Rina Shimomura, Keiko Yamamoto Shimojima, Mutsuki Nakano, Takahiro Tayama, Tatsuo Mori, Eriko Nishi, Ken Inoue, Satoru Nagata, Nobuhiko Okamoto and Toshiyuki Yamamoto : Unique DUP-TRP/INV-DUP Structure Detected by Long-Read Sequencing., American Journal of Medical Genetics. Part A., 197, 7, e64044, 2025.
(要約)
Duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) is one of the mechanisms that causes genomic triplications. There are some characteristics of the DUP-TRP/INV-DUP; the appearance of a moving average of signal log2 ratio in genomic copy number analysis consisting of the highest center with lower steps on both sides; the chromosomal structure is composed of only two junctions; there are inverted repeats at the ends of the triplications and duplications on the same side and those connected in the opposite direction; and the size of the DUP-TRP/INV-DUP structure is generally less than the 1-Mb range. In this study, we analyzed two patients with DUP-TRP/INV-DUP involving PLP1 and MECP2. Whole-genome long-read sequencing was performed, and all breakpoint junctions were confirmed. Patient 1 showed a typical DUP-TRP/INV-DUP pattern involving PLP1, whereas Patient 2 showed a unique DUP-TRP/INV-DUP pattern in the MECP2 region, which involved additional chromosomal breakages at a 46-Mb far remote region of Xq22.3. Based on this finding, we suspected that chromosomal breakage at Xq22.3 was the initial damage. The detected two break ends were considered to be repaired by binding to the Xq28 region adjacent to the inverted repeat structure to form a triplication structure.
(キーワード)
Humans / Methyl-CpG-Binding Protein 2 / Male / Myelin Proteolipid Protein / Female / Chromosomes, Human, X / Chromosome Inversion / Chromosome Duplication
Tatsuo Mori, Mutsuki Nakano, Takahiro Tayama, Aya Goji, Yoshihiro Toda, Shinichi Kameyama, Takeshi Mizuguchi, Maki Urushihara and Naomichi Matsumoto : A female case of L1 syndrome that may have developed due to skewedXinactivation., Brain & Development, 46, 6, 230-233, 2024.
(キーワード)
Humans / Female / X Chromosome Inactivation / Neural Cell Adhesion Molecule L1 / Hydrocephalus / Child, Preschool / Agenesis of Corpus Callosum
Natsue Nozaki, Kenji Mori, Tetsuya Tanioka, Keiko Mori, Kumi Takahashi, Hiroko Hashimoto, Takahiro Tayama, Aya Gohji and Tatsuo Mori : Bilateral Prefrontasl Cortex Blood Flow Dynamics during Silent and Oral Reading Using Near-Infrared Spectroscopy, The Journal of Medical Investigation : JMI, 71, 1,2, 92-101, 2024.
(要約)
This study aimed to investigate blood flow dynamics in the bilateral prefrontal cortex during silent and oral reading using near-infrared spectroscopy (NIRS). The subjects were 40 right-handed university students (20.5±1.8 years old, 20 men and 20 women). After completing the NIRS measurements, the subjects were asked to rate their level of proficiency in silent and oral reading, using a 5-point Likert scale. During oral reading, the left lateral prefrontal cortex (Broca's area) was significantly more active than the right side. During silent reading, prefrontal cortex activity was lower than that during oral reading, and there was no significant difference between both sides of the brain. A significant negative correlation was found between the change in oxy-hemoglobin (oxy-Hb) concentration in the left and right lateral prefrontal cortex during silent reading and silent reading speed. In addition, students with lower self-reported reading proficiency had significantly greater changes in oxy-Hb concentrations in the left and right lateral prefrontal cortex during silent/oral reading than did students with higher self-reported reading proficiency. Reading task assessment using NIRS may be useful for identifying language lateralization and Broca's area. The results demonstrate that NIRS is useful for assessing effortful reading and may be used to diagnose developmental dyslexia in children. J. Med. Invest. 71 : 92-101, February, 2024.
