Kazumoto Iijima

Kobe University, Kōbe, Hyōgo, Japan

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Publications (230)747.2 Total impact

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    ABSTRACT: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.European Journal of Human Genetics advance online publication, 27 May 2015; doi:10.1038/ejhg.2015.113.
    European journal of human genetics: EJHG 05/2015; DOI:10.1038/ejhg.2015.113 · 4.23 Impact Factor
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    ABSTRACT: Phenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features. A total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined. Patients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease. This study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.Genet Med advance online publication 16 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.56.
    Genetics in medicine: official journal of the American College of Medical Genetics 04/2015; DOI:10.1038/gim.2015.56 · 6.44 Impact Factor
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    ABSTRACT: The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), comprises 79 exons that show multiple alternative splicing events. Intron retention, a type of alternative splicing, may control gene expression. We examined intron retention in dystrophin introns by reverse-transcription PCR from skeletal muscle, focusing on the nine shortest (all <1000 bp), because these are more likely to be retained. Only one, intron 40, was retained in mRNA; sequencing revealed insertion of a complete intron 40 (851 nt) between exons 40 and 41. The intron 40 retention product accounted for 1.2% of the total product but had a premature stop codon at the fifth intronic codon. Intron 40 retention was most strongly observed in the kidney (36.6%) and was not obtained from the fetal liver, lung, spleen or placenta. This indicated that intron retention is a tissue-specific event whose level varies among tissues. In two DMD patients, intron 40 retention was observed in one patient but not in the other. Examination of splicing regulatory factors revealed that intron 40 had the highest guanine-cytosine content of all examined introns in a 30-nt segment at its 3' end. Further studies are needed to clarify the biological role of intron 40-retained dystrophin mRNA.Journal of Human Genetics advance online publication, 2 April 2015; doi:10.1038/jhg.2015.24.
    Journal of Human Genetics 04/2015; DOI:10.1038/jhg.2015.24 · 2.53 Impact Factor
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    ABSTRACT: CDKL5-related encephalopathy is an X-linked dominantly inherited disorder that is characterized by early infantile epileptic encephalopathy or atypical Rett syndrome. We describe a 5-year-old Japanese boy with intractable epilepsy, severe developmental delay, and Rett syndrome-like features. Onset was at 2months, when his electroencephalogram showed sporadic single poly spikes and diffuse irregular poly spikes. We conducted a genetic analysis using an Illumina® TruSight™ One sequencing panel on a next-generation sequencer. We identified two epilepsy-associated single nucleotide variants in our case: CDKL5 p.Ala40Val and KCNQ2 p.Glu515Asp. CDKL5 p.Ala40Val has been previously reported to be responsible for early infantile epileptic encephalopathy. In our case, the CDKL5 heterozygous mutation showed somatic mosaicism because the boy's karyotype was 46,XY. The KCNQ2 variant p.Glu515Asp is known to cause benign familial neonatal seizures-1, and this variant showed paternal inheritance. Although we believe that the somatic mosaic CDKL5 mutation is mainly responsible for the neurological phenotype in the patient, the KCNQ2 variant might have some neurological effect. Genetic analysis by next-generation sequencing is capable of identifying multiple variants in a patient. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
    Brain & development 03/2015; DOI:10.1016/j.braindev.2015.03.002 · 1.54 Impact Factor
  • Kazumoto Iijima, Mayumi Sako, Kandai Nozu
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    ABSTRACT: In the past 10 years, many reports have suggested that rituximab, a chimeric anti-CD20 monoclonal antibody, is effective for children with complicated, frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, those reports were case reports, case series, retrospective surveys, and single-arm or short-term trials. Therefore, well-designed controlled trials are required to establish the value of rituximab in this condition. To evaluate the efficacy and safety of rituximab in childhood-onset, complicated FRNS/SDNS, a multicenter, double-blind, randomized, placebo-controlled trial was carried out by the Research Group of Childhood-onset Refractory Nephrotic Syndrome (RCRNS) in Japan (RCRNS01). RCRNS01 showed that rituximab is safe and effective for the treatment of childhood-onset, complicated FRNS/SDNS. In 2014, the use of rituximab for patients with complicated FRNS/SDNS was approved, first in the world, by the Ministry of Health, Labour and Welfare, Japan.
    03/2015; 3(1). DOI:10.1007/s40124-014-0065-5
