Publications by authors named "Jun-Ichi Takanashi"

118 Publications

Kawasaki Disease Shock Syndrome in Japan and Comparison With Multisystem Inflammatory Syndrome in Children in European countries.

Front Pediatr 2021 19;9:625456. Epub 2021 Mar 19.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.

Multisystem inflammatory syndrome in children (MIS-C) is a severe Kawasaki-like illness that was first linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in European countries in the spring of 2020 and has been suggested to have overlap with Kawasaki disease shock syndrome (KDSS). There are few reports of MIS-C from Asia. This observational study aimed to identify the clinical features in children presenting with KDSS in Japan over a 5-year period and to summarize similarities and differences between KDSS and MIS-C. We retrospectively collected data on patient characteristics, clinical signs and symptoms, treatment, and prognosis including coronary artery abnormalities (CAAs), which were compared with data of patients with KDSS worldwide and patients with MIS-C from a review. KDSS was identified in 6 (1.1%) of 552 patients with Kawasaki disease (KD) treated at a single institution in Japan between 2015 and 2020 (1 in 2020). In patients with KDSS in Japan or worldwide vs. patients with MIS-C, KDSS was more likely to have a diagnosis of complete KD (100, 70 vs. 6.3%), a higher incidence of CAAs (50, 65 vs. 11%), and a greater requirement for vasoactive agonists (67, 67 vs. 43%) because of circulatory shock (100, 50 vs. 26%). Both KDSS and MIS-C had good prognosis (mortality 0, 6.7 vs. 1.7%). Although KDSS in Japan and MIS-C show some overlap in clinical symptoms, they are unlikely to be the same disease entity. KDSS is more likely to have a cardiovascular phenotype with CAAs and requires treatment with cardiovascular agents.
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http://dx.doi.org/10.3389/fped.2021.625456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017212PMC
March 2021

Evaluation of the Diagnostic Criteria for Anti-NMDA Receptor Encephalitis in Japanese Children.

Neurology 2021 Mar 2. Epub 2021 Mar 2.

Department of Brain & Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Objective: To evaluate the validity of the 2016 clinical diagnostic criteria proposed for probable anti-NMDA receptor (NMDAR) encephalitis in children, we tested the criteria in a Japanese pediatric cohort.

Methods: We retrospectively reviewed clinical information of patients with neurological symptoms whose CSF were analyzed for NMDAR antibodies (Abs) in our laboratory from January 1, 2015, to March 31, 2019.

Results: Overall, 137 cases were included. Of the 41 cases diagnosed as probable anti-NMDAR encephalitis ("criteria-positive") according to the 2016 criteria, 13 were positive and 28 were negative for anti-NMDAR Abs. Of the 96 criteria-negative cases, three were positive and 93 were negative for anti-NMDAR Abs. The sensitivity of the criteria was 81.2%, specificity was 76.9%, positive predictive value (PPV) was 31.7%, and negative predictive value was 96.9%. Compared with the true-positive group, the false-positive group contained more male than female patients (male:female, 4:9 in the true-positive vs. 19:9 in the false-positive group, p = 0.0425). The majority of the cases with false-positive diagnoses were associated with neurological autoimmunity.

Conclusion: The clinical diagnostic criteria are reliable for deciding to start immunomodulatory therapy in the criteria-positive cases. Low PPV may be caused by a lower prevalence of NMDAR encephalitis and/or lower level of suspicion for encephalitis in the pediatric population. Physicians should therefore continue differential diagnosis, focusing especially on other forms of encephalitis.

Classification Of Evidence: This study provides Class IV evidence that the proposed diagnostic criteria for anti-NMDAR encephalitis in children has a sensitivity of 81.2% and a specificity of 76.9%.
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http://dx.doi.org/10.1212/WNL.0000000000011789DOI Listing
March 2021

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Brain Dev 2021 Apr 9;43(4):505-514. Epub 2021 Jan 9.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.

