Brain Dev. [JOURNAL]
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200 papers
Focus on epilepsy and epilepsy syndromes in children with autism spectrum disorders: a study of 74 patients.
Caraballo RH, Fortini S, Beltrán L … +10 more , Semprino M, Galicchio S, Espeche A, Reyes Valenzuela G, Chacón S, Gamboni B, Adi J, Fasulo L, Calvo A, Cachia P
Brain Dev · 2025 Aug · PMID 40554136 · Publisher ↗
BACKGROUND: Epilepsy is a common finding in children with autism spectrum disorders (ASD), but few studies describe the characteristics of epilepsy in these children. Our study aimed to characterize the electroclinical f...
BACKGROUND: Epilepsy is a common finding in children with autism spectrum disorders (ASD), but few studies describe the characteristics of epilepsy in these children. Our study aimed to characterize the electroclinical features of children with ASD and epilepsy through a retrospective multicenter study. MATERIAL AND METHODS: Patients with ASD who subsequently developed epilepsy seen at nine pediatric neurology departments were included. Patients with developmental and epileptic encephalopathies (DEE), chronic neurological diseases with epilepsy who developed autism, and those with non-epileptic paroxysmal disorders were excluded. RESULTS: Overall, 74 patients were included, accounting for 15 % of 494 children with ASD seen between 2015 and 2023; 39 were female (52.7 %) and 35 male (47.3 %). Focal epilepsies were identified in 43 patients (58.1 %), which were non-self-limited in 24 and self-limited in 19. Generalized epilepsies were observed in 19 (25.7 %), including six with generalized tonic-clonic seizures alone (one in childhood, five in adolescence), nine with juvenile myoclonic epilepsy, one with childhood absence epilepsy, and three with juvenile absence epilepsy. Eight patients (10.8 %) had epileptic encephalopathies: EE-SWAS in six and epilepsy with myoclonic atonic seizures in two. Four patients (5.4 %) had combined focal and generalized epilepsy. No significant differences were found between epilepsy syndrome or type of epilepsy, seizure type, and comorbidities. CONCLUSIONS: No specific epilepsy phenotype was identified in our patients with ASD; the types of epilepsy and syndromes were similar to those seen in the general population. Management should address both epilepsy and the broader complexities of ASD through an integrated approach.
Molecular pathologies and therapies for Pelizaeus-Merzbacher disease.
Inoue K
Brain Dev · 2025 Aug · PMID 40544665 · Publisher ↗
Pelizaeus-Merzbacher disease (PMD) is the most common and representative disorder among hypomyelinating leukodystrophies, affecting myelin in the central nervous system. PMD is caused by various mutations in the PLP1 gen...
Pelizaeus-Merzbacher disease (PMD) is the most common and representative disorder among hypomyelinating leukodystrophies, affecting myelin in the central nervous system. PMD is caused by various mutations in the PLP1 gene, including the most common duplications, point mutations (which often lead to severe forms), deletions/null mutations (resulting in milder forms), and deep intron mutations associated with hypomyelination of early myelinated structures (HEMS), a mild variant with characteristic MRI findings. Each mutation type is known to trigger distinct cellular and molecular mechanisms. Understanding these mutation-specific pathologies provides crucial insights for developing targeted therapies. For instance, duplication mutations lead to overexpression of the wild-type PLP1 protein, which disrupts myelination by oligodendrocytes, suggesting that gene suppression could be a potential treatment strategy. Therapeutic approaches under investigation include antisense oligonucleotides and artificial miRNA gene therapy. On the other hand, point mutations in mutant PLP1 proteins often confer cytotoxicity, which has been linked to endoplasmic reticulum stress responses, ferroptosis, and intracellular transport dysfunction within the secretory pathway. As a result, therapies targeting these molecular mechanisms are being explored, including antisense oligonucleotides and iron chelators. Given these advancements, it is not overly optimistic to anticipate that PMD could become a treatable disease in the near future.
Prevalence and management of gastrointestinal complications in Duchenne muscular dystrophy: A retrospective cohort study.
Aihara Y, Ito Y, Takeshita E … +8 more , Oba M, Yamamoto K, Sumitomo N, Yamamoto H, Baba S, Shimizu-Motohashi Y, Saito T, Komaki H
Brain Dev · 2025 Aug · PMID 40540814 · Publisher ↗
BACKGROUND: Gastrointestinal complications in Duchenne muscular dystrophy (DMD) have been understudied, particularly in Asian populations. This study aimed to determine the frequency and clinical characteristics of gastr...
