Faculty Profiles - TAKASHIMA Hiroshi

Papers - TAKASHIMA Hiroshi

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Yoshimoto Yukiyo, Yoshimoto Shoko, Kakiuchi Kensuke, Miyagawa Rumina, Ota Shin, Hosokawa Takafumi, Ishida Shimon, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi, Arawaka Shigeki . 新規GJB1変異を伴うX連鎖性シャルコー・マリー・トゥース病における中枢神経系病変の空間的変動(Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation) . Internal Medicine63 ( 4 ) 571 - 576 2024.2新規GJB1変異を伴うX連鎖性シャルコー・マリー・トゥース病における中枢神経系病変の空間的変動(Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation)

Language：English Publisher：(一社)日本内科学会

症例は25歳男性で、7歳時に初回発作が出現し、頭部MRIのT2強調画像で頭頂葉と後頭葉の両側脳白質および脳梁膨大部に高信号域を認めた。13歳時に2回目の発作が出現し、MRIの拡散強調画像とT2強調画像で脳梁と頭頂葉の白質に高信号域を認めた。現症の発作では、歩行中に感覚障害と構音障害が出現し、地域病院に入院した。翌日に症状が悪化し、右上下肢の軽度筋力低下も認めたため、搬送されてきた。神経学的検査で見当識障害と右片麻痺が判明し、腱反射が完全に消失し、下肢の振動覚が低下していた。凹足も認めた。家族歴の聴取から、症例の弟がシャルコー・マリー・トゥース病(CMT)と診断されており、症例の母親が下垂足を有していることが判明した。DNA解析を行い、新規のギャップ結合β1(GJB1)変異(c.169C>T、p.Gln57*)が特定された。症例の母親と弟も同様の変異を有していたことから、新規GJB1変異を伴うX連鎖性CMT 1型と診断した。2週後の追跡MRIでは、拡散強調画像における白質の高信号域が消失し、脳梁膨大部に高信号域が出現していた。5ヵ月後、膨大部病変は完全に消失した。

Nozuma S., Yoshimura A., Pai S.C., Chen H.J., Matsuura E., Tanaka M., Kodama D., Dozono M., Matsuzaki T., Takashima H., Yang Y.C., Kubota R. . Geographic characteristics of HTLV-1 molecular subgroups and genetic substitutions in East Asia: Insights from complete genome sequencing of HTLV-1 strains isolated in Taiwan and Japan . PLoS Neglected Tropical Diseases18 ( 2 ) e0011928 2024.2

Language：Japanese Publisher：PLoS Neglected Tropical Diseases

Background Although Japan is a major endemic area for human T-lymphotropic virus type 1 (HTLV-1) and the virus has been well-studied in this region, there is limited research on HTLV-1 in sur-rounding regions. In this study, we determined the complete genome sequences of HTLV-1 strains isolated from Taiwan and Japan and investigated the geographic characteristics of molecular subgroups and substitution mutations to understand the spread of HTLV-1 and its correlation with human migration. Methodology/Principal findings The complete genome sequences of 26 HTLV-1 isolates from Taiwan were determined using next-generation sequencing and were compared with those of 211 isolates from Japan in terms of subgroup and genetic mutations. In total, 15/26 (58%) isolates from Taiwan belonged to the transcontinental subgroup and 11/26 (42%) isolates belonged to the Japanese subgroup. The transcontinental subgroup was significantly more prevalent among Taiwanese isolates than Japanese isolates (58% vs 18%, P < 0.0001). The mutation rate for the complete HTLV-1 sequence was as low as 0.2%. On examining individual base substitutions, the G-to-A mutation was predominant. Bayesian phylogenetic tree analysis estimated the time to the most recent common ancestor for the transcontinental and Japanese subgroups to be 28447 years. The transcontinental subgroups from Taiwan and Japan appeared to form clusters according to their respective regions.Conclusions/Significance The transcontinental subgroup of HTLV-1 is predominant in Taiwan, while the Japanese subgroup is common in Japan. The difference in subgroup distribution may be attributed to the initial spread of the transcontinental subgroup in East Asia, followed by the influx of the Japanese subgroup.

