Publications by authors named "Satoshi Okada"

232 Publications

Pilot Study on Neonatal Screening for Methylmalonic Acidemia Caused by Defects in the Adenosylcobalamin Synthesis Pathway and Homocystinuria Caused by Defects in Homocysteine Remethylation.

Int J Neonatal Screen 2021 Jul 7;7(3). Epub 2021 Jul 7.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Minami-ku, Hiroshima 734-8551, Japan.

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine β-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 μmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 μmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.
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http://dx.doi.org/10.3390/ijns7030039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293178PMC
July 2021

MRI-Based Glucose Assay Using Magnetic Nanoparticle Sensors.

Anal Sci 2021 Jul 9. Epub 2021 Jul 9.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology.

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http://dx.doi.org/10.2116/analsci.21P082DOI Listing
July 2021

Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common Variant.

Int J Neonatal Screen 2021 Jun 28;7(3). Epub 2021 Jun 28.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.

Propionic acidemia (PA) is a disorder of organic acid metabolism which typically presents with acute encephalopathy-like symptoms associated with metabolic acidosis and hyperammonemia during the neonatal period. The estimated incidence of symptomatic PA in Japan is 1/400,000. The introduction of neonatal screening using tandem mass spectrometry has revealed a far higher disease frequency of approximately 1/45,000 live births due to a prevalent variant of c.1304T>C (p.Y435C) in , which codes β-subunit of propionyl-CoA carboxylase. Our questionnaire-based follow-up study reveals that most of these patients remain asymptomatic. However, reports on symptomatic patients exhibiting cardiac complications such as cardiomyopathy and QT prolongation have been increasing. Moreover, there were even cases in which these cardiac complications were the only symptoms related to PA. A currently ongoing study is investigating the risk of cardiac complications in patients with neonatal screening-detected PA caused by this common variant.
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http://dx.doi.org/10.3390/ijns7030035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293189PMC
June 2021

Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

J Immunol 2021 Jun 28. Epub 2021 Jun 28.

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.
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http://dx.doi.org/10.4049/jimmunol.2001451DOI Listing
June 2021

Enhanced osteoclastogenesis in patients with MSMD due to impaired response to IFN-γ.

J Allergy Clin Immunol 2021 Jun 17. Epub 2021 Jun 17.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan. Electronic address:

Background: Patients with Mendelian susceptibility to mycobacterial disease (MSMD) experience recurrent and/or persistent infectious diseases associated with poorly virulent mycobacteria. Multifocal osteomyelitis is among the representative manifestations of MSMD. The frequency of multifocal osteomyelitis is especially high in patients with MSMD etiologies that impair cellular response to IFN-γ, such as IFN-γR1, IFN-γR2, or STAT1 deficiency.

Objectives: This study sought to characterize the mechanism underlying multifocal osteomyelitis in MSMD.

Methods: GM colonies prepared from bone marrow mononuclear cells from patients with autosomal dominant (AD) IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 gain of function (GOF) and from healthy controls were differentiated into osteoclasts in the presence or absence of IFN-γ. The inhibitory effect of IFN-γ on osteoclastogenesis was investigated by quantitative PCR, immunoblotting, tartrate-resistant acid phosphatase staining, and pit formation assays.

Results: Increased osteoclast numbers were identified by examining the histopathology of osteomyelitis in patients with AD IFN-γR1 deficiency or AD STAT1 deficiency. In the presence of receptor activator of nuclear factor kappa-B ligand and M-CSF, GM colonies from patients with AD IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-γ concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-γR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF.

Conclusions: Osteoclast differentiation is increased in AD IFN-γR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-γ, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis.
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http://dx.doi.org/10.1016/j.jaci.2021.05.018DOI Listing
June 2021

A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS.

Nat Immunol 2021 Jul 21;22(7):893-903. Epub 2021 Jun 21.

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.
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http://dx.doi.org/10.1038/s41590-021-00951-zDOI Listing
July 2021

Therapeutic options for CTLA-4 insufficiency.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.

Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.

Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.

Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.

Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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http://dx.doi.org/10.1016/j.jaci.2021.04.039DOI Listing
June 2021

Temporal muscle thickness is associated with the severity of dysphagia in patients with acute stroke.

Arch Gerontol Geriatr 2021 May 24;96:104439. Epub 2021 May 24.

Department of Oral Medicine and Hospital Dentistry, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba 272-8513, Japan.

Background: Post-stroke dysphagia is a common and expensive complication of acute stroke. The relationship between dysphagia and skeletal muscle loss (sarcopenia) has been recently highlighted. This study aimed to determine the relationship between temporal muscle thickness (TMT) measured by head magnetic resonance imaging (MRI) and dysphagia in patients with acute stroke.