(キーワード)
近赤外分光法 (near infrared spectroscopy) / Silent and Oral Reading
Ruriko Yamashita, Kumi Takahashi, Keiko Mori, Takahiro Tayama, Mitsunori Daibatake, Hiroko Hashimoto, Mutsuki Nakano, Aya Goji, Tatsuo Mori and Kenji Mori : Hemodynamics of the left cerebral hemisphere during silent reading: analysis using near-infrared spectroscopy, The Journal of Medical Investigation : JMI, 71, 3.4, 267-272, 2024.
(要約)
The purpose of this study was to investigate the hemodynamic activity in the left cerebral hemisphere during silent reading in college students with typical development using near-infrared spectroscopy (NIRS). Sixty college students with typical development participated in this study. In the silent reading task, participants were asked to read a text from Andersen's fairy tale. Then, the change in oxygenated hemoglobin (oxy-Hb) concentration during silent reading of the text was calculated. The number of letters read during the silent reading task was also measured to calculate the silent reading speed. The average trend graph of 60 college students revealed increased oxy-Hb concentration in both the left inferior frontal gyrus (Broca's area) and the left inferior occipitotemporal gyrus during silent reading. A negative correlation was found between the change in oxy-Hb concentration in Broca's area and silent reading speed. A positive correlation was found between oxy-Hb concentration change in the left inferior occipitotemporal gyrus and silent reading speed. The increase in oxy-Hb concentration in Broca's area observed during silent reading may reflect effortful reading in students with reading difficulty. The increase in oxy-Hb concentration in the left inferior occipitotemporal gyrus observed during silent reading may reflect proficiency in reading. Our findings suggest the usefulness of NIRS in assessing reading function and its potential use in the diagnosis of developmental dyslexia. J. Med. Invest. 71 : 267-272, August, 2024.
Tatsuo Mori, Masamune Sakamoto, Takahiro Tayama, Aya Goji, Yoshihiro Toda, Atsushi Fujita, Takeshi Mizuguchi, Maki Urushihara and Naomichi Matsumoto : A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation., Brain & Development, 45, 7, 395-400, 2023.
(要約)
The patient was a 4-year-old girl. Mild developmental delay was observed during infancy. At the age of one and a half years, she developed atonic seizures once a month. At 4 years of age, her seizures increased to more than 10 times per hour. An ictal electroencephalogram (EEG) showed a 3-4-Hz spike-and-wave complex, which was consistent with atonic and myoclonic seizures of the trunk, eyelids, and lips. Therefore, EMAtS was diagnosed based on the symptoms and EEG findings. After administration of valproic acid (VPA), the epileptic seizures disappeared immediately. At the age of 5 years and 2 months, the seizures recurred but disappeared again when the dose of VPA was increased. Subsequently, no recurrence was observed until 6 years and 3 months of age on VPA and lamotrigine. Chromosome analysis of the patient disclosed 46,XX,t(3;11)(p25;q13.1)dn. Long-read sequencing of the the patient's genomic DNA revealed that the 3p25.3 translocation breakpoint disrupted the intron 7 of the SLC6A1 gene.
Oyundari Gonchigsuren, Masafumi Harada, Sonoka Hisaoka, Kohei Higashi, Yuki Matsumoto, Nami Sumida, Tatsuo Mori, Hiromichi Ito, Kenji Mori and Mitsuharu Miyoshi : Brain abnormalities in children with attention-deficit/hyperactivity disorder assessed by multi-delay arterial spin labeling perfusion and voxel-based morphometry, Japanese Journal of Radiology, 40, 6, 568-577, 2022.
(要約)
To obtain an understanding of the correlation between hemodynamic differences and morphological changes as well as potential sex differences in children with ADHD using multi-delay pseudo-continuous arterial spin labeling (pCASL) imaging and voxel-based morphometry (VBM), especially given that previous findings are limited for girls. We recruited 23 children with ADHD (mean age, 8.3 years; 19 boys; 4 girls) and 24 children without ADHD (mean age, 9.1 years; 13 boys; 11 girls) as controls. All participants underwent 3D multi-delay pCASL and T1-weighted imaging. The voxel-based statistical parameter mapping (SPM) method was used for group-wise comparisons. Compared with controls, children with ADHD exhibited decreased regional cerebral blood flow (rCBF) and gray matter volume (GMV) in the left middle frontal gyrus and left postcentral gyrus. Analysis by sex revealed reduced rCBF and GMV in the left lingual gyrus and left inferior occipital gyrus in boys with ADHD versus controls and increased rCBF and GMV in the left superior frontal gyrus in girls with ADHD. Although our results are preliminary because of small sample sizes, several brain regions exhibit changes in both cerebral perfusion and GMV in the same direction in patients with ADHD, with boys with ADHD showing decreased activity and girls with ADHD displaying increased activity in the fronto-parietal cortices.
