Mitsugu Uematsu - Academia.edu (original) (raw)
Papers by Mitsugu Uematsu
Scientific Reports, May 17, 2022
CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching... more CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2-and Caspspecific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that
Brain & development, 2018
Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently... more Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinic...
Brain & development, Jan 10, 2015
We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cer... more We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome.
Brain & development, Jan 3, 2015
Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for... more Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for humoral immune reactions in central nervous system (CNS) demyelinating diseases, and the results indicated a possible role of these antibodies in the pathogenesis of various demyelinating diseases. To investigate the antibody titer levels against myelin-oligodendrocyte glycoprotein and aquaporin-4 in pediatric patients with inflammatory CNS disorders, and to evaluate clinical significance to study anti-myelin-oligodendrocyte glycoprotein antibodies. Sera at onset from patients with acute disseminated encephalomyelitis (ADEM) in 7, optic neuritis (ON) in 5, pediatric MS in 4 and neuromyelitis optica in one were tested for myelin-oligodendrocyte glycoprotein and aquaporin-4 antibodies using cell-based assays with live transfected cells. The duration of the observation periods ranged from 1 to 21years (median, 10years). We also described clinical course of patients with positive anti-myeli...
No to hattatsu. Brain and development, 2013
Neuroscience letters, Jan 26, 2013
Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged unilatera... more Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged unilateral hemisphere with cortical malformation comprising abnormal hypertrophic cells. To address the proliferative status of HMG, Ki-67 immunoreactivity was investigated in HMG specimens obtained during epilepsy surgery. Nine HMG tissues were stained with a Ki-67 antibody and Ki-67 labeling index in the malformed cortex, and the underlying white matter was measured separately and compared with tissues from focal cortical dysplasias and normal brains from autopsy. In HMG tissues, Ki-67-positive cells were scattered in both the gray and white matter, with a significantly higher Ki-67 labeling index in the white matter compared with gray matter. No dysmorphic neuron or balloon cell was stained for Ki-67. As Ki-67 immunoreactivity overlapped with that of ionized calcium-binding adaptor protein-1, Ki-67-positive cells were identified as microglia. In HMG, microglia were activated and entered into a...
No shinkei geka. Neurological surgery, 2013
Identification of primary epileptogenic tuber is often challenging in patients with bilateral mul... more Identification of primary epileptogenic tuber is often challenging in patients with bilateral multiple tubers in tuberous sclerosis complex. We report a 3 year old girl with tuberous sclerosis complex presenting with intractable epilepsy and multiple tubers, who was successfully treated by corpus callosotomy and subsequent resective surgery. She initially presented with West syndrome which was intractable to ACTH therapy and multiple antiepileptic medications. Her EEG was characterized by generalized and multifocal spikes, and by non-focal changes at seizure onset. Ictal single photon emission computed tomography(SPECT)showed no focal hyperperfusion. Total corpus callosotomy was performed to alleviate her drop attacks. Post-operatively, interictal spikes were completely lateralized to the right hemisphere. Since her seizures were still kept uncontrolled with medications, second pre-surgical evaluation was planned and ictal SPECT disclosed focal hyperperfusion at a tuber in the right...
No to hattatsu. Brain and development, 2011
Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica ... more Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica (NMO), and its target antigen was identified as aquaporin 4 (AQP4) water channel protein. There is no clinical picture of pediatric cases with anti-AQP4 antibody, except one report from North America. Here, we report the clinical features of 18 Japanese anti-AQP4-antibody-positive patients with childhood-onset of NMO. Of the 2000 patients who had been examined for anti-AQP4 antibody at Tohoku University Hospital up until 2008, 60 were under 15 years of age at onset, and 18 of them were positive for anti-AQP4 antibody. We analyzed the clinical information on those patients. There were 14 girls and 4 boys (M:F ratio = 1:3.5). The age of onset ranged from 3 to 15 years old (median 13). The clinical diagnoses of the 18 patients before the anti-AQP4 antibody tests were: NMO in 8 (44%), MS in 7 (39%), and opticospinal MS (OSMS) in 3 (17%). Nine patients developed only optic neuritis at onset. ...
