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Objectives: To investigate the clinical characteristics and management of plexiform neurofibromas (PNs) in Japanese children with neurofibromatosis 1 (NF1) in the beginning of a new era of treatment with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor selumetinib., Study Design: Primary and secondary surveys were conducted targeting 1612 departments of pediatrics and dermatology in hospitals with ≥300 beds and children's hospitals, which followed up pediatric patients with NF1-associated PN between April 1, 2022, and April 30, 2024, in Japan., Results: The response rates in the primary and secondary surveys were 40.4 % and 33.8 %, respectively, and 49 patients were followed up in 23 departments. Their ages at the time ranged from 3.3 to 18.8 years and the onset of PN was most frequently recognized during the first year of life. PN was most often observed superficially in the face (39 %), neck (27 %), and head (24 %), followed by the buttocks (20 %), back (18 %), and thighs (18 %). In addition, PNs could be identified radiologically in the spinal/paraspinal regions (18 %) and pelvis (16 %), where they were rarely visible on the corresponding body surfaces. Major morbidities were cosmetic disfigurement (78 %), pain (53 %), and dysfunction (61 %). Selumetinib use was frequent (69 %) and significantly associated with pain (chi-square test, p = 0.014) and dysfunction (p = 0.014)., Conclusions: This retrospective nationwide study revealed early onset, diverse tumor locations, and varying morbidities in children with NF1-PN, underscoring the need for early evaluation and optimal treatment. A prospective multicenter registry system is warranted to attain better management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HN received honoraria for lectures and manuscript writing from Alexion, AstraZeneca Rare Diseases. YY received honoraria for lectures and travel reimbursement from Alexion, AstraZeneca Rare Disease. AA received honoraria for lectures from Alexion, AstraZeneca Rare Disease. MM received honoraria for lectures and travel reimbursement from Alexion, AstraZeneca Rare Disease. The company was not involved in any of the study design, collection, analysis, interpretation of data, writing of the report, and decision to submit the paper for publication. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology.

Hedgehog signaling is a highly conserved pathway that plays pivotal roles in morphogenesis, tumorigenesis, osteogenesis, and wound healing. Previous investigations in patients with Gorlin syndrome found low harm avoidance traits, and increased volumes in the cerebrum, cerebellum, and cerebral ventricles, suggesting the association between brain morphology and the constitutive hyperactivation of hedgehog signaling, while the changes of regional brain volumes in upregulated hedgehog signaling pathway remains unclear so far. Herein, we investigated comprehensive brain regional volumes using quantitative structural brain MRI, and identified increased volumes of amygdala, striatum, and pallidum on the global segmentation, and increased volumes of the lateral and medial parts of the central nucleus of the amygdala on the detail segmentation in Ptch heterozygous deletion mice. Our data may enhance comprehension of the association between brain morphogenic changes and hyperactivity in hedgehog signaling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shiohama, Uchikawa, Nitta, Takatani, Matsuda, Ortug, Takahashi, Sawada, Shimizu, Fujii, Aoki and Hamada.)

Introduction: Most infants born as small for gestational age (SGA) demonstrate catch up growth by 2-4 years, but some fail to do so. This failure is associated with several health risks, including neuropsychological development issues. However, data on the morphological characteristics of the brains of infants born as SGA without achieving catch up growth are lacking. This study aims to determine the structural aspects of the brains of children born as SGA without catch up growth., Methods: We conducted voxel- and surface-based morphometric analyses of 1.5-T T1-weighted brain images scanned from eight infants born as SGA who could not achieve catch up growth by 3 years and sixteen individuals with idiopathic short stature (ISS) to exclude body size effects. Growth hormone (GH) secretion stimulation tests were used to rule out GH deficiency in all SGA and ISS cases. The magnetic resonance imaging data were assessed using Levene's test for equality of variances and a two-tailed unpaired t -test for equality of means. The Benjamini-Hochberg procedure was used to apply discovery rate correction for multiple comparisons., Results: Morphometric analyses of both t -statical map and surface-based analyses using general linear multiple analysis determined decreased left insula thickness and volume in SGA without catch up growth compared with ISS., Conclusion: The brain scans of patients with SGA who lack catch up growth indicated distinct morphological disparities when compared to those with ISS. The discernible features of brain morphology observed in patients born as SGA without catch up growth may improve understanding of the association of SGA without catch up growth with both intellectual and psychological outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Takatani, Shiohama, Takatani, Hattori, Yokota and Hamada.)

