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Miyatake S.,Yokohama City University | Osaka H.,Clinical Research Institute | Shiina M.,Yokohama City University | Takanashi J.-I.,Kameda Medical Center | And 11 more authors.
Neurology | Year: 2014

Objective: We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated. Methods: Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the ab-tubulin heterodimer. Results: Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule- associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining ab-tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment. Conclusions: TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies. © 2014 American Academy of Neurology.


PubMed | Fukuoka Childrens Hospital, National Hospital Organization, Takahashi Childrens Clinic, Osaka Medical Center and Research Institute for Maternal and Child Health and 14 more.
Type: Journal Article | Journal: Brain & development | Year: 2016

This study aimed to clarify the characteristics of acute encephalopathic episodes in patients with congenital adrenal hyperplasia (CAH), which we termed CAH-associated encephalopathy (CAHE).This retrospective study was conducted using a questionnaire as a nationwide survey of patients with CAH with acute encephalopathy and related episodes.Fifteen patients were recruited on the bases of clinical data that supported a diagnosis of CAHE. Fourteen patients displayed seizures at onset, and 12 patients exhibited refractory seizures. Deep coma lasting >24h was noted in 12 patients. Neuroimaging studies revealed some heterogeneous features. Diffuse or focal edematous lesions in the cerebrum, which produce high signal intensity on diffusion-weighted magnetic resonance imaging or low density on computer tomography, were found in the acute period in all 15 patients. In the chronic period, 14 patients survived, 11 of whom had some degree of neurological sequelae. Moreover, various degrees of cerebral shrinkage were observed in 11 of 14 surviving patients. Surprisingly, there were no abnormal neuroimaging findings in the basal ganglia, brainstem, and cerebellum in any patient.Our results indicated that patients with CAH have a risk of developing CAHE, and thus, they should be followed closely because not only status epilepticus or deep coma but also minor symptoms, such as fever and nausea, may lead to CAHE. Because CAHE may feature some heterogeneous encephalopathic episodes, further validation is needed to clarify its etiology.


Yoneda Y.,Yokohama City University | Haginoya K.,Tohoku University | Haginoya K.,Takuto Rehabilitation Center for Children | Arai H.,Morinomiya Hospital | And 9 more authors.
American Journal of Human Genetics | Year: 2012

Porencephaly is a neurological disorder characterized by fluid-filled cysts or cavities in the brain that often cause hemiplegia. It has been suggested that porencephalic cavities result from focal cerebral degeneration involving hemorrhages. De novo or inherited heterozygous mutations in COL4A1, which encodes the type IV α1 collagen chain that is essential for structural integrity for vascular basement membranes, have been reported in individuals with porencephaly. Most mutations occurred at conserved Gly residues in the Gly-Xaa-Yaa repeats of the triple-helical domain, leading to alterations of the α1α1α2 heterotrimers. Here we report on two individuals with porencephaly caused by a heterozygous missense mutation in COL4A2, which encodes the type IV α2 collagen chain. Mutations c.3455G>A and c.3110G>A, one in each of the individuals, cause Gly residues in the Gly-Xaa-Yaa repeat to be substituted as p.Gly1152Asp and p.Gly1037Glu, respectively, probably resulting in alterations of the α1α1α2 heterotrimers. The c.3455G>A mutation was found in the proband's mother, who showed very mild monoparesis of the left upper extremity, and the maternal elder uncle, who had congenital hemiplegia. The maternal grandfather harboring the mutation is asymptomatic. The c.3110G>A mutation occurred de novo. Our study confirmed that abnormalities of the α1α1α2 heterotrimers of type IV collagen cause porencephaly and stresses the importance of screening for COL4A2 as well as for COL4A1. © 2012 The American Society of Human Genetics.


PubMed | Tohoku University, Yokohama City University, Fukushima Rehabilitation Center for Children and Takuto Rehabilitation Center for Children
Type: Journal Article | Journal: Brain & development | Year: 2016

The clinical phenotypes of neuronal ceroid lipofuscinoses (NCLs) have been determined based on the age of onset and clinical symptoms. NCLs with onset between age 2 and 4years are known as late infantile neuronal ceroid lipofuscinoses (LINCLs). The clinical features of LINCLs include visual loss and progressive myoclonus epilepsy (PME) characterized by myoclonus, seizures, ataxia, and both mental and motor deterioration. There have been reports of several genes associated with LINCLs, with mutations in the CLN6 gene reported to cause variant forms of LINCLs (vLINCLs). Here, we report the first Japanese vLINCL caused by novel CLN6 mutations, found in a patient diagnosed by whole-exome sequencing. Visual acuity in our patient was preserved until the early teens. It remains to be elucidated if preserved visual function is related to the novel mutations of CLN6. Our case reveals the efficacy of whole-exome sequencing for examination of PMEs and highlights the existence of the CLN6 mutation in the Japanese population.


