Publications by authors named "Manami Akasaka"

28 Publications

  • Page 1 of 1

Acute encephalopathy in children with tuberous sclerosis complex.

Orphanet J Rare Dis 2021 Jan 6;16(1). Epub 2021 Jan 6.

Department of Pediatrics, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi, 480-1195, Japan.

Objective: We examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC).

Methods: The clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals.

Results: Of the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE.

Significance: AE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.
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http://dx.doi.org/10.1186/s13023-020-01646-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789140PMC
January 2021

GNAO1 mutation-related severe involuntary movements treated with gabapentin.

Brain Dev 2021 Apr 23;43(4):576-579. Epub 2020 Dec 23.

Department of Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Background: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators.

Case: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely.

Conclusion: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.
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http://dx.doi.org/10.1016/j.braindev.2020.12.002DOI Listing
April 2021

Turner Syndrome Associated With Refractory Seizures and Intellectual Disability: A Case Study.

Cureus 2020 Nov 6;12(11):e11364. Epub 2020 Nov 6.

Pediatrics, Iwate Medical University, Morioka, JPN.

Turner syndrome (TS) is the most frequent sex abnormality in women. The physical features include short stature, webbing of the neck, and gonadal dysgenesis. Typically, patients with Turner syndrome exhibit no intellectual disability, and a few cases of TS have been associated with epilepsy. Herein, we present a case of TS with intractable epilepsy. The patient presented with global developmental delay at the age of two and karyotyping revealed mosaicism [45, X/46, X del (X) (q21.1)]. At the age of seven, she had generalized tonic epilepsy as well as several focal-onset seizures. She developed daily seizures, which were refractory to several antiepileptic drugs. Interictal electroencephalography (EEG) revealed multifocal spikes, and ictal EEG revealed shifting foci. She visited our hospital at the age of 13. Her peripheral white blood cells G-band and fluorescence in situ hybridization (FISH) method chromosome with cheek swab examinations revealed 45, X. Her peripheral white blood cell mosaic pattern may have disappeared over time or become indetectable. We treated her with clobazam, and then lamotrigine and valproic acid combination therapy, which resulted in a reduction in the frequency of seizures by approximately 50%. Epilepsy and intellectual disability in this case may be due to the mosaic deletion at Xq21.1. Further analysis of similar cases may provide valuable information for effective therapeutic strategies.
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http://dx.doi.org/10.7759/cureus.11364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721081PMC
November 2020

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Impact of nitrogen metabolism-associated culture pH changes on regulation of Fusarium trichothecene biosynthesis: revision of roles of polyamine agmatine and transcription factor AreA.

Curr Genet 2020 Dec 18;66(6):1179-1190. Epub 2020 Aug 18.

Department of Biological Mechanisms and Functions, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.

Fusarium graminearum produces trichothecene mycotoxins in infected grains and axenic liquid culture. A proposed regulatory model of trichothecene biosynthesis was examined in relation to nitrogen utilization. First, we showed that an important factor for the stimulation of trichothecene biosynthesis was not the occurrence of agmatine as a specific inducer molecule, but rather continuous acidification of the liquid culture medium arising from agmatine catabolism. When the pH of the L-Gln synthetic medium was frequently adjusted to the pH of the agmatine culture, trichothecene productivity of the L-Gln culture was equal to that of the agmatine culture. For efficient trichothecene biosynthesis, the culture pH should be lowered at an appropriate time point during the early growth stage. Second, we re-evaluated the role of the nitrogen regulatory GATA transcription factor AreA in trichothecene biosynthesis. Since Tri6 encodes a transcription factor indispensable for trichothecene biosynthesis, all fifteen AreA-binding consensus sequences in the Tri6 promoter were mutated. The mutant could catabolize L-Phe as the sole nitrogen source; furthermore, the pH profile of the synthetic L-Phe medium (initial pH 4.2) was the same as that of the wild-type (WT) strain. Under such conditions, the promoter mutant exhibited approximately 72% of the trichothecene productivity compared to the WT strain. Thus, F. graminearum AreA (FgAreAp) is dispensable for the functioning of the Tri6 promoter, but it contributes to the increased production of mycotoxin under mildly acidic conditions to some extent. Further investigations on the culture pH revealed that extremely low pH bypasses the function of FgAreAp.
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http://dx.doi.org/10.1007/s00294-020-01102-xDOI Listing
December 2020

Long-term outcome of a group of Japanese children with myelin-oligodendrocyte glycoprotein encephalomyelitis without preventive immunosuppressive therapy.

