Publications by authors named "Ryutaro Kira"

82 Publications

Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies.

J Hum Genet 2021 May 6. Epub 2021 May 6.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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.
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http://dx.doi.org/10.1038/s10038-021-00932-yDOI Listing
May 2021

A nation-wide survey of Japanese pediatric MOG antibody-associated diseases.

Brain Dev 2021 Jun 18;43(6):705-713. Epub 2021 Feb 18.

Department of Pediatrics, Osaka Medical College, Osaka, Japan.

Objective: To elucidate the clinical characteristics of Japanese pediatric patients with acquired demyelinating diseases (ADS), positive for myelin oligodendrocyte glycoprotein antibody (MOG-IgG), we conducted a nation-wide survey.

Methods: Information about pediatric patients under 18 years old with ADS was solicited with surveys sent to 323 facilities. In an initial survey, we asked whether the center had any patients with ADS, and the MOG-IgG serostatus of the patients. In a follow-up survey, we requested more precise information on patients with ADS.

Results: Initial survey: 263 replies providing information on 175 patients were received. MOG-IgG were examined in 78 patients and 54 of those (69%) were positive for MOG-IgG. Follow-up survey: The characteristic involvement was optic neuritis, with visual disturbance and optic pain as characteristic symptoms. The relapse rate was 44% in patients positive for MOG-IgG, which was higher than that in seronegative patients (38%). For acute phase treatments, corticosteroid (CS), plasma exchange, and intravenous immunoglobulin (IVIG) were useful. To prevent relapse, CS, intermittent IVIG, immunosuppressants, and monoclonal antibodies were useful, but the efficacies of disease modifying drugs were uncertain. Sequelae such as visual disturbance, cognitive impairment, motor dysfunction, and epilepsy were observed in 11% of patients with MOG-IgG.

Conclusions: MOG antibody-associated diseases were found to be common among pediatric ADS patients. Since a variety of sequelae were observed in these patients, it is important to identify the appropriate treatment to ensure the best outcome. The presence of the MOG autoantibody should be taken into consideration as part of the diagnostic criteria for pediatric ADS.
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http://dx.doi.org/10.1016/j.braindev.2021.01.008DOI Listing
June 2021

Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis.

Pediatr Neurol 2021 Mar 3;116:14-19. Epub 2020 Dec 3.

Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address:

Background: We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 outbreak in 2015.

Methods: This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (six months), and chronic (three years) stages. We use the Barthel index, which measures 10 variables describing activity of daily living and mobility to assess the disability level.

Results: Clinical data of 33 patients with AFM (13 females, 20 males; median age = 4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, two of seven, four of thirteen, and two of thirteen exhibited complete recovery without paralysis; of those five of seven, eight of thirteen, and two of thirteen showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of enterovirus D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed (P < 0.001; median difference [95% confidence interval], 53 [40 to 63]), implying an improved disability level even in patients with persistent motor deficits.

Conclusions: AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis. Disability level of patients with AFM, however, generally improved at the three-year time point.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.11.019DOI Listing
March 2021

Acute flaccid myelitis: cause, diagnosis, and management.

Lancet 2021 01 23;397(10271):334-346. Epub 2020 Dec 23.

Department of Infectious Diseases, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
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http://dx.doi.org/10.1016/S0140-6736(20)32723-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909727PMC
January 2021

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

Vaccine 2020 11 1;38(50):8049-8054. Epub 2020 Nov 1.

The Committee on Immunization and Infectious Diseases, Japan Pediatric Society, Japan; Division of Basic Nursing, Fukuoka Nursing College, Fukuoka, Japan.

Background: Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan.

Methods: This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups.

Results: We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01).

Conclusion: The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.049DOI Listing
November 2020

Clinical and genetic characteristics of patients with Doose syndrome.

Epilepsia Open 2020 Sep 23;5(3):442-450. Epub 2020 Jul 23.