PubMed | Tohoku University, Gunma Childrens Medical Center, Iwate Medical University, Yamagata University and Takuto Rehabilitation Center for Children
Type: Journal Article | Journal: Brain & development | Year: 2016

Congenital cytomegalovirus (CMV) infection causes various neurological sequelae. However, most infected infants are asymptomatic at birth, and retrospective diagnosis is difficult beyond the neonatal period.This study aimed to investigate the aspects of neurological sequelae associated with asymptomatic congenital CMV infection.We retrospectively analyzed 182 patients who were suspected of having asymptomatic congenital CMV infection with neurological symptoms in Japan. Congenital CMV infection was diagnosed by quantitative polymerase chain reaction amplification of CMV from dried umbilical cord DNA.Fifty-nine patients (32.4%) who tested positive for CMV were confirmed as having congenital CMV infection. Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n=51, 94.4%), hearing impairment (n=36, 66.7%) and cerebral palsy (n=21, 38.9%), while microcephaly (n=16, 29.6%) and epilepsy (n=14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients. Cerebral palsy, cortical dysplasia and a WM abnormality with a diffuse pattern were associated with marked intellectual disability.Brain MRI investigations are important for making a diagnosis and formulating an intellectual prognosis. Analysis of umbilical cord tissue represents a unique and useful way to retrospectively diagnose congenital CMV infection.


Tanaka S.,Takuto Rehabilitation Center for Children | Tanaka S.,Tohoku University
Brain and Development | Year: 2013

Relative to their numbers, more than twice the number of disabled children fell victim to the Great East Japan Earthquake than did normal people. It was important to find out needs and provide support, as the needs of disabled children vulnerable to the disaster, such as a shortage of diapers of the right size for disabled children in the affected areas, were not given priority. In addition, the role of coordinators to spread word of who needed what and where, and linking this to specific support, was important. Regions and authorities need to determine how disabled children are to be evacuated in a disaster. Each household should prepare, as disaster prevention measures, their own private power generator and carry medical information for oral or other medicine. Each region should prepare, as a local disaster measure, welfare evacuation areas for disabled children. One thing that was felt acutely in this recent disaster is that disaster preparations and manuals need to be revised from the point of view of welfare, and that the most reliable people were those who, whether as assisters or the assisted, were involved with the disabled on a daily basis from before the disaster. The existence of disabled children as a familiar part of society, and supporting agencies networking based around the children as part of normal operations, plays a very large part. Raising children as part of their local communities is the biggest factor in saving them from disasters. © 2012 The Japanese Society of Child Neurology.


Sugiura M.,Tohoku University | Sassa Y.,Tohoku University | Jeong H.,Tohoku University | Wakusawa K.,Tohoku University | And 6 more authors.
Human Brain Mapping | Year: 2012

The concept of "social self" is often described as a representation of the self-reflected in the eyes or minds of others. Although the appearance of one's own face has substantial social significance for humans, neuroimaging studies have failed to link self-face recognition and the likely neural substrate of the social self, the medial prefrontal cortex (MPFC). We assumed that the social self is recruited during self-face recognition under a rich social context where multiple other faces are available for comparison of social values. Using functional magnetic resonance imaging (fMRI), we examined the modulation of neural responses to the faces of the self and of a close friend in a social context. We identified an enhanced response in the ventral MPFC and right occipitoparietal sulcus in the social context specifically for the self-face. Neural response in the right lateral parietal and inferior temporal cortices, previously claimed as self-face-specific, was unaffected for the self-face but unexpectedly enhanced for the friend's face in the social context. Self-face-specific activation in the pars triangularis of the inferior frontal gyrus, and self-face-specific reduction of activation in the left middle temporal gyrus and the right supramarginal gyrus, replicating a previous finding, were not subject to such modulation. Our results thus demonstrated the recruitment of a social self during self-face recognition in the social context. At least three brain networks for self-face-specific activation may be dissociated by different patterns of response-modulation in the social context, suggesting multiple dynamic self-other representations in the human brain. © 2011 Wiley Periodicals, Inc.