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    ABSTRACT: Convulsive status epilepticus with fever is common and may be related to neurological sequela in children. However, there are limited data on the demographics and risk factors of this phenomenon. Thus, we aimed to describe the demographics and risk factors of neurological sequela among children with convulsive status epilepticus with fever. We reviewed convulsive status epilepticus with fever cases in the pediatric intensive care unit at Kobe Children's Hospital between 2002 and 2013. We included patients with intrinsic neurological disease, and excluded those with obvious central nervous system infection. Cases of neurological worsening were categorized as poor outcome using the pediatric cerebral performance category scale. Possible risk factors for poor outcome included age, sex, neurological medical history, seizure duration, body temperature, and level of consciousness. A total of 253 patients (128 males), aged 1 month to 15 years (mean 45 ± 40 months), were enrolled. Three patients (1.2%) died during hospitalization, and 32 (12.6%) patients had a poor outcome. A univariate analysis identified male sex, absence of epilepsy history, body temperature above 40°C on admission, seizure duration longer than 120 minutes, impaired consciousness at 12 hours after onset, and presence of nonconvulsive seizure as potential predictors of poor outcome. A multivariate analysis, revealed that an absence of epilepsy history (odds ratio = 11.18), body temperature above 40°C on admission (odds ratio = 3.39), or impaired consciousness at 12 hours after onset (odds ratio = 41.85) was associated with poor outcome. Our study indicated that absence of epilepsy history, high temperature, and/or prolonged impaired consciousness were associated with brain injury. Copyright © 2015 Elsevier Inc. All rights reserved.
    Pediatric Neurology 02/2015; 52(5). DOI:10.1016/j.pediatrneurol.2015.02.001 · 1.50 Impact Factor
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    ABSTRACT: IntroductionNephrotic syndrome is a disorder characterized by severe proteinuria, hypoproteinemia, and generalized edema resulting from damage to the glomerular basement membrane. In Western countries, nephrotic syndrome affects 2 of 100,000 children per year [1]. In Japan, approximately 1,300 new cases per year of pediatric nephrotic syndrome are reported to the Medical Aid for Specific Chronic Disease of Children and the disease develops in 5 of 100,000 children per year. Approximately 90 % of the cases of pediatric nephrotic syndrome are idiopathic, or of unknown cause. The first-line treatment for an initial episode of pediatric idiopathic nephrotic syndrome is oral steroid therapy, which leads to remission in approximately 80 % of cases (steroid-sensitive nephrotic syndrome) [2]. However, 80 % of children with steroid-sensitive nephrotic syndrome experience one or more relapses, [3] and 50 % of these children have frequent relapses [4]. Those with frequently relapsing nephrotic sy ...
    Clinical and Experimental Nephrology 02/2015; 19(1). DOI:10.1007/s10157-014-1030-x · 1.71 Impact Factor
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    ABSTRACT: IntroductionPediatric idiopathic nephrotic syndrome is a very important disease in the field of pediatric nephrology. The Japanese Society for Pediatric Nephrology published the “Clinical Practice Guideline for Medical Treatment of Pediatric Idiopathic Nephrotic Syndrome (version 1.0) (in Japanese)” in 2005. The guideline, aiming to support appropriate decision and treatment for pediatric idiopathic nephrotic syndrome, illustrated standard regimens of medical treatment of pediatric idiopathic nephrotic syndrome at that time and has been credited with standardization and optimization of the treatment. In 2011, 6 years after the publication, the need to revise the guideline became recognized against the background of changes in care setting including introduction of rituximab. Additionally, development of guideline covering general therapies was required.The Scientific Committee of the Japanese Society for Pediatric Nephrology established a new operation to revise the guideline and publi ...
    Clinical and Experimental Nephrology 02/2015; 19(1). DOI:10.1007/s10157-014-1031-9 · 1.71 Impact Factor
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    ABSTRACT: An MRI-based pre-test to determine the probability of pediatric leukemia prior to bone marrow aspiration would be useful to prevent unnecessary exposure to this invasive test. We aimed to evaluate the clivus-to-pons signal intensity ratio (CPR) and visual scoring (VS) on T1-weighted images (T1WI) and diffusion-weighted images (DWI) to distinguish pediatric leukemia patients from normal controls. We retrospectively reviewed 1.5-T brain MR images of 13 consecutive leukemia patients (3 girls, 10 boys; mean age, 8.23 years; range, 1-17 years) and 40 age- and gender-matched normal controls. We evaluated differences between leukemia patients and normal controls using Wilcoxon rank-sum and Mann-Whitney U tests with respect to the following parameters: (1) CPR on T1WI (CPRT1WI); (2) CPR on DWI (CPRDWI); (3) VS on T1WI (VST1WI); and (4) VS on DWI (VSDWI). The CPRT1WI values for leukemia patients and normal controls were 0.77 ± 0.12 and 1.39 ± 0.47, respectively (P < 0.001). The corresponding CPRDWI values were 1.03 ± 0.38 and 0.50 ± 0.17, respectively (P < 0.001). VST1WI and VSDWI were significantly different between the groups (P < 0.001 for both). MRI-based quantitative and qualitative analyses of clival bone marrow on T1WI and DWI can distinguish pediatric leukemia patients from normal subjects.