Brain Dev 2019 Oct 4;41(9):790-795. Epub 2019 Jul 4.

Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.

Introduction: There is increasing evidence that immunosuppressive therapy is essential for reducing disease activity and avoiding further attacks in patients positive for anti-myelin-oligodendrocyte glycoprotein (MOG) antibodies. However, to date, no placebo-controlled trial has been published.

Objective: We aimed to evaluate the long-term outcome and anti-MOG antibody titers of seropositive Japanese pediatric patients without long-term immunosuppressive therapy.

Methods: Of 11 consecutive patients positive for anti-MOG antibodies seen at Tohoku University Hospital from 1992 to 2013, 5 patients did not receive preventive long-term immunosuppressive treatment and had been followed up longitudinally (more than 60 months).

Results: The follow-up periods were 68-322 months (median, 150 months). The expanded disability status scale scores of all patients were 0 at the last observation. Three patients were negative for the antibody at the last follow-up, and the titers of the two patients whose anti-MOG antibodies were positive at the last follow-up were lower than at the first examinations. The interval to the second attack in three patients was 1-124 months (median, 33 months). Acute attacks were treated with methylprednisolone pulse therapy (four patients) or intravenous immunoglobulin (one patient). All patients achieved full recovery after acute therapy. Oral corticosteroid was tapered over a period of 6-26 weeks (median, 17 weeks).

Conclusions: We reported our experience with very long-term follow-up of 5 Japanese pediatric patients with anti-MOG antibody-positive disease who did not receive long-term immunosuppressive therapy. Persistent positivity to anti-MOG antibody in some patients suggests the necessity for long-term follow up despite infrequent relapse.
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http://dx.doi.org/10.1016/j.braindev.2019.06.004DOI Listing
October 2019

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Familial episodic limb pain in kindreds with novel Nav1.9 mutations.

PLoS One 2018 17;13(12):e0208516. Epub 2018 Dec 17.

Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as". In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6-8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input-current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296736PMC
May 2019

Characteristic proton magnetic resonance spectroscopy in glucose transporter type 1 deficiency syndrome.

Pediatr Int 2018 Oct 15;60(10):978-979. Epub 2018 Oct 15.

Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Morioka, Iwate, Japan.

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http://dx.doi.org/10.1111/ped.13672DOI Listing
October 2018

Identification of amino acids negatively affecting Fusarium trichothecene biosynthesis.

Antonie Van Leeuwenhoek 2019 Mar 28;112(3):471-478. Epub 2018 Sep 28.

Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8601, Japan.

Nitrogen sources in media have a significant impact on the onset of secondary metabolism in fungi. For transcriptional activation of many nitrogen catabolic genes, an AreA transcription factor is indispensable. This also holds true for Fusarium graminearum that produces trichothecenes, an important group of mycotoxin, in axenic culture. Despite the presence of numerous consensus AreA-binding sites in the promoters of Tri genes in the trichothecene cluster core region, the effect of medium amino acids on trichothecene biosynthesis is poorly understood. In this study, we examined the effect of certain amino acids, which were predicted to activate AreA function and increase Tri gene transcription, on trichothecene production in liquid culture. By frequent monitoring and adjustments in the pH of the culture medium, including replacement of the spent medium with fresh medium, we demonstrate the suppressive effects of the amino acids, used as the sole nitrogen source, on trichothecene biosynthesis. When the medium pH was maintained at 4.0, Gly, L-Ser, and L-Thr suppressed trichothecene production by F. graminearum. Enhanced trichothecene-inducing effects were observed when the medium pH was 3.5, with only L-Thr suppressing trichothecene synthesis.
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http://dx.doi.org/10.1007/s10482-018-1172-zDOI Listing
March 2019

Successful Management of Fulminant Guillain-Barré Syndrome and Its Complications.