DOI： 10.1371/journal.pntd.0011928

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Hamada Y., Matsuoka H., Sato S., Kawabata Y., Iwamoto K., Ikeda M., Sato T., Takaguchi G., Takashima H. . Combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter for M2 occlusions: the ONE-SEG technique . Frontiers in Neurology15 1424030 2024

Language：Japanese Publisher：Frontiers in Neurology

Background: Endovascular therapy (EVT) for distal medium vessel occlusions requires prioritizing effectiveness and safety. We developed a technique combining the deployment of only the distal basket segment of the EMBOTRAP III and an aspiration catheter (AC) for M2 occlusions, called the “ONE-SEG technique,” and evaluated its clinical and technical impacts. Methods: This was a retrospective review of 30 consecutive patients with M2 segment middle cerebral artery occlusion treated using the ONE-SEG technique. This method involves deploying the EMBOTRAP III through a microcatheter in only one segment and guiding the AC to the M2 origin or distal M1. The rates of final-pass expanded thrombolysis in cerebral infarction (eTICI) scores of 2c/3 or 2b/2c/3, safety (symptomatic intracranial hemorrhage [sICH]), and clinical outcomes (modified Rankin Scale [mRS] score 0–2, 0–3 at 90 days, and mortality at 90 days) were evaluated. Results: Of the 30 cases, 36.7% were female, and the mean age was 75.6 ± 11.0 years. The ONE-SEG technique was used for 17 cases (56.7%, median NIHSS 10 [5–15.5]) with primary M2 occlusion and 13 cases (43.3%, median NIHSS 20 [14–22.5]) with secondary M2 occlusion after proximal thrombus removal. The successful final reperfusion rate (eTICI 2b/2c/3) was 90% overall (27/30 cases). One case (3.3%) developed sICH with secondary M2 occlusion. At 3 months, mRS scores 0–2 were seen in 64.7% of patients with primary M2 occlusion (11/17 cases) and in 23.1% (3/13 cases) with secondary M2 occlusion. Conclusion: EVT using the ONE-SEG technique appears to be safe and effective for M2 occlusion.

DOI： 10.3389/fneur.2024.1424030

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Takahiro Hobara, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Fumikazu Kojima, Yutaka Noguchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Tadashi Adachi, Keiko Toyooka, Toru Yamashita, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Hiroshi Takashima . Linking LRP12 CGG repeat expansion to inherited peripheral neuropathy. . Journal of neurology, neurosurgery, and psychiatry96 ( 2 ) 140 - 149 2024Reviewed International journal

Language：Japanese Publishing type：Research paper (scientific journal)

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

DOI： 10.1136/jnnp-2024-333403

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Kakumoto T., Orimo K., Matsukawa T., Mitsui J., Ishihara T., Onodera O., Suzuki Y., Morishita S., Tsuji S., Nagata T., Ozaki K., Ishiguro T., Nishida Y., Ishikawa K., Ogata K., Matsushima M., Yabe I., Kira J., Higashi K., Takashima H., Adachi T., Takigawa H., Watanabe Y., Hanajima R., Sawamoto N., Ishimoto T., Sakato Y., Takahashi R., Yamanaka Y., Sugiyama A., Kuwabara S., Tada M., Hara K., Katsuno M., Takahashi Y., Mizusawa H., Yamashita T., Abe K., Ishiura H., Toda T., Chikada A. . Frequency of FGF14 intronic GAA repeat expansion in patients with multiple system atrophy and undiagnosed ataxia in the Japanese population . European Journal of Human Genetics33 ( 3 ) 325 - 333 2024

Language：Japanese Publisher：European Journal of Human Genetics

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic nervous system dysfunction and cerebellar ataxia or parkinsonism. Recently, expanded GAA repeats (≥250 repeat units) in intron 1 of FGF14 have been shown to be responsible for spinocerebellar ataxia type 27B (SCA27B), a late-onset ataxia with an autosomal dominant inheritance. Patients with SCA27B may also exhibit autonomic nervous system dysfunction, potentially overlapping with the clinical presentations of MSA patients. In this study, to explore the possible involvement of expanded GAA repeats in MSA, we investigated the frequencies of expanded GAA repeats in FGF14 in 548 patients with MSA, 476 patients with undiagnosed ataxia, and 455 healthy individuals. To fully characterize the structures of the expanded GAA repeats, long-range PCR products suggesting the expansion of GAA repeats were further analyzed using a long-read sequencer. Of the 548 Japanese MSA patients, we identified one MSA patient (0.2%) carrying an expanded repeat with (GAA)≥250. Among the 476 individuals with undiagnosed ataxia, (GAA)≥250 was observed in six (1.3%); this frequency was higher than that in healthy individuals (0.2%). The clinical characteristics of the MSA patient with (GAA)≥250 were consistent with those of MSA, but not with SCA27B. Further research is warranted to explore the possibility of the potential association of expanded GAA repeats in FGF14 with MSA.