Results: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.

Conclusion: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
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http://dx.doi.org/10.1016/j.braindev.2020.12.006DOI Listing
April 2021

variants dysregulate splicing and cause hypomyelinating leukodystrophy.

Neurol Genet 2020 Dec 13;6(6):e524. Epub 2020 Oct 13.

Department of Pediatrics (H.K.), Minamata City General Hospital & Medical Center, Kumamoto; Department of Mental Retardation and Birth Defect Research (H.L., K.I.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo; Department of Biochemistry (S.M., H.S.), Hamamatsu University School of Medicine, Shizuoka; Department of Pediatrics (H.U.), Kumamoto Takumadai Rehabilitation Hospital; Kanagawa Children's Medical Center (Y.T., Y.E.), Clinical Research Institute, Yokohama, Kanagawa; Department of Pediatrics (C.I., H.K., T.O., T.S., H.I.), National Hospital Organization Kumamoto Saishun Medical Center, Koshi; Clinical Research Institute, Kanagawa Children's Medical Center, (Y.E.), Yokohama, Kanagawa; Department of Pediatric Neurology (J.T.), Tokyo Women's Medical University Yachiyo Medical Center, Chiba; and Division of Medical Genetics (K.K.), Kanagawa Children's Medical Center, Yokohama, Japan.

Objective: To further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic variants at a cellular level and potential effects on its downstream genes.

Methods: Exome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical and MRI findings characteristic of Pol III-related leukodystrophy other than hypomyelination.

Results: Biallelic novel alterations, c.167T>A, p.M56K and c.595A>T, p.I199F, were identified as causal variants. Functional analyses showed that these variants not only resulted in altered protein subcellular localization and decreased protein expression but also caused abnormal inclusion of introns in 85% of the transcripts in patient cells. Unexpectedly, allelic segregation analysis in each carrier parent revealed that each heterozygous variant also caused the inclusion of introns on both mutant and wild-type alleles. These findings suggest that the abnormal splicing is not direct consequences of the variants, but rather reflect the downstream effect of the variants in dysregulating splicing of , and potentially other target genes.

Conclusions: The lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III-related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for variants.
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http://dx.doi.org/10.1212/NXG.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577547PMC
December 2020

Panton-Valentine leukocidin-positive novel sequence type 5959 community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction in a 1-month-old infant.

J Infect Chemother 2021 Jan 26;27(1):103-106. Epub 2020 Sep 26.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a pathogen of major importance in pediatric patients. CA-MRSA can cause skin and soft tissue infection in children and young active adults with no predisposing factors, and life-threatening infections such as meningitis or necrotizing pneumonia have been reported. We report here a case of CA-MRSA meningitis complicated by acute left middle cerebral artery (MCA) infarction and necrotizing pneumonia in a previously healthy 1-month-old Vietnamese boy. He was firstly treated with vancomycin, but changed to linezolid because of persistent fever and low vancomycin trough level. He recovered successfully with residual right-sided hemiparesis. The mode of transmission of CA-MRSA and the mechanism of cerebral infarction (thrombotic or embolic) were unknown. The isolate was genotyped as staphylococcal cassette chromosome (SCC) mec type V with a novel sequence type (ST) 5959 harboring the Panton-Valentine leukocidin (PVL) gene. ST 5959 is a double locus variant of ST 59, which is a major PVL-positive CA-MRSA strain isolated in invasive disease in Asian countries. This case report may serve as a warning about the dissemination of PVL-positive CA-MRSA in and around Japan, with the possibility of causing serious life-threatening disease. The potential of linezolid for the treatment of MRSA meningitis as one of the alternative MRSA therapeutic drugs is also discussed.
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http://dx.doi.org/10.1016/j.jiac.2020.09.011DOI Listing
January 2021

Guidelines for the diagnosis and treatment of acute encephalopathy in childhood.

Brain Dev 2021 Jan 20;43(1):2-31. Epub 2020 Aug 20.