Pediatr Emerg Care 2018 May;34(5):e87-e89

From the Department of Pediatrics, School of Medicine, Iwate Medical University, Morioka, Japan.

A 3-year-old girl presented with muscle weakness of her limbs and trunk 6 days after developing symptoms of common cold. Two days later, she experienced respiratory arrest with a Glasgow Coma Scale score of 3, necessitating endotracheal intubation. Therefore, she was transferred to our hospital with suspected acute encephalopathy. Although no abnormalities were observed on brain and spinal magnetic resonance imaging and electroencephalography, peripheral nerve conduction velocity tests failed to evoke motor and sensory nerve action potentials. Thus, we gave a diagnosis of fulminant Guillain-Barré syndrome and initiated immunoglobulin therapy. On day 3 of admission, she developed sinus tachycardia that induced circulatory failure and oliguria, which was successfully treated with landiolol. Subsequently, we performed plasmapheresis followed by immunoglobulin and steroid pulse therapies. She was weaned off the mechanical ventilator by day 20 of admission, was ambulatory by day 44, and had completely recovered without any adverse sequelae by day 55. In conclusion, landiolol was effective for treating acute sinus tachycardia-induced circulatory failure and played a key role in saving the life of this patient.
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http://dx.doi.org/10.1097/PEC.0000000000001008DOI Listing
May 2018

Intellectual outcomes of extremely preterm infants at school age.

Pediatr Int 2017 May 21;59(5):570-577. Epub 2017 Mar 21.

Department of Pediatrics, School of Medicine, Iwate Medical University, Morioka, Iwate, Japan.

Background: The survival rate of extremely preterm (EP) infants (<28 weeks of gestation) has improved dramatically, and there is great interest in the long-term prognosis. The aim of this study was to elucidate the influence of prenatal and postnatal care on long-term intellectual outcome in EP infants.

Methods: Subjects were EP infants admitted to the neonatal intensive care unit from 1982 to 2005. The survival rate and neurodevelopmental outcomes at 6 years of age were analyzed for the periods 1982-1991 (period 1) and 1992-2005 (period 2). Logistic regression analysis was performed to examine risk factors for intellectual impairment.

Results: Survival rate improved significantly from 84.5% (period 1) to 92.4% (period 2; P = 0.007). Follow-up data were obtained from 92 children in period 1 (69.7% of survivors) and from 245 in period 2 (72.3% of survivors). The incidence of intellectual impairment increased from 16.3% (period 1) to 31.0% (period 2). Significant factors associated with intellectual impairment were period 2 (OR, 3.53; P = 0.007), supplemental oxygen at 36 weeks' corrected age (OR, 2.22; P = 0.012), number of days in the hospital (OR, 1.01; P = 0.012), intraventricular hemorrhage (IVH; OR, 3.05; P = 0.024), and later tube-feeding commencement date (OR, 1.10; P = 0.032).

Conclusions: Despite an increase in survival rate, the rate of intellectual impairment increased in period 2. According to risk factor analysis, reducing the incidence of chronic lung disease and/or apnea, IVH, and nutritional deprivation is a key factor in improving the intellectual outcomes of EP infants.
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http://dx.doi.org/10.1111/ped.13215DOI Listing
May 2017

Temporal brain metabolite changes in preterm infants with normal development.

Brain Dev 2017 Mar 9;39(3):196-202. Epub 2016 Nov 9.

GE Healthcare Japan Corporation, MR Applications and Workflow Asia Pacific, Japan.