BACKGROUND: Gastrointestinal complications in Duchenne muscular dystrophy (DMD) have been understudied, particularly in Asian populations. This study aimed to determine the frequency and clinical characteristics of gastrointestinal complications. METHODS: This single-center, retrospective study reviewed medical records of 459 Asian patients with genetically or biopsy-confirmed DMD, aged 1-48 years, from September 1, 2010, to January 1, 2023. RESULTS: Constipation was the most common complication, affecting 149 patients (32.5 %), followed by dysphagia in 43 patients (9.4 %). Other conditions included irritable bowel syndrome in 8, gastroesophageal reflux disease in 7, hemorrhoids in 6, acute dilatation of stomach in 4, sigmoid colon volvulus in 2, and pneumatosis cystoides intestinalis in 2. Additionally, 1 case each of appendicitis, esophageal diverticulum, paralytic ileus, aerophagia, anal atresia, malabsorption syndrome, fecal incontinence, inflammatory bowel disease, gastrointestinal bleeding, and rectal prolapse was observed. Treatments for constipation included no intervention in 20 patients (13.4 %), sodium picosulfate hydrate in 62 (41.6 %), magnesium oxide in 59 (39.6 %), and polyethylene glycol 4000 in 20 (13.4 %). Logistic regression analysis showed that body mass index (BMI), age and angiotensin converting enzyme inhibitor use was significantly associated with constipation. CONCLUSIONS: This study highlighted constipation as the most frequent gastrointestinal complication in DMD and identified several rare but serious complications, offering key insights into real-world clinical practice.
Epilepsy phenotypes and responses to antiseizure medications in pediatric patients with EEF1A2-related epilepsy.
Yun HJ, Kim SY, Kim W … +4 more , Lee S, Chae JH, Kim KJ, Lim BC
Brain Dev · 2025 Aug · PMID 40540813 · Publisher ↗
OBJECTIVE: To delineate the epilepsy spectrum and evaluate the response of pediatric patients with EEF1A2-related epilepsy to antiseizure medications (ASMs). METHODS: We conducted a retrospective analysis of seven pediat...
OBJECTIVE: To delineate the epilepsy spectrum and evaluate the response of pediatric patients with EEF1A2-related epilepsy to antiseizure medications (ASMs). METHODS: We conducted a retrospective analysis of seven pediatric patients with EEF1A2 mutations identified at our institution, combined with 69 cases from prior literature, resulting in a cohort of 76 patients. Data for age of seizure onset, seizure types, epilepsy syndromes, ASM responses, and neurodevelopmental outcomes were collected and analyzed. Epilepsy syndromes were classified following the International League Against Epilepsy guideline. RESULTS: Among the 76 patients, 61 (80 %) presented with epilepsy, with a median seizure onset age of 4.5 months. Of these, 56 % experienced seizure onset before the age of 12 months. Generalized seizures were predominant (67 %), including epileptic spasms, myoclonic, tonic, and tonic-clonic seizures. Developmental epileptic encephalopathy (DEE) was observed in 59 % of patients, although a range of milder epilepsy phenotypes was also present. Broad-spectrum ASMs, such as valproic acid, lamotrigine, and levetiracetam, demonstrated effectiveness in controlling seizures in 65 % of patients. Recurrent mutations such as p.Gly70Ser and p. Glu122Lys were predominantly associated with severe DEE. CONCLUSIONS: EEF1A2-related epilepsy encompasses a broad spectrum of phenotypes, from early-onset severe syndromes to milder forms. Specific mutations within EEF1A2 seemed to be correlated with severe DEE.
Low excretor glutaric acidemia type 1 with transient lesions in the basal ganglia.
Miyata Y, Murayama K, Okazaki Y … +3 more , Zhang C, Abe M, Narita M
Brain Dev · 2025 Aug · PMID 40517577 · Publisher ↗
BACKGROUND: In some countries, glutaric acidemia type 1 (GA1) is included in newborn screening (NBS) panels using tandem mass spectrometry (MS/MS) analysis of acylcarnitine. However, the low excretor phenotype of glutari...