Committee for the Integration of Guidelines, Japanese Society of Child Neurology, Tokyo, Japan; Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.

The cardinal symptom of acute encephalopathy is impairment of consciousness of acute onset during the course of an infectious disease, with duration and severity meeting defined criteria. Acute encephalopathy consists of multiple syndromes such as acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and clinically mild encephalitis/encephalopathy with reversible splenial lesion. Among these syndromes, there are both similarities and differences. In 2016, the Japanese Society of Child Neurology published 'Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood', which made recommendations and comments on the general aspects of acute encephalopathy in the first half, and on individual syndromes in the latter half. Since the guidelines were written in Japanese, this review article describes extracts from the recommendations and comments in English, in order to introduce the essence of the guidelines to international clinicians and researchers.
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http://dx.doi.org/10.1016/j.braindev.2020.08.001DOI Listing
January 2021

A de novo GABRB2 variant associated with myoclonic status epilepticus and rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS).

Epileptic Disord 2020 Aug;22(4):476-481

Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.

We report a child who developed myoclonic status epilepticus (MSE) at four months of age, associated with rhythmic high-amplitude delta and superimposed (poly) spikes (RHADS), harbouring a GABRB2 (β2 subunit of the GABA A receptor) variant. The patient was treated under a presumptive diagnosis of neonatal-onset Alpers syndrome (AS) and underwent targeted sequence analysis for POLG1 (polymerase gamma 1) and subsequent whole-exome sequence analysis (WES). The patient is currently a 10-year, eight-month-old boy, suffering from daily MSE associated with RHADS and severe global developmental delay from early infancy. Although POLG1 mutation was negative, WES revealed a de novo missense variant of GABRB2 (NM_021911.2: c.784G>T, p.[Val262Phe]). Based on a review of case series with GABRB2 variants, we found that five of the 18 cases shared the clinical and EEG characteristics associated with our patient. In summary, this de novo GABRB2 variant was associated with an AS phenotype, characterized by treatment-resistant MSE and RHADS, and may represent an alternative aetiology for neonatal-onset AS without POLG1 mutation [Published with video sequence].
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http://dx.doi.org/10.1684/epd.2020.1183DOI Listing
August 2020

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan.

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

Neurochemistry of hyponatremic encephalopathy evaluated by MR spectroscopy.

Brain Dev 2020 Nov 25;42(10):767-770. Epub 2020 Jul 25.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan. Electronic address:

MR spectroscopy in a patient with hyponatremic encephalopathy due to the syndrome of inappropriate secretion of antidiuretic hormone revealed decreased N-acetyl-aspartate, creatine plus phosphocreatine, choline-containing compounds, and myo-inositol, with normal glutamate and increased glutamine, which normalized after Na normalization. The decreased concentrations of creatine plus phosphocreatine, choline-containing compounds and myo-inositol are explained by their release as osmolytes from brain cells to adapt to hypo-osmolality induced cerebral edema. Increased glutamine, which not only acts as an osmolyte but also protects neurons under excitotoxic conditions, may suggest that a disrupted glutamate-glutamine cycle may play an important role in the pathogenesis of hyponatremic encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2020.07.005DOI Listing
November 2020

Aspirin Dose and Treatment Outcomes in Kawasaki Disease: A Historical Control Study in Japan.

Front Pediatr 2020 14;8:249. Epub 2020 May 14.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.