Objective: Preterm infants are at high risk for developmental delay, epilepsy, and autism spectrum disorders. Some reports have described associations between these conditions and gamma-aminobutyric acid (GABA) dysfunction; however, no study has evaluated temporal changes in GABA in preterm infants. Therefore, we assessed temporal changes in brain metabolites including GABA using single-voxel 3-Tesla (T) proton magnetic resonance spectroscopy (H-MRS) in preterm infants with normal development.

Methods: We performed 3T H-MRS at 37-46 postmenstrual weeks (PMWs, period A) and 64-73PMWs (period B). GABA was assessed with the MEGA-PRESS method. N-acetyl aspartate (NAA), glutamate-glutamine complex (Glx), creatine (Cr), choline (Cho), and myo-inositol (Ins) were assessed with the PRESS method. Metabolite concentrations were automatically calculated using LCModel.

Results: Data were collected from 20 preterm infants for periods A and B (medians [ranges], 30 [24-34] gestational weeks, 1281 [486-2030]g birth weight). GABA/Cr ratio decreased significantly in period B (p=0.03), but there was no significant difference in GABA/Cho ratios (p=0.58) between the two periods. In period B, NAA/Cr, Glx/Cr, NAA/Cho, and Glx/Cho ratios were significantly increased (p<0.01), whereas Cho/Cr, Ins/Cr, and Ins/Cho ratios were significantly decreased (p<0.01). There was no significant difference for GABA or Cho concentrations (p=0.52, p=0.22, respectively). NAA, Glx, and Cr concentrations were significantly increased (p<0.01), whereas Ins was significantly decreased (p<0.01).

Conclusions: Our results provide new information on normative values of brain metabolites in preterm infants.
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http://dx.doi.org/10.1016/j.braindev.2016.10.006DOI Listing
March 2017

Assessing Temporal Brain Metabolite Changes in Preterm Infants Using Multivoxel Magnetic Resonance Spectroscopy.

Magn Reson Med Sci 2016 13;15(2):187-92. Epub 2015 Nov 13.

Department of Pediatrics, Iwate Medical University.

Purpose: To investigate temporal changes in brain metabolites during the first year of life in preterm infants using multivoxel proton magnetic resonance spectroscopy ((1)H-MRS).

Methods: Seventeen infants born at 29 (25-33) gestational week (median, range) weighing 1104 (628-1836) g underwent 1.5-T multivoxel (1)H-MRS at 42 postconceptional week (PCW) and at 3, 6, 9, and 12 months after. We measured N-acetyl aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (Ins)/Cr, NAA/Cho, and Ins/Cho ratios in the frontal lobe (FL) and basal ganglia and thalamus (BG + Th). Linear regression analyses were performed to identify longitudinal changes in infants showing normal imaging findings and normal development. We also evaluated ratios of subjects with abnormal imaging findings and/or development using the 95% confidence intervals (CIs) of regression equations in normal subjects.

Results: In the 13 infants with normal development, NAA/Cr and NAA/Cho ratios showed significant positive correlations with PCWs in the FL (r = 0.64 and 0.83, respectively, both P < 0.01) and BG + Th (r = 0.79 and 0.87, respectively, both P < 0.01), while Cho/Cr and Ins/Cr ratios revealed significant negative correlations with PCWs in the FL (r =-0.69 and -0.58, respectively, both P < 0.01) and BG + Th (r =-0.74 and -0.72, respectively, both P < 0.01). Ins/Cho ratios in the FL did not significantly correlate with PCWs (r =-0.19, P = 0.18), while those in the BG + Th showed significant negative correlation with PCWs (r =-0.44, P < 0.01). The metrics in the abnormal group were within the normal group 95% CIs in all periods except a few exceptions.

Conclusions: Longitudinal multivoxel MRS is able to detect temporal changes in major brain metabolites during the first year of life in preterm infants.
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http://dx.doi.org/10.2463/mrms.mp.2015-0041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600055PMC
December 2016

Reduction in peripheral regulatory T cell population in childhood ocular type myasthenia gravis.

Brain Dev 2015 Sep 3;37(8):808-16. Epub 2015 Jan 3.

Child and Women's Health Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.