Journal of the Neurological Sciences, 2011
Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease... more Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.
Journal of Child Neurology, 2009
The authors present a 14-year-old girl with 18q— syndrome combined with cyclic vomiting syndrome.... more The authors present a 14-year-old girl with 18q— syndrome combined with cyclic vomiting syndrome. Since the age of 5 years, she has been admitted to hospital 30 times. Despite trying many prophylactic treatments, no medication has inhibited the vomiting attacks successfully. Intranasal sumatriptan was effective at halting the vomiting attacks. This is the first case of 18q— syndrome combined with cyclic vomiting syndrome successfully treated with sumatriptan. This report may allow us to consider sumatriptan use in patients suffering from misery attack of cyclic vomiting syndrome combined with chromosomal abnormality of 18q— syndrome.
Human Mutation, 2010
Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes... more Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes of childhood epileptic disorders, as typified by Dravet syndrome. Here we investigated the upstream regions of the SCN1A 5' noncoding exons and found two major regions with promoter activity. These two major promoters were simultaneously active in various brain regions and in most neurons. Using multiplex ligation-dependent probe amplification (MLPA) assays with probes for the 5' noncoding exons, their upstream regions, and all coding exons of SCN1A, we investigated 130 epileptic patients who did not show any SCN1A mutations by sequence analysis of all coding exons and exon-intron boundaries. Among 71 Dravet syndrome patients, we found two patients with heterozygous microdeletions removing the 5' noncoding exons and regions with promoter activity but not affecting the coding exons. We also identified four patients with deletions/duplication in the coding region. One patient with symptomatic focal epilepsy also showed a deletion in the coding region. This study provides the first case of microdeletion limited to the SCN1A 5' promoter region with the coding sequence preserved, and indicates the critical involvement of this upstream region in the molecular pathology of Dravet syndrome.
Epilepsy Research, 2009
To compare the incidence of West syndrome (WS) and early infantile epileptic encephalopathy (EIEE... more To compare the incidence of West syndrome (WS) and early infantile epileptic encephalopathy (EIEE) in Miyagi Prefecture, Japan, we studied retrospectively the medical records of cases involving WS or EIEE for the period 2000-2005. During this period, 45 children developed WS and one child was diagnosed with EIEE. The estimated incidence rates of WS and EIEE were 4.2 per 10,000 live births (95% CI, 3.0-5.5) and 0.1 per 10,000 live births (95% CI, 0-0.3), respectively. The occurrence of EIEE was one-fortieth that of WS.
Epilepsia, 2011
SummaryPurpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been... more SummaryPurpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome.Methods: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms.Key Findings: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8–184 months). All children had status epilepticus followed by coma as...
Epilepsia, 2010
SummaryWe, for the first time, used functional neuroimaging analyses for a girl with early myoclo... more SummaryWe, for the first time, used functional neuroimaging analyses for a girl with early myoclonic encephalopathy (EME). The interictal single photon emission computed tomography (SPECT) and [18F]‐fluoro‐d‐deoxyglucose positron emission tomography (FDG‐PET) at 1 month of age showed hypoperfusion and hypometabolism of bilateral basal ganglia, thalami, and the right parietooccipital cerebral cortices, showing that there is profound dysfunction of the basal ganglia and thalamus as well as cerebral cortex. On the other hand, subtraction ictal SPECT of tonic spasms clearly showed hyperperfusion of the bilateral basal ganglia, thalami, brainstem, and deep cortical layer of bilateral frontoparietal cortices. The present study suggests that functional deafferentation of the cortex from subcortical structures exists in EME, and that these imaging abnormalities may provide insight into the pathophysiology of suppression‐burst pattern in EME.
Brain & Development, Sep 1, 2016
Background: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage dis... more Background: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse. Patient: The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole-exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM * 605248): c.410T>C (p.Leu137Pro) and c.802_803delAG (p.Ser268Trpfs*17). Although his clinical course was mild (due to a lack of corneal clouding), other relevant features were present. These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2 years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed. Discussion: The present results suggest that MLIV could be added as a differential diagnosis for white matter disorders, regardless of ethnicity. Beyond neurological or ophthalmologic findings, serum gastrin could be a useful diagnostic marker for MLIV.