Chihiro Kawai, Kenji Mori, Tetsuya Tanioka, Feni Betriana, Keiko Mori, Tatsuo Mori and Hiromichi Ito : Usefulness of near-infrared spectroscopy (Nirs) for evaluating drug effects and improvements in medication adherence in children with attention deficit hyperactivity disorder (adhd), The Journal of Medical Investigation : JMI, 68, 1.2, 53-58, 2021.
(要約)
The symptoms of attention deficit hyperactivity disorder (ADHD) are inattention, hyperactivity, and impulsiveness. Physicians often prescribe methylphenidate (MPH) for children with ADHD for long periods of time. The purpose of the present study was to investigate the usefulness of near-infrared spectroscopy (NIRS) for evaluating drug effects and improvements in medication adherence in children with ADHD. Subjects were 10 male children diagnosed with ADHD : average age, 9.3 years, and 10 boys with typical development : average age 9.5 years. Children with intellectual disability, autism, and obvious depressive symptoms were excluded. The present study revealed that in the ADHD group, oxy-Hb concentrations in the left and right lateral prefrontal cortex significantly increased during the execution of the Stroop color-word test in both channels when taking MPH. This method was considered to be useful for assessing drug effects on ADHD because NIRS is an objective indicator for evaluating ADHD executive dysfunction and visualizes the activation of frontal lobe function by MPH. A pediatric neurologist explained the results of NIRS while presenting images to the ADHD group, and medication adherence and the drug-taking ratio both markedly improved. Therefore, this therapeutic explanation is an effective strategy for improving medication compliance and adherence among patients. J. Med. Invest. 68 : 53--58, February, 2021.
(キーワード)
ADHD (attention deficit hyperactivity disorder) / Children / Frontal lobe function / Medication adherence / NIRS (near-infrared spectroscopy)
Ken-ichi Suga, Issei Imoto, Hiromichi Ito, Takuya Naruto, Aya Gohji, Keita Osumi, Narumi Tokaji, Yukako Homma, Akemi Ono, Yuko Ichihara, Miki Shono, Tatsuo Mori, Maki Urushihara, Ryuji Nakagawa, Yasunobu Hayabuchi and Shoji Kagami : Next-generation sequencing for the diagnosis of patients with congenital multiple anomalies and / or intellectual disabilities, The Journal of Medical Investigation : JMI, 67, 3, 4, 246-249, 2020.
(要約)
Background : In clinical practice, a large proportion of patients with multiple congenital anomalies and/or intellectual disabilities (MCA / ID) lacks a specific diagnosis. Recently, next-generation sequencing (NGS) has become an efficient strategy for genetic diagnosis of patients with MCA/ID. To review the utility of NGS for the diagnosis of patients with MCA / ID. Patients with MCA/ID were recruited between 2013 and 2017. Molecular diagnosis was performed using NGS-based targeted panel sequencing for 4,813 genes. Promising causative variants underwent confirmation by Sanger sequencing or chromosomal microarray. Eighteen patients with MCA/ID were enrolled in this study. Of them, 8 cases (44%) were diagnosed by targeted panel sequencing. Most of diagnosed patients were able to receive better counseling and more appropriate medical management. NGS-based targeted panel sequencing seems to be an effective testing strategy for diagnosis of patients with MCA/ID. J. Med. Invest. 67 : 246-249, August, 2020.
