy may be related to the degree and extent of cortical dysplasia. Asymmetric basal ganglia dysplasia is a specific MRI finding of tubulinopathy. The clinical features and MRI findings associated with the TUBB4A variant differ from those of other tubulinopathies.
{"title":"Clinical characteristics and radiological features of tubulinopathy: A single-center retrospective study in Japan","authors":"Tamaki Ikegawa , Kana Osada , Azusa Ikeda , Yu Tsuyusaki , Megumi Tsuji , Mizue Iai , Noriko Aida , Kenji Kurosawa , Naomichi Matsumoto , Tomohide Goto","doi":"10.1016/j.braindev.2025.104356","DOIUrl":"10.1016/j.braindev.2025.104356","url":null,"abstract":"<div><h3>Background</h3><div>Tubulin plays an important role in cell morphogenesis and chromosomal segregation. Tubulinopathies are caused by pathogenic <em>TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB,</em> and <em>TUBG1</em> variants. Although radiological features and genotype–phenotype correlations of tubulinopathy have been described, clinical severity by genotype has not been described in detail. Herein, we discuss the correlations between the clinical and radiological features of head MRI of patients with tubulinopathy and its clinical severity by genotype.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed medical records of patients diagnosed as having tubulinopathy at our hospital between January 2000 and May 2022.</div></div><div><h3>Results</h3><div>Twelve (5 male, 7 female) patients were diagnosed with tubulinopathy: four with the <em>TUBA1A</em> variant<em>,</em> one with the <em>TUBB2B</em> variant<em>,</em> three with the <em>TUBB3</em> variant, one with the <em>TUBB</em> variant, and three with the <em>TUBB4A</em> variant. All patients exhibited psychomotor delay; patients with perisylvian polymicrogyria-like cortical dysplasia had milder symptoms than those with generalized cortical dysplasia. Eight patients with epilepsy had good response to anti-seizure medications. Head MRI of all patients with <em>TUBA1A</em>, <em>TUBB2B</em>, <em>TUBB3,</em> and <em>TUBB</em> variants revealed basal ganglia dysplasia. All patients with the <em>TUBB4A</em> variant had cerebral white matter atrophy and delayed myelination, which were not found in patients with other variants.</div></div><div><h3>Conclusions</h3><div>The severity of psychomotor delay in patients with tubulinopathy may be related to the degree and extent of cortical dysplasia. Asymmetric basal ganglia dysplasia is a specific MRI finding of tubulinopathy. The clinical features and MRI findings associated with the <em>TUBB4A</em> variant differ from those of other tubulinopathies.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104356"},"PeriodicalIF":1.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01DOI: 10.1016/j.braindev.2025.104345
Jun-ichi Takanashi
Recent advancements in molecular biology and radiology have led to the identification of several new leukodystrophies. A key diagnostic feature of leukodystrophies is the increased white matter signal intensity observed on T2-weighted magnetic resonance (MR) images. Leukodystrophies are typically classified into two main categories: hypomyelinating leukodystrophies (HLD) and other forms, including demyelinating leukodystrophies. HLD is characterized by a primary defect in myelin due to genetic variants that affect structural myelin proteins, oligodendrocyte transcription factors, RNA translation, and lysosomal proteins. Radiologically, HLD tends to show less pronounced white matter hyperintensity on T2-weighted images than demyelinating leukodystrophies. A definitive diagnosis can often be made by identifying abnormalities in regions beyond the white matter, such as the basal ganglia or cerebellum, or through the presence of characteristic clinical symptoms. N-acetylaspartate, a neuroaxonal marker observed on MR spectroscopy, is typically reduced in many neurological conditions, but N-acetylaspartate levels often remain normal in HLD, which is considered a distinctive feature of this disorder. This article provides an overview of the latest imaging findings and clinical features associated with HLD.