Epilepsy & Behavior Reports, 2021
We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epi... more We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.
Pediatric neurosurgery, Jan 6, 2015
Hemispheric epileptogenic lesions such as hemimegalencephaly often manifest as intractable epilep... more Hemispheric epileptogenic lesions such as hemimegalencephaly often manifest as intractable epilepsy in early infancy. Hemispherotomy is the treatment of choice for controlling intractable hemispheric epilepsy. Less invasive procedures are desirable for surgery on infants with low body weight. This study compared our experience with interhemispheric vertical hemispherotomy (IVH) and peri-insular lateral hemispherotomy (PIH). Thirteen consecutive patients underwent hemispherotomy for treatment of intractable epilepsy in our institution between 2001 and 2012. The etiology of epilepsy included hemimegalencephaly in 7 patients and cortical dysplasia in 3. PIH was performed on the first 5 patients and IVH on the last 8 patients. In the latter procedure, complete section of the corpus callosum was first performed via the interhemispheric approach. After removing part of the cingulate gyrus, section of the descending fibers was performed anterolaterally to the thalamus. Clinical characteris...
Journal of the neurological sciences, Jan 15, 2015
We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules... more We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules in patients with uncomplicated influenza (n=20) and influenza virus-associated encephalopathy (IE) (n=18) to understand the underlying mechanism of IE. We found that IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, G-CSF, GM-CSF, TNF-α, TIMP-1, MMP-9, sE-selectin, and neutrophil elastase were elevated significantly in sera from patients with uncomplicated influenza and those with IE, compared with normal controls (n=20). Of note, neutrophil elastase, sE-selectin, IL-8, and IL-13 were elevated significantly in IE as compared with uncomplicated influenza. In the present study, for the first time, we found that serum levels of neutrophil elastase were increased in patients with IE compared with uncomplicated influenza, which suggested that cerebral endothelial damage in the development of IE was mediated by neutrophil elastase. The present study implied that anti-elastase agents are poss...
Pediatrics international : official journal of the Japan Pediatric Society, 2014
We read with great interest the article by Takahashi et al. concerning the fifth nationwide surve... more We read with great interest the article by Takahashi et al. concerning the fifth nationwide survey in Japan on vitamin K prophylaxis and late vitamin K deficiency bleeding (VKDB) in infants. In Japan, the frequency of VKDB in infants has decreased significantly since the recommendation made in 1998 that every newborn should receive oral vitamin K prophylaxis with a syrup preparation of menaquinone-4 (vitamin K2[20]) on the day of birth, on the day of discharge from the maternity ward, and at 1 month of age, at a dose of 2 mg on each occasion. But cases of VKDB still occur. The present patient was a Japanese girl born at 40 weeks of gestation at a maternity hospital. She received the first prophylactic 2 mg oral dose of menaquinone-4 (vitamin K2[20]) at 3 days of age and did not receive the second dose on the day of discharge at the maternity hospital. Although she had a medical check-up at the same hospital at 31 days of age, she did not receive the third prophylactic dose of vitamin K2[20]. It was the normal practice of this maternity hospital to give only one dose of vitamin K2[20]. The patient was admitted to the Japanese Red Cross Morioka Hospital at 46 days of age because of persistent crying. On admission she was pale, hypoactive, and had no traumatic injury to her body. Investigations showed a low hemoglobin count of 5.4 g/ dL, a platelet count of 531 × 10/μL, prothrombin and partial thromboplastin times >88 s and 180 s, respectively (vs control times of 11–12 and 50–60 s, respectively), protein induced by vitamin K absence-II (PIVKA-II) at 194 000 mAU/mL (ELISA method, Eisai, Tokyo, Japan; normally <130 mAU/mL), and fibrin degradation product 158 mg/dL (normally <10 mg/dL). Computed tomography of the head indicated unilateral acute subdural hematomas (Fig. 1). The patient immediately received i.v. vitamin K1 (phytomenadione, 2 mg) and the abnormal hemostatic parameters improved. She also received a transfusion of packed red blood cells, as well as a craniotomy and hematoma evacuation. No evidence of an inflammatory reaction was observed. Metabolic screens for amino and organic acids were negative. No evidence of abuse or inadequate child rearing (such as shaken baby syndrome) was observed. The patient was diagnosed with late VKDB. At 1 year of age, the patient had favorable growth