Jun Tohyama

Publications (29)120.2 Total impact

• Article: Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy.

  Hirofumi Kodera, Mitsuhiro Kato, Alex S Nord, Tom Walsh, Ming Lee, Gaku Yamanaka, Jun Tohyama, Kazuyuki Nakamura, Eiji Nakagawa, Tae Ikeda, [......], Sayaka Ohta, Yutaka Nonoda, Kiyomi Nishiyama, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Kiyoshi Hayasaka, Mary-Claire King, Naomichi Matsumoto, Hirotomo Saitsu
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  ABSTRACT: PURPOSE: Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously. METHODS: We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. KEY FINDINGS: We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients. SIGNIFICANCE: Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing.
  Epilepsia 05/2013; · 3.96 Impact Factor
• Article: Early-onset absence epilepsy at eight months of age.

  Yu Kobayashi, Noriyuki Akasaka, Tsukasa Ohashi, Shinji Saitoh, Yuko Tomonoh, Shinichi Hirose, Jun Tohyama
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  ABSTRACT: Early-onset absence epilepsy refers to patients with absence seizures beginning before age four and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a girl with intractable absence seizures with onset at age eight months. Her seizures were characterised by loss of responsiveness, with eyes drifting upwards and some myoclonic jerks of the upper and lower limbs. These symptoms were accompanied by bilaterally symmetric high-amplitude 2-2.5 Hz generalised spike-and-wave discharges on the electroencephalogram. Her seizures were refractory to conventional antiepileptic drugs; treatment with adrenocorticotropic hormone was transiently effective. Comprehensive metabolic screening, cytogenetic, and genetic analysis did not determine an underlying cause of her condition. Patients with intractable, very early-onset absence epilepsy with a myoclonic component have an unfavourable outcome and may be classified under a new epileptic syndrome, such as "early infantile absence epilepsy".
  Epileptic disorders: international epilepsy journal with videotape 12/2011; 13(4):417-21. · 1.50 Impact Factor
• Article: Acute encephalopathy in children with Dravet syndrome.

  Akihisa Okumura, Mitsugu Uematsu, George Imataka, Manabu Tanaka, Tohru Okanishi, Tetsuo Kubota, Akira Sudo, Jun Tohyama, Megumi Tsuji, Iori Ohmori, Misako Naiki, Ayako Hiraiwa-Sofue, Hitoshi Sato, Shinji Saitoh, Toshiaki Shimizu
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  ABSTRACT: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome. Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms. There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8-184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion-weighted images during the acute phase: cerebral cortex-dominant lesions with or without deep gray matter involvement and subcortical-dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae. We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.
  Epilepsia 11/2011; 53(1):79-86. · 3.96 Impact Factor
• Article: Congenital variant of Rett syndrome due to an intragenic large deletion in MECP2.

  Yu Kobayashi, Tsukasa Ohashi, Noriyuki Akasaka, Jun Tohyama
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  ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6 months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.
  Brain & development 10/2011; 34(7):601-4. · 1.74 Impact Factor
• Article: West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14.

  Jun Tohyama, Toshiyuki Yamamoto, Kana Hosoki, Keisuke Nagasaki, Noriyuki Akasaka, Tsukasa Ohashi, Yu Kobayashi, Shinji Saitoh
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  ABSTRACT: FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.
  American Journal of Medical Genetics Part A 09/2011; 155A(10):2584-8. · 2.39 Impact Factor
• Article: Acquired opercular epilepsy with oromotor dysfunction: magnetoencephalographic analysis and efficacy of corticosteroid therapy.

  Jun Tohyama, Noriyuki Akasaka, Tsukasa Ohashi, Yu Kobayashi
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  ABSTRACT: The authors describe herein the magnetoencephalographic findings and long-term outcome of a girl with acquired opercular epilepsy with oromotor dysfunction. She presented with brief episodes of unconsciousness, tremulous movements of the upper limbs, and negative myoclonus, in addition to convulsive seizures. She also had prolonged episodes of dysarthria and oral motor dysfunction, a gradual decrease in speech output, impairment of finger movements, and deterioration in cognitive performance over several years. Her electroencephalography (EEG) recordings showed notable continuous sharp or sharp-slow discharges during sleep. Brain magnetic resonance images revealed no structural anomalies. Magnetoencephalographic analysis showed broadly distributed epileptic foci around the sylvian fissure, including a secondary source, explaining the specific prolonged neurological dysfunction. Antiepileptic drugs could control her seizures; however, they did not improve the other neurological symptoms or epileptiform discharge on EEG. Administration of low-dose prednisolone over a long period was effective for improving the neurological impairments of this patient.
  Journal of child neurology 02/2011; 26(7):885-90. · 1.59 Impact Factor
• Article: Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient.

