Faculty Profiles - TAKASHIMA Hiroshi

Aya Nakamura, Ryo Tanaka, Kazushige Morishita, Hideki Yoshida, Yujiro Higuchi, Hiroshi Takashima, Masamitsu Yamaguchi . Neuron-specific knockdown of the Drosophila fat induces reduction of life span, deficient locomotive ability, shortening of motoneuron terminal branches and defects in axonal targeting . GENES TO CELLS22 ( 7 ) 662 - 669 2017.7Reviewed International journal

Language：English Publisher：WILEY

Mutations in FAT4 gene, one of the human FAT family genes, have been identified in Van Maldergem syndrome (VMS) and Hennekam lymphangiectasia-lymphedema syndrome (HS). The FAT4 gene encodes a large protein with extracellular cadherin repeats, EGF-like domains and Laminin G-like domains. FAT4 plays a role in tumor suppression and planar cell polarity. Drosophila contains a human FAT4 homologue, fat. Drosophila fat has been mainly studied with Drosophila eye and wing systems. Here, we specially knocked down Drosophila fat in nerve system. Neuron-specific knockdown of fat shortened the life span and induced the defect in locomotive abilities of adult flies. In consistent with these phenotypes, defects in synapse structure at neuromuscular junction were observed in neuron-specific fat-knockdown flies. In addition, aberrations in axonal targeting of photoreceptor neuron in third-instar larvae were also observed, suggesting that fat involves in axonal targeting. Taken together, the results indicate that Drosophila fat plays an essential role in formation and/or maintenance of neuron. Both VMS and HS show mental retardation and neuronal defects. We therefore consider that these two rare human diseases could possibly be caused by the defect in FAT4 function in neuronal cells.

DOI： 10.1111/gtc.12500

田畑健太郎, 佐野輝, 石塚貴周, 斉之平一隆, 横塚紗永子, 新井薫, 塩川奈理, 春日井基文, 中村雅之, 荒田仁, 高嶋博, 吉水宗裕 . ドパミン調節異常症候群が考えられ、修正型電気けいれん療法が著効した若年性パーキンソン病の一例 . 精神神経学雑誌 ( 2017特別号 ) S635 - S635 2017.6Reviewed

Satoshi Nozuma, Eiji Matsuura, Daisuke Kodama, Yuichi Tashiro, Toshio Matsuzaki, Ryuji Kubota, Shuji Izumo, Hiroshi Takashima . Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis . RETROVIROLOGY14 ( 1 ) 26 2017.4Reviewed International journal

Language：English Publisher：BIOMED CENTRAL LTD

Background: Although human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.
Results: The subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5 alpha in HAM/TSP patients. The patients with TRIM5 alpha 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/10(4) PBMC, p = 0.003). The patients with the 304L variant of TRIM5 alpha had significantly higher PVLs than those with 304H (1669 vs. 595 copies/10(4) PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.
Conclusions: Transcontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5 alpha polymorphisms were associated with PVLs, indicating that TRIM5 alpha could be implicated in HTLV-1 replication.

DOI： 10.1186/s12977-017-0350-9

Matsuura E, Enose-Akahata Y, Yao K, Oh U, Tanaka Y, Takashima H, Jacobson S. . Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease. . Journal of Neuroimmunology304 43 - 50 2017.3Reviewed

Eiji Matsuura, Yoshimi Enose-Akahata, Karen Yao, Unsong Oh, Yuetsu Tanaka, Hiroshi Takashima, Steven Jacobson . Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease . JOURNAL OF NEUROIMMUNOLOGY304 43 - 50 2017.3Reviewed International journal

Language：English Publisher：ELSEVIER SCIENCE BV

Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/rsp) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFe), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to -cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell -cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18 h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. Published by Elsevier B.V.

DOI： 10.1016/j.jneuroim.2016.09.014

Yu Hiramatsu, Michiyoshi Yoshimura, Ryuji Saigo, Hitoshi Arata, Yuji Okamoto, Eiji Matsuura, Haruhiko Maruyama, Hiroshi Takashima . Toxocara canis myelitis involving the lumbosacral region: a case report . JOURNAL OF SPINAL CORD MEDICINE40 ( 2 ) 241 - 245 2017.3Reviewed International journal