Background: Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS)., Methods: We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events., Results: The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs., Conclusion: ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tohru Okanishi reports financial support was provided by Japan Society for the Promotion of Science. Hiroshi Matsumoto reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Down syndrome (DS) is a genetic disorder characterized by intellectual disability whose etiology includes an additional partial or full copy of chromosome 21. Brain surface morphometry analyses can potentially assist in providing a better understanding of structural brain differences, and may help characterize DS-specific neurodevelopment. We performed a retrospective surface morphometry study of 73 magnetic resonance imaging (MRI) examinations of DS patients (aged 1 day to 22 years) and compared them to a large cohort of 993 brain MRI examinations of neurotypical participants, aged 1 day to 32 years. Surface curvature measurements, absolute surface area measurements, and surface areas as a percentage of total brain surface area (%TBSA) were extracted from each brain region in each examination. Results demonstrate broad reductions in surface area and abnormalities of surface curvature measurements across the brain in DS. After adjusting our regional surface area measurements as %TBSA, abnormally increased presentation in DS relative to neurotypical controls was observed in the left precentral, bilateral entorhinal, left parahippocampal, and bilateral perirhinal cortices, as well as Brodmann's area 44 (left), and the right temporal pole. Findings suggest the presence of developmental abnormalities of regional %TBSA in DS that can be characterized from clinical MRI examinations.

Rett syndrome is characterized by severe global developmental impairments with autistic features and loss of purposeful hand skills. Here we show that human induced pluripotent stem cell (hiPSC) lines derived from four Japanese female patients with Rett syndrome are generated from peripheral blood mononuclear cells using Sendai virus vectors. The generated hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift, missense, or nonsense mutations in the MECP2 gene. Since the molecular pathogenesis caused by MECP2 dysfunction remains unclear, these cell resources are useful tools to establish disease models and develop new therapies for Rett syndrome., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Satoru Takahashi reports financial support was provided by Japan Agency for Medical Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS ( n = 3) and age and sex-matched controls ( n = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens.

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation.

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans . To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy.

Regional anatomical structures of the brain are intimately connected to functions corresponding to specific regions and the temporospatial pattern of genetic expression and their functions from the fetal period to old age. Therefore, quantitative brain morphometry has often been employed in neuroscience investigations, while controlling for the scanner effect of the scanner is a critical issue for ensuring accuracy in brain morphometric studies of rare orphan diseases due to the lack of normal reference values available for multicenter studies. This study aimed to provide across-site normal reference values of global and regional brain volumes for each sex and age group in children and adolescents. We collected magnetic resonance imaging (MRI) examinations of 846 neurotypical participants aged 6.0-17.9 years (339 male and 507 female participants) from 5 institutions comprising healthy volunteers or neurotypical patients without neurological disorders, neuropsychological disorders, or epilepsy. Regional-based analysis using the CIVET 2.1.0. pipeline provided regional brain volumes, and the measurements were across-site combined using ComBat-GAM harmonization. The normal reference values of global and regional brain volumes and lateral indices in our study could be helpful for evaluating the characteristics of the brain morphology of each individual in a clinical setting and investigating the brain morphology of ultra-rare diseases.

Purpose: Central precocious puberty (CPP) is puberty that occurs at an unusually early age with several negative psychological outcomes. There is a paucity of data on the morphological characteristics of the brain in CPP. This study aimed to determine the structural differences in the brain of patients with CPP., Methods: We performed voxel- and surface-based morphometric analyses of 1.5 T T1-weighted brain images scanned from 15 girls with CPP and 13 age-matched non-CPP controls (NC). All patients with CPP were diagnosed by gonadotropin-releasing hormone (GnRH) stimulation test. The magnetic resonance imaging (MRI) data were evaluated using Levene's test for equality of variances and a two-tailed unpaired t-test for equality of means. False discovery rate correction for multiple comparisons was applied using the Benjamini-Hochberg procedure., Results: Morphometric analyses of the brain scans identified 33 candidate measurements. Subsequently, increased thickness of the right precuneus was identified in the patients with CPP using general linear models and visualizations of cortical thickness with a t-statistical map and a random field theory map., Conclusion: The brain scans of the patients with CPP showed specific morphological differences to those of the control. The features of brain morphology in CPP identified in this study could contribute to further understanding the association between CPP and detrimental psychological outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yoshii, Takatani, Shiohama, Takatani, Konda, Hattori, Yokota and Hamada.)