BACKGROUND: In some countries, glutaric acidemia type 1 (GA1) is included in newborn screening (NBS) panels using tandem mass spectrometry (MS/MS) analysis of acylcarnitine. However, the low excretor phenotype of glutaric acidemia type 1 (LE-GA1) has been increasingly recognaized and may lead to false-negative NBS results and can be missed by urine organic acid and plasma acylcarnitine profile analyses. CASE: We report a case of LE-GA1 with an atypical imaging course. NBS by dried blood spot acylcarnitine profile using MS/MS was normal. At 7 months of age, he developed an acute encephalopathic crisis with bilateral striatal lesions. He underwent intravenous methylprednisolone pulse, intravenous immunoglobulin, vitamin B1, biotin, l-carnitine, and coenzyme Q10 therapy. Abnormal basal ganglia signals disappeared within 4 weeks. Serial brain MRI 6 months later revealed linear lesions in both putamen. The plasma acylcarnitine profile and urine organic acid analyses were normal at onset. Whole exome and Sanger sequencing were performed, and compound heterozygosity for the two known pathogenic variants in the glutaryl-CoA dehydrogenase gene were identified. Metabolomic analyses of the patient's urine showed elevated glutaric acid and 3-hydroxyglutaric acid levels similar to those in another LE-GA1 case. Thus, the patient was diagnosed with LE-GA1. CONCLUSIONS: Unlike classical GA1, LE-GA1 may present with variable neuroimaging courses, including transient basal ganglia lesions. If Leigh's encephalopathy-like lesions of the basal ganglia-of unknown cause with acute onset-are present, LE-GA1 should be considered. To ensure timely and accurate diagnosis, genetic analyses should be performed, even if biochemical findings are normal.
Characteristics of febrile seizure after the end of the COVID-19 global health emergency.
Numoto S, Oro Y, Nishida D … +4 more , Yamamoto M, Omori Y, Fujimoto A, Okumura A
Brain Dev · 2025 Aug · PMID 40482502 · Publisher ↗
OBJECTIVE: This study aimed to clarify the characteristics of febrile seizures (FSs) before and after the coronavirus disease 2019 (COVID-19) global health emergency. METHODS: This study was a retrospective study conduct...
OBJECTIVE: This study aimed to clarify the characteristics of febrile seizures (FSs) before and after the coronavirus disease 2019 (COVID-19) global health emergency. METHODS: This study was a retrospective study conducted at a single institution in Japan. Clinical data were retrospectively collected from 797 children with FS, aged <16 years, between January 2018 and July 2024. Participants were categorized into four terms: Term I, pre-COVID-19 period; Term II, pre-Omicron period; Term III, Omicron period; and Term IV, post-COVID-19 global health emergency. Late FS was defined as FS in children aged >60 months. Data were compared across these four periods and between COVID-19-related and non-COVID-19-related groups. RESULTS: The monthly average of FSs was 14.4 in Term I, 7.7 in Term II, 11.6 in Term III, and 12.5 in Term IV. The median age in Term IV was 34 months, significantly older than in Terms I, II, and III. Late FS in the COVID-19-related group was 22.6 % in Term III and 25 % in Term IV. In the non-COVID-19-related group, late FS rates were 5.0 % in Term I, 2.7 % in Term II, 4.7 % in Term III, and 26.0 % in Term IV, significantly higher than in Terms I, II, and III. CONCLUSIONS: After the end of the COVID-19 global health emergency, the rate of late FS caused by COVID-19 remained high, and the rate of late FS caused by non-COVID-19 infections also increased compared to the pre-COVID-19 period.
Endocrinological study of low-dose adrenocorticotropic hormone therapy without tapering in infantile epileptic spasms syndrome.
Morita S, Yamauchi T, Tamura Y … +7 more , Suzuki T, Nomura T, Shiraku H, Takahashi K, Takasawa K, Kashimada K, Mizuno T
Brain Dev · 2025 Aug · PMID 40482501 · Publisher ↗
BACKGROUND: Adrenocorticotropic hormone (ACTH) therapy is effective for infantile epileptic spasms syndrome (IESS) and other types of refractory epilepsy; however, concerns remain regarding the risk of potential adrenal...