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

Objective: To elucidate the genetic background and genotype-phenotype correlations for epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy (MAE) or Doose syndrome.

Methods: We collected clinical information and blood samples from 29 patients with MAE. We performed whole-exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant.

Results: We newly identified four variants: and missense variants and microdeletions at 2q24.2 involving and Xp22.31 involving . Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic-atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention-deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology.

Significance: MAE patients had genetic heterogeneity, and and emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic-atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
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http://dx.doi.org/10.1002/epi4.12417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469791PMC
September 2020

Disseminated cortical and subcortical lesions in neonatal enterovirus 71 encephalitis.

J Neurovirol 2020 10 15;26(5):790-792. Epub 2020 Jul 15.

Department of Pediatric Neurology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha Higashi-ku, Fukuoka, 813-0017, Japan.

Enteroviruses are one of the most important causes of viral encephalitis in the neonatal period. However, the non-specificity of the symptoms presented renders its diagnosis challenging. Intracranial MRI has been reported to be a very useful imaging modality that can detect the characteristic white matter lesions around the periventricular regions. In this study, we report a case of a patient with neonatal encephalitis who presented with normal white blood cell counts in the initial cerebrospinal fluid analysis. A lumbar puncture retap identified pleocytosis, and polymerase chain reaction assays detected enterovirus 71 in the blood and stool samples. Furthermore, MRI revealed atypical disseminated cortical and subcortical white matter lesions on diffusion weighted images, and neuroradiological re-evaluation showed necrotic changes 2 weeks later. This unique case expands our knowledge of the spectrum of neurological disorders due to enterovirus 71 infection in neonatal period.
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http://dx.doi.org/10.1007/s13365-020-00843-2DOI Listing
October 2020

Acute Flaccid Myelitis With Neuroradiological Finding of Brachial Plexus Swelling.

Pediatr Neurol 2020 08 13;109:85-88. Epub 2020 Apr 13.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

Background: Acute flaccid myelitis is a recently defined clinically distinct syndrome of polio-like acute flaccid paralysis. Acute flaccid myelitis cases show characteristic neuroradiological features of longitudinal spinal cord lesions with predominant gray matter involvement. Current evidence suggests injury to the anterior horn neurons as the underlying mechanism.

Methods: We describe three patients with acute flaccid myelitis who developed flaccid upper limb weakness with diminished deep tendon reflexes after prodromal fever. Spinal magnetic resonance imaging (MRI) (axial and sagittal T1- and T2-weighted sequences) and brachial plexus MRI (coronal short tau inversion recovery sequence) at the acute stage were performed.

Results: Spinal MRI showed extensive longitudinal lesion in the spinal cord with predominant gray matter involvement. We were able to demonstrate concurrent swelling and hyperintensity in the brachial plexus in all the three patients at the acute stage.

Conclusion: The coexisting signal intensities suggest an extension of acute flaccid myelitis pathology to the brachial plexus, highlighting the possible peripheral nerve involvement in acute flaccid myelitis.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.004DOI Listing
August 2020

De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms.

J Hum Genet 2020 Sep 27;65(9):727-734. Epub 2020 Apr 27.

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

The ubiquitin-proteasome system is the principal system for protein degradation mediated by ubiquitination and is involved in various cellular processes. Cullin-RING ligases (CRL) are one class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins, leading to decomposition of the substrate. Cullin 3 (CUL3) is a member of the Cullin family proteins, which act as scaffolds of CRL. Here we describe three cases of global developmental delays, with or without epilepsy, who had de novo CUL3 variants. One missense variant c.854T>C, p.(Val285Ala) and two frameshift variants c.137delG, p.(Arg46Leufs*32) and c.1239del, p.(Asp413Glufs*42) were identified by whole-exome sequencing. The Val285 residue located in the Cullin N-terminal domain and p.Val285Ala CUL3 mutant showed significantly weaker interactions to the BTB domain proteins than wild-type CUL3. Our findings suggest that de novo CUL3 variants may cause structural instability of the CRL complex and impairment of the ubiquitin-proteasome system, leading to diverse neuropsychiatric disorders.
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http://dx.doi.org/10.1038/s10038-020-0758-2DOI Listing
September 2020

Isolated cranial neuritis of the oculomotor nerve: Expanding the MOG phenotype?