  Jun Tohyama, Mitsuhiro Kato, Sari Kawasaki, Naoki Harada, Hiroki Kawara, Takeshi Matsui, Noriyuki Akasaka, Tsukasa Ohashi, Yu Kobayashi, Naomichi Matsumoto
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  ABSTRACT: We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.
  American Journal of Medical Genetics Part A 01/2011; 155A(1):130-3. · 2.39 Impact Factor
• Article: Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.

  Hirotomo Saitsu, Jun Tohyama, Tatsuro Kumada, Kiyoshi Egawa, Keisuke Hamada, Ippei Okada, Takeshi Mizuguchi, Hitoshi Osaka, Rie Miyata, Tomonori Furukawa, [......], Kiyomi Nishiyama, Akira Nishimura, Noriko Miyake, Masayuki Komada, Kenji Hayashi, Syu-Ichi Hirai, Kazuhiro Ogata, Mitsuhiro Kato, Atsuo Fukuda, Naomichi Matsumoto
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  ABSTRACT: A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
  The American Journal of Human Genetics 06/2010; 86(6):881-91. · 10.60 Impact Factor
• Article: TULIP1 (RALGAPA1) haploinsufficiency with brain development delay.

  Keiko Shimojima, Yuta Komoike, Jun Tohyama, Sonoko Takahashi, Marco T Páez, Eiji Nakagawa, Yuichi Goto, Kousaku Ohno, Mayu Ohtsu, Hirokazu Oguni, Makiko Osawa, Toru Higashinakagawa, Toshiyuki Yamamoto
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  ABSTRACT: A novel microdeletion of 14q13.1q13.3 was identified in a patient with developmental delay and intractable epilepsy. The 2.2-Mb deletion included 15 genes, of which TULIP1 (approved gene symbol: RALGAPA1)was the only gene highly expressed in the brain. Western blotting revealed reduced amount of TULIP1 in cell lysates derived from immortalized lymphocytes of the patient, suggesting the association between TULIP1 haploinsufficiency and the patient's phenotype, then 140 patients were screened for TULIP1 mutations and four missense mutations were identified. Although all four missense mutations were common with parents, reduced TULIP1 was observed in the cell lysates with a P297T mutation identified in a conserved region among species. A full-length homolog of human TULIP1 was identified in zebrafish with 72% identity to human. Tulip1 was highly expressed in zebrafish brain, and knockdown of which resulted in brain developmental delay. Therefore, we suggest that TULIP1 is a candidate gene for developmental delay.
  Genomics 10/2009; 94(6):414-22. · 3.02 Impact Factor
• Article: Maternal uniparental disomy 14 syndrome demonstrates prader-willi syndrome-like phenotype.

  Kana Hosoki, Masayo Kagami, Touju Tanaka, Masaya Kubota, Kenji Kurosawa, Mitsuhiro Kato, Kimiaki Uetake, Jun Tohyama, Tsutomu Ogata, Shinji Saitoh
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  ABSTRACT: To delineate the significance of maternal uniparental disomy 14 (upd(14)mat) and related disorders in patients with a Prader-Willi syndrome (PWS)-like phenotype. We examined 78 patients with PWS-like phenotype who lacked molecular defects for PWS. The MEG3 methylation test followed by microsatellite polymorphism analysis of chromosome 14 was performed to detect upd(14)mat or other related abnormalities affecting the 14q32.2-imprinted region. We identified 4 patients with upd(14)mat and 1 patient with an epimutation in the 14q32.2 imprinted region. Of the 4 patients with upd(14)mat, 3 had full upd(14)mat and 1 was mosaic. Upd(14)mat and epimutation of 14q32.2 represent clinically discernible phenotypes and should be designated "upd(14)mat syndrome." This syndrome demonstrates a PWS-like phenotype particularly during infancy. The MEG3 methylation test can detect upd(14)mat syndrome defects and should therefore be performed for all undiagnosed infants with hypotonia.
  The Journal of pediatrics 09/2009; 155(6):900-903.e1. · 4.02 Impact Factor
• Article: Stiripentol open study in Japanese patients with Dravet syndrome.

