研究者詳細 - 秋山　倫之

論文 - 秋山　倫之

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Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6-dependent Epilepsy Than Pyridoxal 5'-Phosphate. 査読国際誌

Tomoyuki Akiyama, Yuki Hyodo, Kosei Hasegawa, Taikan Oboshi, Katsumi Imai, Naoko Ishihara, Yuri Dowa, Takayoshi Koike, Toshiyuki Yamamoto, Jun Shibasaki, Hiroko Shimbo, Tetsuhiro Fukuyama, Kyoko Takano, Hiroshi Shiraku, Saoko Takeshita, Tohru Okanishi, Shimpei Baba, Masaya Kubota, Shin-Ichiro Hamano, Katsuhiro Kobayashi

Pediatric neurology 113 33 - 41 2020年9月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid. METHODS: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations. RESULTS: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain. CONCLUSIONS: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.

DOI： 10.1016/j.pediatrneurol.2020.08.020

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Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics. 査読国際誌

Tomiko Kuhara, Tomoyuki Akiyama, Morimasa Ohse, Takayoshi Koike, Jun Shibasaki, Katsumi Imai, ArthurJ L Cooper

Analytical biochemistry 604 113739 - 113739 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

α-Aminoadipic semialdehyde and its cyclic form (Δ1-piperideine-6-carboxylate) accumulate in patients with α-aminoadipic semialdehyde dehydrogenase (AASADH; antiquitin; ALDH7A1) deficiency. Δ1-Piperideine-6-carboxylate is known to react with pyridoxal 5'-phosphate (PLP) to form a Knoevenagel condensation product, resulting in pyridoxine-dependent epilepsy. Despite dramatic clinical improvement following pyridoxine supplementation, many patients still suffer some degree of intellectual disability due to delayed diagnosis. In order to expedite the diagnosis of patients with suspected AASADH deficiency and minimize the delay in treatment, we used gas chromatography-mass spectrometry-based metabolomics to search for potentially diagnostic biomarkers in urine from four patients with ALDH7A1 mutations, and identified Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as candidate biomarkers. In a patient at postnatal day six, but before pyridoxine treatment, Δ2-piperideine-6-carboxylate and pipecolate were present at very high concentrations, indicating that these compounds may be good biomarkers for untreated AASADH deficiency patients. On the other hand, following pyridoxine/PLP treatment, 6-oxopipecolate was shown to be greatly elevated. We suggest that noninvasive urine metabolomics screening for Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate will be useful for prompt and reliable diagnosis of AASADH deficiency in patients within any age group. The most appropriate combination among Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as biomarkers for AASADH deficiency patients appears to depend on the age of the patient and whether pyridoxine/PLP supplementation has been implemented. We anticipate that the present bioanalytical information will also be useful to researchers studying glutamate, proline, lysine and ornithine metabolism in mammals and other organisms.

DOI： 10.1016/j.ab.2020.113739

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Pyridoxal 5'-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy. 査読国際誌

Tomoyuki Akiyama, Takuo Kubota, Keiichi Ozono, Toshimi Michigami, Daisuke Kobayashi, Shinji Takeyari, Yuichiro Sugiyama, Masahiro Noda, Daisuke Harada, Noriyuki Namba, Atsushi Suzuki, Maiko Utoyama, Sachiko Kitanaka, Mitsugu Uematsu, Yusuke Mitani, Kunihiro Matsunami, Shigeru Takishima, Erika Ogawa, Katsuhiro Kobayashi

Molecular genetics and metabolism 125 ( 1-2 ) 174 - 180 2018年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

DOI： 10.1016/j.ymgme.2018.07.006

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A retrospective study on post-operative recovery of daily living activity after total corpus callosotomy. 査読国際誌

Hiroki Tsuchiya, Takashi Shibata, Tatsuya Sasaki, Mari Akiyama, Tomoyuki Akiyama, Katsuhiro Kobayashi

Brain & development 10 339 - 343 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Post-operative complications of corpus callosotomy (CC) in children, prolonged hospitalization due to inactivity as acute disconnection syndrome is occasionally experienced. We aimed to clarify this issue and its risk factors with a hypothesis that electroencephalogram (EEG) findings as measures of functional lateralization may be among prognostic factors for post-operative recovery. MATERIALS AND METHODS: Twenty-three patients with childhood-onset drug-resistant epilepsy who underwent total CC between April 2017 and December 2023 were included in the study and they were divided into two groups based on the duration of post-operative hospitalization as an indicator of recovery of daily living activity. We compared scalp EEG findings and the other factors including clinical characteristics between the two groups. RESULTS: Of 22 patients (14 males) without specific complications, post-operative hospitalization clustered in 9-14 days in 15 patients (Group A) with range 16-118 days in seven patients (Group B). The ratios of patients with non-lateralized spikes on pre-operative EEG and that of patients with symmetric background activity on post-operative EEG were significantly greater in Group B (7/7, 100 %; 6/7, 86 %, respectively) than in Group A (8/15, 53 %; 4/15, 27 %, respectively) (p = 0.038; p = 0.020, respectively, by Fisher's exact test), while other factors were not significantly different between the two groups. CONCLUSIONS: Delayed recovery of living activity should be anticipated, especially in patients with non-lateralized epileptic discharges on pre-operative EEG.