    Japanese journal of radiology 02/2015; 33(3). DOI:10.1007/s11604-015-0394-5 · 0.74 Impact Factor
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    ABSTRACT: This study aimed to evaluate peak serum total bilirubin (TB) and unbound bilirubin (UB) levels in preterm infants with clinical kernicterus (KI) who were diagnosed by clinical findings during infancy.
    Brain and Development 01/2015; DOI:10.1016/j.braindev.2015.01.001 · 1.54 Impact Factor
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    ABSTRACT: Background Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of the human heme oxygenase-1 (HMOX1) gene contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat lengths in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates.Methods Using PCR and the fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in the uridine diphosphoglucuronosyltransferase gene on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates.ResultsThe proportion of short allele (< 22 (GT)n repeats) frequency was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, p=0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, p=0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR: 3.1; 95% CI: 1.03–9.53).Conclusions Infants carrying short alleles (< 22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.
    Pediatrics International 01/2015; DOI:10.1111/ped.12591 · 0.73 Impact Factor
  • The Lancet 01/2015; 385(9964). DOI:10.1016/S0140-6736(15)60052-6 · 45.22 Impact Factor
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    ABSTRACT: Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by a mutation in the uromodulin (UMOD) gene, leading to end-stage renal disease. We herein report the case of a family with UAKD caused by a novel mutation (C135G) in the UMOD gene. A 31-year-old woman had a low estimated glomerular filtration rate (59.7 mL/min per 1.73 m(2)). Her father, grandfather and paternal aunt had received maintenance hemodialysis therapy since their 40's. This case underscores the importance of performing genetic testing in young patients even in cases involving only moderate abnormalities in the kidney function.
    Internal Medicine 01/2015; 54(6):631-5. DOI:10.2169/internalmedicine.54.3151 · 0.97 Impact Factor
  • Natsuki Matsunoshita, Kandai Nozu, Kazumoto Iijima
    Nippon Jinzo Gakkai shi 01/2015; 57(4):743-50.
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    ABSTRACT: Antisense oligonucleotide (AO)-mediated exon skipping is the most promising way to express internally deleted dystrophin in Duchenne muscular dystrophy (DMD), by correcting the reading frame of dystrophin mRNA. An antisense chimeric oligonucleotide consisting of 2´-O-methyl RNA and ethylene-bridged nucleic acid (ENA), targeting exon 45 of the dystrophin gene, AO85, has been shown to induce exon 45 skipping efficiently. Since phosphorothioate (PS)-modification of AO85 has never been explored, we produced a PS-modified AO85 (AO88) and examined its exon skipping capability and cytotoxicity. Exon 45 skipping activity was examined in primary muscle cells established from a DMD patient carrying a deletion of dystrophin exon 44. Cytotoxicity was assessed by MTT assay. AO88 induced dystrophin exon 45 skipping from 50 nM. More than 90% of products lacked exon 45 at 400 nM. AO88 showed significantly higher exon skipping activity than AO85. The EC50 of AO88 was 94.8 nM, while EC50 of AO85 was 66.7 nM. Cytotoxicity was lower for AO88 than for AO85. the PS-modified RNA/ENA chimera displayed stronger exon skipping activity and lower cytotoxicity than the phosphodiester-RNA/ENA chimera. AO88 has better potential for clinical use than AO85.
    The Kobe journal of medical sciences 01/2015; 60(4):E86-94.
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    ABSTRACT: Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurobehavioral problem in children throughout the world. The Stroop test has been widely used for the evaluation of ADHD symptoms. However, the age-related change of the Stroop test results has not been fully clarified until now. Sixty-five ADHD and 70 age-matched control children aged 6-13 years were enrolled in this study. ADHD was diagnosed based on DSM-IV criteria. We examined the completion time and error rates of the Congruent Stroop test (CST) and Incongruent Stroop test (IST) in ADHD and control children. No significant difference was observed in the completion time for CST or IST between the ADHD and control children at 6-9 years old. However, ADHD children at 10-13 years old showed significantly delayed completion time for the CST and IST compared with controls of the same age. As for the error rates of the CST and IST, ADHD and control children at 6-9 years old showed no difference. However, error rates of CST and IST in the ADHD children at 10-13 years were significantly higher than those of control of the same age. Age may influence the results of Stroop test in ADHD children. For the ages of 10-13 years old, the Stroop test clearly separates ADHD children from control children, suggesting that it may be a useful screening tool for ADHD among preadolescent children.