Mult Scler Relat Disord 2020 Jun 5;41:102040. Epub 2020 Mar 5.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

Autoantibody against myelin oligodendrocyte glycoprotein (MOG) has been reported in a range of demyelinating neurological entities. Recent studies demonstrate a wider spectrum of MOG-IgG-associated disorders with the discovery of MOG-IgG-positive brainstem encephalitis, cortical encephalitis, and cranial nerve involvement with concurrent central nervous system involvement. We present a MOG-IgG-positive pediatric patient diagnosed with isolated oculomotor neuritis without concurrent central nervous system neuroimaging lesions, in the absence of a demyelinating event. Brain MRI shows swelling and gadolinium enhancement of the left oculomotor nerve at the cisternal segment. This is the first report to demonstrate MOG-IgG seropositivity in isolated cranial nerve lesions. This case may expand the clinical phenotype of MOG-IgG-associated diseases, and clinicians should not hesitate to test for MOG-IgG in cases with neuroimaging features of cranial neuritis alone.
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http://dx.doi.org/10.1016/j.msard.2020.102040DOI Listing
June 2020

Letter to the Editor.

J Paediatr Child Health 2020 02;56(2):348-349

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

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http://dx.doi.org/10.1111/jpc.14785DOI Listing
February 2020

Influenza-associated encephalopathy with focal late reduced diffusion circumscribing a pre-existing cortical lesion.

J Neuroradiol 2020 May 5;47(3):241-243. Epub 2020 Feb 5.

Department of Pediatric Neurology, Fukuoka Children's Hospital, 5-1-1, Kashiiteriha, Higashi-ku, 813-0017 Fukuoka, Japan.

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http://dx.doi.org/10.1016/j.neurad.2020.01.086DOI Listing
May 2020

West Syndrome in an Infant With Vitamin B12 Deficiency Born to Autoantibodies Positive Mother.

Front Pediatr 2019 20;7:531. Epub 2019 Dec 20.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

Infantile vitamin B12 deficiency, a rare nutritional disorder in developed countries, is characterized by megaloblastic anemia and non-specific symptoms, including failure to thrive, hypotonia, and seizure. Symptoms usually develop at 6 months of age. Exclusively breast-fed infants of vegan-diet mothers are particularly at risk. We report the case of a 7-month-old boy with West syndrome born to a mother with subclinical vitamin B12 deficiency due to autoantibodies. Electroencephalography revealed the characteristic hypsarrhythmia pattern, whereas cranial magnetic resonance imaging revealed cerebral atrophy and hypomyelination. Biochemical analysis revealed elevated urinary methylmalonic acid and homocysteine and reduced plasma methionine. Serum vitamin B12 levels were extremely low in both the child and his mother. The mother tested positive for both anti-intrinsic factor and anti-parietal cell antibodies. Low-dose adrenocorticotropic hormone was effective for seizure control. Contrary to previous reports, age-appropriate neurodevelopment was not achieved despite rapid normalization of metabolic profile with vitamin B12 supplementation. Further investigations failed to detect any causative mutations in the genes associated with developmental and epileptic encephalopathy as well as metabolic and other identifiable disorders known to cause West syndrome. To the best of our knowledge, this is the first reported case in which maternal anti-intrinsic factor antibody was considered to be the reason for infantile vitamin B12 deficiency with West syndrome. Differential diagnosis of West syndrome should include vitamin B12 deficiency due to its treatable nature, and early diagnosis is essential to prevent permanent neurological consequences.
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http://dx.doi.org/10.3389/fped.2019.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951394PMC
December 2019

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature.