Iwasaki M.,Tohoku University | Uematsu M.,Tohoku University | Sato Y.,Tohoku University | Nakayama T.,Tohoku University | And 6 more authors.
Journal of Neurosurgery: Pediatrics | Year: 2012

Object. Corpus callosotomy is usually intended to alleviate - not to achieve total control of - epileptic seizures. A few patients experience complete seizure control after callosotomy, but the associated clinical factors are unknown. The object of this study was to investigate clinical factors associated with long-term seizure remission after total corpus callosotomy in patients with infantile or early childhood onset epilepsy. Methods. Thirteen consecutive patients with infantile or early childhood onset epilepsy underwent 1-stage total corpus callosotomy for alleviation of seizures. Their age at surgery ranged from 1 year and 5 months to 24 years (median 7 years). Eleven patients had West syndrome at the onset of disease, and the other 2 had Lennox-Gastaut syndrome. All patients suffered from spasms, axial tonic seizures, or atonic seizures. Six patients had proven etiology of epilepsy, including tuberous sclerosis, polymicrogyria, trauma, and Smith-Magenis syndrome. The association between postoperative seizure freedom and preoperative factors including age at surgery, no MRI abnormalities, proven etiology, and focal electroencephalographic epileptiform discharges was examined. Results. Postoperative seizure freedom was achieved in 4 of 13 patients for a minimum of 12 months. All 4 patients had no MRI abnormalities and no identified etiology. None of the 8 patients with MRI abnormality, 6 patients with known etiology of epilepsy, or 4 patients aged older than 10 years at surgery achieved seizure freedom. Two of the 7 patients with focal electroencephalographic abnormalities became seizure free. Absence of MRI abnormalities was significantly associated with postoperative seizure freedom (p < 0.01). Conclusions. Complete seizure remission is achieved after total corpus callosotomy in a subgroup of patients with intractable epilepsy following West syndrome or Lennox-Gastaut syndrome. One-stage total corpus callosotomy at a young age may provide a higher rate of seizure freedom, especially for patients with no MRI abnormalities and no identified etiology of epilepsy.


PubMed | Tohoku University and Takuto Rehabilitation Center for Children
Type: Journal Article | Journal: Brain & development | Year: 2016

Takuto Rehabilitation Center for Children is located in Sendai, the capital of the Miyagi prefecture, and faces the Pacific Ocean. The tsunami caused by the Great East Japan Earthquake resulted in tremendous damage to this region. Many physically handicapped patients with epilepsy who are treated at our hospital could not obtain medicine. We surveyed patients with epilepsy, using a questionnaire to identify the problems during the acute phase of the Great East Japan Earthquake.After the earthquake, we mailed questionnaires to physically handicapped patients with epilepsy who are treated and prescribed medications at our hospital, or to their parents.A total of 161 respondents completed the questionnaire. Overall, 68.4% of patients had seven days or less of stockpiled medication when the earthquake initially struck, and 28.6% of patients had no medication or almost no medication during the acute phase after the earthquake. Six patients were forced to stop taking their medication and nine patients experienced a worsening of seizures. Most (93.6%) patients stated they require a stockpile of medication for more than seven days: 20months after the earthquake, 76.9% patients a supply of drugs for more than seven days.We suggest that physically handicapped patients with epilepsy are recommended to prepare for natural disasters by stockpiling additional medication. Even if the stock of antiepileptic drugs is sufficient, stress could cause worsening of seizures. Specialized support is required after a disaster among physically handicapped patients with epilepsy.


PubMed | Red Cross, Sendai City Hospital and Takuto Rehabilitation Center for Children
Type: Case Reports | Journal: Pediatrics international : official journal of the Japan Pediatric Society | Year: 2016

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by repetitive seizures during the acute and chronic phases and has a poor neurological outcome. Burst-suppression coma via continuous i.v. infusion of a short-acting barbiturate is used to terminate refractory seizures, but the severe side-effects of short-acting barbiturates are problematic. We report on a 9-year-old boy with AERRPS who was effectively treated with very-high-dose phenobarbital (VHDPB) combined with intermittent short-acting barbiturates. VHDPB side-effects were mild, especially compared with those associated with continuous i.v. infusion of short-acting barbiturates (dosage, 40-75 mg/kg/day; maximum blood level, 290 g/mL). Using VHDPB as the main treatment, short-acting barbiturates were used intermittently and in small amounts. This is the first report to show that VHDPB, combined with intermittent short-acting barbiturates, can effectively treat AERRPS. After treatment, convulsions were suppressed and daily life continued, but intellectual impairment and high-level dysfunction remained.

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