Keita Osumi, Ken-ichi Suga, Akemi Ono, Aya Gohji, Tatsuo Mori, Yukiko Kinoshita, Mikio Sugano, Yoshihiro Touda, Maki Urushihara, Ryuji Nakagawa, Yasunobu Hayabuchi, Issei Imoto and Shoji Kagami : Molecular diagnosis of an infant with TSC2/ PKD1 contiguous gene syndrome, Human Genome Variation, 7, 21, 2020.
(要約)
A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with / contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of and exons 2-46 of . Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease.
Kentaro Okamoto, Takahiro Motoki, Isao Saito, Risako Urate, Kaori Aibara, Toshihiro Jogamoto, Mitsumasa Fukuda, Hiroyuki Wakamoto, Satoshi Maniwa, Yoichi Kondo, Yoshihiro Toda, Aya Goji, Tatsuo Mori, Tomohiro Soga, Yukihiko Konishi, Shigehiro Nagai, Yoko Takami, Chiho Tokorodani, Ritsuo Nishiuchi, Daisuke Usui, Rina Ando, Satoshi Tada, Yuki Yamanishi, Masahiro Nagai, Reiko Arakawa, Kayoko Saito, Hisahide Nishio, Eiichi Ishii and Mariko Eguchi : Survey of patients with spinal muscular atrophy on the island of Shikoku, Japan., Brain & Development, 42, 8, 594-602, 2020.
(要約)
Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.
Takahiro Tayama, Tatsuo Mori, Aya Goji, Yoshihiro Toda and Shoji Kagami : Improvement of epilepsy with lacosamide in a patient with ring chromosome 20 syndrome., Brain & Development, 42, 6, 473-476, 2020.
(要約)
Although VPA and LTG are generally effective for the treatment of ring chromosome 20 syndrome, they do not completely suppress seizures. LCM can be considered an effective option for seizure control in patients with this syndrome.
Tatsuo Mori, Hiromichi Ito, Masafumi Harada, Sonoka Hisaoka, Yuki Matsumoto, Aya Goji, Yoshihiro Toda, Kenji Mori and Shoji Kagami : Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism., Brain & Development, 42, 4, 315-321, 2020.
(要約)
We concluded that patients with ASD showed a statistically significant decline in CBF in regions associated with the mirror neuron system. The advantages of ASL MRI include low invasiveness (no radiation exposure) and short imaging time (approximately 5 min). Studies with larger sample sizes are required to establish the diagnostic value of ASL MRI for ASD.
Tatsuo Mori, Yoshihiro Touda, Hiromichi Ito, Kenji Mori, Tomohiro Kohmoto, Issei Imoto and Shoji Kagami : A 16q22.2-q23.1 deletion identified in a male infant with West syndrome., Brain & Development, 2019.
(要約)
In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.
Hiromichi Ito, Kenji Mori, Masafumi Harada, Sonoka Hisaoka, Yoshihiro Touda, Tatsuo Mori, Aya Gohji, Yoko Abe, Masahito Miyazaki and Shoji Kagami : A Proton Magnetic Resonance Spectroscopic Study in Autism Spectrum Disorder Using a 3-Tesla Clinical Magnetic Resonance Imaging (MRI) System: The Anterior Cingulate Cortex and the Left Cerebellum., Journal of Child Neurology, 32, 8, 731-739, 2017.
(要約)
The pathophysiology of autism spectrum disorder (ASD) is not fully understood. We used proton magnetic resonance spectroscopy to investigate metabolite concentration ratios in the anterior cingulate cortex and left cerebellum in ASD. In the ACC and left cerebellum studies, the ASD group and intelligence quotient- and age-matched control group consisted of 112 and 114 subjects and 65 and 45 subjects, respectively. In the ASD group, γ-aminobutyric acid (GABA)+/ creatine/phosphocreatine (Cr) was significantly decreased in the anterior cingulate cortex, and glutamate (Glu)/Cr was significantly increased and GABA+/Cr was significantly decreased in the left cerebellum compared to those in the control group. In addition, both groups showed negative correlations between Glu/Cr and GABA+/Cr in the left cerebellum, and positive correlations between GABA+/Cr in the anterior cingulate cortex and left cerebellum. ASD subjects have hypoGABAergic alterations in the anterior cingulate cortex and hyperglutamatergic/hypoGABAergic alterations in the left cerebellum.