Aspirin has been used as a concomitant drug in the treatment of Kawasaki disease (KD). In recent years, there has been discussion concerning whether high-dose aspirin is appropriate for treatment in the acute phase of KD. We retrospectively investigated the incidence of coronary artery abnormalities (CAAs) and the antipyretic effect of 30 to 50 mg/kg/day aspirin, the minimum and the maximum approved doses in Japan. This was a single-center, non-randomized, retrospective, historical cohort study. Patients were routinely treated with 50 mg/kg/day aspirin (50-mg Group) between 2007 and April 2014, and with 30 mg/kg/day aspirin (30-mg Group) between May 2014 and 2016. All patients were given initial and, if necessary, subsequent intravenous immunoglobulin (IVIG) 2.0 g/kg. The primary endpoint was incidence of CAAs defined as a CA diameter with a Z score ≥2.5 at treatment week 4. The secondary endpoint was incidence of further treatment. Incidences were compared using inverse probability weighting analysis adjusting for age, sex, and risk scores. In 587 patients, there was no significant difference in incidence of CAAs (odds ratio in 30-mg Group 0.769, 95% confidence interval (CI): 0.537-1.101, = 0.151). Risk of further treatment after the first IVIG in the 30-mg Group was significantly higher than that in the 50-mg Group (odds ratio 1.379, 95% CI: 1.051-1.811, = 0.021). Although this study has some limitations, the findings suggest that aspirin 50 mg/kg/day may have no significant effect on improving incidence of CAAs compared with 30 mg/kg/day but may have a lower rate of further treatment.
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http://dx.doi.org/10.3389/fped.2020.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241278PMC
May 2020

Epidemiological changes of acute encephalopathy in Japan based on national surveillance for 2014-2017.

Brain Dev 2020 Aug 22;42(7):508-514. Epub 2020 Apr 22.

Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: We previously reported the nationwide, epidemiological data of acute encephalopathy in Japan during 2007-2010. Here we conducted the second national survey of acute encephalopathy during 2014-2017, and compared the results between the two studies to elucidate the trends in the seven years' interval as well as the influence of changes in pediatric viral infections and guidelines for acute encephalopathy in Japan.

Methods: The Research Committee on Acute Encephalopathy supported by the Japanese Government sent a questionnaire to 507 hospitals throughout Japan, and collected the responses by mail.

Results: A total of 1115 cases from 267 hospitals reportedly had acute encephalopathy during April 2014-June 2017. In this study, the age at onset was younger, the ratios of recently established syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), were higher, and the ratio of influenza-associated encephalopathy was lower, than in the previous study. The age at onset of influenza-associated encephalopathy was lower, and that of HHV-6/7-associated encephalopathy higher, compared to the first survey. The outcomes of entire acute encephalopathy remained unchanged.

Conclusion: Some of these changes reflected the recent trends of viral infectious diseases including 2009 influenza pandemic, and others the standardization of the diagnosis of acute encephalopathy in Japan.
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http://dx.doi.org/10.1016/j.braindev.2020.04.006DOI Listing
August 2020

Altered MR imaging findings in a Japanese female child with PRUNE1-related disorder.

Brain Dev 2020 Mar 25;42(3):302-306. Epub 2019 Dec 25.

Department of Radiology, Jichi Medical University, School of Medicine, Japan.

Autosomal recessive PRUNE1 mutations on chromosome 1q21.3 are reported to cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations. Here, we report a Japanese case with a reported PRUNE1 mutation whose brain magnetic resonance imaging (MRI) showed specific imaging findings that have not been reported before. The patient was a 12-month-old girl, the first child of healthy and nonconsanguineous Japanese parents. She showed global developmental delay, intellectual disability, hypotonia, spastic quadriparesis, and hyperreflexia. Brain MRI showed cerebral and cerebellar atrophy, thin corpus callosum, white matter changes, and abnormal signal intensity of the brainstem, all of which were reported in the literature. In addition, we emphasize the three following imaging findings: a transient cerebral subcortical white matter lesion, atrophy of the midbrain and pontine tegmentum with a preserved pontine base, and abnormal signal intensity of the bilateral swelling putamina and medial portions of the thalami, which emerged after 4 years of age. The whole-exome sequencing (WES) analysis performed at the age of 4 years identified biallelic PRUNE1 variants, namely compound heterozygous mutations (c.[316G > A];[540 T > A],p.[Asp106Asn];[Cys180*]). Although the diagnosis of PRUNE1-related disorder requires WES, we think that these new characteristic MRI findings may help in the diagnosis of PRUNE1-related disorder.
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http://dx.doi.org/10.1016/j.braindev.2019.12.001DOI Listing
March 2020

Prognostic value of MR spectroscopy in patients with acute excitotoxic encephalopathy.