{"title":"Magnetic resonance imaging and spectroscopy in hypomyelinating leukodystrophy","authors":"Jun-ichi Takanashi","doi":"10.1016/j.braindev.2025.104345","DOIUrl":"10.1016/j.braindev.2025.104345","url":null,"abstract":"<div><div>Recent advancements in molecular biology and radiology have led to the identification of several new leukodystrophies. A key diagnostic feature of leukodystrophies is the increased white matter signal intensity observed on T2-weighted magnetic resonance (MR) images. Leukodystrophies are typically classified into two main categories: hypomyelinating leukodystrophies (HLD) and other forms, including demyelinating leukodystrophies. HLD is characterized by a primary defect in myelin due to genetic variants that affect structural myelin proteins, oligodendrocyte transcription factors, RNA translation, and lysosomal proteins. Radiologically, HLD tends to show less pronounced white matter hyperintensity on T2-weighted images than demyelinating leukodystrophies. A definitive diagnosis can often be made by identifying abnormalities in regions beyond the white matter, such as the basal ganglia or cerebellum, or through the presence of characteristic clinical symptoms. <em>N</em>-acetylaspartate, a neuroaxonal marker observed on MR spectroscopy, is typically reduced in many neurological conditions, but <em>N</em>-acetylaspartate levels often remain normal in HLD, which is considered a distinctive feature of this disorder. This article provides an overview of the latest imaging findings and clinical features associated with HLD.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104345"},"PeriodicalIF":1.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BVVLS (Brown-Vialetto-Van Laere syndrome), a rare genetic condition characterized by progressive neuropathy, is caused by defects in SLC52A2 and SLC52A3 genes coding for hRFVT-2 and hRFVT-3.
Methods
Five BVVLS cases were screened for disease-causing variants using exome sequencing and their functional contributions were evaluated by in silico analysis, riboflavin transport assay and confocal imaging.
Results
Probands enrolled in this study were presented with unusual phenotypes like syndactyly, polydactyly, pedal edema and chronic osteomyelitis. Genetic testing disclosed heterozygous variants in all five cases including c.229G>A p.E77K, c.384G>A p.S128S, c.1245C>T p.G415G and c.843del p.L282Cfs*8 in SLC52A2 gene and c.833C>T p.T278M, c.907A>G p.I303V and c.62A>G p.N21S in SLC52A3 gene. Among them, p.L282Cfs*8 was diagnosed here for first-time, whereas p.E77K and p.S128S were reported previously with a variation at nucleotide position. Functional analysis of the variant p.E77K, p.S128S, p.T278M and p.I303V evidenced impairment in riboflavin transport, whereas p.G415G and p.L282Cfs*8 showed no significant changes. Despite of having reduction in riboflavin uptake, the presence of same polymorphic variant (p.T278M and p.I303V) in asymptomatic father suggests it as not likely associated with disease phenotypes. Meantime, membranous expression of hRFVT-2 variants p.S128S and p.E77K were abrogated and mostly internalized in cytoplasmic regions of transfected cells, whereas no change was observed with other variants than wild-type.
Conclusion
These results show for the first-time that BVVLS associated hRFVT-2 variants p.S128S and p.E77K affected riboflavin transport function due to abrogation in membranous localization and/or activity of the transporter. The polymorphic variants p.T278M and p.I303V of hRFVT-3 are unlikely to be implicated functionally in the pathogenesis of the disease.
{"title":"Brown-Vialetto-Van Laere syndrome patients with unusual phenotypes from Indian ethnicity: Functional analysis of clinical variants in SLC52A2 and SLC52A3 genes","authors":"Santhalingam Gayathri , Manikka Kubendran Aravind , Vykuntaraju K. Gowda , Perumal Varalakshmi , Chitral Chatterjee , Saravanan Matheshwaran , Stephanie Efthymiou , Henry Houlden , Balasubramaniem Ashokkumar","doi":"10.1016/j.braindev.2025.104355","DOIUrl":"10.1016/j.braindev.2025.104355","url":null,"abstract":"<div><h3>Background</h3><div>BVVLS (Brown-Vialetto-Van Laere syndrome), a rare genetic condition characterized by progressive neuropathy, is caused by defects in <em>SLC52A2</em> and <em>SLC52A3</em> genes coding for hRFVT-2 and hRFVT-3.</div></div><div><h3>Methods</h3><div>Five BVVLS cases were screened for disease-causing variants using exome sequencing and their functional contributions were evaluated by <em>in silico</em> analysis, riboflavin transport assay and confocal imaging.</div></div><div><h3>Results</h3><div>Probands enrolled in this study were presented with unusual phenotypes like syndactyly, polydactyly, pedal edema and chronic osteomyelitis. Genetic testing disclosed heterozygous variants in all five cases including c.229G>A p.E77K, c.384G>A p.S128S, c.1245C>T p.G415G and c.843del p.L282Cfs*8 in <em>SLC52A2</em> gene and c.833C>T p.T278M, c.907A>G p.I303V and c.62A>G p.N21S in <em>SLC52A3</em> gene. Among them, p.L282Cfs*8 was diagnosed here for first-time, whereas p.E77K and p.S128S were reported previously with a variation at nucleotide position. Functional analysis of the variant p.E77K, p.S128S, p.T278M and p.I303V evidenced impairment in riboflavin transport, whereas p.G415G and p.L282Cfs*8 showed no significant changes. Despite of having reduction in riboflavin uptake, the presence of same polymorphic variant (p.T278M and p.I303V) in asymptomatic father suggests it as not likely associated with disease phenotypes. Meantime, membranous expression of hRFVT-2 variants p.S128S and p.E77K were abrogated and mostly internalized in cytoplasmic regions of transfected cells, whereas no change was observed with other variants than wild-type.