Objective: Myasthenia gravis (MG) is a T-cell dependent and antibody mediated autoimmune disease. Recent studies of adult patients and animal models have shown that regulatory T cells (Tregs) play an important role in the pathogenesis of MG, but little is known about MG in children. This study evaluated the role of peripheral blood Tregs in childhood ocular MG and assessed if Tregs could be an index for estimating immunological status.

Patients And Methods: Clinical data and peripheral lymphocytes were obtained from 13 children with serum AChR antibody-positive ocular type MG and 18 age-matched controls. Committed cells from MG patients were divided into two clinical stages: active (n=12) and remission (n=11). Tregs and Th17 cells were analyzed by flow cytometric analysis based on CD4(+)CD25(+) intracellular Foxp3(+) and CD4(+) intracellular IL-17A(+) fractions, respectively.

Results: The percentage of Tregs among peripheral blood CD4(+) T cells in active stage, remission stage, and control groups was 3.3±1.3%, 4.8±1.7%, and 5.0±0.6%, respectively. The Treg population was significantly lower in the active stage than in the remission stage and controls. Furthermore, Treg percentage was significantly lower during relapse of myasthenia symptoms. We witnessed no remarkable associations between the percentage of Tregs and immune suppressant dosages.

Conclusions: A significant reduction in the peripheral Treg population is considered to contribute to the pathophysiology of ocular type childhood MG and may be a marker of immunological state in these patients.
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http://dx.doi.org/10.1016/j.braindev.2014.12.007DOI Listing
September 2015

Clinical and genetic features of acute encephalopathy in children taking theophylline.

Brain Dev 2015 May 23;37(5):463-70. Epub 2014 Aug 23.

Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Japan.

Background: Theophylline has recently been suspected as a risk factor of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), although there has been no systematic study on the relationship between acute encephalopathy in children taking theophylline (AET) and AESD.

Methods: We recruited 16 Japanese patients (11 male and 5 female, median age of 2 years and 7 months) with AET from 2008 to 2013. We evaluated their clinical features, such as the duration of first seizure, biphasic clinical course and cranial CT/MRI imaging and compared them with those of AESD. We analyzed the polymorphisms or mutations of genes which are associated with AESD.

Results: Clinically, 12 patients had neurological and/or radiological features of AESD. Only one patient died, whereas all 15 surviving patients were left with motor and/or intellectual deficits. Genetically, 14 patients had at least one of the following polymorphisms or mutations associated with AESD: thermolabile variation of the carnitine palmitoyltransferase 2 (CPT2) gene, polymorphism causing high expression of the adenosine receptor A2A (ADORA2A) gene, and heterozygous missense mutation of the voltage gated sodium channel 1A (SCN1A) and 2A (SCN2A) gene.

Conclusions: Our results demonstrate that AET overlaps with AESD, and that AET is a multifactorial disorder sharing a genetic background with AESD.
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http://dx.doi.org/10.1016/j.braindev.2014.07.010DOI Listing
May 2015

Efficacy and safety of fosphenytoin for acute encephalopathy in children.

Brain Dev 2015 Apr 5;37(4):418-22. Epub 2014 Jul 5.

Department of Pediatrics, Juntendo University Faculty of Medicine, Japan; Department of Pediatrics, Aichi Medical University, Japan.

Purpose: To evaluate the efficacy and safety of fosphenytoin (fPHT) for the treatment of seizures in children with acute encephalopathy.

Methods: Using responses from physicians on the Annual Zao Conference on Pediatric Neurology mailing list we chose patients who met the following criteria: clinical diagnosis of acute encephalopathy and use of intravenous fPHT for the treatment of seizures. We divided the patients into two groups: acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and other encephalopathies. The efficacy of fPHT was considered effective when a cessation of seizures was achieved.