DOI： 10.1038/s41431-024-01743-3

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Takashima Hiroshi . Brain localization of functional disorders including hysterical symptoms from the perspective of higher brain functions : A new neural anatomy and motor physiological model . Neurological Therapeutics41 ( 4 ) 634 - 641 2024Brain localization of functional disorders including hysterical symptoms from the perspective of higher brain functions : A new neural anatomy and motor physiological model

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

Hysterical symptoms, commonly referred to as functional neurological disorder, encompass various neurological manifestations not explainable by current neurology frameworks, suggesting involvement of psychogenic mechanisms. On the other hand, advances in neurophysiological anatomy have revealed that beyond the traditionally identified primary motor cortex (pyramidal tract), once regarded as the final output pathway, other essential output pathways have been functionally verified, such as the cortico–reticulospinal tract. Currently, motor output from the brain to the spinal cord should be considered through dual pathways. In this review, we elucidate hysterical symptoms through the prospective of a new functional brain anatomy paradigm that integrates motor output with dual pathways. Most hysterical motor symptoms can be attributed to disorders affecting the premotor cortex and supplementary motor area–reticulospinal tract. Since this cortico–reticular spinal tract is bilaterally innervated, symptoms arise from bilateral brain lesions. Bilateral abnormalities within this pathway are frequently identified through techniques such as 123I–IMP–SPECT or diffusion tensor imaging. In addition, the function of the reticular formation is considered to correlate with symptoms observed in PNES (psychogenic non–epileptic seizure), including impaired consciousness, tonic seizures of internal muscles, abnormalities in blood pressure and breathing, hypersensitivity to sound and light, as well as hyperalgesia. The origin of hysterical symptoms is primarily attributed to disorders involving the reticular formation and cortico–reticulospinal tract, caused by bilateral diffuse brain damage. Most hysterical symptoms could be explained through adept application of the new neurophysiological model, which delineates motor output into dual pathways. To comprehend complex brain symptoms, neurologists require an update of functional neurophysiological models.

DOI： 10.15082/jsnt.41.4_634

Nakahashi Takumi, Matsuura Ryuki, Kikuchi Kenjiro, Takeda Rikako, Takeuchi Hirokazu, Nonoyama Hazuki, Hirata Yuko, Koichihara Reiko, Hashiguchi Akihiro, Takashima Hiroshi, Hamano Shin-ichiro . A case of childhood Charcot-Marie-Tooth disease type 2A with nerve root enlargement in longitudinal evaluation of spinal MR neurography . NO TO HATTATSU56 ( 6 ) 427 - 431 2024

Language：Japanese Publisher：The Japanese Society of Child Neurology

A 7-years-old girl was admitted with the principal complaint of abnormal gait. She presented with distal muscle weakness, bilateral Achilles tendon reflex depression, and peripheral sensory disturbance. The results of the spinal cord magnetic resonance (MR) neurography were normal ; however, she had median nerve conduction disorders. As a genetic analysis revealed a mitofusin 2 mutation (c.718T＞G, p.F240V), she was diagnosed with Charcot-Marie-Tooth (CMT) type 2A. Despite continued physical therapy, her symptoms progressed slowly. At the age of 10 years and 4 months, she was unable to walk without support, and spinal MR neurography demonstrated bilateral nerve root enlargement in L2-5 regions. In children with CMT type 2A, the morphology of the spinal cord nerve root is not abnormal in the early stages, but nerve root enlargement may be observed as symptoms progress. Spinal MR neurography may be useful in evaluating disease activity.

DOI： 10.11251/ojjscn.56.427

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HAMADA Yuki, MIYASHITA Fumio, MATSUOKA Hideki, NISHINAKAMA Yuki, KAI Yusuke, YAMASHITA Yusuke, IKEDA Mei, TAKAGUCHI Go, MASUDA Keisuke, KUBO Fumikatsu, TAKASHIMA Hiroshi . Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches . NMC Case Report Journal10 ( 0 ) 273 - 278 2023.12

Language：English Publisher：The Japan Neurosurgical Society

Herein, we report a case of carotid artery stenting with proximal flow protection for severe stenosis of the left internal carotid artery using transbrachial and transradial artery approaches. Because an abdominal aortic aneurysm was present, we avoided the transfemoral approach. The procedure was successfully performed with a combination of an 8-Fr balloon guide catheter and microballoon catheter on separate axes. No complications such as pseudoaneurysm, thrombosis, or dissection were observed at the puncture site. The patient was discharged without complications and showed good outcomes at 3 months. This technique may offer a useful alternative for patients with severe stenosis who cannot be treated using a femoral artery approach.

