Wiley Acta Medica Okayama 1552-4825 2025 Giant Choledochal Cyst in a Child With Spinocerebellar Ataxia: A Potential Molecular Link Through Aberrant Cytosolic Calcium Signaling e64296 EN Hiromi Sumitomo Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tadashi Kaname Department of Genome Medicine, National Center for Child Health and Development Toshiki Takenouchi Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2470-9239 10 3 2025 Decreased homovanillic acid and 5‐hydroxyindoleacetic acid levels in the cerebrospinal fluid of patients with Dravet syndrome with parkinsonism 965 970 EN Ryo Sugiyama Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry Takashi Saito Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry Atsuko Katsumoto Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry Shota Yoneno Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Hirofumi Komaki Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry Dravet syndrome (DS) is an early onset, developmental, and epileptic encephalopathy characterized by drug-resistant seizures and multiple comorbidities. It has been reported that in adulthood, it may be accompanied by parkinsonism, but the pathogenesis of this condition remains unclear. We performed dopamine transporter single-photon emission computed tomography (DAT SPECT) and measured monoamine metabolite levels in the cerebrospinal fluid (CSF) in two adult patients with DS who developed parkinsonism around the age of 30 years. DAT SPECT showed no abnormalities in either patient, whereas CSF tests revealed significant decreases in the levels of homovanillic and 5-hydroxyindoleacetic acids. One patient with severe symptoms was treated with levodopa–carbidopa, which improved parkinsonism manifestations. The other patient initiated treatment with a low dose and has been continuing the treatment without any reported side effects. In conclusion, CSF testing can detect a decrease in dopamine synthesis and may be useful in monitoring the efficacy of levodopa treatment in patients with DS and parkinsonism. Plain Language Summary: Dravet syndrome (DS) is an early onset, developmental, and epileptic encephalopathy. DS can lead to the development of parkinsonism in adulthood, a clinical syndrome characterized by tremor, slowed movements, and rigidity. Although parkinsonism is a significant issue for patients, its underlying pathology has not yet been elucidated. In this study, we confirmed that the levels of monoamine metabolites in the CSF were low in two patients, potentially shedding light on the pathology involved. No potential conflict of interest relevant to this article was reported.

Bioscientifica Acta Medica Okayama 2052-0573 2025 1 2025 Adult hypophosphatasia presenting with recurrent acute joint pain e240121 EN Hayao Yoshida Department of Diabetes and Endocrinology, Shiga General Hospital Takaaki Murakami Department of Diabetes and Endocrinology, Shiga General Hospital Atsubumi Ogawa Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine Takashi Sunouchi Division of Nephrology and Endocrinology, The University of Tokyo Hospital Naoko Hidaka Division of Nephrology and Endocrinology, The University of Tokyo Hospital Nobuaki Ito Osteoporosis Center, The University of Tokyo Hospital Hiromi Murakami Department of Genomic Medicine, Kyoto University Graduate School of Medicine Hidenori Kawasaki Department of Genomic Medicine, Kyoto University Graduate School of Medicine Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Katsumi Nakajima Department of Diabetes and Endocrinology, Shiga General Hospital Daisuke Yabe Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine Taizo Yamamoto Department of Diabetes and Endocrinology, Shiga General Hospital Hypophosphatasia (HPP) is a genetic disorder due to pathological variants in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP is typically associated with bone-related symptoms, such as bone deformity, fractures and bone pain in children, but can appear in adults with symptoms resembling arthritis. A 22-year-old male experienced repeated and severe sudden attacks of joint pain in the elbows and knees. Magnetic resonance imaging and joint ultrasonography showed joint effusions indicating chronic inflammation. Blood biochemical tests revealed a remarkably low serum ALP level, and repeated examination confirmed a sustained low ALP level; urine phosphoethanolamine, plasma inorganic pyrophosphate and plasma pyridoxal-5′-phosphate levels were elevated, raising concern for HPP. While the patient had no history of premature loss of primary teeth, fragility fractures, muscle weakness or abnormalities in growth, genetic testing revealed a likely pathogenic and a pathogenic heterozygous variant in the ALPL gene, i.e., c.979T>C (p.Phe327Leu) and c.1559del (p.Leu520Argfs), confirming HPP. Additional genetic testing of his parents showed a heterozygous c.1559del variant in his father and a heterozygous c.979T>C variant in his mother. A diagnosis of adult HPP due to compound heterozygous mutations was therefore confirmed. Enzyme replacement therapy with asfotase alfa was then introduced; no attacks of arthralgia occurred in the 1-year period since then. This case highlights the possibility of HPP in adults who present clinically with repeated joint symptoms and low serum ALP levels but without bone-related symptoms. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 79 4 2025 Effectiveness of Pallidal Stimulation for Dystonic Storm and Subsequent Ssevere Posterior Reversible Encephalopathy Syndrome in a Patient with GNAO1 Variant 293 297 EN Koji Kawai Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tatsuya Sasaki Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shun Tanimoto Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoya Saijo Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Susumu Sasada Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuya Hiraide Department of Biochemistry, Hamamatsu University School of Medicine Hirotomo Saitsu Department of Biochemistry, Hamamatsu University School of Medicine Shota Tanaka Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Case Report 10.18926/AMO/69156 GNAO1 variant affects primarily the brain and neurodevelopment, leading to a range of motor disorders including seizures beginning in infancy and involuntary movements such as dyskinesia and dystonia. Our patient, a 15-year-old Japanese female, began exhibiting involuntary movements at age 4. A de novo missense mutation (NM_020988.3: c.228C>G, NP_066268.1: p.(Asn76Lys)) in the GNAO1 gene was identified when the patient was 15, and during the same year she developed influenza pneumonia, accompanied by dystonic storm. She required intensive care with mechanical ventilation and underwent a tracheostomy. She also developed posterior reversible encephalopathy syndrome. Globus pallidal stimulation was administered, leading to an improvement in the dystonic storm. Early consideration of globus pallidal stimulation is recommended when treating difficult-to-manage dystonic storms. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 2589-9864 31 2025 Investigation of the relationship between 0.5–1200 Hz signal characteristics of cortical high-frequency oscillations and epileptogenicity through multivariate analysis 100776 EN Takashi Shibata Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Hiroki Tsuchiya Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Mari Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Masao Matsuhashi Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University Katsuhiro Kobayashi Department of Pediatric Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Fast ripples (FRs) (250–500 Hz) on the electroencephalogram (EEG) are closely related to epileptogenicity and are important to determine cortical regions resected in epilepsy surgery. However, FR-related epileptogenicity may be variable, and may depend on information associated with FRs. We enrolled nine epilepsy patients who had undergone intracranial 5 kHz-sampling-rate EEG for surgical treatment and had final Engel class I outcomes. Three electrodes were selected from each epileptogenic area (EA) and the unlikely EA (the region outside the EA) in each patient. Up to 100 candidate FRs were automatically detected from interictal nocturnal EEG at each of the selected electrodes and were visually reviewed independently by two researchers. Multivariate logistic regression analysis was performed using the frequency and log-power value of the corresponding FRs, presence of concurrent spike, ripple, very-high-frequency oscillations (vHFO)1 (500–600 Hz), and vHFO2 (600–1200 Hz), and whether the timing of the spectral peak of corresponding FRs was in the peak–trough or trough–peak transition of each slow activity (0.5–1, 1–2, 2–3, 3–4, and 4–8 Hz) as independent variables. Factors significantly related to epileptogenicity were FR power, the concurrent presence of spike and vHFO2, coupling with 0.5–1 and 1–2 Hz slow waves in the peak–trough transition, and coupling with 3–4 and 4–8 Hz slow waves in the trough–peak transition. Multifactorial analysis of FRs may increase their usefulness, potentially leading to improved treatment outcomes in epilepsy surgery. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0387-7604 47 1 2025 Hypotheses of pathophysiological mechanisms in epileptic encephalopathies: A review 104318 EN Katsuhiro Kobayashi Department of Pediatrics, Asahigawaso Rehabilitation and Medical Center Takashi Shibata Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroki Tsuchiya Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Mari Akiyama Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoyuki Akiyama Department of Pediatric Neurology, Okayama University Hospital and Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Introduction: Epileptic encephalopathy (EE) is a serious clinical issue that manifests as part of developmental and epileptic encephalopathy (DEE), particularly in childhood epilepsy. In EE, neurocognitive functions and behavior are impaired by intense epileptiform electroencephalogram (EEG) activity. Hypotheses of pathophysiological mechanisms behind EE are reviewed to contribute to an effective solution for EE. Review: Current hypotheses are as follows: 1) neuronal dysfunction based on genetic abnormalities that may affect neurocognitive functions and epilepsy separately; 2) impairment of synaptic homeostasis during sleep that may be responsible for DEE/EE with spike-and-wave activation in sleep; 3) abnormal subcortical regulation of the cerebral cortex; 4) abnormal cortical metabolism and hemodynamics with impairment of the neural network including default mode network; 5) neurotransmitter imbalance and disordered neural excitability; 6) the effects of neuroinflammation that may be caused by epileptic seizures and in turn aggravate epileptogenesis; 7) the interaction between physiological and pathological high-frequency EEG activity; etc. The causal relationship between epileptiform EEG activity and neurocognitive dysfunctions is small in DEE based on genetic abnormalities and it is largely unestablished in the other hypothetical mechanisms. Conclusion: We have not yet found answers to the question of whether the single-central or multiple derangements are present and what seizures and intense epileptiform EEG abnormalities mean in EE. We need to continue our best efforts in both aspects to elucidate the pathophysiological mechanisms of DEE/EE and further develop epilepsy treatment and precision medicine. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0387-7604 46 4 2024 Exploration of urine metabolic biomarkers for new-onset, untreated pediatric epilepsy: A gas and liquid chromatography mass spectrometry-based metabolomics study 180 186 EN Tomoyuki Akiyama Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Saigusa Laboratory of Biomedical and Analytical Sciences, Faculty of Pharma-Science, Teikyo University Takushi Inoue Department of Pediatric Neurology, NHO Okayama Medical Center Chiho Tokorodani Department of Pediatrics, Kochi Health Sciences Center Mari Akiyama Department of Pediatrics (Child Neurology), Okayama University Hospital Rie Michiue Department of Pediatrics (Child Neurology), Okayama University Hospital Atsushi Mori Department of Neurology, Shiga Medical Center for Children Eiji Hishinuma Tohoku Medical Megabank Organization, Tohoku University Naomi Matsukawa Tohoku Medical Megabank Organization, Tohoku University Takashi Shibata Department of Pediatrics (Child Neurology), Okayama University Hospital Hiroki Tsuchiya Department of Pediatrics (Child Neurology), Okayama University Hospital Katsuhiro Kobayashi Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 136 1 2024 脳クレアチン欠乏症候群 26 28 EN Tomoyuki Akiyama Department of Pediatrics (Child Neurology), Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 77 5 2023 Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma 561 566 EN Hiroki Tsuchiya Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Takashi Shibata Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Tatsuya Sasaki Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Takushi Inoue Department of Pediatrics, National Hospital Organization Okayama Medical Center Isao Date Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Tomoyuki Akiyama Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Katsuhiro Kobayashi Department of Pediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Case Report 10.18926/AMO/65980 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. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 1059-1311 107 2023 Comprehensive study of metabolic changes induced by a ketogenic diet therapy using GC/MS- and LC/MS-based metabolomics 52 59 EN Mari Akiyama Department of Child Neurology, Okayama University Hospital Tomoyuki Akiyama Department of Paediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Daisuke Saigusa Tohoku Medical Megabank Organization, Tohoku University Eiji Hishinuma Tohoku Medical Megabank Organization, Tohoku University Naomi Matsukawa Tohoku Medical Megabank Organization, Tohoku University Takashi Shibata Department of Child Neurology, Okayama University Hospital Hiroki Tsuchiya Department of Child Neurology, Okayama University Hospital Atsushi Mori Department of Neurology, Shiga Medical Centre for Children Yuji Fujii Department of Paediatrics, Hiroshima City Funairi Citizens Hospital Yukiko Mogami Department of Paediatric Neurology, Osaka Women's and Children's Hospital Chiho Tokorodani Department of Paediatrics, Kochi Health Sciences Centre Kozue Kuwahara Department of Paediatrics, Ehime Prefectural Central Hospital, Yurika Numata-Uematsu Department of Paediatrics, Tohoku University School of Medicine Kenji Inoue Department of Neurology, Shiga Medical Centre for Children Katsuhiro Kobayashi Department of Paediatrics (Child Neurology), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Objective: The ketogenic diet (KD), a high-fat and low-carbohydrate diet, is effective for a subset of patients with drug-resistant epilepsy, although the mechanisms of the KD have not been fully elucidated. The aims of this observational study were to investigate comprehensive short-term metabolic changes induced by the KD and to explore candidate metabolites or pathways for potential new therapeutic targets. Methods: Subjects included patients with intractable epilepsy who had undergone the KD therapy (the medium-chain triglyceride [MCT] KD or the modified Atkins diet using MCT oil). Plasma and urine samples were obtained before and at 2–4 weeks after initiation of the KD. Targeted metabolome analyses of these samples were performed using gas chromatography-tandem mass spectrometry (GC/MS/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). Results: Samples from 10 and 11 patients were analysed using GC/MS/MS and LC/MS/MS, respectively. The KD increased ketone bodies, various fatty acids, lipids, and their conjugates. In addition, levels of metabolites located upstream of acetyl-CoA and propionyl-CoA, including catabolites of branched-chain amino acids and structural analogues of γ-aminobutyric acid and lactic acid, were elevated. Conclusions: The metabolites that were significantly changed after the initiation of the KD and related metabolites may be candidates for further studies for neuronal actions to develop new anti-seizure medications. No potential conflict of interest relevant to this article was reported.

Frontiers Media SA Acta Medica Okayama 1662-5161 15 2021 Exclusion of the Possibility of "False Ripples" From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy 696882 EN Katsuhiro Kobayashi Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Takashi Shibata Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Hiroki Tsuchiya Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital Aim Ripple-band epileptic high-frequency oscillations (HFOs) can be recorded by scalp electroencephalography (EEG), and tend to be associated with epileptic spikes. However, there is a concern that the filtration of steep waveforms such as spikes may cause spurious oscillations or "false ripples." We excluded such possibility from at least some ripples by EEG differentiation, which, in theory, enhances high-frequency signals and does not generate spurious oscillations or ringing. Methods The subjects were 50 pediatric patients, and ten consecutive spikes during sleep were selected for each patient. Five hundred spike data segments were initially reviewed by two experienced electroencephalographers using consensus to identify the presence or absence of ripples in the ordinary filtered EEG and an associated spectral blob in time-frequency analysis (Session A). These EEG data were subjected to numerical differentiation (the second derivative was denoted as EEG ''). The EEG '' trace of each spike data segment was shown to two other electroencephalographers who judged independently whether there were clear ripple oscillations or uncertain ripple oscillations or an absence of oscillations (Session B). Results In Session A, ripples were identified in 57 spike data segments (Group A-R), but not in the other 443 data segments (Group A-N). In Session B, both reviewers identified clear ripples (strict criterion) in 11 spike data segments, all of which were in Group A-R (p < 0.0001 by Fisher's exact test). When the extended criterion that included clear and/or uncertain ripples was used in Session B, both reviewers identified 25 spike data segments that fulfilled the criterion: 24 of these were in Group A-R (p < 0.0001). Discussion We have demonstrated that real ripples over scalp spikes exist in a certain proportion of patients. Ripples that were visualized consistently using both ordinary filters and the EEG '' method should be true, but failure to clarify ripples using the EEG '' method does not mean that true ripples are absent. Conclusion The numerical differentiation of EEG data provides convincing evidence that HFOs were detected in terms of the presence of such unusually fast oscillations over the scalp and the importance of this electrophysiological phenomenon. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 2214-4269 25 2020 Marked motor function improvement in a 32-year-old woman with childhood-onset hypophosphatasia by asfotase alfa therapy: Evaluation based on standardized testing batteries used in Duchenne muscular dystrophy clinical trials 100643 EN Hitomi Nishizawa Faculty of Health Sciences, Department of Medicine, Shinshu University Yoshihiko Sato Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University School of Medicine, Matsumoto Masumi Ishikawa Center for Medical Genetics, Shinshu University Hospital Yuko Arakawa Department of Dentistry and Oral Surgery, Shinshu University School of Medicine Mari Iijima Department of Clinical Nutrition, Shinshu University Hospital Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Kyoko Takano Center for Medical Genetics, Shinshu University Hospital Atsushi Watanabe Division of Clinical Genetics, Kanazawa University Hospital Tomoki Kosho Center for Medical Genetics, Shinshu University Hospital Hypophosphatasia (HPP) is a rare disorder resulting from biallelic loss-of-function variants or monoallelic dominant negative variants in the ALPL gene. We herein describe the clinical outcome of a 32-year-old woman with childhood-onset HPP caused by compound heterozygous variants in ALPL. Her chief complaints were severe musculoskeletal pain, muscle weakness, and impaired daily activities necessitating assistance in housework and child-rearing in addition to a history of early tooth loss and mildly short stature. Asfotase alfa therapy produced a remarkable increase in muscle strength and daily activities and markedly reduced musculoskeletal pain. Drug efficacy was clearly demonstrated through multiple test batteries (muscle strength test using microFET®2, six-minute walking test, Stair Climb Test, rising-from-floor-time test, and number-of-steps test using Actigraph®) currently adopted as standardized evaluations in Duchenne muscular dystrophy clinical trials since no test batteries for HPP have been established to date. These tests may also be promising for the assessment of HPP. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0887-8994 113 2020 Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6–dependent Epilepsy Than Pyridoxal 5′-Phosphate 33 41 EN Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Yuki Hyodo Department of Child Neurology, Okayama University Hospital Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Taikan Oboshi Department of Pediatric Neurology, Osaka Women’s and Children’s Hospital Katsumi Imai Department of Pediatrics, NHO Shizuoka Institute of Epilepsy and Neurological Disorders Naoko Ishihara Department of Pediatrics, Fujita Health University School of Medicine Yuri Dowa Department of Neurology, Gunma Children’s Medical Center Takayoshi Koike Department of Pediatrics, NHO Shizuoka Institute of Epilepsy and Neurological Disorders Toshiyuki Yamamoto Institute of Clinical Genomics, Tokyo Women’s Medical University Jun Shibasaki Department of Neonatology, Kanagawa Children’s Medical Center Hiroko Shimbo Clinical Institute, Kanagawa Children’s Medical Center Tetsuhiro Fukuyama Department of Pediatrics, Shinshu University Kyoko Takano Center for Medical Genetics, Shinshu University Hospital Hiroshi Shiraku Department of Pediatrics, JA Toride Medical Center Saoko Takeshita Department of Pediatrics, Yokohama City University Medical Center Tohru Okanishi Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital Shimpei Baba Department of Child Neurology, Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital Masaya Kubota Division of Neurology, National Center for Child Health and Development Shin-ichiro Hamano Division of Neurology, Saitama Children’s Medical Center Katsuhiro Kobayashi Department of Child Neurology, Okayama University Hospital 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. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 0387-7604 40 9 2018 Differential diagnosis of nonepileptic twilight state with convulsive manifestations after febrile seizures 781 785 EN Hiroyuki Miyahara Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kenji Waki Department of Pediatrics, Kurashiki Central Hospital Yoshio Arakaki Department of Pediatrics, Kurashiki Central Hospital Background Nonepileptic twilight state with convulsive manifestations (NETC) is a nonepileptic state following a febrile seizure (FS), which may be misdiagnosed as a prolonged seizure and result in overtreatment. We aimed to describe clinical manifestations of NETC and to determine characteristics that are helpful to distinguish NETC from other pathological conditions. Methods We conducted a retrospective chart review from January 2010 to December 2016 and selected the patients who presented with symptoms resembling status epilepticus with fever and a confirmed diagnosis using an electroencephalogram (EEG). We compared the NETC clinical features and venous blood gas analysis results with those of other conditions that mimic NETC. We also compared the characteristics of NETC with past reports. Results Our NETC patients presented with short durations of the preceding generalized convulsions followed by tonic posturing, closed eyes, no cyanosis, responsiveness to painful stimulation, and no accumulation of CO2 in the venous blood gas. Most of these characteristics were consistent with past reports. Prolonged FS or acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) showed several of these features, but all the characteristics were not consistent with our study. Conclusions Prolonged FS and AESD need to be differentiated from NETC, and close clinical observation makes it possible to partially distinguish NETC from the other conditions. EEG is recommended for patients with symptoms that are inconsistent with these features. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1328-8067 62 5 2020 Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions 587 592 EN Hiroyuki Miyahara Department of Pediatrics, Okayama University Hospital Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Kosei Hasegawa Department of Pediatrics, Okayama University Hospital Mari Akiyama Department of Child Neurology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Makio Oka Department of Child Neurology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Katsuhiro Kobayashi Department of Child Neurology, Okayama University Hospital Hirokazu Tsukahara Department of Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Background Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high‐risk cases with renal calcified lesions are yet to be clarified. Methods In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. Results After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. Conclusions The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 10967192 125 1-2 2018 Pyridoxal 5′-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy 174 180 EN Tomoyuki Akiyama Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takuo Kubota Department of Pediatrics, Osaka University Graduate School of Medicine Keiichi Ozono Department of Pediatrics, Osaka University Graduate School of Medicine Toshimi Michigami Department of Bone and Mineral Research, Osaka Women's and Children's Hospital Daisuke Kobayashi Department of Food and Chemical Toxicology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido Shinji Takeyari Department of Pediatrics, Osaka University Graduate School of Medicine Yuichiro Sugiyama Department of Pediatrics, Nagoya University Graduate School of Medicine Masahiro Noda Department of Pediatrics, Showa General Hospital Daisuke Harada Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization Noriyuki Namba Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization Atsushi Suzuki Department of Neonatology and Pediatrics, Nagoya City University Graduate School of Medical Sciences Maiko Utoyama Department of Pediatrics, Faculty of Medicine, University of Miyazaki Sachiko Kitanaka Department of Pediatrics, Graduate School of Medicine, University of Tokyo Mitsugu Uematsu Department of Pediatrics, Tohoku University Graduate School of Medicine Yusuke Mitani Department of Pediatrics, Kanazawa University Hospital Kunihiro Matsunami Department of Pediatrics, Gifu Prefectural General Medical Center Shigeru Takishima Department of Pediatrics, Soka Municipal Hospital Erika Ogawa Department of Pediatrics and Child Health, Nihon University School of Medicine Katsuhiro Kobayashi Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 03877604 42 5 2020 Vitamin B6 in acute encephalopathy with biphasic seizures and late reduced diffusion 402 407 EN Tomoyuki Akiyama Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Soichiro Toda Nobusuke Kimura Department of Pediatrics, Japanese Red Cross Otsu Hospital Yukiko Mogami