Objective: Guillain-Barré syndrome (GBS), Fisher syndrome (FS), and Bickerstaff brainstem encephalitis (BBE) are immune-mediated neuropathies presenting with symptoms such as weakness, ophthalmoplegia, ataxia, and consciousness disturbances. Although the epidemiology of GBS and BBE in patients of all ages has been reported, childhood data have not been well-investigated. We aimed to determine the clinical features, therapeutics, and prognoses of childhood GBS, FS, and BBE in Japan., Methods: We sent questionnaires to 1068 pediatric neurologists in Japan from 2014 to 2016 to determine the number of children less than 15 years old with GBS, FS, or BBE and their age and sex. We subsequently performed a secondary survey to investigate the clinical features, laboratory data, treatment, and prognosis., Results: Five-hundred thirty-eight pediatric neurology specialists (50.4%) responded to the first survey. The total number of children with GBS, FS, and BBE in Japan from 2014 to 2016 were 87, 10, and 6, respectively. GBS was classified as acute inflammatory demyelinating neuropathy (35.6%), acute motor axonal neuropathy (20.7%), or acute motor-sensory axonal neuropathy (10.3%), with a male-to-female ratio of 1.29:1.0 and a wide distribution of onset ages. The disease severities of GBS, FS, and BBE were variable, but all children could walk within one year., Conclusion: The prognoses of childhood GBS, FS, and BBE were generally favorable, as long as the patient was promptly treated with either intravenous immunoglobulin or plasma exchange., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition for which we have an incomplete understanding, and so brain imaging methods, such as magnetic resonance imaging (MRI), may be able to assist in characterising and understanding the presentation of the brain in an ADHD population. Statistical and computational methods were used to compare participants with ADHD and neurotypical controls at a variety of developmental stages to assess detectable abnormal neurodevelopment potentially associated with ADHD and to assess our ability to diagnose and characterise the condition from real-world clinical MRI examinations. T1-weighted structural MRI examinations (n = 993; 0-31 years old [YO]) were obtained from neurotypical controls, and 637 examinations were obtained from patients with ADHD (0-26 YO). Measures of average (mean) regional cortical thickness were acquired, alongside the first reporting of regional cortical thickness variability (as assessed with the standard deviation [SD]) in ADHD. A comparison between the inattentive and combined (inattentive and hyperactive) subtypes of ADHD is also provided. A preliminary independent validation was also performed on the publicly available ADHD200 dataset. Relative to controls, subjects with ADHD had, on average, lowered SD of cortical thicknesses and increased mean thicknesses across several key regions potentially linked with known symptoms of ADHD, including the precuneus and supramarginal gyrus., (© 2022 International Society for Developmental Neuroscience.)

Proper brain development requires the precise coordination and orchestration of various molecular and cellular processes and dysregulation of these processes can lead to neurological diseases. In the past decades, post-transcriptional regulation of gene expression has been shown to contribute to various aspects of brain development and function in the central nervous system. MicroRNAs (miRNAs), short non-coding RNAs, are emerging as crucial players in post-transcriptional gene regulation in a variety of tissues, such as the nervous system. In recent years, miRNAs have been implicated in multiple aspects of brain development, including neurogenesis, migration, axon and dendrite formation, and synaptogenesis. Moreover, altered expression and dysregulation of miRNAs have been linked to neurodevelopmental and psychiatric disorders. Magnetic resonance imaging (MRI) is a powerful imaging technology to obtain high-quality, detailed structural and functional information from the brains of human and animal models in a non-invasive manner. Because the spatial expression patterns of miRNAs in the brain, unlike those of DNA and RNA, remain largely unknown, a whole-brain imaging approach using MRI may be useful in revealing biological and pathological information about the brain affected by miRNAs. In this review, we highlight recent advancements in the research of miRNA-mediated modulation of neuronal processes that are important for brain development and their involvement in disease pathogenesis. Also, we overview each MRI technique, and its technological considerations, and discuss the applications of MRI techniques in miRNA research. This review aims to link miRNA biological study with MRI analytical technology and deepen our understanding of how miRNAs impact brain development and pathology of neurological diseases.

