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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.)

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objectives: Niemann-Pick type C (NPC) is a rare lysosomal storage disease characterized by hepatosplenomegaly and progressive neurological deterioration due to abnormal intracellular cholesterol transport. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPBCD) is an effective treatment for NPC; however, few reports have shown its long-term efficacy and safety. To demonstrate long-term efficacy and safety of intrathecal HPBCD (IT-HPBCD) treatment for NPC, we herein reports five patients with NPC treated using IT-HPBCD for 4-11 years., Cases and Results: Patients' ages at the onset ranged from 1.5 to 20 years. Notably, all patients showed rapid disease progression despite treatment with miglustat before IT-HPBCD treatment. Similarly, some patients showed transient improvement; however, all patients' conditions stabilized after long-term IT-HPBCD therapy. Mild-to-moderate hearing loss was observed in three patients. Furthermore, long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, patients still experience some disease progression., Conclusions: Long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, the treatment outcome is dependent on the neurological status at the time of diagnosis, and disease progression is not completely inhibited. Awareness of the disease and newborn screening is needed for earlier disease detection. In addition, further optimization of the treatment protocol and additional treatments are needed to improve patient outcomes., 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 © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Introduction: Patients with Chiari I malformation (CM1) may have chronic symptoms of syringomyelia, including numbness and weakness of the upper limbs, typically during young adulthood. Acute or subacute presentation of unilateral foot drop has been rarely reported as a first symptom of CM1-associated syringomyelia exclusively in childhood or adolescence. Why these patients do not show any symptoms of the upper limbs although holocord syringomyelia is always observed on magnetic resonance imaging (MRI) is unclear., Case Presentation: A four-year-old girl presented rapidly with isolated left foot drop. Conventional MRI revealed holocord syringomyelia associated with CM1. Three-dimensional constructive interference in steady state (3D-CISS) imaging further demonstrated that the syringomyelia was comprised of two differential cavities that communicated with each other via a small pore: a centrally positioned upper cavity and a left-deviated lower one. Surgical decompression of the foramen magnum resolved the symptom with radiological improvement of the two cavities., Conclusion: In contrast to a centrally enlarged syrinx that is often asymptomatic, a paracentrally extended syrinx usually produces segmental signs related to its levels. Thus, the left foot drop in this case would have been due to the ipsilaterally deviated lower cavity that was distinguished from the central upper cavity by 3D-CISS imaging. Further reports using this imaging technique are needed to verify the hypothetic pathology., 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 © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with aphasia is a rare disorder, with the associated aphasia reported as either Wernicke's or Broca's. Herein, we report a patient with MELAS complicated by thalamic aphasia., Case: A 15-year-old right-handed girl presented with headache, nausea, right homonymous hemianopsia, and aphasia. She could repeat words said by others, but had word-finding difficulty, paraphasia, and dysgraphia. Brain MRI revealed abnormal signals from the left occipital lobe to the temporal lobe and left thalamus, but Wernicke's area and Broca's area were not involved. Additionally, she had short stature, lactic acidosis, bilateral sensorineural hearing loss, and a maternal family history of diabetes and mild deafness. Based on clinical findings and the presence of a mitochondrial A3243G mutation, she was diagnosed with MELAS. With treatment, the brain MRI lesions disappeared and her symptoms improved. Her aphasia was classified as amnesic aphasia because she could repeat words, despite having word-finding difficulty, paraphasia, and dysgraphia. Based on MRI findings of a left thalamic lesion, we diagnosed her with thalamic aphasia., Conclusion: Thalamic aphasia may be caused by MELAS. Assessment of whether repetition is preserved is important for classifying aphasia., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: To clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE)., Methods: We retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups., Results: The response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH 3 , procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3 - < 20 mmol/L (1 point), Cl <100 mEq/L (1 point), Cr ≥0.35 mg/dL (1 point), glucose ≥200 mg/dL (1 point), and PCT ≥1.7 pg/mL (2 points). The scoring system had sensitivity of 84.2% and specificity of 81.0%., Conclusion: Incidence data and prediction scores for AESD will be useful for future intervention trials for AESD., Competing Interests: Conflict of Interest Disclosures Study funding: This work was supported by scholarship grants for M. Matsuo from Otsuka Pharmaceutical Co., Ltd. and Shionogi & Co., Ltd. The other authors declare no competing interests., (Copyright © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Transient periictal MRI abnormalities (TPMA) are caused by seizures, and may completely or partially reverse within a few days following seizure. Although TPMA are usually observed in patients with status epilepticus (SE), they have also been rarely reported after isolated/recurrent seizures not fulfilling the criteria for SE. Herein, we present a case of a 1-year-old girl with TPMA., Case: A 1-year-old girl with Apert syndrome and epilepsy showed MRI abnormalities in the cortico-subcortical areas of the left temporal, occipital and parietal lobes, as well as the left thalamus. These abnormalities showed as a hyperintense signal on diffusion-weighted imaging and a hypointense signal on apparent-diffusion coefficient maps. On follow-up MRI after 3 days, the abnormal signals were completely reversed. We confirmed TPMA after eliminating other possibilities. When treatment was withdrawn, the patient regained consciousness immediately and did not show any abnormality on subsequent MRI., Conclusion: TPMA may occur in young children; recognizing this possibility is important for making the diagnosis and conducting appropriate treatment. As a previous study revealed, the distribution of signal changes in cortico-subcortical areas and the ipsilateral thalamus may be a characteristic feature of TPMA., 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 © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant., 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 © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Subacute combined degeneration of the spinal cord (SACD) is a rare neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. Herein we present an autopsy case of SACD caused by folic acid and copper deficiency. A 16-year-old male presented with gradually worsening unsteady gait, and bladder and rectal dysfunction. He had a medical history of T-cell acute lymphoblastic leukemia (T-ALL), diagnosed 1.5 years previously. The patient had undergone chemotherapy, including methotrexate, as well as allogeneic bone mallow transplantation. Laboratory tests revealed normal vitamin B 12 and methylmalonic acid concentration, but reduced serum copper, ceruloplasmin and folic acid concentrations. Magnetic resonance imaging revealed symmetrical T2 signal hyperintensities in the posterior and lateral spinal cord. The patient was treated with oral copper, oral folate, and intravenous vitamin B 12 . A month after this treatment, the patient's symptoms were unchanged, and 2 months later he died of acute adrenal insufficiency. The pathological findings of the spinal cord were compatible with SACD. Because SACD is usually reversible with early treatment, it should be suspected in high-risk patients undergoing chemotherapy or those who are malnourished with characteristic symptoms of SACD, even in young patients., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells., Methods: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined., Results: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis., Conclusion: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: We retrospectively evaluated the imaging spectrum of Pelizaeus-Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality., Methods: We collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings., Results: The clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age "before birth" on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were > 4months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum., Conclusion: Our multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies., (Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined., Methods: Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced., Results: Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR., Conclusion: Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

