塩浜 直

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.

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.

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.

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.

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.

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.

We encountered a pediatric case of pulmonary hypertension triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 14-year-old girl was brought to the emergency department of our hospital with fever, respiratory distress, and impaired consciousness. She tested positive for SARS-CoV-2 upon a polymerase chain reaction examination and had prolonged hypoxemia without pneumonia. An echocardiography revealed elevated right ventricular pressure. She was diagnosed with pilocytic astrocytoma at the age of 10 years and underwent a resection of a pituitary tumor. Hormone replacement therapy was administered postoperatively, but her growth hormones were not activated because of concerns about tumor recurrence. Echocardiography at the age of 13 years showed normal right ventricular pressure. On admission, she had an abnormal liver function, elevated liver fibrosis markers, a decreased platelet count, and hepatosplenomegaly, suggesting pulmonary and portal hypertension. The diagnosis was pulmonary hypertension associated with SARS-CoV-2 infection. The mechanism of the pulmonary hypertension was thought to be portal hypertension owing to growth hormone deficiency and SARS-CoV-2 infection. The patient's symptoms improved with oxygenation and bed rest without additional targeted pulmonary hypertension therapy, and her right ventricular pressure decreased. This case demonstrates that a pediatric patient with subclinical pulmonary hypertension may develop pulmonary hypertension triggered by SARS-CoV-2 infection.

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.

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.

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.

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)–Vakt murine thymoma viral oncogene homolog (AKT)–mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

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.

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.

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.

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.

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 to 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 to 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.

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.

Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.

Attention deficit hyperactivity disorder 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 characterizing and understanding the presentation of the brain in an ADHD population. Statistical and computational methods were used to compare participants with attention deficit hyperactivity disorder (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 characterize the condition from real-world clinical magnetic resonance imaging (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, supramarginal gyrus, etc.

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.

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.

Moyamoya disease (MMD) is a rare, progressive cerebrovascular disorder, with an unknown etiology 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 (15-20 year old cohort, left AUC: 0.74, right AUC: 0.71), and the lateral orbitofrontal region (5-10 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 may help overcome standardization challenges in multi-protocol 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.

神経発達症や先天異常症候群の脳MRI検査では、明確な中枢神経症状があるにもかかわらず、定性的な異常を認めないことが多く、脳MRI定量解析が注目されている。3D-T1強調画像を用いた解剖学的構造解析と拡散強調画像を用いた神経線維トラクトグラフィーについて概説した。また、脳MRI定量解析の臨床応用として、自閉スペクトラム症、Rett症候群、感音難聴について述べた。

<title>Abstract</title>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.

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.

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.

Moyamoya disease (MMD) is a progressive cerebrovascular disorder, with an unknown pathogenesis and etiology. 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 ischemic 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.

BACKGROUND: Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a hereditary disorder caused by biallelic variants in the EARS2 gene. Patients exhibit developmental delay, hypotonia, and hyperreflexia. Brain magnetic resonance imaging (MRI) reveals T2-hyperintensities in the deep white matter, thalamus, and brainstem, which generally stabilize over time. Herein, we report a case of LTBL, showing remitting and exacerbating white matter lesions. CASE DESCRIPTION: A non-consanguineous Japanese boy exhibited unsteady head control with prominent hypotonia, with no family history of neurological diseases. Brain MRI at one year of age revealed extensive T2-hyperintensities on the cerebral white matter, cerebellum, thalamus, basal ganglia, pons, and medulla oblongata. Magnetic resonance spectroscopy of the lesions showed lactate and myoinositol peaks. Whole-exome sequencing yielded novel compound heterozygous EARS2 variants of c.164G>T, p.Arg55Leu and c.484C>T, p.Arg162Trp. Interestingly, the lesions were reduced at three years of age, and new lesions emerged at eight years of age. At 10 years of age, the lesions were changed in the corpus callosum, deep cerebral white matter, and cerebellum, without physical exacerbation. The lesions improved one year later. CONCLUSION: We present the first case with remitting and exacerbating brain lesions in LTBL. EARS2 could relate to selective and specific brain regions and age dependency. Although the exact role of EARS2 remains unknown, the remitting and exacerbating imaging changes may be a clue in elucidating a novel EARS2 function in LTBL.

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.

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.