and no neurological sequelae. Infants who are born in some Japanese maternity hospitals do not receive prophylactic vitamin K in accordance with recommendations. Several years ago, we treated another infant with VKDB who had not received vitamin K at another maternity hospital and an infant who received only an unknown Chinese herbal drug for prophylaxis of VKDB at yet another maternity hospital. The total membership of the Japan Pediatric Society at the time was approximately 20 000 people, only approximately 100 of whom were not pediatricians (Japan Pediatric Society, unpubl. data, 2005). We reasoned that almost all of the obstetricians and maternity nurses who worked in maternity hospitals did not Correspondence: Akimune Kaga, MD PhD, Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Email: kagakimune@yahoo.co.jp Received 25 June 2013; revised 17 October 2013; accepted 22 October 2013. doi: 10.1111/ped.12265 Fig. 1 Computed tomography scan of the head showing unilateral acute subdural hematomas. bs_bs_banner
Scientific Reports, May 17, 2022
CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching... more CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2-and Caspspecific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that
Brain & development, 2018
Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently... more Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinic...
Brain & development, Jan 10, 2015
We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cer... more We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome.
Brain & development, Jan 3, 2015
Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for... more Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for humoral immune reactions in central nervous system (CNS) demyelinating diseases, and the results indicated a possible role of these antibodies in the pathogenesis of various demyelinating diseases. To investigate the antibody titer levels against myelin-oligodendrocyte glycoprotein and aquaporin-4 in pediatric patients with inflammatory CNS disorders, and to evaluate clinical significance to study anti-myelin-oligodendrocyte glycoprotein antibodies. Sera at onset from patients with acute disseminated encephalomyelitis (ADEM) in 7, optic neuritis (ON) in 5, pediatric MS in 4 and neuromyelitis optica in one were tested for myelin-oligodendrocyte glycoprotein and aquaporin-4 antibodies using cell-based assays with live transfected cells. The duration of the observation periods ranged from 1 to 21years (median, 10years). We also described clinical course of patients with positive anti-myeli...
No to hattatsu. Brain and development, 2013
Neuroscience letters, Jan 26, 2013
Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged unilatera... more Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged unilateral hemisphere with cortical malformation comprising abnormal hypertrophic cells. To address the proliferative status of HMG, Ki-67 immunoreactivity was investigated in HMG specimens obtained during epilepsy surgery. Nine HMG tissues were stained with a Ki-67 antibody and Ki-67 labeling index in the malformed cortex, and the underlying white matter was measured separately and compared with tissues from focal cortical dysplasias and normal brains from autopsy. In HMG tissues, Ki-67-positive cells were scattered in both the gray and white matter, with a significantly higher Ki-67 labeling index in the white matter compared with gray matter. No dysmorphic neuron or balloon cell was stained for Ki-67. As Ki-67 immunoreactivity overlapped with that of ionized calcium-binding adaptor protein-1, Ki-67-positive cells were identified as microglia. In HMG, microglia were activated and entered into a...
No shinkei geka. Neurological surgery, 2013
Identification of primary epileptogenic tuber is often challenging in patients with bilateral mul... more Identification of primary epileptogenic tuber is often challenging in patients with bilateral multiple tubers in tuberous sclerosis complex. We report a 3 year old girl with tuberous sclerosis complex presenting with intractable epilepsy and multiple tubers, who was successfully treated by corpus callosotomy and subsequent resective surgery. She initially presented with West syndrome which was intractable to ACTH therapy and multiple antiepileptic medications. Her EEG was characterized by generalized and multifocal spikes, and by non-focal changes at seizure onset. Ictal single photon emission computed tomography(SPECT)showed no focal hyperperfusion. Total corpus callosotomy was performed to alleviate her drop attacks. Post-operatively, interictal spikes were completely lateralized to the right hemisphere. Since her seizures were still kept uncontrolled with medications, second pre-surgical evaluation was planned and ictal SPECT disclosed focal hyperperfusion at a tuber in the right...