Methods: Seventy participants (43 men and 27 women; mean age, 75.6 ± 12.7 years) were included in this study. TMT was measured by T2-magnetic resonance images within seven days of hospitalization. The severity of dysphagia was assessed using the Functional Oral Intake Scale (FOIS). Participants were classified into three categories according to the severity of dysphagia (severe: FOIS score, 1-3; mild: FOIS score, 4-6; normal: FOIS score, 7). Linear regression analysis was used to determine the independent explanators of dysphagia severity.

Results: Twenty participants (28.6%) had severe dysphagia, 31 participants (44.3%) had mild dysphagia, and 19 participants (27.1%) had normal swallowing function at discharge. The results of the linear regression analysis showed that TMT was a significant explanator of dysphagia severity following stroke, along with age and National Institute of Health Stroke Scale (NIHSS) score (P < 0.05, effect size: f = 0.72).

Conclusions: TMT was an independent risk factor for dysphagia in patients with acute stroke. Skeletal muscle loss may be secondarily involved in dysphagia with acute stroke, and measurement of TMT with head MRI is a useful method to assess skeletal muscle loss.
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http://dx.doi.org/10.1016/j.archger.2021.104439DOI Listing
May 2021

Novel STAT-3 gain-of-function variant with hypogammaglobulinemia and recurrent infection phenotype.

Clin Exp Immunol 2021 May 29. Epub 2021 May 29.

Primary Immunodeficiency Clinical Unit and Laboratory, Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary.

Signal transducer and activator of transcription 3 (STAT-3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT-3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. In addition, the patient had lymphoproliferation, short stature and interstitial lung disease. Chest computerized tomography examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. Using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT-3 variant affecting the coiled coil domain of STAT-3. Functional studies confirmed that p.D170H was a GOF variant, as shown by increased phosphorylated STAT-3 (pSTAT-3) and STAT-3 transcriptional activity. Our observation suggests that STAT-3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections. We suggest that patients with lymphoproliferation, hypogammaglobulinemia and severe recurrent infections should be screened for STAT-3 variants, even if autoimmune manifestations are missing.
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http://dx.doi.org/10.1111/cei.13625DOI Listing
May 2021

Inborn errors of STAT1 immunity.

Curr Opin Immunol 2021 Apr 8;72:59-64. Epub 2021 Apr 8.

Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. Electronic address:

Signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor that is activated by multiple stimuli, including type I, II, and III interferons and interleukin-27. Inborn errors of human STAT1 immunity underlie 4 distinct disorders: autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function. Each disease presents distinct clinical manifestations, excluding the difference in two AR STAT1 deficiencies, which are mainly explained by severity. This observation reflects the multiple and complex roles of STAT1 and how STAT1-mediated signaling is finely tuned in host immune systems.
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http://dx.doi.org/10.1016/j.coi.2021.02.009DOI Listing
April 2021

Review of Cognitive Characteristics of Autism Spectrum Disorder Using Performance on Six Subtests on Four Versions of the Wechsler Intelligence Scale for Children.

J Autism Dev Disord 2021 Mar 7. Epub 2021 Mar 7.

Fukushima Medical University, Fukushima, Japan.

This study was a systematic review of research using the Wechsler Intelligence Scale for Children (WISC) with Autism Spectrum Disorder (ASD) to examine cognitive characteristics of children with ASD beyond the impact of revisions based on WISC and diagnostic criteria changes. The classic "islets of ability" was found in individuals with full-scale IQs < 100. The "right-descending profiles" were observed among high IQ score individuals. High levels on the Block Design and low Coding levels were consistently found regardless of the variation in intellectual functioning or diagnosis. This review identified patterns of cognitive characteristics in ASD individuals using empirical data that researchers may have previously been aware of, based on their experiences, owing to the increased prevalence of ASD.
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http://dx.doi.org/10.1007/s10803-021-04932-xDOI Listing
March 2021

A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency.

Front Immunol 2020 15;11:517544. Epub 2021 Feb 15.

National Clinical Research Center for Child Health and Disorders, Chongqing, China.

Mutations in the gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.
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http://dx.doi.org/10.3389/fimmu.2020.517544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917045PMC
April 2021

Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings.

J Clin Immunol 2021 Jul 8;41(5):975-986. Epub 2021 Feb 8.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, Hiroshima, Japan.

Purpose: Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported.

Methods: Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed.

Results: Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14 monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype.

Conclusions: CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.
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http://dx.doi.org/10.1007/s10875-021-00988-7DOI Listing
July 2021

Functional analysis of novel A20 variants in patients with atypical inflammatory diseases.