Tourette syndrome (TS) is a neurological disorder characterized by involuntary and repetitive movements known as tics. A retrospective analysis of magnetic resonance imaging (MRI) scans from 39 children and adolescents with TS was performed and subsequently compared with MRI scans from 834 neurotypical controls. The purpose of this study was to identify any differences in the regions of motor circuitry in TS to further our understanding of their disturbances in motor control (i.e., motor tics). Measures of volume, cortical thickness, surface area, and surface curvature for specific motor regions were derived from each MRI scan. The results revealed increased surface curvature in the opercular part of the inferior frontal gyrus and the triangular part of the inferior frontal gyrus in the TS group compared with the neurotypical control group. These novel findings offer some of the first evidence for surface curvature differences in motor circuitry regions in TS, which may be associated with known motor and vocal tics., (© 2022 International Society for Developmental Neuroscience.)

Background and Purpose: Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings., (© 2022 American Society of Neuroimaging.)

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder characterized by various neurological symptoms. Almost all RTT cases are caused by mutations in the X-linked methyl-CpG-binding protein 2 ( MeCP2 ) gene, and several mouse models have been established to understand the disease. However, the neuroanatomical abnormalities in each brain region of RTT mouse models have not been fully understood. Here, we investigated the global and local neuroanatomy of the Mecp2 gene-deleted RTT model ( Mecp2 -KO) mouse brain using T2-weighted 3D magnetic resonance imaging with different morphometry to clarify the brain structural abnormalities that are involved in the pathophysiology of RTT. We found a significant reduction in global and almost all local volumes in the brain of Mecp2 -KO mice. In addition, a detailed comparative analysis identified specific volume reductions in several brain regions in the Mecp2 -deficient brain. Our analysis also revealed that the Mecp2 -deficient brain shows changes in hemispheric asymmetry in several brain regions. These findings suggest that MeCP2 affects not only the whole-brain volume but also the region-specific brain structure. Our study provides a framework for neuroanatomical studies of a mouse model of RTT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Akaba, Shiohama, Komaki, Seki, Ortug, Sawada, Uchida, Kamagata, Shimoji, Aoki, Takahashi, Suzuki, Natsume, Takahashi and Tsujimura.)

Congenital genetic disorders often present with neurological manifestations such as neurodevelopmental disorders, motor developmental retardation, epilepsy, and involuntary movement. Through qualitative morphometric evaluation of neuroimaging studies, remarkable structural abnormalities, such as lissencephaly, polymicrogyria, white matter lesions, and cortical tubers, have been identified in these disorders, while no structural abnormalities were identified in clinical settings in a large population. Recent advances in data analysis programs have led to significant progress in the quantitative analysis of anatomical structural magnetic resonance imaging (MRI) and diffusion-weighted MRI tractography, and these approaches have been used to investigate psychological and congenital genetic disorders. Evaluation of morphometric brain characteristics may contribute to the identification of neuroimaging biomarkers for early diagnosis and response evaluation in patients with congenital genetic diseases. This mini-review focuses on the methodologies and attempts employed to study Rett syndrome using quantitative structural brain MRI analyses, including voxel- and surface-based morphometry and diffusion-weighted MRI tractography. The mini-review aims to deepen our understanding of how neuroimaging studies are used to examine congenital genetic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shiohama and Tsujimura.)

Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder, with an unknown aetiology and pathogenesis. It is characterized by steno-occlusive changes at the terminal portion of the internal carotid artery (ICA), which is accompanied by variable development of the basal collaterals called moyamoya vessels. In this study, we investigate the potential for structural T1 magnetic resonance imaging (MRI) to help characterize MMD clinically, with the help of regionally distributed relative signal intensities (RRSIs) and volumes (RRVs). These RRSIs and RRVs provide the ability to characterize aspects of regional brain development and represent an extension to existing automated biomarker extraction technologies. This study included 269 MRI examinations from MMD patients and 993 MRI examinations from neurotypical controls, with regional biomarkers compared between groups with the area under the receiver operating characteristic curve (AUC). Results demonstrate abnormal presentation of RRSIs and RRVs in the insula (15- to 20-year old cohort, left AUC: 0.74, right AUC: 0.71) and the lateral orbitofrontal region (5- to 10-year old cohort, left AUC: 0.67; 15-20 year cohort, left AUC: 0.62, right AUC: 0.65). Results indicate that RRSIs and RRVs may help in characterizing brain development, assist in the assessment of the presentation of the brains of children with MMD and help overcome standardization challenges in multiprotocol clinical MRI. Further investigation of the potential for RRSIs and RRVs in clinical imaging is warranted and supported through the release of open-source software., (© 2021 International Society for Developmental Neuroscience.)