J Neurol Sci 2020 Jan 16;408:116636. Epub 2019 Dec 16.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.

Purpose: Acute excitotoxic encephalopathy is the most common encephalopathy syndrome in Japan, and consists of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and mild encephalopathy associated with excitotoxicity (MEEX). Neurological sequelae remain in approximately 70% of patients with AESD, however, it is difficult to predict the prognosis early in the course. We evaluated the brain metabolites observed on MRS as to whether they can predict the neurological outcome.

Methods: 16 previously healthy Japanese patients with excitotoxic encephalopathy (8 with AESD and 8 with MEEX) were included in this study. MR spectroscopy (MRS) was acquired from the fronto-parietal white matter (TR/TE = 5000/30 msec) with a 3.0 T scanner. Quantification of metabolites was performed using an LCModel. Neurological outcome was assessed with the Pediatric Cerebral Performance Category score, score 1 being classified as G1 (normal), scores 2 and 3 as G2 (mild to moderate), and scores 4-6 as G3 (severe).

Results: MRS data which predict a poor neurological outcome (G2 and 3) include the following: decreased N-acetyl aspartate (NAA) (sensitivity 88%, specificity 100%), decreased creatine (47%, 100%), increased lactate (47%, 100%), and decreased glutamate (sensitivity 35%, specificity 100%). Limited to the acute stage within seven days of onset, those for a poor prognosis are as follows, decreased NAA (88%, 100%), decreased creatine (38%, 100%), and increased lactate (38%, 100%).

Conclusion: MRS is useful for prognosis prediction of acute excitotoxic encephalopathy. Decreased NAA will be the most effective metabolite for neurological prognosis prediction.
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http://dx.doi.org/10.1016/j.jns.2019.116636DOI Listing
January 2020

Cerebral white matter lacerations in children caused by repetitive head trauma.

Brain Dev 2020 Jan 25;42(1):83-87. Epub 2019 Sep 25.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Japan.

It has been known that infants less than 1 year develop cerebral white matter (WM) lacerations associated with head trauma, however, there has been no report of similar WM lesions over 1 year. We report three teenage boys (11, 12, and 18 years at final MRI studies) with acquired WM lacerations associated with recurrent head trauma who developed neurologic symptoms such as spastic paralysis, afebrile convulsions, and cognitive impairment. Two of them (patients 1 and 2) were given a diagnosis of autism spectrum disorder and had a history of repeated severe self-inflicted head trauma from preschool age. Patient 3, who practiced karate and boxing from preschool age, showed gradual declining intellectual ability. Brain MRI of the three patients revealed severe lacerations in the bilateral cerebral WM. Previous neuroimaging showed no WM lacerations at 4 and 5 years in patients 1 and 2, or mild WM lacerations at 17 years in patient 3, indicating the WM lacerations could have been acquired in childhood. It is suggested that repetition of head trauma in children can cause cerebral WM lacerations and brain dysfunction.
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http://dx.doi.org/10.1016/j.braindev.2019.08.014DOI Listing
January 2020

Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy.

Brain Dev 2019 Nov 24;41(10):862-869. Epub 2019 Jul 24.

Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes.

Methods: The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test.

Results: Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome.

Conclusions: This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2019.07.008DOI Listing
November 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Neurochemistry evaluated by MR spectroscopy in a patient with xeroderma pigmentosum group A.