Arthritis Res Ther 2021 02 6;23(1):52. Epub 2021 Feb 6.

Department of Pediatrics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.

Background: A20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in the TNFAIP3 gene, which encodes the protein A20. Numerous truncating mutations in the TNFAIP3 gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of the TNFAIP3 gene in suspected cases of HA20.

Methods: We obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance of TNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay using TNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated.

Results: The inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study.

Conclusions: Among the three variants in the TNFAIP3 gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity of TNFAIP3 missense variants for the accurate diagnosis of HA20.
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http://dx.doi.org/10.1186/s13075-021-02434-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866758PMC
February 2021

T2-FLAIR Mismatch Sign and Response to Radiotherapy in Diffuse Intrinsic Pontine Glioma.

Pediatr Neurosurg 2021 3;56(1):1-9. Epub 2021 Feb 3.

Department of Radiation Oncology, Hiroshima University Hospital, Hiroshima, Japan.

Purpose: The T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign was previously reported as a diagnostic indicator of diffuse astrocytoma, isocitrate dehydrogenase-mutant, and 1p/19q noncodeletion. Subsequently, it was reported that the same findings were observed in diffuse intrinsic pontine glioma (DIPG). We investigated the clinical significance of T2-FLAIR mismatch sign in DIPG.

Methods: Twenty-one patients with DIPG (Male: Female = 12:9) were treated at our institute between 2004 and 2019. All patients were treated with local radiotherapy of 54 Gy/30 fractions. The positive T2-FLAIR mismatch sign was defined if it fulfilled the following criteria: (1) T2-FLAIR mismatch volume was >50% of T2 high volume at nonenhanced area, (2) the FLAIR low lesion is not associated with gadolinium enhancement (inside of enhancement or just outside of enhancement defined as edema), and (3) signal-intensity of FLAIR lowest lesion at tumor is lower than the normal cerebellar cortex.

Results: In our patient series, T2-FLAIR mismatch sign was found in 5 out of 21 patients. Objective response rate of radiotherapy was 100% in patients positive for T2-FLAIR mismatch, while it was 25.0% in patients negative for T2-FLAIR mismatch, and this difference was statistically significant (p < 0.01, Fisher's exact test). In patients under the age of 18-years, T2-FLAIR mismatch positive had a slightly better prognosis (p < 0.05, Wilcoxon test).

Conclusion: T2-FLAIR mismatch sign in DIPG may be an indicator for better response to radiotherapy and a better prognostic factor.
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http://dx.doi.org/10.1159/000513360DOI Listing
February 2021

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Sci Adv 2021 Jan 20;7(4). Epub 2021 Jan 20.

Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in , encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.
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http://dx.doi.org/10.1126/sciadv.abe2116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817106PMC
January 2021

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

J Clin Immunol 2021 May 26;41(4):780-790. Epub 2021 Jan 26.

Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Purpose: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients.

Methods: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information.

Results: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable.

Conclusion: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.
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http://dx.doi.org/10.1007/s10875-021-00975-yDOI Listing
May 2021

Pneumococcal Serotype-specific Opsonophagocytic Activity in Interleukin-1 Receptor-associated Kinase 4-deficient Patients.

Pediatr Infect Dis J 2021 May;40(5):460-463

Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Background: The antibody response after pneumococcal vaccines and their effectiveness against invasive pneumococcal disease (IPD) in patients with interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency have not been fully evaluated. Here, we evaluated pneumococcal serotype-specific opsonophagocytic activity (OPA) in IRAK4-deficient patients along with their clinical course.

Methods: We investigated 6 IRAK4-deficient patients in Japan, whose attending physicians could be contacted. We performed OPA measurements using stored and more recent serum samples obtained from these patients.

Results: All patients had received pneumococcal vaccination. Among the 3 patients who had IPD, 2 had an episode of pneumococcal meningitis and the other developed pneumococcal bacteremia 3 years after the occurrence of pneumococcal meningitis. Only one episode of invasive bacterial infection was caused by a Streptococcus pneumoniae vaccine-type strain. An increased opsonization index was found in the sera after vaccination for all IRAK-deficient patients, including when the 23-valent pneumococcal polysaccharide vaccine was used.

Conclusions: A significant increase in levels of OPA against most of the pneumococcal vaccine antigens was observed for all IRAK4-deficient patients. However, IPD could not be prevented by pneumococcal vaccination alone. Therefore, adequate prophylaxis should be provided with antibiotics at least until 8 years of age, along with regular immunoglobulin therapy, particularly during the infantile period.
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http://dx.doi.org/10.1097/INF.0000000000003060DOI Listing
May 2021

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability.