Early interventions for autism spectrum disorder (ASD) are increasingly available, while only 42-50% of ASD children are diagnosed before 3 years old (YO). To identify neuroimaging biomarkers for early ASD diagnosis, we evaluated surface- and voxel-based brain morphometry in participants under 3YO who were later diagnosed with ASD. Magnetic resonance imaging data were retrospectively obtained from patients later diagnosed with ASD at Boston Children's Hospital. The ASD participants with comorbidities such as congenital disorder, epilepsy, and global developmental delay/intellectual disability were excluded from statistical analyses. Eighty-five structural brain magnetic resonance imaging images were collected from 81 participants under 3YO and compared with 45 images from 45 gender- and age-matched nonautistic controls (non-ASD). Using an Infant FreeSurfer pipeline, 236 regionally distributed measurements were extracted from each scan. By t-tests and linear mixed models, the smaller nucleus accumbens and larger bilateral lateral, third, and fourth ventricles were identified in the ASD group. Vertex-wise t-statistical maps showed decreased thickness in the caudal anterior cingulate cortex and increased thickness in the right medial orbitofrontal cortex in ASD. The smaller bilateral accumbens nuclei and larger cerebral ventricles were independent of age, gender, or gestational age at birth, suggesting that there are MRI-based biomarkers in prospective ASD patients before they receive the diagnosis and that the volume of the nucleus accumbens and cerebral ventricles can be key MRI-based early biomarkers to predict the emergence of ASD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Moyamoya disease (MMD) is a progressive cerebrovascular disorder, with an unknown pathogenesis and aetiology. MMD is characterized by steno-occlusive changes at the terminal portion of the internal carotid artery (ICA), which is accompanied by variable development of the basal collaterals, also known as moyamoya vessels. Patients with MMD show variable patterns of brain damage and may experience recurrent multiple transient ischaemic attacks, intracranial bleeding and cerebral infarction. In this study, we investigate the potential for structural T1 magnetic resonance imaging (MRI) to help characterize abnormal cortical development in MMD clinically, with an analysis of both average and variability of regional cortical thicknesses. This study also included a machine learning analysis to assess the predictive capacity of the cortical thickness abnormalities observed in this research. This study included 993 MRI examinations from neurotypical controls and 269 MRI examinations from MMD patients. Results demonstrate abnormal cortical presentation of the insula, caudate, postcentral, precuneus and cingulate regions, in agreement with previous literature cortical thickness findings as well as alternative methods such as functional MRI (fMRI) and digital angiography. To the best of our knowledge, this is the first manuscript to report cortical thickness abnormalities in the middle temporal visual area in MMD and the first study to report on cortical thickness variability abnormalities in MMD., (© 2021 International Society for Developmental Neuroscience.)

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

We aimed to identify symptom-related neuroimaging biomarkers for patients with dysgenesis of the corpus callosum (dCC) by summarizing neurological symptoms reported in clinical evaluations and correlating them with retrospectively collected structural/diffusion brain magnetic resonance imaging (MRI) measures from 39 patients/controls (mean age 8.08 ± 3.98). Most symptoms/disorders studied were associated with CC abnormalities. Total brain (TB) volume was related to language, cognition, muscle tone, and metabolic/endocrine abnormalities. Although white matter (WM) volume was not related to symptoms studied, gray matter (GM) volume was related to cognitive, behavioral, and metabolic/endocrine disorders. Right hemisphere (RH) cortical thickness (CT) was linked to language abnormalities, while left hemisphere (LH) CT was linked to epilepsy. While RH gyrification index (GI) was not related to any symptoms studied, LH GI was uniquely related to cognitive disorders. Between patients and controls, GM volume and LH/RH CT were significantly greater in dCC patients, while WM volume and LH/RH GI were significantly greater in controls. TB volume and diffusion indices for tissue microstructures did not show differences between the groups. In summary, our brain MRI-based measures successfully revealed differential links to many symptoms. Specifically, LH GI abnormality can be a predictor for dCC patients, which is uniquely associated with the patients' symptom. In addition, patients with CC abnormalities had normal TB volume and overall tissue microstructures, with potentially deteriorated mechanisms to expand/fold the brain, indicated by GI., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring's HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children's Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring's body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387-1.969) for the impact of maternal smoking during pregnancy on their offspring's smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring's HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring's neurological impairment even after pregnancy., (© 2021. The Author(s).)