Aya Goji, Hiromichi Ito, Kenji Mori, Masafumi Harada, Sonoka Hisaoka, Yoshihiro Touda, Tatsuo Mori, Yoko Abe, Masahito Miyazaki and Shoji Kagami : Assessment of Anterior Cingulate Cortex (ACC) and Left Cerebellar Metabolism in Asperger's Syndrome with Proton Magnetic Resonance Spectroscopy (MRS)., PLoS ONE, 1, e0169288, 2017.
(要約)
Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging method to quantify biochemical metabolites in vivo and it can serve as a powerful tool to monitor neurobiochemical profiles in the brain. Asperger's syndrome (AS) is a type of autism spectrum disorder, which is characterized by impaired social skills and restrictive, repetitive patterns of interest and activities, while intellectual levels and language skills are relatively preserved. Despite clinical aspects have been well-characterized, neurometabolic profiling in the brain of AS remains to be clear. The present study used proton magnetic resonance spectroscopy (1H MRS) to investigate whether pediatric AS is associated with measurable neurometabolic abnormalities that can contribute new information on the neurobiological underpinnings of the disorder. Study participants consisted of 34 children with AS (2-12 years old; mean age 5.2 (±2.0); 28 boys) and 19 typically developed children (2-11 years old; mean age 5.6 (±2.6); 12 boys) who served as the normal control group. The 1H MRS data were obtained from two regions of interest: the anterior cingulate cortex (ACC) and left cerebellum. In the ACC, levels of N-acetylaspartate (NAA), total creatine (tCr), total choline-containing compounds (tCho) and myo-Inositol (mI) were significantly decreased in children with AS compared to controls. On the other hand, no significant group differences in any of the metabolites were found in the left cerebellum. Neither age nor sex accounted for the metabolic findings in the regions. The finding of decreased levels of NAA, tCr, tCho, and mI in the ACC but not in left cerebellar voxels in the AS, suggests a lower ACC neuronal density in the present AS cohort compared to controls.
Tomokazu Kimizu, Yukitoshi Takahashi, Taikan Oboshi, Asako Horino, Takayoshi Koike, Shinsaku Yoshitomi, Tatsuo Mori, Tokito Yamaguchi, Hiroko Ikeda, Nobuhiko Okamoto, Mitsuko Nakashima, Hirotomo Saitsu, Mitsuhiro Kato, Naomichi Matsumoto and Katsumi Imai : A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy., Brain & Development, 39, 3, 256-260, 2016.
(要約)
This report reviewed the clinical features of patients with a SLC35A2 mutation. ACTH therapy may be effective for refractory epilepsy in these patients.
(キーワード)
Age of Onset / Brain Diseases / Congenital Disorders of Glycosylation / Electroencephalography / Epilepsy / Female / Humans / Infant / Magnetic Resonance Imaging / Monosaccharide Transport Proteins / Mutation / Spasms, Infantile
Tatsuo Mori, Yukitoshi Takahashi, Nami Araya, Taikan Oboshi, Hirokazu Watanabe, Kazuki Tsukamoto, Tokito Yamaguchi, Shinsaku Yoshitomi, Hirosato Nasu, Hiroko Ikeda, Hideyuki Otani, Katsumi Imai, Hideo Shigematsu and Yushi Inoue : Antibodies against peptides of NMDA-type GluR in cerebrospinal fluid of patients with epileptic spasms., European Journal of Paediatric Neurology, 20, 6, 865-873, 2016.
(要約)
The levels of antibodies against the n-terminal of GluN2B (GluN2B-NT2), c-terminal of GluN2B (GluN2B-CT) and n-terminal of GluN1 (GluN1-NT), were significantly higher in patients with ES than in disease controls (p < 0.01, p < 0.01 & p = 0.03). Levels of antibodies to GluN2B-NT2 & CT were not related with ACTH therapy nor conventional CSF factors (cell counts, protein level, etc). Levels of antibodies to GluN2B-NT2 & CT showed evidence of correlation within a linear regression model with intervals from the onset to the examination of CSF until 25 months (p = 0.01 & p = 0.01). The correlation was significant in patients with unknown cause (p = 0.01). Five of 33 patients (four unknown cause & one chromosomal anomaly) had higher level of antibodies to GluN2B-NT2 exceeding mean + 1 SD of all ES patients, and they had poor motor (score 0) and cognitive outcomes (score 0 or 1).