BACKGROUND: Adrenocorticotropic hormone (ACTH) therapy is effective for infantile epileptic spasms syndrome (IESS) and other types of refractory epilepsy; however, concerns remain regarding the risk of potential adrenal insufficiency, particularly when ACTH therapy is discontinued without dose tapering. Studies on comprehensive endocrinological evaluation of adrenocortical function following low-dose ACTH therapy without tapering are limited. METHODS: We collected the data of patients who were diagnosed with IESS and received ACTH therapy using synthetic ACTH at 0.005-0.0125 mg/kg/day (equivalent to natural ACTH at 0.2-0.5 IU/kg/day) for 14 days without tapering, and underwent an ACTH stimulation test following ACTH therapy completion for adrenocortical function evaluation. Moreover, body weight, blood pressure, and electrolytes were measured before and after treatment. RESULTS: A total of 11 patients, aged between 3 months and 1 year and 6 months, were enrolled. ACTH therapy was effective in all 11 patients. During the observation period, 3 patients developed seizure recurrence; however, none of the patients exhibited symptoms of adrenal insufficiency. The ACTH stimulation test confirmed normal adrenocortical function in all cases, with peak cortisol levels exceeding 20 μg/dL. After treatment, a significant increase in body weight and blood pressure were observed. CONCLUSION: Low-dose ACTH therapy without tapering can be endocrinologically safe. The result provides useful information for reducing hospitalization duration and minimizing side effects. To validate these findings, further studies with larger cohorts are needed.
Genetic analysis of leukodystrophies in children: towards improved diagnostic yield.
Saitsu H, Miyamoto S
Brain Dev · 2025 Aug · PMID 40482500 · Publisher ↗
The formation of the myelin sheath in the central nervous system is carried out by oligodendrocytes, and leukodystrophies develop when myelination by oligodendrocytes is impaired. It has been found that the activity of t...
The formation of the myelin sheath in the central nervous system is carried out by oligodendrocytes, and leukodystrophies develop when myelination by oligodendrocytes is impaired. It has been found that the activity of the neurons undergoing myelination is also necessary for complete myelination, meaning that not only abnormalities in oligodendrocytes but also abnormalities in neurons can lead to defective myelination. Many genes involved in leukodystrophy in children have been identified, and comprehensive genetic analysis has been proven useful for genetic diagnosis. However, target panel sequencing, exome sequencing targeting almost all exons, and genome sequencing does not identify the genetic cause in substantial proportion of patients, making it essential to advance research targeting these unresolved cases. Transcriptome analysis has been reported to improve diagnostic rates in individuals with suspected Mendelian conditions, by confirming aberrant splicing caused by candidate DNA variants or by revealing candidate loci through detecting abnormalities in RNA transcription. Because transcription has a tissue specificity, selection of tissues from which RNA extract is of importance. In this mini-review, we first briefly review genetics of leukodystrophies in children along with methodology of genetic analysis, and discuss utility of urine-derived cells for transcriptome analysis of leukodystrophy in children.
Motor skills and neurological soft signs: Are they only clinical differences or reflection of distinct etiopathogenesis in tic disorder and primary stereotypic movement disorder?
Akbas Aliyev ES, Ünal D
Brain Dev · 2025 Aug · PMID 40449188 · Publisher ↗
BACKGROUND: While tic disorders and stereotypic movement disorder are commonly comorbid in pediatric clinics, their clinical and etiological differences remain poorly understood. OBJECTIVES: We aimed to investigate the c...
BACKGROUND: While tic disorders and stereotypic movement disorder are commonly comorbid in pediatric clinics, their clinical and etiological differences remain poorly understood. OBJECTIVES: We aimed to investigate the clinical features that differentiate between tic disorders and primary stereotypic movement disorder by evaluating neurological soft signs and motor skills. METHODS: The Kiddie-Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version DSM-5 and Sociodemographic and Clinical Data Form were administered to the children. The clinician completed Yale Global Tic Severity Scale, Repetitive Behavior Scale-Revised and Neurological Evaluation Scale. Nine-Hole Peg Test was used for fine motor skills, 1-Minute Sit-to-Stand Test for gross motor skills, Flamingo Balance Test for static balance, Finger-to-Nose Test for bilateral coordination. Parents completed the Conners Parent Rating Scale-Revised Short Form and the Revised Developmental Coordination Disorder Questionnaire. RESULTS: Our sample consisted of 20 tic disorders, 20 primary stereotypic movement disorder, 13 attention deficit hyperactivity disorder patients, and 20 healthy controls. Sequencing of the complex motor acts scores of Neurological Evaluation Scale were significantly higher in the primary stereotypy group than in healthy controls. The primary stereotypy group demonstrated significantly lower dominant hand performance on the Nine-Hole Peg Test than the tic group. Children with stereotypy had significantly lower scores of 1-min sit-to-stand test; higher total and subscale scores of Revised Developmental Coordination Disorder Questionnaire. and higher developmental coordination disorder risk than healthy controls. CONCLUSIONS: Our findings offer valuable insights into the distinct etiopathogenesis of tic disorders and primary stereotypic movement disorder, providing a foundation for future neurobiological research.
