RESUMEN
Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.
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Mucopolisacaridosis I , Humanos , Mucopolisacaridosis I/terapia , Mucopolisacaridosis I/tratamiento farmacológico , Iduronidasa/efectos adversos , Iduronidasa/genética , Iduronidasa/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Receptores de Transferrina/genética , Heparitina Sulfato/metabolismoRESUMEN
BACKGROUND: SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A. METHODS: We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses. RESULTS: A 2.8 kb insertion was detected deep within the intron of the patient's ATP7A gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago. CONCLUSION: This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.
RESUMEN
Microglia play versatile roles in progression of and protection against neuroinflammatory diseases. Little is known, however, about the mechanisms underlying the diverse reactivity of microglia to inflammatory conditions. We investigated how human induced microglia-like (iMG) cells respond to innate immune ligands. Quantitative PCR showed that poly-I:C and lipopolysaccharide (LPS) activated the expression of IL1B and TNF. Immunoreactivity of iMG did not differ between controls (n = 11) and patients with neuroinflammatory diseases (n = 24). Flow cytometry revealed that CD14high cells expressed interleukin (IL) -1ß after LPS treatment. Immunoblotting showed that poly-I:C and LPS differentially activated inflammatory pathways but commonly induced mitochondrial instability and the expression of pyruvate kinase isoform M2 (PKM2). Furthermore, a potent stimulator of PKM2 (DASA-58) alleviated IL-1ß production after LPS treatment. These data indicate that heterogeneous cell populations and mitochondrial stability underlie the divergent immunoreactivity of human iMG in environments.
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Microglía , Enfermedades Neuroinflamatorias , Humanos , Microglía/metabolismo , Lipopolisacáridos/farmacología , Citometría de Flujo , Expresión GénicaRESUMEN
BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.
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Eritromelalgia , Enfermedades del Sistema Nervioso Periférico , Humanos , Células HEK293 , Canal de Sodio Activado por Voltaje NAV1.7/genética , Eritromelalgia/genética , Eritromelalgia/patología , Dolor , Mutación/genéticaRESUMEN
Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is an autoantibody associated with acquired demyelinating syndrome (ADS) in childhood and adults. The pathogenic roles of MOG-Ab and long-term outcomes of children with MOG-Ab-associated disease (MOGAD) remain elusive. We investigated the clinical features of children with ADS during follow-up in our institute. Clinical data were retrospectively analyzed using medical charts of patients managed in Kyushu University Hospital from January 1st, 2001, to March 31st, 2022. Participants were children of < 18 years of age when they received a diagnosis of ADS in our hospital. Cell-based assays were used to detect MOG-Ab in serum or cerebrospinal fluid at the onset or recurrence of ADS. The clinical and neuroimaging data of MOG-Ab-positive and MOG-Ab-negative patients were statistically analyzed. Among 31 patients enrolled in this study, 22 (13 females, 59%) received tests for MOG antibodies. Thirteen cases (59%) were MOG-Ab-positive and were therefore defined as MOGAD; 9 (41%) were MOG-Ab-negative. There were no differences between MOGAD and MOG-Ab-negative patients in age at onset, sex, diagnostic subcategories, or duration of follow-up. MOGAD patients experienced headache and/or somatosensory symptoms more frequently than MOG-Ab-negative patients (12/13 (92%) vs. 3/9 (22%); p = 0.0066). Somatosensory problems included persistent pain with hyperesthesia in the left toe, perineal dysesthesia, and facial hypesthesia. No specific neuroimaging findings were associated with MOGAD or the presence of somatosensory symptoms. CONCLUSIONS: Long-lasting somatosensory disturbances are prominent comorbidities in children with MOGAD. Prospective cohorts are required to identify molecular and immunogenetic profiles associated with somatosensory problems in MOGAD. WHAT IS KNOWN: ⢠Recurrence of demyelinating events occurs in a group of children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). WHAT IS NEW: ⢠Long-lasting headache and somatosensory problems are frequent comorbidities with pediatric MOGAD. Pain and somatosensory problems may persist for more than 5 years. ⢠Neuroimaging data do not indicate specific findings in children with somatic disturbances.
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Dolor Crónico , Humanos , Femenino , Niño , Glicoproteína Mielina-Oligodendrócito , Estudios Prospectivos , Estudios Retrospectivos , Cefalea , Hospitales Universitarios , Síndrome , AutoanticuerposRESUMEN
Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism.