Tatsuo Mori, Katsumi Imai, Taikan Oboshi, Yuh Fujiwara, Saoko Takeshita, Hirotomo Saitsu, Naomichi Matsumoto, Yukitoshi Takahashi and Yushi Inoue : Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy., Brain & Development, 38, 6, 601-604, 2016.
(要約)
Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion. Ictal scalp electroencephalogram showed migrating focal seizures. MPSI was suspected and she was transferred to our hospital for further treatment. Potassium bromide (KBr) was partially effective, but the effect was transient. High-dose KBr caused severe adverse effects such as over-sedation and hypercapnia, with no further effects on the seizures. At age 9months, we started a ketogenic diet, which improved seizure frequency and severity without obvious adverse effects, allowing her to be discharged from hospital. Ketogenic diet should be tried in patients with MPSI unresponsive to antiepileptic drugs. In MPSI, the difference in treatment response in patients with and those without KCNT1 mutation remains unknown. Accumulation of case reports would contribute to establish effective treatment options for MPSI.
Kenji Mori, Yoshihiro Touda, Hiromichi Ito, Tatsuo Mori, Keiko Mori, Aya Goji, Hiroko Hashimoto, Hiroe Tani, Masahito Miyazaki, Masafumi Harada and Shoji Kagami : Neuroimaging in autism spectrum disorders: 1H-MRS and NIRS study, The Journal of Medical Investigation : JMI, 62, 1-2, 29-36, 2015.
(要約)
Using proton magnetic resonance spectroscopy ((1)H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N-acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of ASD. We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD.
Tatsuo Mori, Kenji Mori, Hiromichi Ito, Aya Goji, Masahito Miyazaki, Masafumi Harada, Kenji Kurosawa and Shoji Kagami : Age-related changes in a patient with Pelizaeus-Merzbacher disease determined by repeated 1H-magnetic resonance spectroscopy., Journal of Child Neurology, 29, 2, 283-288, 2014.
(要約)
A boy with Pelizaeus-Merzbacher disease underwent repeated evaluations by 3-Tesla (1)H-magnetic resonance spectroscopy (MRS). The patient showed overlap of the PLP1. Individuals selected as normal controls for (1)H-magnetic resonance spectroscopy consisted of healthy age-matched children. For (1)H-magnetic resonance spectroscopy, the center of a voxel was positioned in the right parietal lobe. (1)H-magnetic resonance spectroscopy was performed when the patient was 2, 6, 14, and 25 months old. γ-Aminobutyric acid concentration in early childhood was increased compared with that in normal controls. However, the γ-aminobutyric acid concentration in the Pelizaeus-Merzbacher disease patient was normalized at 14 and 25 months. No remarkable changes were observed in choline-containing compounds concentration at any time. These results suggest that the changes in metabolite concentrations during growth can reflect the pathological condition of Pelizaeus-Merzbacher disease. Furthermore, the lack of change in the choline-containing compounds concentration can be useful for differentiating Pelizaeus-Merzbacher disease from other white matter disorders.
Tatsuo Mori, Kenji Mori, Masashi Suzue, Hiromichi Ito and Shoji Kagami : Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus, Brain & Development, 35, 5, 445-448, 2013.
(要約)
Over the past several years, tacrolimus has attracted attention as a new therapeutic drug for myasthenia gravis (MG), but few reports have considered its use for MG in pediatric patients, and most of these have focused on severe systemic MG. In this case report, we used tacrolimus to successfully treat a 13-year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis. He first showed symptoms of ocular MG at age 2 years 3 months. At age 13 years, he was receiving PSL (3.75 mg/day), but the symptoms of ocular MG recurred. We increased the dosage of oral PSL up to 30 mg/day, and three courses of mPSL pulse therapy were applied, but these therapies had only limited effect, and his symptoms worsened. Tacrolimus was started at 0.4 mg/day (0.011 mg/kg/day), and every 2 weeks the dose was gradually increased by 0.2 mg/day. His symptoms of MG began to improve 3 weeks after the initial administration of tacrolimus. Approximately 3 months after the start of tacrolimus administration, PSL was discontinued. Currently, at 1 year and 4 months after the start of tacrolimus administration, while slight ptosis is observed in the evening, it does not influence his daily life, and his condition remains comparable to that when he stopped taking PSL. No adverse effects of tacrolimus have been recognized. In pediatric patients with steroid-dependent ocular MG without thymectomy, tacrolimus may be a safe and effective alternative to steroid and thymectomy.