Long-term outcome prediction after pediatric cardiac arrest by continuous electroencephalography.
Ohashi E, Hayakawa I, Kato H … +4 more , Ide K, Matsumoto S, Pak K, Abe Y
Brain Dev · 2025 Aug · PMID 40449187 · Publisher ↗
OBJECTIVE: Continuous electroencephalography (cEEG) features after cardiac arrest (CA) are associated with short-term outcome predictions. However, the association between cEEG features and long-term neurobehavioral outc...
OBJECTIVE: Continuous electroencephalography (cEEG) features after cardiac arrest (CA) are associated with short-term outcome predictions. However, the association between cEEG features and long-term neurobehavioral outcomes in children remains unclear. This study aimed to identify cEEG features that can accurately predict neurobehavioral outcomes in children 6 months after CA. METHODS: A single-center, retrospective, observational study was performed at the tertiary care pediatric intensive care unit (PICU) of a national children's hospital. This study included a consecutive cohort of children admitted to the PICU after CA who underwent cEEG monitoring. The initial EEG background, electrographic seizures, and changes in EEG background over time were documented for each time point. The primary outcome was neurobehavioral outcomes at 6 months after resuscitation. To assess the reliability of the predictive model, the area under the receiver operating characteristic curve (AUROC) of models was compared for different combinations of EEG features. RESULTS: The study included 62 infants and children. Unfavorable neurobehavioral outcomes were reported in 39 patients (63 %), including mortality in 20 patients. The combination of initial EEG background category and the EEG change from initial EEG initiation to 24 h, or variability/reactivity alone, were minimal optimal predictive models for unfavorable neurobehavioral outcomes at 6 months (AUROC, 0.99 [95 % confidence interval, 0.98-1.00], and 0.99 [95 % confidence interval 0.97-1.00], respectively). CONCLUSIONS: Early cEEG features in the PICU can accurately predict neurobehavioral outcomes in children at 6 months after CA. These results can enhance prognostication and guide clinical decision-making in pediatric CA cases.
Drug-resistant epilepsy in children post-neonatal seizures: Clinical profiles and predictors.
Saenchai W, Manopunya S, Kosarat S … +5 more , Khuwuthyakorn V, Tantiprabha W, Katanyuwong K, Sanguansermsri C, Wiwattanadittakul N
Brain Dev · 2025 Aug · PMID 40424739 · Publisher ↗
OBJECTIVES: To investigate the clinical profile, etiologies, and outcomes of neonatal seizures and identify predictors of drug-resistant epilepsy (DRE) in children. METHOD: A retrospective chart review was performed on n...
OBJECTIVES: To investigate the clinical profile, etiologies, and outcomes of neonatal seizures and identify predictors of drug-resistant epilepsy (DRE) in children. METHOD: A retrospective chart review was performed on neonates with seizures admitted to Chiang Mai University Hospital, Thailand, from January 2008 to December 2023. The diagnosis of neonatal seizures was based on clinical findings and/or electroencephalography. Severe impairment refers to limited mobility and minimal speech, while profound impairment indicates being bedridden. DRE is defined as the failure of two antiseizure medications to control seizures. RESULTS: Among 218 patients (58.3 % male), the median seizure onset was 12 h (interquartile range [IQR]: 2.9-87 h). The leading etiology was perinatal asphyxia (58.7 %), followed by hemorrhage (7.8 %). The median follow-up was 27 months (IQR: 31.5 months). Epilepsy developed in 39 (27.3 %) patients, with 19 (48.7 %) meeting DRE criteria. Risk factors for epilepsy included marked abnormal neuroimaging, refractory neonatal seizures and severe to profound developmental impairment (P <0.05). In the multivariate model, profound developmental impairment (odds ratio [OR] = 2.89, p = 0.04, 95 % confidence interval [CI]: 1.79-24.19) and the development of epileptic spasms or multiple seizure types (OR = 114.80, p = 0.01, 95 % CI: 4.79-2746.07) were identified as an independent risk factor for DRE. CONCLUSION: Perinatal asphyxia is the most common cause of neonatal seizures. One-third of neonates with seizures developed epilepsy, with half of them meeting the criteria for DRE. Neonates who develop epileptic spasms, exhibit multiple seizure types, or have profound developmental impairment are key DRE predictors.