Neurofibromatosis type 2 (NF2) is an autosomal dominant multiple neoplasia syndrome of the central nervous system. The aim of the present study was to characterize the clinical course of early onset NF2. The specific Japanese disease registry for NF2 in 2010 was analyzed retrospectively. The male:female ratio for the 312 patients identified in the database was 1:1.29. The median age at onset was 25years (range 2-76years), with 31.3% of patients exhibiting symptoms at <20years of age. Patients with an age at onset of <20years were found to have more frequent spinal cord and extravestibular cranial nerve involvement, cutaneous signs, and convulsions than patients with a later age at onset. Of patients younger than 18years of age, half did not exhibit hearing problems; in contrast, they frequently had other cranial nerve schwannomas, cranial meningioma, spinal cord tumors, and subcutaneous schwannoma. There were weak but significant positive correlations between symptomatic periods and disability scores in patients with an age of onset of ⩾20years (R=0.225; P<0.01) and those with an earlier age of onset (R=0.306; P<0.01). Although there were no significant differences in disability scores between genders or patients with an age at onset of <20 versus ⩾20years, patients with an earlier age at onset had significantly higher disability scores for spinal symptoms than patients with an age at onset of ⩾20years. Atypical extravestibular presentation is common in early onset NF2, with more prominent spinal symptoms., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) has a close relationship with epilepsy. This study retrospectively examined patients with epilepsy associated with ASD. Among the 519 patients with epilepsy, 79 patients (15.2%) had ASD. Sixty-two patients had idiopathic ASD and 17 had secondary ASD. The epilepsy patients with idiopathic ASD were retrospectively analyzed. There were 47 males and 15 females, ranging from 2 to 43 years of age (median 11 years). The most frequent age at the onset of seizures was 4 years, and 85% occurred before 10. ASD was detected after the onset of epilepsy in 29 cases (46.8%), and eight of them had been overlooked for more than five years. Most of these were high-functioning ASD cases. The most frequent type of seizure was a complex partial seizure (CPS; 68%). Paroxysmal activities on EEG were localized in the frontal area in about half of the cases. Multiple anti-epileptic drugs were used in 33.8% cases (two in 17.7%, three in 16.1%), and 67.3% of the patients were seizure-free for more than two years. An amelioration of the autistic symptoms occurred after epilepsy treatment in five cases (8%). CPS with frontal paroxysms occurring from one to nine years of age seems to be characteristic of epilepsy associated with ASD., (Copyright © 2010 Elsevier B.V. All rights reserved.)