Kenji Mori, Yoshihiro Toda, Hiromichi Ito, Tatsuo Mori, Aya Goji, Emiko Fujii, Masahito Miyazaki, Masafumi Harada and Shoji Kagami : A proton magnetic resonance spectroscopic study in autism spectrum disorders: Amygdala and orbito-frontal cortex, Brain & Development, 35, 2, 139-145, 2012.
(要約)
We previously reported neural dysfunction in the anterior cingulate cortex and dorsolateral prefrontal cortex in autistic patients using proton magnetic resonance spectroscopy ((1)H-MRS). In this investigation, we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC), which are the main components of the social brain. We also examined the association between these metabolic findings and social abilities in subjects with autism. The study group included 77 autistic patients (3-6years old; mean age 4.1; 57 boys and 20 girls). The control subjects were 31 children (3-6years old; mean age 4.0; 23 boys and 8 girls). Conventional proton MR spectra were obtained using the STEAM sequence with parameters of TR=5 sec and TE=15 msec by a 1.5-tesla clinical MRI system. We analyzed the concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) using LCModel (Ver. 6.1). The concentrations of NAA in the left amygdala and the bilateral OFC in autistic patients were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in autism. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of autism.
Tatsuo Mori, Kenji Mori, Emiko Fujii, Yoshihiro Touda, Masahito Miyazaki, Masafumi Harada, Toshiaki Hashimoto and Shoji Kagami : Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study., Brain & Development, 34, 8, 648-654, 2012.
(要約)
To evaluate the GABA(A) receptor in the autistic brain, we performed (123)I-IMZ SPECT in patients with ASD. We compared (123)I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. The subjects consisted of 24 patients with ASD (mean age, 7.3±3.5 years), including 9 with autistic disorder (mean age, 7.0±3.7 years) and 15 with Asperger's disorder (mean age, 7.5±3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8±3.6 years) without intellectual delay as a control group. For an objective evaluation of the (123)I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of (123)I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of (123)I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).
Tatsuo Mori, Kenji Mori, Emiko Fujii, Yoshihiro Touda, Masahito Miyazaki, Masafumi Harada and Shoji Kagami : Neuroradiological and neurofunctional examinations for patients with 22q11.2 deletion., Neuropediatrics, 42, 6, 215-221, 2011.
(要約)
Since the neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 22q11.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery patterns and decreased accumulation of IMZ in 123I-IMZ SPECT. Although all 4 patients showed epileptic discharges in their electroencephalograms (EEG), one patient with polymicrogyria had no seizure episodes. Decreases in γ-aminobutyric acid (GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome.
Kenji Mori, Tatsuo Mori, Yoshihiro Toda, Emiko Fujii, Masahito Miyazaki, Masafumi Harada and Shoji Kagami : Decreased benzodiazepine receptor and increased GABA level in cortical tubers in tuberous sclerosis complex, Brain & Development, 34, 6, 478-486, 2011.