Results: Data of 38 children were obtained (median age, 27 months). Eighteen children were categorized into the AESD group and 20 into the other encephalopathies group. fPHT was administered in 48 clinical events. The median loading dose of fPHT was 22.5 mg/kg and was effective in 34 of 48 (71%) events. The rate of events in which fPHT was effective did not differ according to the presence or absence of prior antiepileptic treatment, subtype of acute encephalopathy, or the type of seizures. One patient experienced apnea and oral dyskinesia as adverse effects of fPHT, whereas arrhythmia, hypotension, obvious reduction of consciousness, local irritation, phlebitis and purple grove syndrome were not observed in any patient.

Conclusion: fPHT is effective and well tolerated among children with acute encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2014.06.009DOI Listing
April 2015

Hypofibrinogenemia caused by adrenocorticotropic hormone for infantile spasms: a case report.

Brain Dev 2015 Jan 13;37(1):137-9. Epub 2014 Apr 13.

Department of Pediatrics, Iwate Medical University School of Medicine, Morioka, Iwate, Japan.

We report the case of a 7-month-old boy who developed hypofibrinogenemia (66.6 mg/dL; reference value, 170-405 mg/dL) during adrenocorticotropic hormone (ACTH) therapy for infantile spasms. Although the patient showed no clinical signs of a bleeding diathesis, we recommend that plasma fibrinogen levels should be monitored during ACTH therapy, which should be discontinued when fibrinogen levels fall below hemostatic levels (60.0mg/dL) or when bleeding tendencies are recognized.
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http://dx.doi.org/10.1016/j.braindev.2014.03.004DOI Listing
January 2015

A nationwide survey of Aicardi-Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study.

Rheumatology (Oxford) 2014 Mar 3;53(3):448-58. Epub 2013 Dec 3.

Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

Objectives: Aicardi-Goutières syndrome (AGS) is a rare, genetically determined, early onset progressive encephalopathy associated with autoimmune manifestations. AGS is usually inherited in an autosomal recessive manner. The disease is rare, therefore the clinical manifestations and genotype-phenotype correlations, particularly with regard to autoimmune diseases, are still unclear. Here we performed a nationwide survey of AGS patients in Japan and analysed the genetic and clinical data.

Methods: Patients were recruited via questionnaires sent to paediatric or adult neurologists in Japanese hospitals and institutions. Genetic analysis was performed and clinical data were collected.

Results: Fourteen AGS patients were identified from 13 families; 10 harboured genetic mutations. Three patients harboured dominant-type TREX1 mutations. These included two de novo cases: one caused by a novel heterozygous p.His195Tyr mutation and the other by a novel somatic mosaicism resulting in a p.Asp200Asn mutation. Chilblain lesions were observed in all patients harbouring dominant-type TREX1 mutations. All three patients harbouring SAMHD1 mutations were diagnosed with autoimmune diseases, two with SLE and one with SS. The latter is the first reported case.

Conclusion: This study is the first to report a nationwide AGS survey, which identified more patients with sporadic AGS carrying de novo dominant-type TREX1 mutations than expected. There was a strong association between the dominant-type TREX1 mutations and chilblain lesions, and between SAMHD1 mutations and autoimmunity. These findings suggest that rheumatologists should pay attention to possible sporadic AGS cases presenting with neurological disorders and autoimmune manifestations.
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http://dx.doi.org/10.1093/rheumatology/ket372DOI Listing
March 2014

Use of magnetic resonance imaging to identify the edge of a dural tear in an infant with growing skull fracture: a case study.

Childs Nerv Syst 2012 Nov 16;28(11):1951-4. Epub 2012 Aug 16.

Department of Neurosurgery, Iwate Medical University, Uchimaru 19-1, Morioka 020-8505, Japan.

Purpose: Growing skull fractures can be a challenging surgical problem facing pediatric neurosurgeons. The goal of this manuscript was to describe an effective surgical method used to treat a growing skull fracture.

Methods: We present a case study of a 2-month-old boy who fell from his mother's arms and hit his head on the floor; he underwent X-ray, magnetic resonance (MR), and computed tomography (CT) imaging before cranioplasty with dural plasty.