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Hipopigmentación , Mosaicismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Humanos , Hipopigmentación/genética , Serina-Treonina Quinasas TOR/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
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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Enfermedades Virales del Sistema Nervioso Central/diagnóstico por imagen , Enfermedades Virales del Sistema Nervioso Central/rehabilitación , Infecciones por Enterovirus/epidemiología , Hipotonía Muscular , Debilidad Muscular , Mielitis/diagnóstico por imagen , Mielitis/rehabilitación , Enfermedades Neuromusculares/diagnóstico por imagen , Enfermedades Neuromusculares/rehabilitación , Enfermedades Virales del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades Virales del Sistema Nervioso Central/virología , Niño , Infecciones por Enterovirus/líquido cefalorraquídeo , Infecciones por Enterovirus/complicaciones , Salud Global , Humanos , Imagen por Resonancia Magnética , Hipotonía Muscular/etiología , Debilidad Muscular/etiología , Mielitis/líquido cefalorraquídeo , Mielitis/virología , Enfermedades Neuromusculares/líquido cefalorraquídeo , Enfermedades Neuromusculares/virología , Evaluación del Resultado de la Atención al PacienteRESUMEN
BACKGROUND: The COVID-19 pandemic has affected the lives of people of all ages. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than do adults. This is the first nationwide study in Japan focusing on pediatric cases reported by pediatricians, including cases with no or mild symptoms. METHODS: We analyzed the epidemiological and clinical characteristics and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database which was maintained voluntarily by members of the Japan Pediatric Society. RESULTS: Almost half of the patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively). CONCLUSIONS: COVID-19 symptoms in children are less severe than those in adults. School closure appeared to have a limited effect on transmission. Controlling household transmission from adult family members is the most important measure for prevention of COVID-19 among children.
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COVID-19 , Adolescente , Adulto , Niño , Humanos , Japón/epidemiología , Pandemias , SARS-CoV-2 , Instituciones AcadémicasRESUMEN
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.
Asunto(s)
Agenesia del Cuerpo Calloso/diagnóstico , Encéfalo/diagnóstico por imagen , Anomalías Congénitas/diagnóstico , Malformaciones del Sistema Nervioso/diagnóstico , Adolescente , Adulto , Agenesia del Cuerpo Calloso/complicaciones , Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Encéfalo/patología , Encefalopatías/complicaciones , Encefalopatías/diagnóstico , Encefalopatías/genética , Encefalopatías/patología , Niño , Preescolar , Anomalías Congénitas/genética , Anomalías Congénitas/patología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Japón , Ventrículos Laterales/anomalías , Ventrículos Laterales/patología , Masculino , Trastornos Motores/complicaciones , Trastornos Motores/diagnóstico , Trastornos Motores/genética , Trastornos Motores/patología , Mutación/genética , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Fenotipo , Secuenciación del Exoma , Adulto JovenRESUMEN
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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Alelos , Codón , Estudios de Asociación Genética , Variación Genética , Placa Neural/metabolismo , Fenotipo , Proteína de Unión al GTP rhoA/genética , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Modelos Moleculares , Placa Neural/anomalías , Placa Neural/embriología , Conformación Proteica , Relación Estructura-Actividad , Adulto Joven , Proteína de Unión al GTP rhoA/químicaRESUMEN
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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Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Espasmos Infantiles/genética , Niño , Preescolar , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/fisiopatología , Femenino , Mutación del Sistema de Lectura , Células HEK293 , Humanos , Lactante , Masculino , Mutación Missense , Unión Proteica , Espasmos Infantiles/complicaciones , Ubiquitina-Proteína Ligasas/metabolismo , Secuenciación del ExomaRESUMEN
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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Encefalitis Viral/diagnóstico por imagen , Enterovirus Humano A/patogenicidad , Infecciones por Enterovirus/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/virología , Imagen de Difusión por Resonancia Magnética/métodos , Encefalitis Viral/tratamiento farmacológico , Encefalitis Viral/patología , Encefalitis Viral/virología , Enterovirus Humano A/efectos de los fármacos , Enterovirus Humano A/genética , Enterovirus Humano A/crecimiento & desarrollo , Infecciones por Enterovirus/tratamiento farmacológico , Infecciones por Enterovirus/patología , Infecciones por Enterovirus/virología , Humanos , Recién Nacido , Masculino , Neuroimagen/métodos , Punción Espinal/métodos , Sustancia Blanca/patología , Sustancia Blanca/virologíaRESUMEN
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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Estado Epiléptico/patología , Sustancia Blanca/patología , Astrocitos/patología , Imagen de Difusión por Resonancia Magnética , Humanos , Lactante , Masculino , Microglía/patología , Estado Epiléptico/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagenRESUMEN
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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Procedimientos Neuroquirúrgicos/métodos , Enfermedades de la Piel/cirugía , Médula Espinal/anomalías , Médula Espinal/patología , Médula Espinal/cirugía , Preescolar , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Lactante , Masculino , Melanocitos/patología , Fibras Nerviosas/patología , Cresta Neural/patología , Nervios Periféricos/patología , Estudios Retrospectivos , Enfermedades de la Piel/patologíaRESUMEN
Background: Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015. Methods: An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens. Results: Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status. Conclusions: EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.