No to hattatsu. Brain and development, 2011
Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica ... more Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica (NMO), and its target antigen was identified as aquaporin 4 (AQP4) water channel protein. There is no clinical picture of pediatric cases with anti-AQP4 antibody, except one report from North America. Here, we report the clinical features of 18 Japanese anti-AQP4-antibody-positive patients with childhood-onset of NMO. Of the 2000 patients who had been examined for anti-AQP4 antibody at Tohoku University Hospital up until 2008, 60 were under 15 years of age at onset, and 18 of them were positive for anti-AQP4 antibody. We analyzed the clinical information on those patients. There were 14 girls and 4 boys (M:F ratio = 1:3.5). The age of onset ranged from 3 to 15 years old (median 13). The clinical diagnoses of the 18 patients before the anti-AQP4 antibody tests were: NMO in 8 (44%), MS in 7 (39%), and opticospinal MS (OSMS) in 3 (17%). Nine patients developed only optic neuritis at onset. ...
Journal of the Neurological Sciences, 2011
Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease... more Hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) is a rare disease, characterized by both central and peripheral hypomyelination. We describe a 21-year-old male with mildly progressive ataxia, mental retardation, pituitary hypogonadotropic hypogonadism, delayed dentition, and cataract. Brain magnetic resonance imaging showed hypomyelinated white matter, cerebellar atrophy, and a thin corpus callosum. The literature suggests that abnormal findings upon sural nerve biopsy may indicate peripheral hypomyelination, even in the absence of clinically and physiologically evident peripheral neuropathy. A sural nerve biopsy of this patient was normal, and this finding is further discussed. Taken together with previous reports, this case suggests that 4H syndrome can be regarded as a spectrum disorder, the cardinal signs of which may be central hypomyelination, ataxia, hypogonadotropic hypogonadism, and hypodontia.
Journal of Child Neurology, 2009
The authors present a 14-year-old girl with 18q— syndrome combined with cyclic vomiting syndrome.... more The authors present a 14-year-old girl with 18q— syndrome combined with cyclic vomiting syndrome. Since the age of 5 years, she has been admitted to hospital 30 times. Despite trying many prophylactic treatments, no medication has inhibited the vomiting attacks successfully. Intranasal sumatriptan was effective at halting the vomiting attacks. This is the first case of 18q— syndrome combined with cyclic vomiting syndrome successfully treated with sumatriptan. This report may allow us to consider sumatriptan use in patients suffering from misery attack of cyclic vomiting syndrome combined with chromosomal abnormality of 18q— syndrome.
Human Mutation, 2010
Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes... more Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes of childhood epileptic disorders, as typified by Dravet syndrome. Here we investigated the upstream regions of the SCN1A 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; noncoding exons and found two major regions with promoter activity. These two major promoters were simultaneously active in various brain regions and in most neurons. Using multiplex ligation-dependent probe amplification (MLPA) assays with probes for the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; noncoding exons, their upstream regions, and all coding exons of SCN1A, we investigated 130 epileptic patients who did not show any SCN1A mutations by sequence analysis of all coding exons and exon-intron boundaries. Among 71 Dravet syndrome patients, we found two patients with heterozygous microdeletions removing the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; noncoding exons and regions with promoter activity but not affecting the coding exons. We also identified four patients with deletions/duplication in the coding region. One patient with symptomatic focal epilepsy also showed a deletion in the coding region. This study provides the first case of microdeletion limited to the SCN1A 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; promoter region with the coding sequence preserved, and indicates the critical involvement of this upstream region in the molecular pathology of Dravet syndrome.
Epilepsy Research, 2009
To compare the incidence of West syndrome (WS) and early infantile epileptic encephalopathy (EIEE... more To compare the incidence of West syndrome (WS) and early infantile epileptic encephalopathy (EIEE) in Miyagi Prefecture, Japan, we studied retrospectively the medical records of cases involving WS or EIEE for the period 2000-2005. During this period, 45 children developed WS and one child was diagnosed with EIEE. The estimated incidence rates of WS and EIEE were 4.2 per 10,000 live births (95% CI, 3.0-5.5) and 0.1 per 10,000 live births (95% CI, 0-0.3), respectively. The occurrence of EIEE was one-fortieth that of WS.