Eur J Med Genet 2020 Apr 16;63(4):103825. Epub 2019 Dec 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations.

Case Report: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge.

Results: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy.

Conclusions: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.
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http://dx.doi.org/10.1016/j.ejmg.2019.103825DOI Listing
April 2020

The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype.

Hum Mutat 2020 03 24;41(3):591-599. Epub 2019 Dec 24.

Cologne Center for Genomics, University of Cologne, Cologne, Germany.

RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.
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http://dx.doi.org/10.1002/humu.23964DOI Listing
March 2020

Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0.

Ann Neurol 2019 11 3;86(5):801-802. Epub 2019 Oct 3.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka.

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http://dx.doi.org/10.1002/ana.25596DOI Listing
November 2019

Decision-making dilemmas of paediatricians: a qualitative study in Japan.

BMJ Open 2019 08 19;9(8):e026579. Epub 2019 Aug 19.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care.

Design: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis.

Participants: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data.

Results: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence).

Conclusions: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.
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http://dx.doi.org/10.1136/bmjopen-2018-026579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707677PMC
August 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

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders.

Brain Dev 2019 Oct 4;41(9):776-782. Epub 2019 Jun 4.

Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.

Background: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders.

Methods: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM).

Results: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1.

Conclusion: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.
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http://dx.doi.org/10.1016/j.braindev.2019.05.007DOI Listing
October 2019

Description of Restrictively Defined Acute Flaccid Myelitis.

JAMA Pediatr 2019 07;173(7):702

Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.

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http://dx.doi.org/10.1001/jamapediatrics.2019.1269DOI Listing
July 2019

Long surviving classical Menkes disease treated with weekly intravenous copper therapy.

J Trace Elem Med Biol 2019 Jul 1;54:172-174. Epub 2019 May 1.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

Menkes diseases (MD) is an X-linked recessive neurodegenerative disorder of copper metabolism, characterized by progressive multisystemic involvement. Death in the early childhood is usually observed in classical patients. Although a definite cure has not been established, copper replacement therapy administered parenterally may modify the severity of MD and permitted survival into adolescence. Subcutaneous copper-histidine supplementation is the current choice of therapy, and long-term administration is not desirable because of the expected nephrotoxicity. We report here the case of a 29-year-old male with MD who tolerated long-term intravenous copper therapy initiated at 2 months. Molecular analysis revealed hemizygous deletion mutation of ATP7A previously reported in classical MD. Although neurodevelopement is poor, no major event of central nervous system is observed, and he enjoys a good social life by interacting using gestures. Optimum management is unknown, and closed follow-up is mandatory for clarification of this phenotype.
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http://dx.doi.org/10.1016/j.jtemb.2019.04.020DOI Listing
July 2019

Serial MRI findings of acute flaccid myelitis during an outbreak of enterovirus D68 infection in Japan.

Brain Dev 2019 May 26;41(5):443-451. Epub 2018 Dec 26.

Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.

Objecive: To clarify the neuroimaging findings of children with acute flaccid myelitis during an outbreak of EV-D68 infection.

Methods: We performed a detailed review of the spinal and cranial MRI results of 54 children with acute flaccid myelitis. We focused on the range of longitudinal lesions, the localization and appearance of lesions within a horizontal section, Gadolinium-enhancement, and changes over time.

Results: All children had longitudinal spinal lesions involving central gray matter. Twenty-six children had lesions spanning the entire spine. Six of them had weakness in all limbs, whereas seven had weakness of only one limb. Thirty-eight children had lesions in both gray and white matter and limb weakness tended to be more severe in these children. During the acute period, spinal lesions showed bilateral ill-defined widespread T2 hyperintensity. During the subacute period, lesions were well defined and confined to the anterior horn. The distribution of limb weakness was correlated with the appearance of lesions during the subacute period. Gadolinium enhancement was performed in 37 children, and enhancement was seen in the cauda equina in 29 children. Enhancement was infrequent within 2 days after onset but was seen in almost all children thereafter. Twenty-two children had brainstem lesions continuous with spinal lesions.