DOI： 10.2176/jns-nmc.2023-0071

PubMed

Matsuura E., Nozuma S., Shigehisa A., Dozono M., Nakamura T., Tanaka M., Kubota R., Hashiguchi A., Takashima H. . HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report . BMC Musculoskeletal Disorders24 ( 1 ) 355 2023.12

Language：Japanese Publisher：BMC Musculoskeletal Disorders

Background: Sporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date. Case presentation: A 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment. Conclusion: This is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

DOI： 10.1186/s12891-023-06461-3

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Hamada Yuki, Miyashita Fumio, Matsuoka Hideki, Nishinakama Yuki, Kai Yusuke, Yamashita Yusuke, Ikeda Mei, Takaguchi Go, Masuda Keisuke, Kubo Fumikatsu, Takashima Hiroshi . 経上腕動脈および経橈骨動脈アプローチを併用した頸動脈ステント留置術における代替的近位保護法(Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches) . NMC Case Report Journal10 ( 1 ) 273 - 278 2023.12経上腕動脈および経橈骨動脈アプローチを併用した頸動脈ステント留置術における代替的近位保護法(Alternative Proximal Protection Method during Carotid Artery Stenting Using Combined Transbrachial and Transradial Artery Approaches)

Language：English Publisher：(一社)日本脳神経外科学会

症例は67歳男性。頸動脈超音波検査で左内頸動脈の高度狭窄が偶然発見され、当院を受診した。高血圧、脂質異常症、腹部大動脈、慢性閉塞性肺疾患の既往があった。経上腕動脈および経橈骨動脈アプローチを用いて、左内頸動脈の高度狭窄に対する近位フローを伴う頸動脈ステント留置術を施行した。術後合併症は認められず、超音波検査でもプラークの突出はみられなかった。頸動脈ステント留置術施行5日後のCT血管造影で、上腕動脈および橈骨動脈に異常はみられなかった。最終的にmodified Rankin scale(mRS)スコア0点で退院した。退院後3ヵ月もmRSは依然として0のままであった。

Arimura Yoshihiro, Sobue Gen, Hattori Naoki, Takashima Hiroshi, Harigai Masayoshi, Nagata Koichi, Makino Hirofumi . 慢性末梢神経障害が残存する顕微鏡的多発血管炎に対する免疫グロブリン静注療法　多施設無作為化二重盲検試験(Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial) . Modern Rheumatology33 ( 6 ) 1125 - 1136 2023.11慢性末梢神経障害が残存する顕微鏡的多発血管炎に対する免疫グロブリン静注療法　多施設無作為化二重盲検試験(Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial)

Language：English Publisher：Oxford University Press

顕微鏡的多発血管炎に伴うグルココルチコイド抵抗性神経障害を有する患者に対する免疫グロブリン静注療法(IVIg)の有効性と安全性を評価する目的で、第III相多施設無作為化二重盲検プラセボ対照並行群間比較試験を実施した。37例をIVIg群(19例)またはプラセボ群(18例)に割り付け、第1週および第5週にIVIgまたはプラセボ投与を5日間行い、第9週はIVIg群にプラセボ投与、プラセボ群にIVIgを行った。有効性解析対象は36例(それぞれ19例、17例)であった。8週後(第9週の治療開始前)における徒手筋力テストの合計スコア変化量(最小二乗平均値)は、IVIg群で9.02、プラセボ群で6.71(群間差2.32、95%CI -2.60～7.23、p=0.345)、4週後(第5週の治療開始前)ではそれぞれ6.81、2.83(同3.99、-1.22～9.19、p=0.129)であり、IVIgにより合計スコアは改善したものの両群間に有意差は認めなかった。IVIg群において安全性に関する新たな懸念は認めなかった。