Nucleic Acids Res 2021 01;49(2):954-968

Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Catalytically inactive Cas9 (dCas9) has become an increasingly popular tool for targeted gene activation/inactivation, live-cell imaging, and base editing. While dCas9 was reported to induce base substitutions and indels, it has not been associated with structural variations. Here, we show that dCas9 impedes replication fork progression to destabilize tandem repeats in budding yeast. When targeted to the CUP1 array comprising ∼16 repeat units, dCas9 induced its contraction in most cells, especially in the presence of nicotinamide. Replication intermediate analysis demonstrated replication fork stalling in the vicinity of dCas9-bound sites. Genetic analysis indicated that while destabilization is counteracted by the replisome progression complex components Ctf4 and Mrc1 and the accessory helicase Rrm3, it involves single-strand annealing by the recombination proteins Rad52 and Rad59. Although dCas9-mediated replication fork stalling is a potential risk in conventional applications, it may serve as a novel tool for both mechanistic studies and manipulation of genomic instability.
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http://dx.doi.org/10.1093/nar/gkaa1241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826275PMC
January 2021

Successful Hematopoietic Stem Cell Transplantation for Autosomal Recessive STAT1 Complete Deficiency.

J Clin Immunol 2021 Apr 4;41(3):684-687. Epub 2021 Jan 4.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, 1-2-3 Kasumi, Minami-Ku, Hiroshima-Shi, Hiroshima, 734-8551, Japan.

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http://dx.doi.org/10.1007/s10875-020-00948-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780594PMC
April 2021

Clinical Significance of Serum Soluble TNF Receptor I/II Ratio for the Differential Diagnosis of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome From Other Autoinflammatory Diseases.

Front Immunol 2020 14;11:576152. Epub 2020 Oct 14.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.

Genetic analysis of can confirm the diagnosis of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), but interpretation of the pathogenesis of variants of unknown significance is sometimes required. The aim of this study was to evaluate the clinical significance of serum soluble tumor necrosis factor receptor type I (sTNFR-I)/II ratio to differentiate TRAPS from other autoinflammatory diseases. Serum sTNFR-I and sTNFR-II levels were measured using an enzyme-linked immunosorbent assay in patients with TRAPS ( = 5), familial Mediterranean fever (FMF) ( = 14), systemic juvenile idiopathic arthritis (s-JIA) ( = 90), and Kawasaki disease (KD) ( = 37) in the active and inactive phase, along with healthy controls (HCs) ( = 18). In the active phase, the serum sTNFR-I/II ratio in patients with s-JIA, KD, and FMF was significantly elevated compared with that in HCs, whereas it was not elevated in patients with TRAPS. In the inactive phase, the serum sTNFR-I/II ratio in patients with s-JIA and FMF was significantly higher compared with that in HCs, and the ratio was lower in TRAPS patients than in patients with s-JIA and FMF. Low serum sTNFR-I/II ratio in the active and inactive phase might be useful for the differential diagnosis of TRAPS and other autoinflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2020.576152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591697PMC
June 2021

[Lymphoproliferative disorders and inborn errors of immunity].

Rinsho Ketsueki 2020 ;61(9):1365-1372

Department of Pediatrics, Hiroshima University Institute of Biomedical and Health Sciences.

Lymphoproliferative disease (LPD) is a comprehensive concept covering diseases ranging from transient lymphadenopathy to lymphoma. LPD is frequently associated with Epstein-Barr virus (EBV) infections and tends to occur in patients with inborn errors of immunity (IEI) and in patients after organ transplantation. Most patients with severe combined immunodeficiency or X-linked lymphoproliferative disease develop LPD. Autoimmune lymphoproliferative syndrome (ALPS), a typical LPD disease, is caused by germline mutations in FAS, FASL, CASP10, CASP8 and FADD, which are involved in the apoptosis pathway. ALPS patients develop autoimmune diseases and LPDs such as hepatosplenomegaly and lymphadenopathy. On the other hand, RAS-associated ALPS-like syndrome and CTLA4 haploinsufficiency also belong to ALPS-associated diseases. EBV-associated LPD is a clinical condition that should be noted in patients with IEI. Patients with genetic defects in SH2D1A, XIAP, CD27, CD70, CD137, ITK, CTPS, RASGRP1, and MAGT1 are prone to EBV-associated LPD.
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http://dx.doi.org/10.11406/rinketsu.61.1365DOI Listing
January 2021

Impaired B-Cell Differentiation in a Patient With Gain-of-Function Mutation.