DOI： 10.1016/j.braindev.2024.09.006

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Alectinib maintenance therapy following cord blood transplantation for relapsed pediatric anaplastic large cell lymphoma with central nervous system involvement. 査読国際誌

Kosuke Tamefusa, Hisashi Ishida, Daisuke Miyahara, Takahiro Shiwaku, Motoharu Ochi, Kiichiro Kanamitsu, Kaori Fujiwara, Yasuhisa Tatebe, Kana Washio, Tomoyuki Akiyama, Hirokazu Tsukahara

Annals of hematology 103 ( 11 ) 4805 - 4809 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pediatric ALK-positive anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphoma, and approximately 30% of patients relapse following treatment with conventional chemotherapy. Alectinib monotherapy has demonstrated excellent activity in relapsed and refractory ALCL, but its role as a maintenance therapy after hematopoietic cell transplantation is unclear. We experienced a relapse case of pediatric ALK-positive ALCL with central nervous system involvement treated with alectinib maintenance therapy following cord blood transplantation. The patient has maintained complete remission for more than 3 years after transplantation. There were no remarkable adverse effects that led to discontinuation of alectinib.

DOI： 10.1007/s00277-024-06000-7

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Editorial comments on “Two cases of cerebrospinal fluid hypovolemia that had been interpreted as orthostatic dysregulation” 査読

Tomoyuki Akiyama, Shinji Saitoh

Brain and Development Case Reports 2 ( 3 ) 100033 - 100033 2024年9月

新生児低血糖症による両側後頭葉病変を背景としたWest症候群の1手術例

竹中暁, 土屋弘樹, 柴田敬, 所谷知穂, 佐々木達也, 伊達勲, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 64 - 64 2024年6月

脳腫瘍摘出術後に発作の完全抑制を得られた乳児てんかん性スパズム症候群の男児例

塚原理恵, 土屋弘樹, 秋山麻里, 佐々木達也, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 77 - 77 2024年6月

8歳MRI陰性側頭葉てんかんの一手術例

佐々木達也, 井本良二, 松田奈央子, 柴田敬, 秋山麻里, 亀田雅博, 安原隆雄, 秋山倫之, 小林勝弘, 伊達勲

てんかん研究 42 ( 1 ) 58 - 59 2024年6月

広範な脳形成異常に伴う新生児期発症難治てんかんに対して緩和的半球離断術を施行した1乳児例

兵頭勇紀, 松田奈央子, 金聖泰, 秋山麻里, 佐々木達也, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 58 - 58 2024年6月

髄液グリシン濃度の解釈におけるいくつかのpit fall

土屋弘樹, 住友裕美, 島崎敦, 榎本早也香, 大野友香子, 塚原理恵, 時岡礼恵, 竹中暁, 道上理絵, 秋山倫之, 小林勝弘

脳と発達 56 ( Suppl. ) S217 - S217 2024年5月

Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep. 査読国際誌

Takashi Shibata, Hiroki Tsuchiya, Mari Akiyama, Tomoyuki Akiyama, Katsuhiro Kobayashi

Epilepsy research 202 107359 - 107359 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

DOI： 10.1016/j.eplepsyres.2024.107359

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低ホスファターゼ症患児における成長障害の臨床的特性

藤原誠, 植田郁実, 石見壮史, 山田知絵子, 中野由佳子, 山本賢一, 中山尋文, 大幡泰久, 北岡太一, 秋山倫之, 大薗恵一, 窪田拓生

日本内分泌学会雑誌 100 ( 1 ) 390 - 390 2024年5月

A case report of odonto-hypophosphatasia with a novel variant in the ALPL gene. 査読国際誌

Yuji Oto, Daiki Suzuki, Tsubasa Morita, Takeshi Inoue, Akihisa Nitta, Nobuyuki Murakami, Yuuka Abe, Yoshinobu Hamada, Tomoyuki Akiyama, Tomoyo Matsubara

Journal of pediatric endocrinology & metabolism : JPEM 37 ( 3 ) 276 - 279 2024年3月