Conclusion: Extensive longitudinal spinal lesions were characteristic in children with acute flaccid myelitis. Lesions were usually bilateral and widespread during the acute period, whereas localization to the anterior horn could become obvious. Although enhancement of the cauda equina was often observed, its appearance was sometimes delayed.
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http://dx.doi.org/10.1016/j.braindev.2018.12.001DOI Listing
May 2019

Cytotoxic lesion of the corpus callosum exclusively at the genu in a case of callosal hypogenesis.

J Neuroradiol 2019 May 27;46(3):222-223. Epub 2018 Nov 27.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

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http://dx.doi.org/10.1016/j.neurad.2018.11.001DOI Listing
May 2019

Subcortical axonal loss with glial reactions following partial status epilepticus with neuroradiological findings of reduced subcortical diffusion.

Neurol Sci 2019 Apr 15;40(4):851-855. Epub 2018 Nov 15.

Department of Pediatric Neurology, Fukuoka Children's Hospital, 5-1-1 Kashii-Teriha, Higashi-ku, Fukuoka, 813-0017, Japan.

Hyperintensity in the subcortical white matter on the diffusion-weighted magnetic resonance image has been described recently, in association with partial status epilepticus. Although this reduced subcortical diffusion is typically seen in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), the exact pathophysiological mechanism is unclear. We report the case of a 3-month-old boy who underwent surgery for intractable epilepsy associated with cortical dysplasia in the left peri-Rolandic area, coincident with the appearance of reduced subcortical diffusion. Neurohistological findings revealed that the most prominent finding was axonal loss with marked astroglial and microglial reactions in the white matter. Neither degenerated neurons nor neurophagocytic microglial accumulation was evident in the cortex. These findings confirm that white matter can be secondarily damaged in patients with partial status epilepticus, and possible pathomechanism of reduced subcortical diffusion is discussed.
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http://dx.doi.org/10.1007/s10072-018-3635-4DOI Listing
April 2019

An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome.

Brain Dev 2019 Apr 7;41(4):378-381. Epub 2018 Nov 7.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood.

Case Report: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45-min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case.

Conclusion: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood.
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http://dx.doi.org/10.1016/j.braindev.2018.10.012DOI Listing
April 2019

Leucine-rich alpha-2 glycoprotein in the cerebrospinal fluid is a potential inflammatory biomarker for meningitis.

J Neurol Sci 2018 09 10;392:51-55. Epub 2018 Jul 10.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan. Electronic address:

Background: Leucine-rich alpha-2 glycoprotein (LRG) is a novel biomarker for inflammatory diseases. We evaluated the levels of LRG, interleukin (IL)-6, and tumor necrosis factor (TNF)-α in the cerebrospinal fluid (CSF) of children with meningitis.

Methods: CSF samples from 10 patients with bacterial meningitis (BM) and 10 with aseptic meningitis (AM) were evaluated. Samples from 10 patients with febrile status (FS) were used as controls. LRG levels were measured using a two-site enzyme immunoassay. IL-6 and TNF-α levels were measured using a multiplex bead-based assay. CSF examination of patients with BM at the convalescent stage was also conducted.

Results: LRG and TNF-α levels in patients with BM, and IL-6 levels in patients with BM and AM showed significant increase compared with those in FS. Patients with BM at the convalescent stage showed significantly diminished LRG and IL-6 levels. LRG and IL-6 levels in CSF were indicated to be effective predictors for BM (LRG, AUC = 0.91; IL-6, AUC = 0.85). Only LRG levels showed a significant difference between patients with BM and AM (AUC = 0.78, P = 0.034).