(要約)
To elucidate the functional characteristics of cortical tubers that might be responsible for epilepsy in tuberous sclerosis complex (TSC), proton magnetic resonance spectroscopy ((1)H-MRS) and [123I] iomazenil (123I-IMZ) single photon emission computed tomography (SPECT) were performed. (1)H-MRS using a clinical 3-tesla magnetic resonance imager was performed in four children with TSC and 10 age-and sex-matched healthy control subjects. A single voxel was set on the right parietal lobe in control subjects. In patients with TSC, a single voxel was set on the epileptogenic tuber in the parietal or temporal lobe, and another voxel was set on the contralateral normal-appearing brain region. N-Acetylaspartate (NAA), myo-Inositol (mIns) and Glutamate (Glu) were analyzed using a conventional STEAM (Stimulated Echo Acquisition Mode) method. The concentration of gamma-aminobutyric acid (GABA) was quantified using MEGA-Point Resolved Spectroscopy (PRESS). Interictal 123I-IMZ SPECT was examined in all four patients with TSC. A significant decrease in the NAA concentration and significant increases in the mIns and GABA concentrations were detected in the cortical tubers of all 4 patients. No significant difference was observed in Glu concentrations. In all of the cortical tubers detected by magnetic resonance imaging, 123I-IMZ binding was significantly decreased. Epileptogenesis in TSC might be caused by decreased inhibition secondary to the decrease in GABA receptors in dysplastic neurons of cortical tubers. An increase in the GABA concentration may compensate for decreased inhibition.
Narumi Tokaji, Hiromichi Ito, Tomohiro Kohmoto, Takuya Naruto, Rizu Takahashi, Aya Gohji, Tatsuo Mori, Yoshihiro Touda, Masako Saito, Shoichiro Tange, Kiyoshi Masuda, Shoji Kagami and Issei Imoto : A rare male patient with classic Rett syndrome caused by MeCP2_e1 mutation, American Journal of Medical Genetics. Part A., 176A, 3, 699-702, 2018.
(要約)
Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype.
(キーワード)
Alternative Splicing / Base Sequence / 脳 (brain) / Child, Preschool / DNA Mutational Analysis / Exons / Genetic Association Studies / Genetic Predisposition to Disease / Humans / 磁気共鳴映像法 (magnetic resonance imaging) / 男性 (male) / Methyl-CpG-Binding Protein 2 / Mutation / Phenotype / Rett Syndrome
Hiromichi Ito, Kenji Mori, Tatsuo Mori, A Goji and Shoji Kagami : Case of early childhood-onset narcolepsy with cataplexy: comparison with a monozygotic co-twin., Pediatrics International, 56, 5, 789-793, 2014.
(要約)
We describe here a rare case of early childhood-onset (5 years of age) narcolepsy. This case was interesting because of the ability to compare the patient's symptoms to the condition of her healthy monozygotic co-twin sister. The only environmental difference between the co-twins was head injury, which may be associated with the presence of narcolepsy. The co-twin was extroverted, sociable, reliable, and dexterous. In contrast, the patient could be described as introverted, gentle, honest and persevering, but was weak at conversation, assessment of a situation, memory, planning, activity (she was inactive), a sense of time, understanding of an analog clock, operating efficiency, and physical education (due to obesity). The sisters showed the same degree of appetite and dexterity with their fingers. Narcolepsy is often under-recognized or underdiagnosed, especially when the onset occurs in childhood. When we observe preschoolers with excessive daytime sleepiness, we should consider the possibility of narcolepsy with cataplexy.
Aya Gohji, Hiromichi Ito, N Tokaji, T Kohmoto, T Naruto, R Takahashi, Tatsuo Mori, Yoshihiro Touda, M Saito, S Tange, K Masuda, Shoji Kagami and I Imoto : A Rare Male Patient with Classic Rett Syndrome Caused by MeCP2_e1 Mutation., ASHG 2017 annual meeting, Oct. 2017.
2.
Aya Gohji, Hiromichi Ito, Kenji Mori, S Hisaoka, Yoshihiro Touda, Tatsuo Mori, Y Abe, M Miyazaki and Shoji Kagami : Metabolic dysfunction in anterior cingulate cortex using a magnetic resonance spectroscopy in Asperger's syndrome., Pediatric Academic Societies Meeting, May 2016.
Aya Gohji, Hiroyuki Morino, Asami Okada, Tatsuo Mori, Ken-ichi Suga, Yumiko Kotani, 瀬山 理惠, 内山 由理 and 松本 直通 : Coffin-siris syndrome with persistent open anterior fontanelle in a boy arising from a novel de novo ARID2 variant, 日本人類遺伝学会第67回大会, Dec. 2022.