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Saitsu H.,Yokohama City University | Nishimura T.,Tokyo Medical and Dental University | Nishimura T.,University of Tokyo | Muramatsu K.,Gunma University | And 18 more authors.
Nature Genetics | Year: 2013

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.


Fujita A.,Yokohama City University | Kusaka K.,National Hospital Organization Tokyo National Hospital | Tanaka H.,National Rehabilitation Center for Children with Disabilities | Miyake N.,Yokohama City University | Matsumoto N.,Yokohama City University
American Journal of Medical Genetics, Part A | Year: 2015

Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development. © 2015 Wiley Periodicals, Inc.


Taira T.,Tokyo Women's Medical University | Ueta T.,Spinal Injuries Center | Katayama Y.,Nihon University | Kimizuka M.,National Rehabilitation Center for Children with Disabilities | And 6 more authors.
Neuromodulation | Year: 2013

Objective To evaluate the incidence of complications of intrathecal baclofen (ITB) therapy for spasticity in Japan, where a unique training course and nationwide registration are required. Materials and Methods An analysis of complications was performed in all patients who underwent ITB in Japan from 2005 to 2011. Prior to surgery, all the doctors involved took a one-day training course, which included hands-on training. Surgical techniques that avoided complications were emphasized. Results A total of 406 pumps were implanted in 400 patients (277 men, 123 women) having severe spasticity. Because this study is currently in progress, among the 400 patients, 78.3% (313/400) had finished a one-year observation follow-up. There were 369 adult and 31 juvenile (under 17 years old) patients, including 12 patients under nine years old. All-cause adverse events were seen in 148 patients (37%), and 93 (23.3%) of these were regarded as severe. Catheter problems were observed in 34 (8.5%) patients: catheter migration in 25 (6.3%), breakage in 6 (1.5%), obstruction in 2 (0.5%), kinking in 1 (0.3%), and dislodgement in 1 (0.3%). Pump trouble was observed in seven (1.8%) patients: alarm abnormality in one (0.3%), memory error in one (0.3%), delayed recovery in one (0.3%), rotation in one (0.3%), malfunction in one (0.3%), and abnormal infusion rate in two (0.6%). Device-related and surgical wound infection occurred in 12 patients (3%), and nine were regarded as severe. Leakage or subcutaneous accumulation of the cerebrospinal fluid was seen in 13 patients (3.3%). Conclusion The requirement of taking of a training course before starting ITB seemed to reduce complications. Although there were surgery-related complications, the rate of complications in Japan appeared to be lower than those reported in larger series of ITB. However, whether the reported rates can be primarily ascribed to a mandatory training course requires further investigations. © 2012 International Neuromodulation Society.


Takenouchi T.,Keio University | Matsuzaki Y.,Keio University | Yamamoto K.,National Rehabilitation Center for Children with Disabilities | Kosaki K.,Rehabilitation Center for the Handicapped | And 3 more authors.
European Journal of Medical Genetics | Year: 2014

The classification of bone dysplasia has relied on a clinical/radiographic interpretation and the identification of specific genetic alterations. The clinical presentation of the SOX9 mutation and type 2 collagen disorders overlap with the Pierre-Robin sequence and talipes equinovarus, but the former is often accompanied by the bent long bones. In its milder form, the SOX9 mutation is not necessarily associated with the bent long bones. Here, we report a patient with the Pierre-Robin sequence and talipes equinovarus who did not exhibit either bent long bones or scapular hypoplasia; thus, this patient was instead classified as having a type 2 collagen disorder. Despite this phenotypic presentation, the proposita was found to have a de novo SOX9 mutation. The peculiar location of the mutation within the dimerization domain might account for the relatively mild phenotypic effect of the SOX9 mutation to a degree that is compatible with a clinical diagnosis of type 2 collagen disorder, except for a developmental delay. We concluded that mutations in SOX9 can mimic a type 2 collagen disorder-like phenotype. © 2014.