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients., Methods: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven-dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image-processing software., Results: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426)., Conclusions: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality., (© 2020 Japan Pediatric Society.)

Down syndrome (DS) is a genetic disorder caused by the presence of an extra full or partial copy of chromosome 21 and characterized by intellectual disability. We hypothesize that performing a retrospective analysis of 73 magnetic resonance imaging (MRI) examinations of participants with DS (aged 0 to 22 years) and comparing them to a large cohort of 993 brain MRI examinations of neurotypical participants (aged 0 to 32 years), will assist in better understanding what brain differences may explain phenotypic developmental features in DS, as well as to provide valuable confirmation of prospective literature findings clinically. Measurements for both absolute volumes and volumes corrected as a percentage of estimated total intracranial volume (%ETIV) were extracted from each examination. Our results presented novel findings such as volume increases (%ETIV) in the perirhinal cortex, entorhinal cortex, choroid plexus, and Brodmann's areas (BA) 3a, 3b, and 44, as well as volume decreases (%ETIV) in the white matter of the cuneus, the paracentral lobule, the postcentral gyrus, and the supramarginal gyrus. We also confirmed volumetric brain abnormalities previously discussed in the literature. Findings suggest the presence of volumetric brain abnormalities in DS that can be detected clinically with MRI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Sensorineural hearing loss (SNHL) is the most common developmental sensory disorder due to a loss of function within the inner ear or its connections to the brain. While successful intervention for auditory deprivation with hearing amplification and cochlear implants during a sensitive early developmental period can improve spoken-language outcomes, SNHL patients can suffer several cognitive dysfunctions including executive function deficits, visual cognitive impairment, and abnormal visual dominance in speaking perception even after successful intervention. To evaluate whether long association fibers are involved in the pathogenesis of impairment on the extra-auditory cognitive process in SNHL participants, we quantitatively analyzed high-angular resolution diffusion imaging (HARDI) tractography-derived fibers in participants with SNHL. After excluding cases with congenital disorders, perinatal brain damage, or premature birth, we enrolled 17 participants with SNHL aged under 10 years old. Callosal pathways (CP) and six types of cortico-cortical association fibers (arcuate fasciculus [AF], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], uncinate fasciculus [UF], cingulum fasciculus [CF], and fornix [Fx]) in both hemispheres were identified and visualized. The ILF and IFOF were partly undetected in three profound SNHL participants. Compared to age- and gender-matched neurotypical controls (NC), decreased volumes, increased lengths, and high apparent diffusion coefficient (ADC) values without difference in fractional anisotropy (FA) values were identified in multiple types of fibers in the SNHL group. The impairment of long association fibers in SNHL may partly be related to the association of cognitive dysfunction with SNHL., (© 2020 International Society for Developmental Neuroscience.)

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS., (© 2020 Wiley Periodicals, Inc.)