Results: X-ray performed on admission revealed a diastatic fracture with a gap of 8 mm in the right frontal bone and a linear fracture in the right occipital bone. X-ray performed 37 days after injury demonstrated that the gap had increased to 25 mm, and the patient was diagnosed with a growing skull fracture of the right parietal bone. Cranioplasty with dural plasty was performed on day 39. A combination of MR and CT images enabled the edge of the dural tear to be plotted on a three-dimensional image of the skull, and this was used to estimate the location of the edge of the dural tear on the scalp.

Conclusions: We achieved excellent outcomes in terms of bony coverage and dural plasty. The combination of MR and CT images may be recommended for surgical repair of growing skull fracture in children.
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http://dx.doi.org/10.1007/s00381-012-1891-9DOI Listing
November 2012

Aicardi-Goutières syndrome with systemic lupus erythematosus and hypothyroidism.

Brain Dev 2013 Jan 21;35(1):87-90. Epub 2012 Apr 21.

Department of Pediatrics, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505, Japan.

We report a case of Aicardi-Goutières syndrome with systemic lupus erythematosus and hypothyroidism. A 3-year-old girl, diagnosed with Aicardi-Goutières syndrome at 9 months, was transferred to our hospital for fever of unknown origin. Severe spasticity with dystonic posturing and flexion contracture of the limbs were noted. Interstitial pneumonia with pleural effusion was evident. Immunological investigations revealed positive antinuclear antibodies and reduced thyroid function. Prompt treatment with steroids, cyclophosphamide, and levothyroxine sodium hydrate elicited a good response. It is necessary to emphasize that its possible relationship between Aicardi-Goutières syndrome and systemic lupus erythematosus and/or hypothyroidism.
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http://dx.doi.org/10.1016/j.braindev.2012.03.012DOI Listing
January 2013

Hemorrhagic infarction at 33 days after birth in a healthy full-term neonate.

Vasc Health Risk Manag 2011 8;7:667-70. Epub 2011 Nov 8.

Department of Neurosurgery, Iwate Medical University, Morioka, Japan.

Intraparenchymal hemorrhage in the full-term neonate rarely occurs more than 2 weeks after birth, and its definitive cause remains unclear. In the present report, a case of a patient with intraparenchymal hemorrhage occurring 33 days after birth is described. Histological examination of the brain tissue obtained during hematoma evacuation through craniotomy showed hemorrhagic infarction. Patent foramen ovale may have been present and this may have led to spontaneous paradoxical cerebral embolism followed by hemorrhagic infarction.
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http://dx.doi.org/10.2147/VHRM.S23332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225349PMC
April 2012

Proton magnetic resonance spectroscopic images in preterm infants with bilirubin encephalopathy.

J Pediatr 2012 Feb 1;160(2):342-4. Epub 2011 Nov 1.

Department of Pediatrics, School of Medicine, Iwate Medical University, Morioka, Japan.

Two preterm infants with athetoid cerebral palsy due to bilirubin encephalopathy were examined by magnetic resonance spectroscopic imaging at age 3 years. An increased glutamate/glutamine complex/creatine ratio was found in the basal ganglia. Chemical metabolic abnormalities of the basal ganglia were clearly demonstrated by color-coded metabolite images.
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http://dx.doi.org/10.1016/j.jpeds.2011.09.036DOI Listing
February 2012

Unique discrepancy between cerebral blood flow and glucose metabolism in hemimegalencephaly.

Epilepsy Res 2010 Dec 20;92(2-3):201-8. Epub 2010 Oct 20.

Department of Pediatrics, Tohoku University School of Medicine, Aoba-ku, Sendai 980-8574, Japan.