    The Kobe journal of medical sciences 01/2015; 61(1):E19-26.
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    ABSTRACT: Despite the introduction of 13-cis-retinoic acid (13-cis-RA) into the current chemotherapy, more than half of high-risk neuroblastoma patients have experienced tumor relapses driven by chemoresistant cancer stem cells (CSCs) that can be isolated by their ability to grow as spheres. Although aldehyde dehydrogenase (ALDH) has been used to characterize CSCs in certain cancers, ALDH remains elusive in neuroblastoma. In the present study, we determined ALDH activity and expression of its 19 isoforms in spheres and parental cells of neuroblastoma. ALDH activity and several ALDH isoforms were consistently induced in spheres of different neuroblastoma cells. While ALDH1A2, ALDH1L1 and ALDH3B2 expression was consistently induced in spheres and associated with the sphere and colony formation, only ALDH1A2 expression was significantly correlated with the poor prognosis of neuroblastoma patients. ALDH1A2 expression was further associated with the growth and undifferentiation of neuroblastoma xenografts and the resistance of neuroblastoma cells to 13-cis-RA. These results suggest that ALDH1A2 is involved in the regulation of CSC properties in neuroblastoma.
    International Journal of Oncology 12/2014; 46(3). DOI:10.3892/ijo.2014.2801 · 3.03 Impact Factor
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    ABSTRACT: Although a 2-year combination therapy is effective for severe childhood immunoglobulin A (IgA) nephropathy, proteinuria persists in some patients even after the treatment. Seventy-nine patients aged <18 years with IgA nephropathy in which >80 % of glomeruli showed mesangial proliferation were enrolled in the study. Risk factors for persistent proteinuria after combination therapy were investigated using multivariate logistic regression analysis. Proteinuria (≥0.2 g/1.73 m(2)/day) persisted in 27 patients (34 %) after the combination therapy. Twenty-four-hour urinary protein excretion, rate of glomeruli with crescents, rate of glomeruli with segmental sclerosis and rate of glomeruli with global sclerosis at diagnosis were higher in patients with persistent proteinuria than those without. In the multivariate analysis, 24-h urinary protein excretion [odds ratio (OR) 6.9; 95 % confidence interval (CI) 2.1-27.8; p = 0.001] and rate of glomeruli with crescents (OR 3.8; 95 % CI 1.1-13.9; p = 0.03) were independent risk factors for persistent proteinuria. Analysis of the receiver operating characteristic curve demonstrated that the most accurate cut-off values to detect persistent proteinuria were a urinary protein excretion of 1.32 g/1.73 m(2)/day and a 14 % rate of glomeruli with crescents. In our cohort, urinary protein excretion and rate of glomeruli with crescents at diagnosis were independent risk factors for persistent proteinuria after the combination therapy.
    Pediatric Nephrology 12/2014; 30(6). DOI:10.1007/s00467-014-3019-9 · 2.88 Impact Factor
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    ABSTRACT: In very low birth weight infants (VLBWI), intestinal obstruction (IO) tends to increase in severity due to the immaturity of the intestine and perinatal events. We examined the clinical comorbid factors related to IO in VLBWI. Clinical data of 160 VLBWI admitted to our neonatal intensive care unit from 2006-2011 were retrospectively reviewed. Patients were divided into 2 groups: IO group (n=62) and Non-IO group (n=98). IO was defined as bile excretion via the mouth or nasogastric tube within 30 days after birth. The relation between clinical factors and the incidence of IO was analyzed. The univariate analysis showed that gestational age, birth weight, and the incidence of chronic lung disease, patent ductus arteriosus, intraventricular hemorrhage (IVH), retinopathy of prematurity, and the postnatal use of mechanical ventilation, catecholamines, steroids, and sedatives were associated with IO. The multivariate analysis showed that only IVH strongly associated with IO (odds ratio 4.74; p<0.01). IVH is a significant comorbid factor of IO in VLBWI. This article is protected by copyright. All rights reserved.
    Pediatrics International 12/2014; DOI:10.1111/ped.12548 · 0.73 Impact Factor
  • Pediatric Nephrology 12/2014; 29(12):2443-2443. · 2.88 Impact Factor

Publication Stats

2k Citations
747.20 Total Impact Points

Institutions

  • 2001–2015
    • Kobe University
      • Division of Pediatrics
      Kōbe, Hyōgo, Japan
  • 2012
    • Aichi Children's Health and Medical Center
      Nagoya, Aichi, Japan
  • 2005–2011
    • Wakayama Medical University
      • Department of Pediatrics
      Wakayama, Wakayama, Japan
  • 2002–2011
    • National Center for Child Health and Development
      Edo, Tōkyō, Japan
  • 2003–2008
    • Tokyo Metropolitan Children's Medical Center
      Edo, Tōkyō, Japan
  • 2000
    • Osaka Rosai Hospital
      Ōsaka, Ōsaka, Japan
  • 1999
    • University of Shizuoka
      • Department of Biochemistry
      Sizuoka, Shizuoka, Japan