Nozuma Satoshi, Yuji-Takeuchi Mika, Nakamura Tomonori, Saigo Ryuji, Masuda Mirai, Ando Masahiro, Sakiyama Yusuke, Miyata Ryo, Tabata Kazuhiro, Matsuura Eiji, Takashima Hiroshi . 外科的介入前の免疫療法により改善した重症腫瘍随伴性グルタミン酸脱炭酸酵素抗体スペクトラム障害の1例(A case of severe paraneoplastic glutamic acid decarboxylase antibody-spectrum disorder with improvement through prior immunotherapy before surgical intervention) . Clinical and Experimental Neuroimmunology14 ( 4 ) 202 - 206 2023.11外科的介入前の免疫療法により改善した重症腫瘍随伴性グルタミン酸脱炭酸酵素抗体スペクトラム障害の1例(A case of severe paraneoplastic glutamic acid decarboxylase antibody-spectrum disorder with improvement through prior immunotherapy before surgical intervention)

Language：English Publisher：(一社)日本神経免疫学会

症例は65歳女性で、高血圧の既往があった。めまいとふらつき歩行を初発症状として呈していた。嚥下障害や歩行障害が悪化したため、発症12ヵ月後に入院となった。各種検査の結果、小脳失調とスティッフパーソン症候群を重複するGAD抗体-スペクトル障害と診断された。外科的介入は不可能と判断され、免疫療法が開始された。メチルプレドニゾロン静注および免疫グロブリン静注を含む免疫療法が実施され、神経症状は著しく改善した。しかし、経口プレドニゾロン(PSL)漸減により構音障害および歩行失調の悪化が認められた。発症27ヵ月後に胸腔鏡下胸腺摘出術が施行された。神経学的症状はさらに改善し、PSL漸減に成功した。

Makito Hirano, Motoi Kuwahara, Yuko Yamagishi, Makoto Samukawa, Kanako Fujii, Shoko Yamashita, Masahiro Ando, Nobuyuki Oka, Mamoru Nagano, Taro Matsui, Toshihide Takeuchi, Kazumasa Saigoh, Susumu Kusunoki, Hiroshi Takashima, Yoshitaka Nagai . CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy. . Scientific reports13 ( 1 ) 17801 - 17801 2023.10International journal

Language：English Publishing type：Research paper (scientific journal)

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

DOI： 10.1038/s41598-023-45011-8

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Nozaki Ichiro, Hashiguchi Akihiro, Takashima Hiroshi, Yamashita Yoko, Higashide Tomomi, Iwasa Kazuo, Ono Kenjiro . 視野欠損を認めたギャップジャンクションタンパクβ1の新規バリアントを伴うCharcot-Marie-Tooth病(Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects) . Internal Medicine62 ( 20 ) 3033 - 3036 2023.10視野欠損を認めたギャップジャンクションタンパクβ1の新規バリアントを伴うCharcot-Marie-Tooth病(Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects)

Language：English Publisher：(一社)日本内科学会

症例は45歳男性。12歳時に両側下肢遠位筋の筋力低下を認め、18歳時に握力低下を自覚した。症例の母親も手に軽度の筋力低下と萎縮を有していたことから、臨床所見と電気生理学的検査の所見をあわせ、遺伝性運動感覚多発神経障害と診断された。その後、症状が緩徐に悪化し、38歳時に健康診断で視神経乳頭陥凹の両側対称性縦拡大および網膜神経線維束欠損と診断された。両眼の視力は正常であったが、視野検査で視神経乳頭異常に一致する部分的視野欠損が明らかとなった。43歳時、両足関節不安定のために支えなしでの立位維持が困難となった。45歳時、神経学的検査で四肢の遠位筋萎縮、腱反射消失、振動覚低下が判明した。18歳時にCharcot-Marie-Tooth(CMT)病1型と診断されていたが、原因遺伝子が特定されていなかった。45歳時、64のCMT関連原因遺伝子における病的バリアントのスクリーニングを行い、ギャップジャンクションタンパクβ1に新規バリアント(c.173C>A[p.P58H])が判明した。

Numahata Kyoko, Sugawara Miki, Watanabe Kazuyoshi, Takizawa Yoshinori, Katayanagi Junya, Ogawa Tomohiro, Onoue Hiroyuki, Akaiwa Yasuhisa, Hashiguchi Akihiro, Takashima Hiroshi, Miyamoto Tomoyuki . 特発性側彎症に対する術中神経生理モニタリングで異常がみられ、Charcot-Marie-Tooth病1B型と診断された症例(A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B) . Dokkyo Medical Journal2 ( 3 ) 245 - 250 2023.9特発性側彎症に対する術中神経生理モニタリングで異常がみられ、Charcot-Marie-Tooth病1B型と診断された症例(A Case of Idiopathic Scoliosis with Intraoperative Neurophysiological Monitoring Abnormalities Leading to the Diagnosis of Charcot-Marie-Tooth Disease 1B)