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Brotes de Enfermedades , Enterovirus Humano D/aislamiento & purificación , Infecciones por Enterovirus/epidemiología , Hipotonía Muscular/epidemiología , Mielitis/epidemiología , Parálisis/virología , Enfermedad Aguda/epidemiología , Niño , Preescolar , Medios de Contraste , Infecciones por Enterovirus/complicaciones , Femenino , Humanos , Lactante , Japón/epidemiología , Masculino , Hipotonía Muscular/virología , Mielitis/diagnóstico , Mielitis/virología , Nasofaringe/virología , Pronóstico , Encuestas y CuestionariosRESUMEN
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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Enfermedad de Fabry/diagnóstico , Adolescente , Diagnóstico Precoz , Enfermedad de Fabry/orina , Humanos , Masculino , Dolor/etiología , Urinálisis , Orina/citologíaRESUMEN
BACKGROUND: The coexistence of venous anomalies, such as vertical embryonic positioning of the straight sinus (VEP of SS), has been reported in patients with atretic cephalocele (AC). VEP of SS has been exclusively encountered when the AC is found above the torcular. CLINICAL PRESENTATION: We report a patient with suboccipital AC associated with venous anomalies analogous to VEP of SS, consisted of the Galenic venous system which did not drain into the straight sinus in the tentorium, but into the falcine sinus instead. Differences with VEP of SS in our case had no anatomical relationship between the falcine sinus and the suboccipital AC and no large cerebrospinal fluid space around the falcine sinus. A detailed neuroradiological examination was helpful for detecting these minute anomalies.
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Senos Craneales/anomalías , Encefalocele/complicaciones , Encefalocele/patología , Malformaciones Vasculares/complicaciones , Femenino , Humanos , LactanteRESUMEN
A 6-year-old girl experienced nausea and vomiting for 3 weeks and double vision for 1 week prior to her first visit to our hospital. She had bilateral ophthalmoplegia from sixth cranial nerve palsy and papilledema. Her brain MRI showed normal brain parenchyma. The lumbar cerebrospinal fluid (CSF) opening pressure was 1000 mm of water measured with normal CSF contents. From these findings, she was diagnosed with idiopathic intracranial hypertension (IIH). Initial lumbar puncture (LP) immediately improved her symptoms, but acetazolamide, a first line drug for the treatment of IIH, failed to maintain the remission, and three more periodical LP were required to relieve her symptoms every 2 weeks. After the fourth LP, acetazolamide was switched to a second line drug for IIH, topiramate, which was found to be highly effective in controlling IIH in a short time period. The long process of IIH causes vision loss, therefore, its prompt treatment is vital. In cases refractory to medical treatment, surgical treatments such as CSF shunt are considered. Acetazolamide is used in most IIH cases after the initial diagnosis, but in this case, it was ineffective, and topiramate was highly effective. Both acetazolamide and topiramate are inhibitors of carbonic anhydrase isoforms involved in CSF secretion. Inhibition of choroid plexus carbonic anhydrase by these drugs leads to decreased CSF secretion and the consequent control of intracranial pressure. Higher isoform specificity and increased lipophilic nature of topiramate, which are advantageous for passing through the blood brain barrier, may be the reasons for better activity than acetazolamide, at least in the present case. Topiramate might be effective and should be considered for refractory IIH cases before surgical treatments.