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Context: Toxocara canis is a parasite known to cause visceral larva migrans. The infection rarely affects the central nervous system but there have been several reports of myelitis caused by visceral larva migrans due to Toxocara canis. In previous reported cases, the lesions were located in the thoracic or cervical spinal cord. To the best of our knowledge, this is the first report of a lesion involving the lumbosacral region.
Findings: A 60-year-old man developed weakness and dysesthesia in the lower limbs. The symptoms resolved spontaneously, but recurred after five months. One month later, the patient developed pollakiuria and constipation. He was a dog owner and frequently ate raw chicken meat and beef liver. Sagittal T2-weighted image (T2WI) showed swelling and hyperintensity in the spinal cord from T10 to the lumbosacral region and focal nodular enhancement on the posterior segment of the lumbar spinal cord. Blood cell counts showed slight eosinophilia and elevated serum immunoglobulin E level. Cerebrospinal fluid examination showed slight pleocytosis with eosinophilia. Enzyme-linked immunosorbent assay showed high levels of anti-Toxocara antibodies in the serum and cerebrospinal fluid. In addition, confirmatory test by Western blot was positive. The patient was initially treated with intravenous methylprednisolone with slight improvement in muscle weakness. Albendazole was added with a second course of intravenous methylprednisolone. The muscle weakness in the lower limbs improved considerably, and swelling and hyperintensity on T2WI almost disappeared.
Conclusion: Our results suggest that Toxocara canis myelitis cannot be discounted even if the myelitis involves the lumbosacral region.

DOI： 10.1080/10790268.2015.1114230

Yoshimura A, Yuan JH, Hashiguchi A, Hiramatsu Y, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Matsumura K, Hamano T, Sawaura N, Shimatani Y, Kumada S, Okumura Y, Miyahara J, Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J, Ishiura H, Tsuji S, Takashima H. . Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. . Clinical Genetics 2017.2Reviewed

Yuan JH, Hashiguchi A, Yoshimura A, Yaguchi H, Tsuzaki K, Ikeda A, Wada-Isoe K, Ando M, Nakamura T, Higuchi Y, Hiramatsu Y, Okamoto Y, Takashima H. . Clinical diversity caused by novel IGHMBP2 variants. . Journal of Human Genetics 2017.2Reviewed

Emi Motokura, Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Akihiro Hashiguchi, Hiroshi Takashima, Koji Abe . An AOA2 patient with a novel compound heterozygous SETX frame shift mutations . JOURNAL OF THE NEUROLOGICAL SCIENCES372 294 - 296 2017.1Reviewed

Arata Hitoshi, Takashima Hiroshi . I. Neurological Findings to Identify Autoimmune Encephalopathy . Nihon Naika Gakkai Zasshi106 ( 8 ) 1542 - 1549 2017

Yamamoto Yuki, Matsui Naoko, Hiramatsu Yu, Miyazaki Yoshimichi, Nodera Hiroyuki, Izumi Yuishin, Takashima Hiroshi, Kaji Ryuji . Mitochondrial trifunctional protein deficiency: an adult patient with similar progress to Charcot-Marie-Tooth disease . Rinsho Shinkeigaku57 ( 2 ) 82 - 87 2017Reviewed

Language：Japanese Publisher：Societas Neurologica Japonica

A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in HADHB. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by HADHA or HADHB mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.

DOI： 10.5692/clinicalneurol.cn-000976

CiNii Research

Fujisawa Miwako, Sano Yasuteru, Omoto Masatoshi, Ogasawara Jyun-ichi, Koga Michiaki, Takashima Hiroshi, Kanda Takashi . Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy . Rinsho Shinkeigaku57 ( 9 ) 515 - 520 2017Reviewed

Language：Japanese Publisher：Societas Neurologica Japonica

We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.

DOI： 10.5692/clinicalneurol.cn-001036

CiNii Research

Taniguchi Takaki, Hokezu Youichi, Okada Takashi, Ishibashi Masato, Hashiguchi Akihiro, Matsuura Eiji, Takashima Hiroshi . A amyotrophic lateral sclerosis (ALS) 4 family misdiagnosed as hereditary spastic paraplegia―a case report― . Rinsho Shinkeigaku57 ( 11 ) 685 - 690 2017Reviewed

Authorship：Last author Publisher：Societas Neurologica Japonica

We report a 44 years old man with slowly progressive muscular atrophy of the extremities for over 30 years. He experienced difficulty in walking in his 10's and was diagnosed as hereditary spastic paraplegia (HSP) in his 20's. And then, muscle atrophy of the extremities slowly progressed especially in his distal muscles. Sensory axonal neuropathy was detected with sural nerve biopsy. His father and uncle have been diagnosed as HSP in their early days. His father noticed weakness of his leg in his 20's. He lost motor function of the leg in his 60's. In addition, marked disturbance of thermal sensation, vibration, and sense of position were found by physical examination. Our genetic study detected senataxin (SETX) gene mutation (c.8C>T,p.T3I) in the blood of those two patients, and they had been identified as family cases of amyotrophic lateral sclerosis (ALS) 4. As clinical symptoms of ALS4 would be similar to those of HSP at the onset, we suggest considering ALS4 in seeing patients with HSP without gene diagnosis.

DOI： 10.5692/clinicalneurol.cn-000996