Ebihara T.,National Rehabilitation Center for Children with Disabilities | Oshima S.,Josai University | Okita M.,Josai University | Shiina S.,Josai University | And 7 more authors.
Current Therapeutic Research - Clinical and Experimental | Year: 2015

Background: Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development. Objectives: The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID. Methods: CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method. Results: Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs. Conclusions: The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID. © 2014 The Authoes.


Takeshita E.,National Center Hospital | Takeshita E.,Dokkyo Medical University | Takeshita E.,National Institute of Neuroscience | Nakagawa E.,National Center Hospital | And 3 more authors.
Brain and Development | Year: 2012

Angiotensin II type-2 receptor gene (AGTR2) mutations have been recently detected in patients with mental retardation. AGTR2 plays a role in central nervous system development and cognitive functions. We identified a novel missense mutation of c.572G>A (p.G191E) in a 6-year-old boy showing severe mental retardation, pervasive developmental disorder, and epilepsy. This is the first report on . AGTR2 mutation in a Japanese boy with mental retardation. © 2012 The Japanese Society of Child Neurology.


Ebihara T.,National Rehabilitation Center for Children with Disabilities | Oshima S.,Josai University | Yasuda Y.,Josai University | Okita M.,Josai University | And 7 more authors.
Journal of International Medical Research | Year: 2016

Objectives: To investigate subcutaneous blood flow rate (SBFR) in healthy volunteers and patients with severe motor and intellectual disabilities (SMID), and evaluate the effect of mentholated warm compresses (MWCs) on SBFR and subcutaneous ceftazidime absorption in healthy volunteers. Methods: SBFR at the forearm, chest and abdomen were evaluated in Japanese healthy volunteers and in adults with SMID. The effects of MWCs on blood flow rate and ceftazidime pharmacokinetics were evaluated in healthy volunteers. Results: SBFR was significantly lower in the forearms of female patients with SMID (n = 11) than in the forearms of healthy females (n = 6); it was not significantly lower in the abdomen or chest. There were no significant differences between male patients (n = 18) or controls (n = 12) in SBFR at any site. MWC application increased SBFR 1.3- to 2.0-fold compared with baseline in healthy controls (n = 6). MWC application increased ceftazidime maximum blood concentration, SBFR and time above mutant prevention concentration in a single healthy subject. Conclusions: Abdominal SBFR in patients with SMID did not differ from that of healthy subjects. MWC application increases SBFR and subcutaneous drug absorption rate in healthy humans. © 2016, © The Author(s) 2016.


PubMed | National Rehabilitation Center for Children with Disabilities and Josai University
Type: | Journal: Current therapeutic research, clinical and experimental | Year: 2015

Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development.The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID.CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method.Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs.The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID.


PubMed | National Rehabilitation Center for Children With Disabilities, International University of Health and Welfare, Tokyo Medical University and University of Tokyo
Type: | Journal: Journal of the neurological sciences | Year: 2016

d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood.


PubMed | Josai International University, National Rehabilitation Center for Children with Disabilities and Josai University
Type: Journal Article | Journal: The Journal of international medical research | Year: 2016

To investigate subcutaneous blood flow rate (SBFR) in healthy volunteers and patients with severe motor and intellectual disabilities (SMID), and evaluate the effect of mentholated warm compresses (MWCs) on SBFR and subcutaneous ceftazidime absorption in healthy volunteers.SBFR at the forearm, chest and abdomen were evaluated in Japanese healthy volunteers and in adults with SMID. The effects of MWCs on blood flow rate and ceftazidime pharmacokinetics were evaluated in healthy volunteers.SBFR was significantly lower in the forearms of female patients with SMID (n=11) than in the forearms of healthy females (n=6); it was not significantly lower in the abdomen or chest. There were no significant differences between male patients (n=18) or controls (n=12) in SBFR at any site. MWC application increased SBFR 1.3- to 2.0-fold compared with baseline in healthy controls (n=6). MWC application increased ceftazidime maximum blood concentration, SBFR and time above mutant prevention concentration in a single healthy subject.Abdominal SBFR in patients with SMID did not differ from that of healthy subjects. MWC application increases SBFR and subcutaneous drug absorption rate in healthy humans.

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