記述言語：英語

OBJECTIVES: Hypophosphatasia (HPP) is a rare skeletal dysplasia caused by variants in the alkaline phosphatase (ALPL) gene. More than 400 pathogenic variants of the ALPL gene have been registered in the ALPL gene variant database. Here, we describe the case of a Japanese child with odonto-hypophsphatasia (odonto-HPP) and a novel ALPL variant. CASE PRESENTATION: At the age of 2 years and 1 month, he prematurely lost one deciduous tooth, with the root intact, when he fell and hit his face lightly. Three months later, he lost another adjacent deciduous tooth without incentive. His serum alkaline phosphatase (ALP) level was 72 U/L. His urine phosphoethanolamine (PEA) level was extremely high at 938 μmol/mg·Cre. The serum pyridoxal 5'-phosphaye (PLP) level was 255.9 nmol/L. Based on the clinical symptoms and laboratory findings, the patient was clinically diagnosed with odonto-HPP. Genetic analysis of the ALPL gene revealed a heterozygous variant (NM_000478.6:c.1151C>A, p.Thr384Lys). CONCLUSIONS: We report a case of odonto-HPP with a novel variant in the ALPL gene. HPP is a rare disease, and the heterozygous mutation in the ALPL gene highlights the novelty of this case.

DOI： 10.1515/jpem-2023-0549

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眼球運動障害で発症した多発性ミトコンドリア機能障害症候群type3の乳児例

時岡礼恵, 土屋弘樹, 秋山倫之, 高梨潤一, 才津浩智, 小林勝弘

日本小児科学会雑誌 128 ( 2 ) 253 - 253 2024年2月

Exploration of urine metabolic biomarkers for new-onset, untreated pediatric epilepsy: A gas and liquid chromatography mass spectrometry-based metabolomics study. 査読国際誌

Tomoyuki Akiyama, Daisuke Saigusa, Takushi Inoue, Chiho Tokorodani, Mari Akiyama, Rie Michiue, Atsushi Mori, Eiji Hishinuma, Naomi Matsukawa, Takashi Shibata, Hiroki Tsuchiya, Katsuhiro Kobayashi

Brain & development 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: The discovery of objective indicators for recent epileptic seizures will help confirm the diagnosis of epilepsy and evaluate therapeutic effects. Past studies had shortcomings such as the inclusion of patients under treatment and those with various etiologies that could confound the analysis results significantly. We aimed to minimize such confounding effects and to explore the small molecule biomarkers associated with the recent occurrence of epileptic seizures using urine metabolomics. METHODS: This is a multicenter prospective study. Subjects included pediatric patients aged 2 to 12 years old with new-onset, untreated epilepsy, who had had the last seizure within 1 month before urine collection. Controls included healthy children aged 2 to 12 years old. Those with underlying or chronic diseases, acute illnesses, or recent administration of medications or supplements were excluded. Targeted metabolome analysis of spot urine samples was conducted using gas chromatography (GC)- and liquid chromatography (LC)-tandem mass spectrometry (MS/MS). RESULTS: We enrolled 17 patients and 21 controls. Among 172 metabolites measured by GC/MS/MS and 41 metabolites measured by LC/MS/MS, only taurine was consistently reduced in the epilepsy group. This finding was subsequently confirmed by the absolute quantification of amino acids. No other metabolites were consistently altered between the two groups. CONCLUSIONS: Urine metabolome analysis, which covers a larger number of metabolites than conventional biochemistry analyses, found no consistently altered small molecule metabolites except for reduced taurine in epilepsy patients compared to healthy controls. Further studies with larger samples, subjects with different ages, expanded target metabolites, and the investigation of plasma samples are required.

DOI： 10.1016/j.braindev.2023.12.004

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尿中メタボローム解析を用いた未治療てんかんのバイオマーカー探索

秋山倫之, 三枝大輔, 秋山麻里, 柴田敬, 土屋弘樹, 道上理絵, 小林勝弘

脳と発達 56 ( 1 ) 71 - 71 2024年1月

Epileptic Seizure Detection Using a Recurrent Neural Network With Temporal Features Derived From a Scale Mixture EEG Model 査読

Akira Furui, Ryota Onishi, Tomoyuki Akiyama, Toshio Tsuji

IEEE Access 12 162814 - 162824 2024年

Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma. 査読

Hiroki Tsuchiya, Takashi Shibata, Tatsuya Sasaki, Takushi Inoue, Isao Date, Tomoyuki Akiyama, Katsuhiro Kobayashi

Acta medica Okayama 77 ( 5 ) 561 - 566 2023年10月

記述言語：英語

West syndrome, an infantile developmental and epileptic encephalopathy with a deleterious impact on long-term development, requires early treatment to minimize developmental abnormality; in such cases, epilepsy surgery should be considered a powerful therapeutic option. We describe a 10-month-old female admitted with West syndrome associated with a hemispheric lesion following abusive head trauma. Her seizures were suppressed by hemispherotomy at 12 months of age, leading to developmental improvement. Surgical treatment of West syndrome following traumatic brain injury has not been reported previously but is worth considering as a treatment option, depending on patient age and brain plasticity.

DOI： 10.18926/AMO/65980

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West症候群に対するVGBの6年間の使用経験

道上理絵, 土屋弘樹, 柴田敬, 秋山麻里, 秋山倫之, 小林勝弘

てんかん研究 41 ( 2 ) 403 - 403 2023年9月

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