MECP2 duplication syndrome: Recent advances in pathophysiology and therapeutic perspectives.
Akaba Y, Takahashi S
Brain Dev · 2025 Aug · PMID 40382977 · Publisher ↗
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epil...
MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.
Awareness and knowledge of pediatricians regarding genetic testing for Fragile X syndrome in Japan: A National Survey of Pediatricians Managing Developmental Delay/Intellectual disability.
Okazaki T, Aoki C, Shinzato S … +2 more , Adachi K, Nanba E
Brain Dev · 2025 Aug · PMID 40349415 · Publisher ↗
BACKGROUND: Fragile X syndrome (FXS) commonly cause developmental delay, intellectual disability, and autism spectrum disorder. Although genetic testing has been available and included in Japan's national health insuranc...
BACKGROUND: Fragile X syndrome (FXS) commonly cause developmental delay, intellectual disability, and autism spectrum disorder. Although genetic testing has been available and included in Japan's national health insurance since 2016, the number of cases diagnosed with FXS remains low. This study aimed to explore the levels of awareness and understanding of FXS among pediatricians managing developmental delay/ intellectual disability in Japan, particularly between pediatrician with and without clinical genetics certification (or clinical experience with FXS). METHODS: A survey involving 1217 certified pediatric neurologists from the Japanese Society of Pediatric Neurology and 367 members of the Japanese Society of Pediatric Genetics was conducted. Additional participants were recruited from an online mailing list of 1469 pediatric neurologists. The survey comprised questions on demographics, knowledge about FXS, and genetic testing practices. The responses were analyzed using Chi-square and Fisher's exact tests, and a p-value <0.05 was considered statistically significant. RESULTS: Out of 386 respondents, 326 had experience ordering some kind of genetic testing, including 78 certified clinical geneticists. Knowledge gaps were significant between clinical geneticists and non-genetic specialists. While 20 % of non-genetic specialists were unaware of insurance-covered FXS genetic testing, this percentage was lower among those with clinical experience in FXS cases. Many respondents, irrespective of certification, struggled to determine the indications for requesting FXS genetic testing. Furthermore, non-genetic specialists reported more difficulty providing genetic counseling owing to the psychological burden on mothers. CONCLUSION: This study highlights the necessity for expanding education and training on FXS among pediatricians in Japan. Addressing these knowledge gaps may enhance FXS diagnostic rates and improve the management of affected individuals and families. Future efforts should focus on strengthening the collaboration between clinical geneticists and general pediatricians and establishing reliable genetic counseling support systems.
The first case of Al-Raqad syndrome in Japan is associated with a homozygous DCPS exonic variant resulting in aberrant splicing.
Nozaki H, Sakakibara N, Hanafusa H … +11 more , Inoki Y, Tanaka Y, Kitakado H, Ueda C, Nagano C, Horinouchi T, Yamamura T, Ishimori S, Yamaguchi H, Nozu K, Morisada N
Brain Dev · 2025 Aug · PMID 40344930 · Publisher ↗
BACKGROUND: Cases of unexplained neurodevelopmental disorder (NDD) are often accompanied by multiple congenital anomalies. With recent advances in genetic analysis technology, whole-exome sequencing (WES) has become a po...