Epilepsia, 2011
SummaryPurpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been... more SummaryPurpose: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome.Methods: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms.Key Findings: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8–184 months). All children had status epilepticus followed by coma as...
Epilepsia, 2010
SummaryWe, for the first time, used functional neuroimaging analyses for a girl with early myoclo... more SummaryWe, for the first time, used functional neuroimaging analyses for a girl with early myoclonic encephalopathy (EME). The interictal single photon emission computed tomography (SPECT) and [18F]‐fluoro‐d‐deoxyglucose positron emission tomography (FDG‐PET) at 1 month of age showed hypoperfusion and hypometabolism of bilateral basal ganglia, thalami, and the right parietooccipital cerebral cortices, showing that there is profound dysfunction of the basal ganglia and thalamus as well as cerebral cortex. On the other hand, subtraction ictal SPECT of tonic spasms clearly showed hyperperfusion of the bilateral basal ganglia, thalami, brainstem, and deep cortical layer of bilateral frontoparietal cortices. The present study suggests that functional deafferentation of the cortex from subcortical structures exists in EME, and that these imaging abnormalities may provide insight into the pathophysiology of suppression‐burst pattern in EME.
Brain & Development, Sep 1, 2016
Background: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage dis... more Background: Mucolipidosis IV (MLIV; OMIM #252650) is an autosomal recessive lysosomal storage disorder, frequently observed in the Ashkenazi Jewish population. MLIV typically results in intellectual disability, corneal opacities, and delayed motor milestones during infancy, with a relatively static course. To date, reports of MLIV in other ethnic groups have been sparse. Patient: The present study is a case report of a 9-year-old Japanese boy, diagnosed via whole-exome sequencing, with compound heterozygous mutations of MCOLN1 (OMIM * 605248): c.410T>C (p.Leu137Pro) and c.802_803delAG (p.Ser268Trpfs*17). Although his clinical course was mild (due to a lack of corneal clouding), other relevant features were present. These included strabismus, white matter signal abnormalities, and a hypoplastic corpus callosum at 2 years of age. After a molecular diagnosis, a markedly elevated serum gastrin level (which is also common in MLIV) was confirmed. Discussion: The present results suggest that MLIV could be added as a differential diagnosis for white matter disorders, regardless of ethnicity. Beyond neurological or ophthalmologic findings, serum gastrin could be a useful diagnostic marker for MLIV.
Epilepsy & Behavior Reports, 2021
We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epi... more We report a patient with a 6q22.1 deletion, who presented with a rare syndrome of generalized epilepsy, myoclonic tremor, and intellectual disability. There was no clinical progression after follow-up for more than 10 years. Our report presents the genetic basis for a phenotype involving a non-progressive generalized epilepsy with tremor. The efficacy of valproic acid for seizure control and the partial efficacy of deep brain stimulation with propranolol for myoclonic tremor is detailed.
Pediatric neurosurgery, Jan 6, 2015
Hemispheric epileptogenic lesions such as hemimegalencephaly often manifest as intractable epilep... more Hemispheric epileptogenic lesions such as hemimegalencephaly often manifest as intractable epilepsy in early infancy. Hemispherotomy is the treatment of choice for controlling intractable hemispheric epilepsy. Less invasive procedures are desirable for surgery on infants with low body weight. This study compared our experience with interhemispheric vertical hemispherotomy (IVH) and peri-insular lateral hemispherotomy (PIH). Thirteen consecutive patients underwent hemispherotomy for treatment of intractable epilepsy in our institution between 2001 and 2012. The etiology of epilepsy included hemimegalencephaly in 7 patients and cortical dysplasia in 3. PIH was performed on the first 5 patients and IVH on the last 8 patients. In the latter procedure, complete section of the corpus callosum was first performed via the interhemispheric approach. After removing part of the cingulate gyrus, section of the descending fibers was performed anterolaterally to the thalamus. Clinical characteris...