</div></div><div><h3>Conclusion</h3><div>These results show for the first-time that BVVLS associated hRFVT-2 variants p.S128S and p.E77K affected riboflavin transport function due to abrogation in membranous localization and/or activity of the transporter. The polymorphic variants p.T278M and p.I303V of hRFVT-3 are unlikely to be implicated functionally in the pathogenesis of the disease.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104355"},"PeriodicalIF":1.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739151","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}
Early-onset scoliosis, which develops before 2 years of age and progresses rapidly, has been reported as an inevitable complication in spinal muscular atrophy (SMA) patients with 2 copies of the survival motor neuron 2 (SMN2) gene that receive post-onset disease-modifying therapy (DMT) within 6 months after birth. We describe a case of SMA type 0 in a patient with 2 copies of SMN2 that was treated with nusinersen, in which the patient's motor function improved and no progression of spinal deformity was observed.
Case presentation
The patient was born after an unremarkable gestation, but presented with severe muscle weakness immediately after birth. A genetic analysis conducted at 9 weeks of age revealed homozygous deletion of SMN1 and 2 copies of SMN2. He was diagnosed with SMA type 0 and treated with nusinersen from the age of 10 weeks. However, he required a tracheostomy and ventilatory management due to pharyngomalacia at 4 months. Slight spinal deformity was observed after sitting training was initiated at 1 year and 3 months. Physical therapy with careful postural management using a seating system and a supine stander was conducted twice a week to promote motor development. He was restricted to sitting without support for 30 min a day. At age 6, he can stand with support for several minutes, and scoliosis has been prevented.
Conclusion
Our case suggests that early proactive, non-surgical management with targeted rehabilitation can prevent scoliosis progression in SMA patients with 2 copies of SMN2 that receive post-onset DMT within 6 months of birth.
{"title":"A case of spinal muscular atrophy type 0 treated with nusinersen without progression of early-onset scoliosis – possibility of preventing scoliosis with a rehabilitation program focusing on postural management","authors":"Tomokazu Kimizu , Saki Yokawa , Takuya Horibe , Keisuke Oki , Ken Nakajima , Koji Tominaga , Yukiko Mogami , Daisuke Tamura , Keiko Yanagihara","doi":"10.1016/j.braindev.2025.104354","DOIUrl":"10.1016/j.braindev.2025.104354","url":null,"abstract":"<div><h3>Background</h3><div>Early-onset scoliosis, which develops before 2 years of age and progresses rapidly, has been reported as an inevitable complication in spinal muscular atrophy (SMA) patients with 2 copies of the survival motor neuron 2 (<em>SMN2</em>) gene that receive post-onset disease-modifying therapy (DMT) within 6 months after birth. We describe a case of SMA type 0 in a patient with 2 copies of <em>SMN2</em> that was treated with nusinersen, in which the patient's motor function improved and no progression of spinal deformity was observed.</div></div><div><h3>Case presentation</h3><div>The patient was born after an unremarkable gestation, but presented with severe muscle weakness immediately after birth. A genetic analysis conducted at 9 weeks of age revealed homozygous deletion of <em>SMN1</em> and 2 copies of <em>SMN2</em>. He was diagnosed with SMA type 0 and treated with nusinersen from the age of 10 weeks. However, he required a tracheostomy and ventilatory management due to pharyngomalacia at 4 months. Slight spinal deformity was observed after sitting training was initiated at 1 year and 3 months. Physical therapy with careful postural management using a seating system and a supine stander was conducted twice a week to promote motor development. He was restricted to sitting without support for 30 min a day. At age 6, he can stand with support for several minutes, and scoliosis has been prevented.</div></div><div><h3>Conclusion</h3><div>Our case suggests that early proactive, non-surgical management with targeted rehabilitation can prevent scoliosis progression in SMA patients with 2 copies of <em>SMN2</em> that receive post-onset DMT within 6 months of birth.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104354"},"PeriodicalIF":1.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to clarify the status of coronavirus disease 2019 (COVID-19) infection and vaccination among children with infantile-onset drug-resistant epilepsy through an internet survey involving Dravet syndrome (DS) and infantile epileptic spasms syndrome (IESS) family associations.