  Yushi Inoue, Yoko Ohtsuka, Hirokazu Oguni, Jun Tohyama, Hiroshi Baba, Katsuyuki Fukushima, Hideyuki Ohtani, Yukitoshi Takahashi, Shunya Ikeda
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  ABSTRACT: To survey the treatment situation of Dravet syndrome in Japan and to compare this result with effectiveness of stiripentol (STP) add-on therapy in an open-label multicenter study. Medical records of patients with Dravet syndrome who visited the study institutions during 2006 were surveyed to examine the effect of antiepileptic drugs (AEDs) on clonic or tonic-clonic seizures (GTCS). Patients older than 1 year of age treated with at least one conventional AED and more than four GTCS per month were invited to participate in the STP study. Seizure status and adverse effects during the first 4 weeks of STP (50 or 1,000 mg/day) add-on therapy (early period) and during long-term treatment were compared with baseline. Only 15% of the treatment trials with 15 conventional AEDs in 112 patients succeeded in reducing seizures by more than 50%. With STP, GTCS were reduced more than 50% in 14 of 23 patients (61%), including 2 who became seizure-free, in the early period. Moreover, duration of seizures was shortened in 10 patients and status epilepticus decreased in 6. These effects continued in the long-term although to a lesser degree. Adverse effects (loss of appetite, sleep disturbance, ataxia, hyperactivity/irritability) disappeared after dose modification in most cases. STP was effective at a lower than initial dose in five patients. Some patients benefited from STP added on clobazam despite mutation in CYP2C19. Our data suggest that an early introduction of STP into Japan will result in substantial patient benefit.
  Epilepsia 07/2009; 50(11):2362-8. · 3.96 Impact Factor
• Article: Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications.

  Keiko Shimojima, Takehiko Inoue, Ai Hoshino, Satsuki Kakiuchi, Yoshiaki Watanabe, Masayuki Sasaki, Akira Nishimura, Akiko Takeshita-Yanagisawa, Go Tajima, Hiroshi Ozawa, Masaya Kubota, Jun Tohyama, Akira Oka, Kayoko Saito, Makiko Osawa, Toshiyuki Yamamoto
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  ABSTRACT: Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10-25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.
  Brain & development 04/2009; 32(3):171-9. · 1.74 Impact Factor
• Article: CSF neurofilament and soluble TNF receptor 1 levels in subacute sclerosing panencephalitis.

  Takeshi Matsushige, Takashi Ichiyama, Banu Anlar, Jun Tohyama, Keiko Nomura, Yushiro Yamashita, Susumu Furukawa
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  ABSTRACT: Neurofilament (NF) is one of the major cytoskeleton proteins of neurons and sTNFR1 is thought to reflect the true biological activity of TNF-alpha. To evaluate the levels of the heavy subunit of neurofilament (NF-H) and soluble TNF receptor 1 (sTNFR1) in cerebrospinal fluid (CSF) as biomarkers of clinical severity of subacute sclerosing panencephalitis (SSPE), concentrations of NF-H and sTNFR1 in CSF of 34 patients with SSPE and in control subjects were measured by ELISA. The CSF NF-H levels were significantly higher in patients with SSPE than in controls (p<0.0001), and those in patients in Jabbour stage III were significantly higher than in patients in stage II (p=0.015). The CSF sTNFR1 levels in SSPE patients were significantly higher than those in controls (p=0.004), but there were no significant differences in CSF sTNFR1 levels between patients in Jabbour stages II and III. There was a significant correlation between CSF NF-H and sTNFR1 levels in patients with SSPE (p=0.011). We suggest that CSF NF-H levels can be used as a marker of development of neuronal degeneration in SSPE, and that TNF-alpha modifies the neurodestructive pathogenesis in SSPE.
  Journal of Neuroimmunology 10/2008; 205(1-2):155-9. · 2.96 Impact Factor
• Article: De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.

  Hirotomo Saitsu, Mitsuhiro Kato, Takeshi Mizuguchi, Keisuke Hamada, Hitoshi Osaka, Jun Tohyama, Katsuhisa Uruno, Satoko Kumada, Kiyomi Nishiyama, Akira Nishimura, Ippei Okada, Yukiko Yoshimura, Syu-ichi Hirai, Tatsuro Kumada, Kiyoshi Hayasaka, Atsuo Fukuda, Kazuhiro Ogata, Naomichi Matsumoto
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  ABSTRACT: Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.
  Nature Genetics 07/2008; 40(6):782-8. · 35.53 Impact Factor
• Article: Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter.

  Jun Tohyama, Noriyuki Akasaka, Hitoshi Osaka, Yoshihiro Maegaki, Mitsuhiro Kato, Naka Saito, Sumimasa Yamashita, Kousaku Ohno
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  ABSTRACT: Numerous numbers of pre-, peri- and postnatal damages cause West syndrome in early infancy, however, etiology in many cases are not still elucidated despite intensive biochemical and neuroradiologic investigations. We described four patients having early onset epileptic encephalopathy with severe hypomyelination and reduction in cerebral white matter. The clinical symptoms of these patients are impaired visual attention, acquired microcephaly, spastic tetraplegia, profound psychomotor delay and infantile spasms since early infancy. All patients had striking hypomyelination of cerebrum, reduced volume of white matter and cortical atrophy on MRI. Serial MRI investigations in three patients showed absence of myelination of the white matter. On EEG, one patient revealed suppression-burst and other three had hypsarrhythmia. Despite having intractable seizures, no patient showed deterioration of neurological development. The group of these findings is mimicking to clinical manifestations of 3-phosphoglycerate dehydrogenase deficiency, and has some overlap with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) like syndrome, however it is not compatible with these two conditions. The findings observed in our patients can be regarded as a new clinical condition associated with early onset West syndrome.
  Brain and Development 06/2008; 30(5):349-55. · 2.12 Impact Factor
• Article: Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures.