Background: Down syndrome (DS) is the most prevalent chromosomal disorder characterized by intellectual disability, multiple organ anomalies, generalized muscular hypotonia, and characteristic physical features. The presence of DS-associated medical comorbidities has contributed to brain morphologic changes. The aim of this study was to evaluate brain morphologic characteristics during infant and toddler ages in patients with DS using structural brain magnetic resonance imaging., Methods: Structural brain T1-weighted magnetic resonance images from participants with DS with complete chromosome 21 trisomy (n = 20; 1.6 ± 0.6 [mean ± standard deviation] years old) were analyzed using FreeSurfer. The measurements were compared with those of 60 gender- and age-matched neurotypical controls by Cohen's d statistic and unpaired t test with false discovery rate correction for multiple comparisons and analyzed using a univariate general linear model with the following DS-associated medical comorbidities: congenital cardiac disease, infantile spasms, and hypothyroidism., Results: We identified 27 candidate measurements with large effect sizes (absolute d > 0.8) and statistically significant differences (P < 6.9 × 10 -3 ). Among them were decreased volumes in bilateral cerebellar gray matter and right cerebellar white matter and brainstem and cortical abnormalities in the right superior temporal, right rostral anterior cingulate, and left rostral middle frontal gyrus, independent of comorbid effects. Only bilateral cerebellar gray matter volumes and brainstem volume showed differences between DS and healthy groups during infancy., Conclusion: These results suggest that cerebellar gray matter and brainstem may represent the primary regions affected by the presence of an additional copy of chromosome 21., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Gorlin syndrome (GS) is a hereditary disorder with tumorigenicity, caused by constitutive hyperactivity of hedgehog signaling. Smoothened (SMO) antagonists have been effectively used in the clinical treatment of hedgehog signaling-related cancer. However, these treatments have led to problematic side effects, including severe adverse reactions and drug resistance from additional somatic mutations. We profiled microRNAs in GS fibroblasts to explore a novel therapeutic target for controlling hyper-activated hedgehog signaling. To identify GS-related microRNAs, we analyzed dermal fibroblasts from five patients with GS and three normal controls. We used microarray comparative genomic hybridization to screen 632 human microRNAs in GS fibroblasts. We identified 16 down- and 19 upregulated microRNAs with over twofold change in expression. We validated the increased expression of four microRNAs, confirming hsa-miR-196a-5p downregulation and hsa-miR-4485 upregulation using real-time PCR. Moreover, hsa-miR-196a-5p is complementary to sites in the 3' UTR of MAP3K1, which exhibits upregulated expression at mRNA and protein levels in GS fibroblasts. In addition, hedgehog signal induction with exogenous components decreased miR-196a-5p expression and increased map3k1 expression in a mouse mesenchymal cell line. Given that MAP3K1 has been reported to activate hedgehog signaling, hsa-miR-196a-5p may contribute to the positive feedback loop in this pathway.

Patients with sensorineural hearing loss (SNHL) tend to show language delay, executive functioning deficits, and visual cognitive impairment, even after intervention with hearing amplification and cochlear implants, which suggest altered brain structures and functions in SNHL patients. In this study, we investigated structural brain MRI in 30 children with SNHL (18 mild to moderate [M-M] SNHL and 12 moderately severe to profound [M-P] SNHL) by comparing gender- and age-matched normal controls (NC). Region-based analyses did not show statistically significant differences in volumes of the cerebrum, basal ganglia, cerebellum, and the ventricles between SNHL and NC. On surface-based analyses, the global and lobar cortical surface area, thickness, and volumes were not statistically significantly different between SNHL and NC participants. Regional surface areas, cortical thicknesses, and cortical volumes were statistically significantly smaller in M-P SNHL compared to NC in the left middle occipital cortex, and left inferior occipital cortex after a correction for multiple comparisons using random field theory (p < 0.02). These regions were identified as areas known to be related to high level visual cognition including the human middle temporal area, lateral occipital area, occipital face area, and V8. The observed regional decreased thickness in M-P SNHL may be associated with dysfunctions of visual cognition in SNHL detectable in a clinical setting., (Copyright © 2019 ISDN. Published by Elsevier Ltd. All rights reserved.)

The development of cortical convolutions, gyri and sulci, is a complex process that takes place during prenatal development. Lissencephaly, a rare genetic condition characterized by the lack of cortical convolutions, offers a model to look into biological processes that lead to the development of convolutions. Retrospective, qualitative, and quantitative analyses of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed in patients with lissencephaly ( N = 10) and age-/sex-matched controls ( N = 10). In order to identify microstructural correlates of structural MRI and DTI findings, postmortem brains of patients with lissencephaly ( N = 4) and age-matched controls ( N = 4) were also examined with histology. Patients with lissencephaly had significantly smaller gyrification index and volumes of hemispheric white and gray matter, compared to the age-/sex-matched control group. However, there was no significant difference between groups in the subcortical gray matter volumes. Although the majority of patients with lissencephaly had a preserved normal-like appearance of major fissures and primary sulci, the spatial distribution of agyric cortical regions was different in patients with lissencephaly-1 ( LIS1 ) and doublecortin ( DCX ) mutations. Lastly, in patients with lissencephaly, the spatiotemporal distribution of projection pathways was preserved while short- to medium-range cortico-cortical pathways were absent or fewer in number. Our results indicate that in the patients with lissencephaly cortical system is affected more than the subcortical one.