Language：English Publisher：獨協医学会

症例は16歳女児。特発性側彎症であり、当院整形外科で前方腰椎固定術が施行された。経頭蓋電気刺激運動誘発電位と体性感覚誘発電位を用いて術中神経生理モニタリング(IONM)が行われたが、異常所見が認められた。また、術後神経伝導検査でも異常所見がみられ、当科紹介となった。両側上下肢で腱反射が消失していた。ビタミンB1値が低く(17ng/mL)、右正中神経の運動および感覚神経伝導速度が顕著に減少しており、遠位潜時の延長と振幅の減少を伴っていた。Charcot-Marie-Tooth病(CMT)疑いのための遺伝子検査を行ったところ、ミエリンタンパク質ゼロ(MPZ)変異が同定され、CMT 1B型と診断した。患者の両親にはMPZ遺伝子に変異がみられなかったため、de novo変異と考えられた。

Language：English Publisher：The Japanese Society of Internal Medicine

Two patients, 48- and 50-year-old sisters, presented with a characteristic facial appearance with slowly progressive deafness and cerebellar ataxia starting in their 30s. Genetic testing identified compound heterozygous pathogenic variants in the ERCC6 gene: c.1583G>A (p.G528E) and c.1873T>G (p.Y625D). A diagnosis of Cockayne syndrome (CS) B type III was made. CS is usually diagnosed in childhood with well-defined facial characteristics and photosensitivity. This case report describes rare cases of adulthood CS with a primary presentation of slowly progressing deafness and cerebellar ataxia. CS should be considered in adults with characteristic facial and skin findings, deafness, and cerebellar ataxia.

DOI： 10.2169/internalmedicine.0061-22

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Takahashi Nobutaka, Mishima Takayasu, Fujioka Shinsuke, Izumi Kohtarou, Ando Masahiro, Higuchi Yujiro, Takashima Hiroshi, Tsuboi Yoshio . Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia(タイトル和訳中) . Internal Medicine62 ( 15 ) 2253 - 2259 2023.8Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia(タイトル和訳中)

Language：English Publisher：(一社)日本内科学会

症例1は50歳女性。30歳時から難聴と歩行不安定が出現し、緩徐に進行していた。症例の妹(症例2)も同様の症状を有していた。特徴的顔貌と小脳性運動失調を認め、ミニメンタルステート検査(MMSE)スコアは20/30、改訂長谷川式簡易知能評価スケール(HDS-R)スコアは20/30、運動失調評価スケール(SARA)スコアは9/40であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。症例2は48歳女性(症例1の妹)。30歳時から難聴と歩行不安定が出現していた。身体的所見、神経学的所見、生化学的所見、画像所見は症例1とほぼ同様で、SARAスコアは9/40、MMSEスコアは21/30、HDS-Rスコアは21/30であった。遺伝子検査でERCC6遺伝子の複合ヘテロ接合体病的バリアント(c.1583G>A[p.G528E]、c.1873T>G[p.Y625D])が特定されたことから、Cockayne症候群BタイプIIIと診断した。

Okamoto Y., Takashima H. . The Current State of Charcot–Marie–Tooth Disease Treatment . Genes14 ( 7 ) 2023.7

Language：Japanese Publisher：Genes

Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research.

DOI： 10.3390/genes14071391

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Matsuura E., Nozuma S., Dozono M., Kodama D., Tanaka M., Kubota R., Takashima H. . Iliopsoas Muscle Weakness as a Key Diagnostic Marker in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) . Pathogens12 ( 4 ) 2023.4

Language：Japanese Publisher：Pathogens

Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected.

DOI： 10.3390/pathogens12040592

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Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Mika Dozono, Takahiro Hobara, Fumikazu Kojima, Yutaka Noguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Jun Sone, Hiroshi Takashima . Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan. . Journal of neurology, neurosurgery, and psychiatry94 ( 8 ) 622 - 630 2023.3International journal

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

DOI： 10.1136/jnnp-2022-330769

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<TAKASHIMA Hiroshi>

Papers - TAKASHIMA Hiroshi