BACKGROUND: Cases of unexplained neurodevelopmental disorder (NDD) are often accompanied by multiple congenital anomalies. With recent advances in genetic analysis technology, whole-exome sequencing (WES) has become a powerful diagnostic tool for unexplained NDD patients, but variants of unknown significance are sometimes detected in them. METHODS: WES identified a variant in a 2-year-old boy with NDD associated with multiple congenital anomalies who had no abnormal findings in G-banding and array comparative genomic hybridization (array CGH). mRNA analysis was performed on the variant using the patient's peripheral blood leukocytes following in silico analysis to confirm its effect on splicing. RESULTS: WES revealed a novel homozygous single base substituting variant of unknown significance (VUS), which was carried heterozygously by the patient's parents (DCPS, NM_014026.6: c.200A>G, p.(Lys67Arg)). In silico analysis predicted that this variant may cause aberrant splicing, and mRNA analysis revealed a 48-bp deletion from the 3' end of exon 1. Biallelic variants of DCPS are known to cause Al-Raqad syndrome, a quite rare disorder which presents NDD with multiple malformations. This disease has been reported in only eight individuals from five Middle Eastern or Caucasian families but never in the Japanese but the symptoms of the present case were similar to reported cases of this syndrome. DISCUSSION: We successfully diagnosed a case of unexplained NDD as Al-Raqad syndrome by WES along with mRNA analysis. Single base substitution with judged VUS can be pathogenic by causing aberrant splicing and, therefore, in silico analysis and subsequent RNA sequence are necessary to prove its pathogenicity.
Development of a manual for an upper extremity intensive rehabilitation program for pediatric hemiplegia in Japan and assessment of its effectiveness and usability.
Katori S, Kitai Y, Tanabe R … +3 more , Kawahara Y, Miura M, Toyoda E
Brain Dev · 2025 Jun · PMID 40319727 · Publisher ↗
OBJECTIVES: The aim of this study was to develop a manual for an upper extremity intensive rehabilitation program for pediatric hemiplegia in Japan, and to clarify its effectiveness and usability. METHODS: The manual was...
OBJECTIVES: The aim of this study was to develop a manual for an upper extremity intensive rehabilitation program for pediatric hemiplegia in Japan, and to clarify its effectiveness and usability. METHODS: The manual was created through discussions among nine experts with sufficient pediatric clinical experience in Japan. A total of 39 children with hemiplegia aged 2 to 16 years underwent 44 intensive therapy sessions using the manual. Each child's upper limb function was assessed pre-, post- and 6-month after the intervention using the Canadian Occupational Performance Measure (COPM), ABILHAND-Kids, the Quality of Upper Extremity Skills Test (QUEST), and Box and Block Test (BBT). Questionnaire assessments were also conducted to evaluate usability of the manual. RESULTS: All four indices showed statistically significant improvements from pre- to post-intervention; COPM improved by 4 points in both performance and satisfaction; the ABILHAND-Kids logit score improved by 0.78; the total QUEST score improved by 2.8 in total score; and BBT improved by 5 on the affected side and 6 on the non-affected side. These effects were maintained 6 months later. Most therapists responded that the manual is useful, and most children and their parents were satisfied with the rehabilitation. CONCLUSIONS: An upper extremity intensive rehabilitation program for pediatric hemiplegia using our manual was clinically effective. The manual was useful for therapists, and the level of satisfaction among parents and children who received the therapy was high.
Brain dysfunction underlying visual snow syndrome: Insights into therapeutic implications.
Shibata M
Brain Dev · 2025 Jun · PMID 40311549 · Publisher ↗
Visual snow (VS) is defined as dynamic, continuous tiny dots across the entire visual field persisting for more than three months. VS is frequently associated with enhanced entoptic phenomenon, palinopsia, photophobia an...
Visual snow (VS) is defined as dynamic, continuous tiny dots across the entire visual field persisting for more than three months. VS is frequently associated with enhanced entoptic phenomenon, palinopsia, photophobia and night blindness. This constellation of symptoms is now referred to as visual snow syndrome (VSS). VSS is reported to affect approximately 2 % of the UK population. Neuroimaging has contributed to a better understanding of VSS disease mechanism. While the dysfunction of visual association area is likely to play a pivotal role in its pathophysiology, functional and microstructural abnormalities extend beyond the visual system. Nevertheless, no specific marker for VSS has been identified, which makes the diagnosis of VSS challenging. The treatment of VSS remains to be established. There has been only sporadic therapeutic success with lamotrigine and cognitive behavioral therapy. Given the complexity of its disease state, multidisciplinary therapeutic approaches appear to be required for more effective symptom management.
Volumetric and microstructural changes in the Hippocampus and cingulum in children with west syndrome.