Brain Dev 2018 Nov 13;40(10):931-933. Epub 2018 Jul 13.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. Electronic address:

MRI of a female patient with xeroderma pigmentosum group A (XP-A) showed progressive cerebral atrophy, but no disease-specific lesion. MR spectroscopy with short TE sequences in the bilateral white matter revealed decreased N-acetyl aspartate (neuro-axonal marker) and increased myo-inositol (astroglial marker) with a normal concentration of choline (membrane marker), which are compatible with the neuropathology of XP-A, consisting of a reduced number of neurons, and fibrillary astrogliosis with preservation of myelinated fibers. MR spectroscopy reveals neurochemical derangement in XP-A, which cannot be observed on conventional MRI, and will be useful to monitor the neurochemical derangements of XP-A.
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http://dx.doi.org/10.1016/j.braindev.2018.06.013DOI Listing
November 2018

Loss of myelinated axons and astrocytosis in an autopsy case of acute encephalopathy with biphasic seizures and late reduced diffusion.

Brain Dev 2018 Nov;40(10):947-951

Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common pediatric encephalopathy in Japan, however, the exact neuropathology remains uncertain. The postmortem neuropathology in a patient with AESD revealed reduction of myelinated axons with early stage of astrocytosis in the absence of neuronal loss, which suggests the primary pathological damage in AESD involves myelinated axons and astrocytes rather than cortical neurons. An increased number of gemistocytic astrocytes at the corticomedullary junction may cause reduced diffusion, leading to the so-called bright tree appearance on magnetic resonance imaging, characteristic to AESD.
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http://dx.doi.org/10.1016/j.braindev.2018.06.004DOI Listing
November 2018

An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU.

Brain Dev 2018 Oct 29;40(9):813-818. Epub 2018 May 29.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. Electronic address:

Microdeletions in the 1q44 region encompassing the HNRNPU gene have been associated with infantile spasms and hemiconvulsion-hemiplegia-epilepsy syndrome. Recent studies have revealed that heterozygous HNRNPU variants resulted in early onset epilepsy and severe intellectual disability. A de novo frameshift mutation in HNRNPU was identified in a 5-year-old boy with developmental delay associated with Rett-like features including stereotypic hand movements and respiratory abnormalities with episode of apnea and hyperpnea followed by falling. He also showed an episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy. Unique and variable clinical features are related to loss-of-function or haploinsufficiency of HNRNPU.
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http://dx.doi.org/10.1016/j.braindev.2018.05.010DOI Listing
October 2018

Infantile traumatic brain injury with a biphasic clinical course and late reduced diffusion.

J Neurol Sci 2018 07 10;390:63-66. Epub 2018 Apr 10.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. Electronic address:

Reduced diffusion in the subcortical white matter has been reported in some infants with traumatic brain injury (TBI), including abusive head trauma. However, the pathomechanisms of the lesions and clinical features are uncertain. We herein report two infants with TBI who presented with biphasic clinical courses and late reduced diffusion in the subcortical white matter, and reviewed seven clinically and radiologically similar patients with TBI. Their clinical features (secondary neurological symptoms on days 3 to 6) and radiological findings (normal diffusion on days 1 to 2, followed by reduced diffusion on days 3 to 6) are very similar to those observed in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). MR spectroscopy in one patient revealed a transient increase of glutamine, which is also observed in AESD, suggesting excitotoxicity as a possible pathomechanism.
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http://dx.doi.org/10.1016/j.jns.2018.04.010DOI Listing
July 2018

Vital Signs as Predictor Factors of Intravenous Immunoglobulin Resistance in Patients With Kawasaki Disease.

Clin Pediatr (Phila) 2018 09 27;57(10):1148-1153. Epub 2018 Feb 27.

1 Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan.