Methods
A web-based survey was conducted between October and November 2023, targeting parents of children aged ≤15 years with DS or IESS who were members of the Dravet Syndrome JP or West Syndrome JP family associations, covering patient characteristics, COVID-19 infection, and vaccination.
Results
A total of 151 and 112 responses were obtained. COVID-19 infections occurred in 68.2 % and 52.7 % of DS and IESS cases, respectively. Fever-triggered seizures were reported in 61.8 % of DS and 3.6 % of IESS cases. Among DS cases, 22.8 % (8.0 % vaccinated), 36.6 % (20.0 % vaccinated), and 34.0 % (16.0 % vaccinated) required temporary visits for seizure exacerbation, emergency visits for seizure clusters/status epilepticus, and seizure-related hospitalizations, respectively. Vaccination rates were 25.3 % for DS and 17.3 % for IESS. Post-vaccination fever-triggered seizures occurred in 2.9 % and 3.5 % of DS cases after the first and second doses, respectively, and 0.0 % of IESS cases. Among DS cases, temporary visits were required in 2.9 % and 0.0 %, emergency visits in 0.0 % for both doses and hospitalizations in 2.9 % and 3.5 %, respectively. Vaccine hesitancy arising from seizure concerns was reported by 66.4 % and 23.0 % of DS and IESS caregivers, respectively.
Conclusion
COVID-19 vaccination is well-tolerated and may lower seizure risks in children with DS. However, caregivers should monitor those with a history of fever-triggered seizures.
{"title":"COVID-19 infection and vaccination in children with Dravet syndrome or infantile epileptic spasms syndrome: An internet survey in Japan","authors":"Susumu Ito , Aiko Nishikawa , Ruby Kuroiwa , Kaori Honda , Satoru Nagata","doi":"10.1016/j.braindev.2025.104352","DOIUrl":"10.1016/j.braindev.2025.104352","url":null,"abstract":"<div><h3>Background</h3><div>This study aimed to clarify the status of coronavirus disease 2019 (COVID-19) infection and vaccination among children with infantile-onset drug-resistant epilepsy through an internet survey involving Dravet syndrome (DS) and infantile epileptic spasms syndrome (IESS) family associations.</div></div><div><h3>Methods</h3><div>A web-based survey was conducted between October and November 2023, targeting parents of children aged ≤15 years with DS or IESS who were members of the Dravet Syndrome JP or West Syndrome JP family associations, covering patient characteristics, COVID-19 infection, and vaccination.</div></div><div><h3>Results</h3><div>A total of 151 and 112 responses were obtained. COVID-19 infections occurred in 68.2 % and 52.7 % of DS and IESS cases, respectively. Fever-triggered seizures were reported in 61.8 % of DS and 3.6 % of IESS cases. Among DS cases, 22.8 % (8.0 % vaccinated), 36.6 % (20.0 % vaccinated), and 34.0 % (16.0 % vaccinated) required temporary visits for seizure exacerbation, emergency visits for seizure clusters/status epilepticus, and seizure-related hospitalizations, respectively. Vaccination rates were 25.3 % for DS and 17.3 % for IESS. Post-vaccination fever-triggered seizures occurred in 2.9 % and 3.5 % of DS cases after the first and second doses, respectively, and 0.0 % of IESS cases. Among DS cases, temporary visits were required in 2.9 % and 0.0 %, emergency visits in 0.0 % for both doses and hospitalizations in 2.9 % and 3.5 %, respectively. Vaccine hesitancy arising from seizure concerns was reported by 66.4 % and 23.0 % of DS and IESS caregivers, respectively.</div></div><div><h3>Conclusion</h3><div>COVID-19 vaccination is well-tolerated and may lower seizure risks in children with DS. However, caregivers should monitor those with a history of fever-triggered seizures.</div></div>","PeriodicalId":56137,"journal":{"name":"Brain & Development","volume":"47 3","pages":"Article 104352"},"PeriodicalIF":1.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735312","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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