Hemimegalencephaly (HME) presents as severe refractory seizures and requires early surgical treatment to prevent progression to catastrophic epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are useful imaging techniques for the presurgical evaluation of patients with intractable epilepsy. However, the results in HME are variable and no study has compared SPECT and PET performed at around the same time. We performed SPECT and PET for nine patients with HME, which was defined as a whole or part of affected hemisphere enlargement (three males, six females; age range 0.5-20 years). The ictal and interictal states were determined based on the presence or absence of clinical seizures during all PET examinations and majority of SPECT examinations. The perfusion pattern in the malformed hemisphere was increased or equal, despite the reduced glucose metabolism in six out of nine patients. Five of the six patients who underwent early surgical treatment showed this kind of perfusion/metabolism discrepancy. Importantly, even the non-affected hemisphere in early infantile cases already lacked the normal hypoperfusion and hypometabolism patterns of immature frontal lobes, which was most prominent in case with poor surgical prognosis. In all six surgical patients, epileptic seizures appeared before 4 months of age. By contrast, none of the non-surgical patients had seizures before 4 months of age. In conclusion, although the number of patients examined is small and the result is still preliminary, the perfusion/metabolism discrepancy found in this study may show potential characteristic aspect of HME and further study with simultaneous EEG recording will make clear if this finding can be useful indicator for early surgical treatment in HME.
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http://dx.doi.org/10.1016/j.eplepsyres.2010.09.010DOI Listing
December 2010

Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders.

Mitochondrion 2009 Apr 21;9(2):115-22. Epub 2009 Jan 21.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, Japan.

Two novel mitochondrial DNA base changes were identified at both sides of the 3243A>G mutation, the most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). One was a 3244G>A transition in a girl with MELAS. The other was a 3242G>A transition in a girl with a mitochondrial disorder without a MELAS phenotype. Although the two base changes were adjacent to the 3243A>G mutation, they had different effects on the clinical phenotype, muscle pathology, and respiratory chain enzyme activity. Investigations of the different effects of the 3244G>A and 3242G>A base changes may provide a better understanding of tRNA dysfunction in mitochondrial disorders.
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http://dx.doi.org/10.1016/j.mito.2009.01.005DOI Listing
April 2009

A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).

Am J Hum Genet 2007 Aug 11;81(2):361-6. Epub 2007 Jun 11.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, and Nishi-Niigata Chuo National Hospital, Niigata, Japan.

Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.
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http://dx.doi.org/10.1086/518903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950814PMC
August 2007

Transient decrease in cerebral white matter diffusivity on MR imaging in human herpes virus-6 encephalopathy.

Brain Dev 2005 Jan;27(1):30-3

Department of Pediatrics, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan.

We report a 16-month-old boy with human herpes virus-6 (HHV-6) encephalopathy showing transient abnormalities of the cerebral white matter on magnetic resonance imaging. Diffusion-weighted imaging (DWI) demonstrated diffuse high signal intensity in the bilateral cerebral white matter areas. The signal changes on DWI subsequently resolved, and cerebral atrophy resulted. The transient decrease in the cerebral white matter diffusivity seen in the present case may reflect axonal involvement secondary to the glial or neuronal damage in HHV-6 encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2004.03.009DOI Listing
January 2005

[Abnormal magnetic resonance imaging in a child with Alice in Wonderland syndrome following Epstein-Barr virus infection].

No To Hattatsu 2002 Jul;34(4):348-52

Department of Pediatrics, Iwate Medical University, Morioka, Iwate.

Characteristic pathologic changes of cranial computed tomography (CT) and magnetic resonance imaging (MRI) have never been reported in "Alice in Wonderland" syndrome (AIWS) caused by Epstein-Barr (EB) virus infection. We present here a 10-year-old girl with AIWS with an abnormal MR finding. During the course of serologically confirmed EB virus encephalopathy, she had distortion of the body image, visual hallucinations and depersonalization characteristic of AIWS. MRI demonstrated transient T2 prolongation and swelling of the cerebral cortex, especially at the bilateral temporal lobes, bilateral cingulate gyrus, right upper frontal gyrus, bilateral caudate nucleus, and bilateral putamen, whereas CT showed no abnormalities. Transient MRI lesions were occasionally reported in patients with EB virus encephalopathy/encephalitis who presented visual illusions and psychotic reactions, although the diagnosis of AIWS was not described. We consider that any patient with symptoms of AIWS should have MRI because the abnormal MRI findings may disappear in a short period.
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July 2002