Kawasaki disease (KD) is the most common cause of acquired heart disease in children. Intravenous immunoglobulin (IVIG) may significantly lower the frequency of coronary artery complications. However, some patients do not respond to initial therapy and are at higher risk of developing coronary artery lesion. A retrospective analysis of data from 419 KD patients was performed. The patients were divided into IVIG responders (n = 318) and IVIG nonresponders (n = 101). Multivariate logistic regression analysis revealed neutrophil percentage, albumin, aspartate aminotransferase, heart rate, and body temperature were independent predictors of IVIG resistance. We generated a predictive scoring system by assigning 1 point for the presence of these parameters (neutrophil >80%, albumin <3.4 g/dL, aspartate aminotransferase >100 IU/L, heart rate >146 bpm, and body temperature >38.8°C). This scoring system had a sensitivity of 76.2% and specificity of 64.8%, and a positive predictive value of 40.1% and a negative predictive value of 89.4%. Vital signs may be helpful to detect KD patients with IVIG resistance.
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http://dx.doi.org/10.1177/0009922818759320DOI Listing
September 2018

Excitotoxicity in encephalopathy associated with STEC O-157 infection.

Brain Dev 2018 Apr 14;40(4):357-360. Epub 2017 Dec 14.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. Electronic address:

Cytokines play an important role in the pathogenesis of the severe complications of Shiga toxin-producing Escherichia coli (STEC) infection, such as hemolytic uremic syndrome (HUS) and acute encephalopathy. A 3-year-old boy with acute encephalopathy associated with STEC O-157 HUS showed increased levels of IL-6 and IL-10, which normalized after methylprednisolone pulse therapy, and additionally exhibited a transient increase of glutamine on MR spectroscopy. This finding suggests that excitotoxicity, in addition to hypercytokinemia, may play an important role in the pathogenesis of HUS encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2017.11.008DOI Listing
April 2018

Prevalence and characteristics of human parechovirus and enterovirus infection in febrile infants.

Pediatr Int 2018 Feb;60(2):142-147

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan.

Background: Human parechovirus (HPeV) and human non-polio enterovirus (EV) are important causes of fever without source (FWS) in young infants. Their prevalence and clinical characteristics are largely unknown in Asian countries. This study was conducted to elucidate the epidemiology and clinical characteristics of HPeV and EV infection in febrile young infants in Japan.

Methods: During February 2010-August 2015, we obtained 53 stool, 44 throat swab, and 20 cerebrospinal fluid samples from 56 infants (<3 months) with FWS at a single hospital. To each sample, we applied reverse transcription-polymerase chain reaction for HPeV and EV. We compared the clinical characteristics of HPeV and EV patients.

Results: HPeV was detected in 11 and EV in 17 patients. HPeV was detected during July-September. HPeV patients, compared with EV patients, had lower age (32 vs 47 days; P = n.s.), higher prevalence of exclusive breast-feeding (81.8 vs 29.4%; P = 0.024), and lower prevalence of sick contacts (36.4 vs 88.2%; P = 0.010). More HPeV than EV patients met the systemic inflammatory response syndrome criteria (90.9 vs 52.9%; P = 0.049). In the HPeV group, leukopenia, thrombopenia, and elevated deviation enzyme were observed, although the prevalence of abnormal cerebrospinal fluid was significantly lower than in the EV group. HPeV patients had longer hospital stay (7 vs 5 days; P = 0.025).

Conclusion: HPeV and EV are important causal viruses of FWS. Characteristic clinical pictures exist in these virus infections, but further research is needed to accumulate more cases to produce a comprehensive picture of these virus infections.
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http://dx.doi.org/10.1111/ped.13467DOI Listing
February 2018

A novel mutation in a Japanese patient with leukoencephalopathy with brainstem and spinal cord involvement but no lactate elevation.

Hum Genome Var 2017 9;4:17051. Epub 2017 Nov 9.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.

The mitochondrial aspartyl-tRNA synthetase 2 gene () is responsible for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). A Japanese patient with LBSL showed compound heterozygous mutations c.358_359delinsTC (p.Gly120Ser) and c.228-15C>G (splicing error). This provides further evidence that most patients with LBSL show compound heterozygous mutations in in association with a common splicing mutation in the splicing acceptor site of intron 2.
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http://dx.doi.org/10.1038/hgv.2017.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678206PMC
November 2017

[A case of anti-MOG antibody-positive multiphasic disseminated encephalomyelitis co-occurring with unilateral cerebral cortical encephalitis].