上斜筋麻痺では斜視、複視、頭位異常などの症状が出現する。診断にはParks-Bielschowsky three-step testが使われるが、3 stepsを満たさない場合や所見の評価が難しい場合もある。斜視、頭位異常が軽微の場合には所見として認識されず、複視の原因となる他の全身性疾患の鑑別が必要となることもあり、上斜筋麻痺の診断に苦慮する場合がある。今回、複視で発症した上斜筋麻痺に対して、単眼視による頭部傾斜変化が他覚的診断に有用であったため報告する。症例は13歳女子。2年前より複視を自覚、増悪し受診した。右眼はわずかに外上方の斜位で、眼球運動9方向に制限はなかったが全方向に複視を認めた。眼瞼下垂はなかったが、夕方に増悪する日内変動があった。血液検査、脳MRI検査、神経伝導検査、テンシロン試験に異常はなく、重症筋無力症、脳腫瘍、Fisher症候群などは否定された。左右の単眼視で頭部傾斜を比較すると、健側である左単眼視で頭位は正中であるのに対し、右単眼視で健側に頸部を傾ける代償性頭位の所見が顕著となり、上斜筋麻痺と診断した。眼科手術により複視は著明に改善した。斜視、頭位異常が軽微で上斜筋麻痺の診断に苦慮する場合には、単眼視による頭部傾斜変化がBielschowsky徴候を強調し、他覚的な診断に有用となりうると考えられた。(著者抄録)

BACKGROUND: Peripheral nerve imaging is increasingly recognized as a powerful tool to evaluate nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth diseases (CMT), whereas data in pediatric patients are limited. CASE DESCRIPTION: We describe the case of a 15-year-old Japanese girl with asymmetric demyelinating polyneuropathy, who, at the age of 10 years, was initially diagnosed with a demyelinating form of CMT. Fluorescence in situ hybridization for peripheral myelin 22 was negative, and already-known pathogenic variants were not detected by whole-genome sequencing, and nerve conduction studies revealed multifocal conduction blocks. Over the next 5 years, the patient showed gradual improvement in muscle weakness and sensory disturbance without immunological treatment and was referred to our hospital. RESULTS: At the age of 15 years, magnetic resonance (MR) neurography showed asymmetric multifocal fusiform enlargement of nerve roots, brachial and lumbosacral plexuses, and intermediated nerve trunks, as well as cranial nerves. Based on the MR neurography findings and multifocal nerve conduction blocks, she was diagnosed as having multifocal CIDP (multifocal demyelinating sensory and motor neuropathy [MADSAM]) according to the European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria. DISCUSSION: Clinical diagnosis of childhood CIDP is challenging because its neurological manifestations and nerve conduction study findings occasionally resemble those of inherited demyelinating neuropathies. MR neurography is helpful for the assessment of patterns of nerve hypertrophy; MADSAM-CIDP is characterized by multiple fusiform nerve enlargement, whereas CMT shows symmetric and diffuse nerve hypertrophy. CONCLUSION: The MR neurography patterns would help in diagnosing pediatric demyelinating neuropathies.

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.

Superior oblique palsy causes deviation, diplopia, and abnormal head posture. The Parks-Bielschowsky three-step test is used for diagnosis however. we experience cases that do not meet these 3 steps, or whose findings are difficult to evaluate. We were unable to detect findings in cases where deviation and abnormal head posture were mild. As we have to consider differential diagnoses, including systemic disorders causing diplopia, diagnosis is occasionally difficult. Here, we report the usefulness of the change of head tilt with monocular vision in the objective diagnosis of superior oblique palsy associated with diplopia. A 13-year-old Japanese girl experienced diplopia 2 years ago and presented to our hospital with exacerbated diplopia. She showed subtle right exotropic hypertropia and omnidirectional diplopia while her eye movements were preserved in 9 directions. She did not present with ptosis, but complained about circadian changes in diplopia that worsened in the evening. Blood examination, brain magnetic resonance imaging, a nerve conduction test, and a Tensilon test yielded normal results. Diagnosis of Myasthenia gravis, brain tumor, and Fisher syndrome was excluded. While comparing head tilt with the patient's right monocular vision to her left, we identified that head posture with left monocular vision, or the unaffected side was vertical. Alternatively, head posture with the patient's right monocular vision and the affected side revealed a compensating head posture. In this regard, the patient was diagnosed with superior oblique palsy. Diplopia was responsive to ophthalmic surgery. We conclude that the change of head tilt with monocular vision highlights the Bielschowsky sign and can be useful for objective diagnosis.

●学童期に急性・亜急性に発症する末梢神経疾患について、Guillain-Barre症候群を中心に概説する。●末梢神経疾患では、運動麻痺、疼痛を含む感覚障害、自律神経障害、深部腱反射の減弱に着目する。●検査としては、末梢神経伝導検査、脳・脊髄MRI、髄液検査などを行う。●Guillain-Barre症候群の頻度が多いが、他にもCritical illness polyneuropathy、遺伝性圧脆弱性ニューロパチー、神経痛性筋萎縮症、代謝疾患、中毒性、感染性、外傷性、血管炎、薬剤性と多彩な原因がある。(著者抄録)

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.

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.

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.