Palanci Ö, Kamaşak T, Aydin Kasap Z … +3 more , Eyüboğlu İ, Dilber B, Cansu A
Brain Dev · 2025 Jun · PMID 40311548 · Publisher ↗
PURPOSE: We aimed to investigate structural changes in the hippocampus using automated segmentation techniques to evaluate the anatomy and function of the hippocampus in patients with West syndrome (WS). METHODS: The stu...
PURPOSE: We aimed to investigate structural changes in the hippocampus using automated segmentation techniques to evaluate the anatomy and function of the hippocampus in patients with West syndrome (WS). METHODS: The study included 48 participants (24 with WS and 24 healthy controls) aged 0-4 years. Automated segmentation methods were used to measure hippocampal volume and evaluate diffusion tensor imaging (DTI) parameters such as fractional anisotropy (FA) and mean diffusivity (MD). Bonferroni correction was applied for multiple comparisons, setting the adjusted significance threshold at p < 0.0033. RESULTS: Children with WS exhibited significantly reduced total hippocampal volume and diminished volumes in the CA2-CA3, CA4-dentate gyrus (CA4-DG), and SR-SL-SM regions compared to healthy controls (padj <0.0033). After correction, no significant differences were found in the CA1 and subiculum regions (padj >0.0033). Although initial comparisons between ongoing WS and seizure-controlled WS suggested increased volumes in several hippocampal regions in the seizure-controlled group, these differences did not remain significant after adjustment and must be interpreted with caution. Notably, patients with seizure-controlled WS displayed larger hippocampal volumes, higher FA, and lower MD values, indicating a possible link between seizure activity and structural alterations. Additionally, DTI analysis of the cingulum revealed lower FA and higher MD values in WS patients, suggesting compromised microstructural integrity. CONCLUSIONS: These findings emphasize the potential role of hippocampal alterations in the pathophysiology of WS and suggest that DTI parameters may serve as useful measures for monitoring disease progression and treatment response.
Challenges in genetic counseling for RYR1-related myopathies.
Shimomura R, Kihara Y, Yanagishita T … +11 more , Ishiguro K, Shichiji M, Sato T, Shimojima Yamamoto K, Ishihara Y, Nagata M, Miyashita Y, Asano Y, Ishigaki K, Nagata S, Yamamoto T
Brain Dev · 2025 Jun · PMID 40311547 · Publisher ↗
BACKGROUND: Ryanodine receptor 1 (RYR1)-related myopathy is inherited in an autosomal dominant (AD) or recessive (AR) manner. We experienced two sporadic cases of RYR1-related myopathy. One patient harbored a de novo mis...
BACKGROUND: Ryanodine receptor 1 (RYR1)-related myopathy is inherited in an autosomal dominant (AD) or recessive (AR) manner. We experienced two sporadic cases of RYR1-related myopathy. One patient harbored a de novo missense variant, whereas the other harbored compound heterozygous variants inherited from each parent. The possibility of dual inheritance makes it challenging to distinguish between these two inheritance patterns based only on clinical information. METHODS: In this study, PubMed was used to perform literature review on genetic counseling for RYR1-related myopathy. RESULTS: Recently published manuscripts have emphasized the importance of comprehensive genomic analysis of all RYR1 coding regions. CONCLUSION: RYR1-related myopathy without family history may be associated with de novo heterozygous AD variants and biallelic involvement in AR. In cases of AR traits, a prenatal diagnosis may be required from the parents. Therefore, precise genetic information is essential for genetic counseling. It would be impossible to assess the inheritance patterns from genotypes only if monoallelic missense variants were identified in patients with congenital myopathy. This review emphasizes the importance of comprehensively analyzing all coding regions using trio samples for better genetic counseling.
Japanese pediatric neurologist's decision regarding genetic testing for patients with developmental delay/intellectual disability: A nationwide survey.
Okazaki T, Aoki C, Adachi K … +3 more , Yorifuji T, Hirasawa A, Nanba E
Brain Dev · 2025 Jun · PMID 40286760 · Publisher ↗
BACKGROUND: 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 test...
BACKGROUND: 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.
Tryptophan metabolism in children with migraine: The role of kynurenine pathway.
Şahin ŞS, Hataysal EP, Karatoprak EY … +4 more , Ovalı F, Özel A, Durankuş F, Vatansev H
Brain Dev · 2025 Jun · PMID 40252602 · Publisher ↗
BACKGROUND: 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 i...
BACKGROUND: 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.
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