Department of Pediatric Neurology, Osaka Women’s and Children’s Hospital Chiho Tokorodani Department of Pediatrics, Kochi Health Sciences Center Tomoshiro Ito Department of Pediatrics, Sapporo City General Hospital Hiroyuki Miyahara Department of Pediatrics, Kurashiki Central Hospital Yuki Hyodo Department of Child Neurology, Okayama University Hospital Katsuhiro Kobayashi Department of Child Neurology, Okayama University Hospital Background The initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD. Methods We obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5′-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection. Results The subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS. Conclusions Although it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 74 1 2020 Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy 65 72 EN Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Daisuke Saigusa Tohoku Medical Megabank Organization, Tohoku University Yuki Hyodo Department of Child Neurology, Okayama University Hospital Keiko Umeda Tohoku Medical Megabank Organization, Tohoku University Reina Saijo Tohoku Medical Megabank Organization, Tohoku University Seizo Koshiba Tohoku Medical Megabank Organization, Tohoku University Katsuhiro Kobayashi Department of Child Neurology, Okayama University Hospital Original Article 10.18926/AMO/57955 To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine. No potential conflict of interest relevant to this article was reported.

Elsevier Acta Medica Okayama 22144269 21 2019 Clinical and genetic aspects of mild hypophosphatasia in Japanese patients 100515 EN Katsuyuki Yokoi Department of Pediatrics, Fujita Health University School of Medicine Yoko Nakajima Department of Pediatrics, Fujita Health University School of Medicine Yasuko Shinkai Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University Yoshimi Sano Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine Mototaka Imamura Department of Plastic Surgery, Division of Pediatric Dentistry & Orthodontics, Fujita Health University of Medicine Tomoyuki Akiyama Department of Child Neurology, Okayama University Hospital Tetsushi Yoshikawa Department of Pediatrics, Fujita Health University School of Medicine Tetsuya Ito Department of Pediatrics, Fujita Health University School of Medicine Hiroki Kurahashi Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University Background: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from a dysfunctional tissue non-specific alkaline phosphatase enzyme (TNSALP). Although genotype-phenotype correlations have been described in HPP patients, only sparse information is currently available on the genetics of mild type HPP. Methods: We investigated 5 Japanese patients from 3 families with mild HPP (patients 1 and 2 are siblings; patient 4 is a daughter of patient 5) who were referred to Fujita Health University due to the premature loss of deciduous teeth. Physical and dental examinations, and blood, urine and bone density tests were conducted. Genetic analysis of the ALPL gene was performed in all patients with their informed consent. Results: After a detailed interview and examination, we found characteristic symptoms of HPP in some of the study cases. Mobile teeth or the loss of permanent teeth were observed in 2 patients, and 3 out of 5 patients had a history of asthma. The serum ALP levels of all patients were 30% below the lower limit of the age equivalent normal range. ALPL gene analysis revealed compound heterozygous mutations, including Ile395Val and Leu520Argfs in family 1, Val95Met and Gly491Arg in family 2, and a dominant missense mutation (Gly456Arg) in family 3. The 3D-modeling of human TNSALP revealed three mutations (Val95Met, Ile395Val and Gly456Arg) at the homodimer interface. Severe collisions between the side chains were predicted for the Gly456Arg variant. Discussion: One of the characteristic findings of this present study was a high prevalence of coexisting asthma and a high level serum IgE level. These characteristics may account for the fragility of tracheal tissues and a predisposition to asthma in patients with mild HPP. The genotypes of the five mild HPP patients in our present study series included 1) compound heterozygous for severe and hypomorphic mutations, and 2) dominant-negative mutations. All of these mutations were at the homodimer interface, but only the dominant-negative mutation was predicted to cause a severe collision effect between the side chains. This may account for varying mechanisms leading to different effects on TNSALP function. No potential conflict of interest relevant to this article was reported.