  Naoko Suenaga, Takashi Ichiyama, Masaya Kubota, Hiroshi Isumi, Jun Tohyama, Susumu Furukawa
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  ABSTRACT: Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.
  Journal of the Neurological Sciences 04/2008; 266(1-2):126-30. · 2.35 Impact Factor
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  Available from: niigata-u.ac.jp

  Article: Brain maturation-related spike localization in Panayiotopoulos syndrome: magnetoencephalographic study.

  Naka Saito, Osamu Kanazawa, Jun Tohyama, Noriyuki Akasaka, Takanori Kamimura, Shin-ichi Toyabe, Makoto Uchiyama
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  ABSTRACT: Focal spike activities in Panayiotopoulos syndrome involve all brain regions in electroencephalography, and commonly reveal multiple foci, often through occipital predominance. To investigate correlations between developmental brain maturation and spike origin in Panayiotopoulos syndrome, we evaluated age-related or duration-related magnetoencephalographic spike localization in 25 patients with Panayiotopoulos syndrome. Regarding age at examination, patients with frontal spikes were significantly older than patients with spikes on rolandic, parieto-occipital, or calcarine sulci. Occipital spikes were classified into two subgroups, located at the calcarine sulcus and parieto-occipital sulcus. Both calcarine and parieto-occipital localizations were seen in patients around the same age. Follow-up magnetoencephalography was performed on three patients, and demonstrated shifting localization or disappearance of magnetoencephalographic spikes. These results suggest that the location of spike discharges is not directly related to seizure symptoms, but instead indicates maturation-related cortical hyperexcitability in patients with Panayiotopoulos syndrome.
  Pediatric Neurology 03/2008; 38(2):104-10. · 1.52 Impact Factor
• Article: Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures.

  Takashi Ichiyama, Naoko Suenaga, Madoka Kajimoto, Jun Tohyama, Hiroshi Isumi, Masaya Kubota, Masato Mori, Susumu Furukawa
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  ABSTRACT: It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects. CSF IL-6 levels in AEPFS were significantly higher than those in PFS, but not serum IL-6, IL-10, or sTNFR1. The CSF IL-6 levels were significantly higher than the serum levels in AEPFS, but not PFS. The serum levels of sTNFR1 and IL-10 were significantly higher than those in the CSF in AEPFS and PFS. The serum IL-10 and sTNFR1 levels in patients who did not experience a second seizure were significantly higher than those in patients who experienced a second seizure, which was characterized by clusters of complex partial seizures several days after the initial prolonged febrile seizure. Our results suggest that serum IL-6, IL-10, TNF-alpha, and CSF IL-6 are part of the regulatory system of cytokines in AEPFS.
  Brain and Development 02/2008; 30(1):47-52. · 2.12 Impact Factor
• Article: Megalencephaly and polymicrogyria with polydactyly syndrome.

  Jun Tohyama, Noriyuki Akasaka, Naka Saito, Junichi Yoshimura, Kenichi Nishiyama, Mitsuhiro Kato
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  ABSTRACT: We report the clinical manifestations of a 26-month-old Japanese girl with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. She was born to healthy, nonconsanguineous parents at 37 weeks by caesarian section after prenatal ultrasonography suggested hydrocephalus. Macrocephaly and polydactyly of both lower extremities were noted at birth. At 3 months of age, epileptic seizures developed. The patient displayed impaired vision and profound global developmental delay. Magnetic resonance imaging of the brain revealed dilatation of the lateral and third ventricles with cavum septi pellucidi et vergae and generalized polymicrogyria, most prominent in both perisylvian regions and the right frontal region. Despite ventriculomegaly, radionuclide cisternography indicated normal cerebrospinal circulation, suggesting that pathogenesis of the megalencephaly was unrelated to obstructive hydrocephalus. Decreased white matter volume and abnormal signal intensity in the occipital lobes were also noted. Visual disturbance due to white matter abnormality appears to represent a significant characteristic of this syndrome. The genetic background of the syndrome remains unclear.
  Pediatric Neurology 09/2007; 37(2):148-51. · 1.52 Impact Factor
• Article: A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).

  Mitsuhiro Kato, Shinji Saitoh, Atsushi Kamei, Hideaki Shiraishi, Yuki Ueda, Manami Akasaka, Jun Tohyama, Noriyuki Akasaka, Kiyoshi Hayasaka
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  ABSTRACT: Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.
  The American Journal of Human Genetics 09/2007; 81(2):361-6. · 10.60 Impact Factor