Rinsho Shinkeigaku 2017 Nov 26;57(11):723-728. Epub 2017 Oct 26.

Division of Neurology, Department of Internal Medicine, Tokyo Women's Medical University Yachiyo Medical Center.

A 20-year-old woman first developed acute disseminated encephalomyelitis (ADEM) at 11 years of age. At 17 years of age, she was hospitalized due to generalized seizure and diagnosed with encephalitis. Brain MRI revealed a FLAIR-hyperintense lesion in the unilateral cerebral cortex. At 18 years of age, serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody was detected. At 20 years of age, she was admitted to our hospital, diagnosed with multifocal disseminated encephalomyelitis (MDEM). MDEM has been observed in patients that are seropositive for the anti-MOG antibody. More recently, unilateral cerebral cortex encephalitis with epilepsy has also been reported in such patients. The co-occurrence of MDEM and cortical encephalitis in the same patient has important implications for the pathogenesis of anti-MOG antibody-associated autoimmune diseases.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001078DOI Listing
November 2017

A new infectious encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX).

J Neurol Sci 2017 Sep 29;380:27-30. Epub 2017 Jun 29.

Department of Pediatrics, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan. Electronic address:

Acute infectious encephalopathy is often observed in children in East Asia including Japan. More than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanisms in those with unclassified encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among seven patients with acute encephalopathy admitted to our hospital from June 2016 to May 2017, three were classified into acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). The other four showed consciousness disturbance lasting more than three days with no parenchymal lesion visible on MRI, which led to a diagnosis of unclassified encephalopathy. MR spectroscopy in these four patients, however, revealed an increase of glutamine with a normal N-acetyl aspartate level on days 5 to 8, which had normalized by follow-up studies on days 11 to 16. The four patients clinically recovered completely. Among 27 patients with encephalopathy, including the present seven patients, admitted to our hospital from January 2015 to March 2017, seven (26%) were classified into this type, which we propose is a new encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX). MEEX is the second most common subtype, following AESD (30%). This study suggests that excitotoxicity may be a common underlying pathomechanism of acute infectious encephalopathy, and prompt astrocytic neuroprotection from excitotoxicity may prevent progression of MEEX into AESD.
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http://dx.doi.org/10.1016/j.jns.2017.06.045DOI Listing
September 2017

Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH).

PLoS One 2017 7;12(8):e0181791. Epub 2017 Aug 7.

Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546575PMC
September 2017

Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.

Clin Genet 2017 Aug 30;92(2):180-187. Epub 2017 Mar 30.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively.

Materials And Methods: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families.

Results: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%).

Conclusion: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.
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http://dx.doi.org/10.1111/cge.12991DOI Listing
August 2017

Clinically mild infantile encephalopathy associated with excitotoxicity.

J Neurol Sci 2017 Feb 24;373:138-141. Epub 2016 Dec 24.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. Electronic address:

Acute infectious encephalopathy is very frequently observed in children in East Asia including Japan. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype in Japan; however, more than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanism in those with unclassified acute encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among 20 patients with acute encephalopathy admitted to our hospital during January 2015 to May 2016, 12 could not be classified into specific syndromes. MR spectroscopy was performed in 8 of these 12 patients with unclassified encephalopathy. MR spectroscopy showed an increase of glutamine with a normal N-acetyl aspartate level on days 3 to 8 in three of the 8 patients, which had normalized by follow-up studies. The three patients clinically recovered completely. This study suggests that excitotoxicity may be the underlying pathomechanism in some patients with unclassified mild encephalopathy.
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http://dx.doi.org/10.1016/j.jns.2016.12.043DOI Listing
February 2017