About 80% of female patients with Rett syndrome (RTT) display a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, but most males with MECP2 mutation experience severe fatal encephalopathy or non-specific X-linked mental retardation (XLMR). The existence of male RTT has been extensively discussed. We report herein a boy with classic RTT in a family with a missense mutation in MECP2. The mother exhibited slight mental retardation and was a carrier for R133C. The patient could stand with support at 12-months-old, and stereotypic hand movements appeared at 3-years-old. He became bed-ridden by 8-years-old. The R133C mutation was present in MECP2 without somatic mosaicism. A sister with R133C displayed classic RTT. The R133C mutation has been detected in female patients with classic and preserved speech variant RTT, but not in males with non-specific XLMR. These results suggest that clinical phenotypes caused by DNA mutation in MECP2 are determined by position of the mutation in the gene, and R133 represents a critical amino acid residue in the induction of RTT symptoms in humans.

Carotid-anterior cerebral artery anastomosis is a rare anomaly of the anterior part of the circle of Willis. We report here magnetic resonance (MR) angiographic findings in 2 patients with this anomaly. MR angiographic source images are useful in evaluating the anatomical details of this anomaly. Including the 2 present cases, 27 patients with this anomaly have been reported in the English-language literature. Thirty anomalous arteries were found in the 27 patients (R/L/bilateral=22/2/3). The reason for the right-sided predominance is unknown.

This is the first report of a case of Bickerstaff's brainstem encephalitis (BBE) associated with IgM antibodies to GM1b and GalNAc-GD1a. Subsequent to Campylobacter jejuni enteritis, the patient rapidly developed consciousness disturbance and hyperreflexia in addition to external ophthalmoplegia and cerebellar-like ataxia. EEG showed transient 7 Hz monorhythmic theta activities, predominantly in the front-central area. He received high doses of immunoglobulin intravenously and had completely recovered 3 months later. High anti-GM1b and anti-GalNAc-GD1a IgM antibody titers present during the acute phase decreased with his clinical improvement. An absorption study showed the anti-GM1b and anti-GalNAc-GD1a IgM antibodies to be cross-reactive. Anti-GM1b and anti-GalNAc-GD1a antibodies have been detected in some patients who developed Guillain-Barré syndrome after C. jejuni enteritis, whereas the anti-GQ1b IgG antibody is associated with BBE. Infection by C. jejuni bearing a GM1b-like or GalNAc-GD1a-like lipooligosaccharide may trigger the production of anti-GalNAc-GD1a and anti-GM1b IgM antibodies. It is not clear why our patient developed BBE rather than Guillain-Barré syndrome. These antibodies may, however, prove useful serological markers for identifying BBE patients who do not have the anti-GQ1b IgG antibody.

We report on a 13-year-old boy with temporal lobe epilepsy associated with left hippocampal sclerosis and a contralateral arachnoid cyst in the middle cranial fossa (ACMCF). Chronic intracranial recording from subdural grid electrodes showed the left medial temporal lobe to be the ictal onset zone. After left anterior temporal lobectomy with hippocampectomy, seizure control was improved. ACMCF was not considered the direct cause of epilepsy; instead the seizures were attributed to hippocampal sclerosis., (Copyright 2002 BEA Trading Ltd.)