Front Immunol 2020 29;11:557521. Epub 2020 Sep 29.

Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

Hypogammaglobulinemia is a rare complication of gain-of-function (GOF) mutations. We report an adult patient diagnosed with hypogammaglobulinemia caused by B-cell depletion during the treatment of disseminated cryptococcosis. The patient carried the GOF mutation (c.820C>T, p.R274W). The flow cytometric analysis of his bone marrow revealed that B-cell differentiation was blocked in the stages between pre-B1b and pre-B2 cells. On the other hand, his brother who carried the same mutation displayed normal B-cell counts, thereby indicating that the unrecognized variants in same or other gene might be associated with abnormal B-cell differentiation in the patients. In conclusion, impaired B-cell differentiation in the bone marrow can cause hypogammaglobulinemia in patients with GOF mutations.
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http://dx.doi.org/10.3389/fimmu.2020.557521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550620PMC
May 2021

IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation.

J Clin Immunol 2021 Jan 20;41(1):125-135. Epub 2020 Oct 20.

Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Science, 1-2-3 Kasumi, Minami-Ku, Hiroshima-Shi, Hiroshima, 734-8551, Japan.

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
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http://dx.doi.org/10.1007/s10875-020-00885-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846526PMC
January 2021

Bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor in a case with C1q deficiency associated with refractory systemic lupus erythematosus.

Int J Hematol 2021 Feb 30;113(2):302-307. Epub 2020 Sep 30.

Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.
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http://dx.doi.org/10.1007/s12185-020-03004-7DOI Listing
February 2021

Effects of perampanel add-on therapy on immunoglobulin levels in pediatric patients with epilepsy.

Epilepsy Res 2020 11 21;167:106447. Epub 2020 Aug 21.

Department of Pediatrics, Hiroshima University Hospital, Japan.

Background: Perampanel (PER) has a unique pharmacological mechanism and marked efficacy in both focal and generalized epilepsy, but may cause adverse events similar to those of other antiepileptic drugs (AEDs). AEDs can affect multiple organ systems, as well as thyroid function, lipid profiles, and immunoglobulin levels; the low free T4 levels, hyperlipidemia, and low immunoglobulin levels can be caused by AEDs. While many studies have examined conventional AEDs, little is known about the long-term effects of PER on blood parameters.

Methods: We retrospectively reviewed the medical records of 18 pediatric patients with epilepsy who were treated with PER added to >1 other AED. Blood parameters (e.g., blood cell counts, biochemical and thyroid function, and immunoglobulin levels) were investigated at baseline and at 6 and 12 months after initiation of PER.

Results: PER did not affect the blood counts, transaminase levels, lipid profile, or thyroid function at 12 months after initiation of PER. However, IgA levels significantly increased (p = 0.00319) without symptoms. IgM levels increased temporarily, but had returned to baseline by 12 months after initiation of PER.

Conclusions: IgA levels were elevated at 12 months after initiation of PER in pediatric patients with intractable epilepsy, although no symptoms were observed. PER did not affect other parameters, including lipid profile and thyroid function.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106447DOI Listing
November 2020

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy.

J Clin Immunol 2020 11 27;40(8):1065-1081. Epub 2020 Aug 27.

St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.
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http://dx.doi.org/10.1007/s10875-020-00847-xDOI Listing
November 2020

Cyclic RGD-Functionalized -Dodecaborate Albumin Conjugates as Integrin Targeting Boron Carriers for Neutron Capture Therapy.

Mol Pharm 2020 10 9;17(10):3740-3747. Epub 2020 Sep 9.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan.

Cyclic RGD (cRGD) peptide-conjugated boronated albumin was developed to direct toward integrin αβ which overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)] and maleimide-conjugated -dodecaborate (MID) to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic toward both U87MG and A549 cells. As compared with l-BPA, selective antitumor activity of cRGD-MID-BSA toward U87MG cells overexpressing integrin αβ was identified after thermal neutron irradiation. In vivo fluorescence live imaging of Cy5-conjugated cRGD-MID-BSA and MID-BSA revealed that both cRGD-MID-BSA and MID-BSA similarly reached the maximum accumulation during 8-12 h after injection. The selective accumulation and retention of Cy5-cRGD-MID-BSA was more pronounced than Cy5-MID-BSA after 24 h. An in vivo boron neutron capture therapy (BNCT) study revealed that the cRGD peptide ligand combination enhanced accumulation of MID-BSA into tumor cells in U87MG xenograft models. The significant tumor growth suppression was observed in U87MG xenograft models at a dose of 7.5 mg [B]/kg after neutron irradiation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00478DOI Listing
October 2020
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