Conclusions: LRG level could be a sensitive inflammatory biomarker for inflammatory diseases of the central nervous system, comparable with IL-6 level.
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http://dx.doi.org/10.1016/j.jns.2018.07.006DOI Listing
September 2018

Surgical histopathology of limited dorsal myeloschisis with flat skin lesion.

Childs Nerv Syst 2019 01 22;35(1):119-128. Epub 2018 Jun 22.

Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Purpose: Limited dorsal myeloschisis (LDM) is characterized by two invariable features: a focal closed neural tube defect and a fibroneural stalk linking the skin lesion to the underlying spinal cord. Although detailed histopathological findings of the LDM stalk were originally described by Pang et al., the precise relationship between the histopathological findings and clinical manifestations including intraoperative findings has not been fully determined.

Methods: We retrospectively analyzed the histopathological findings of the almost entire stalk and their relevance to the clinical manifestations in six Japanese LDM patients with flat skin lesions.

Results: Glial fibrillary acidic protein (GFAP)-immunopositive neuroglial tissues were observed in three of the six patients. Unlike neuroglial tissues, peripheral nerve fibers were observed in every stalk. In four patients, dermal melanocytosis, "Mongolian spot," was seen surrounding the cigarette-burn lesion. In three of these four patients, numerous melanocytes were distributed linearly along the long axis of the LDM stalk, which might represent migration of melanocytes from trunk neural crest cells during formation of the LDM stalk.

Conclusion: Immunopositivity for GFAP in the LDM stalk was observed in as few as 50% of our patients, despite the relatively extensive histopathological examination. We confirm that the clinical diagnosis of LDM should be made based on comprehensive histopathological examination as well as clinical manifestations. The profuse network of peripheral nerve fibers in every stalk and the high incidence of melanocyte accumulation associated with dermal melanocytosis might assist the histopathological diagnosis of LDM.
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http://dx.doi.org/10.1007/s00381-018-3870-2DOI Listing
January 2019

Deletions of SCN2A and SCN3A genes in a patient with West syndrome and autistic spectrum disorder.

Seizure 2018 Aug 13;60:91-93. Epub 2018 Jun 13.

Department of Pediatric Neurology, Fukuoka Children's Hospital, Fukuoka, Japan.

SCN2A encodes the alpha-subunit of voltage-gated sodium channel, Nav1.2, which is highly expressed at an early stage of the postnatal brain. Genetic studies revealed that de novo heterozygous mutations of SCN2A caused severe developmental disorders in childhood, such as autism and epileptic encephalopathy. However, few reports have demonstrated the cases carrying segmental deletions at the SCN2A locus for those with epileptic disorders. In this study, we report a 1.8-year-old boy, who presented with West syndrome in infancy and developed the sequelae of psychomotor delay and autism. Since whole-exome sequencing did not detect pathogenic mutations, we extensively searched for microdeletions and duplications by applying the eXome Hidden Markov Model (XHMM) for read depths of sequenced intervals. Using this approach, we identified a de novo deletion spanning the 1.1-Mb region of chromosome 2q24.3. We found that the deleted interval included the SCN2A and SCN3A loci. These data validate the utility of XHMM and support that SCN2A is involved in the pathogenic processes underlying epileptic encephalopathy in childhood.
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http://dx.doi.org/10.1016/j.seizure.2018.06.012DOI Listing
August 2018

Mulberries in the urine: a tell-tale sign of Fabry disease.

J Inherit Metab Dis 2018 07 27;41(4):745-746. Epub 2018 Feb 27.

Department of Pediatric Neurology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka, 813-0017, Japan.

Fabry disease is a treatable progressive illness of inborn error causing eventual multiple organ dysfunction in advanced untreated cases. We report on a classic Fabry child patient presenting with urinary mulberry cells and bodies without renal involvement. This report emphasizes the usefulness of urinary microscopic findings in the early diagnosis of Fabry disease.
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http://dx.doi.org/10.1007/s10545-018-0155-6DOI Listing
July 2018