Journal of the neurological sciences, Jan 15, 2015
We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules... more We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules in patients with uncomplicated influenza (n=20) and influenza virus-associated encephalopathy (IE) (n=18) to understand the underlying mechanism of IE. We found that IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, G-CSF, GM-CSF, TNF-α, TIMP-1, MMP-9, sE-selectin, and neutrophil elastase were elevated significantly in sera from patients with uncomplicated influenza and those with IE, compared with normal controls (n=20). Of note, neutrophil elastase, sE-selectin, IL-8, and IL-13 were elevated significantly in IE as compared with uncomplicated influenza. In the present study, for the first time, we found that serum levels of neutrophil elastase were increased in patients with IE compared with uncomplicated influenza, which suggested that cerebral endothelial damage in the development of IE was mediated by neutrophil elastase. The present study implied that anti-elastase agents are poss...
Pediatrics international : official journal of the Japan Pediatric Society, 2014
We read with great interest the article by Takahashi et al. concerning the fifth nationwide surve... more We read with great interest the article by Takahashi et al. concerning the fifth nationwide survey in Japan on vitamin K prophylaxis and late vitamin K deficiency bleeding (VKDB) in infants. In Japan, the frequency of VKDB in infants has decreased significantly since the recommendation made in 1998 that every newborn should receive oral vitamin K prophylaxis with a syrup preparation of menaquinone-4 (vitamin K2[20]) on the day of birth, on the day of discharge from the maternity ward, and at 1 month of age, at a dose of 2 mg on each occasion. But cases of VKDB still occur. The present patient was a Japanese girl born at 40 weeks of gestation at a maternity hospital. She received the first prophylactic 2 mg oral dose of menaquinone-4 (vitamin K2[20]) at 3 days of age and did not receive the second dose on the day of discharge at the maternity hospital. Although she had a medical check-up at the same hospital at 31 days of age, she did not receive the third prophylactic dose of vitamin K2[20]. It was the normal practice of this maternity hospital to give only one dose of vitamin K2[20]. The patient was admitted to the Japanese Red Cross Morioka Hospital at 46 days of age because of persistent crying. On admission she was pale, hypoactive, and had no traumatic injury to her body. Investigations showed a low hemoglobin count of 5.4 g/ dL, a platelet count of 531 × 10/μL, prothrombin and partial thromboplastin times >88 s and 180 s, respectively (vs control times of 11–12 and 50–60 s, respectively), protein induced by vitamin K absence-II (PIVKA-II) at 194 000 mAU/mL (ELISA method, Eisai, Tokyo, Japan; normally <130 mAU/mL), and fibrin degradation product 158 mg/dL (normally <10 mg/dL). Computed tomography of the head indicated unilateral acute subdural hematomas (Fig. 1). The patient immediately received i.v. vitamin K1 (phytomenadione, 2 mg) and the abnormal hemostatic parameters improved. She also received a transfusion of packed red blood cells, as well as a craniotomy and hematoma evacuation. No evidence of an inflammatory reaction was observed. Metabolic screens for amino and organic acids were negative. No evidence of abuse or inadequate child rearing (such as shaken baby syndrome) was observed. The patient was diagnosed with late VKDB. At 1 year of age, the patient had favorable growth and no neurological sequelae. Infants who are born in some Japanese maternity hospitals do not receive prophylactic vitamin K in accordance with recommendations. Several years ago, we treated another infant with VKDB who had not received vitamin K at another maternity hospital and an infant who received only an unknown Chinese herbal drug for prophylaxis of VKDB at yet another maternity hospital. The total membership of the Japan Pediatric Society at the time was approximately 20 000 people, only approximately 100 of whom were not pediatricians (Japan Pediatric Society, unpubl. data, 2005). We reasoned that almost all of the obstetricians and maternity nurses who worked in maternity hospitals did not Correspondence: Akimune Kaga, MD PhD, Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Email: kagakimune@yahoo.co.jp Received 25 June 2013; revised 17 October 2013; accepted 22 October 2013. doi: 10.1111/ped.12265 Fig. 1 Computed tomography scan of the head showing unilateral acute subdural hematomas. bs_bs_banner