Publications by authors named "Hirofumi Kashii"

12 Publications

  • Page 1 of 1

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Association of early-onset epileptic encephalopathy with involuntary movements - Case series and literature review.

Epilepsy Behav Rep 2021 17;15:100417. Epub 2020 Dec 17.

Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan.

Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent seizures, severe developmental delay and accompanying involuntary movements. We detected four genetic mutations, including and variants. The involuntary movements were drug-resistant. However, pallidal electrocoagulation followed by gabapentin were partially effective in treating chorea and ballismus of the extremities in patients with variants, and perampanel partially suppressed seizures and involuntary movements in one patient with a variant. Movement disorders are common to many neurodevelopmental disorders, including a variety of EOEEs. Although we could not establish a definitive correlation using genetic variants in patients with EOEE and movement disorders, involuntary movements in patients with EOEEs may be a key diagnostic finding. The usage of genetic variants could prove beneficial in the future as more patients are investigated with epileptic-dyskinetic encephalopathies.
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http://dx.doi.org/10.1016/j.ebr.2020.100417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808918PMC
December 2020

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Early administration of vitamins B1 and B6 and l-carnitine prevents a second attack of acute encephalopathy with biphasic seizures and late reduced diffusion: A case control study.

Brain Dev 2019 Aug 9;41(7):618-624. Epub 2019 Mar 9.

Division of Neurology, National Center for Child Health and Development, Japan.

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most prevalent encephalopathy in Japanese children. AESD is characterized by a prolonged febrile seizure on day 1 followed by secondary seizures and MRI abnormality on days 4-6, resulting in high incidence of neurological sequelae. We aimed to clarify whether early administration of vitamins (vitamin B1, vitamin B6, and l-carnitine) would improve the clinical course of AESD.

Methods: We retrospectively reviewed 34 patients with acute encephalopathy who were admitted to our hospital between January 2009 and August 2016. Of the retrospectively registered 34 patients, 22 (65%) since 2011 were treated with the drug cocktail (prescription group) within 24 h of onset, whereas 12 (35%) before 2011 were not (non-prescription group). We compared clinical course, laboratory data, and MRI findings historically in both groups.

Results: The two groups did not differ in terms of laboratory findings except for blood lactate values. There were no differences between the two groups regarding duration of ICU admission, intubation, or the duration of seizures. Among the prescription group, two patients developed AESD while 20 had mild encephalopathy (single phasic). In contrast, seven patients inthe non-prescription group developed AESD while five did not. The incidence of AESD was lower in the prescription group (P = 0.004). As for outcomes, the rate of developmental delay and epilepsy was significantly lower in the prescription group.

Conclusions: Our data suggested that early administration of vitamins would improve the clinical course of acute encephalopathy. Mitochondrial rescue and neuroprotection are thought to be responsible for the favorable results.
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http://dx.doi.org/10.1016/j.braindev.2019.02.015DOI Listing
August 2019

Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero.

Mol Brain 2019 01 8;12(1). Epub 2019 Jan 8.

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, Japan.

The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cell metabolism, growth, and proliferation. The overactivation of mTOR has been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor rapamycin improved social interaction deficits in mouse models of TSC. Prenatal exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that are exposed to VPA in utero have been used as an animal model of ASD. Activation of the mTOR signaling pathway was recently observed in rodents that were exposed to VPA in utero, and rapamycin ameliorated social interaction deficits. The present study investigated the effect of rapamycin on social interaction deficits in both adolescence and adulthood, and gene expressions in mice that were exposed to VPA in utero. We subcutaneously injected 600 mg/kg VPA in pregnant mice on gestational day 12.5 and used the pups as a model of ASD. The pups were intraperitoneally injected with rapamycin or an equal volume of vehicle once daily for 2 consecutive days. The social interaction test was conducted in the offspring after the last rapamycin administration at 5-6 weeks of ages (adolescence) or 10-11 weeks of age (adulthood). Whole brains were collected after the social interaction test in the adulthood, and microarray and Western blot analyses were performed. Mice that were exposed to VPA and treated with vehicle exhibited a decrease in social interaction compared with control mice that were treated with vehicle. Rapamycin treatment in VPA-exposed mice improved social deficits. Mice that were exposed to VPA and treated with vehicle exhibited the aberrant expression of genes in the mTOR signaling pathway, and rapamycin treatment recovered changes in the expression of some genes, including Fyb and A330094K24Rik. Rapamycin treatment suppressed S6 phosphorylation in VPA-exposed mice. Aberrant gene expression was associated with social interaction deficits in VPA-exposed mice. Rapamycin may be an effective treatment for non-syndromic ASD in adolescent and adult patients who present impairments in the mTOR signaling pathway.
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http://dx.doi.org/10.1186/s13041-018-0423-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325753PMC
January 2019

Brain hyperserotonemia causes autism-relevant social deficits in mice.

Mol Autism 2018 26;9:60. Epub 2018 Nov 26.

1Department of Psychiatry and Behavioral Sciences, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506 Japan.

Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms.

Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter () knockout mice.

Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in HZ and KO mice. The expression of rather distinct sets of genes was altered in HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the gene was altered in both HZ and KO mice. expression and ASD-relevant social deficits normalized after dietary tryptophan restriction.

Conclusions: These findings reveal a gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.
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http://dx.doi.org/10.1186/s13229-018-0243-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258166PMC
January 2019

[Scintigraphic imaging in the diagnosis of failed intrathecal baclofen therapy: a case report of a 7-year-old boy with ventriculoperitoneal shunt].

No To Hattatsu 2015 Sep;47(5):367-71

Intrathecal baclofen (ITB) therapy is popular for the management of intractable spasticity. In 2007, the indications of ITB therapy expanded to include spasticity of children in Japan. In this report, we assessed the utility of radioisotopic scintigraphy in the diagnosis of failed ITB therapy. A 7-year-old boy with schizencephaly, hydrocephalus, and spastic quadriplegia had an ITB pump implanted. In his infancy, he had undergone ventriculoperitoneal shunt implantation. One month after the ITB operation, the ITB therapeutic effect diminished. Several examinations confirmed that the pump function was normal and catheter failure had not occurred. However, radioisotopic scintigraphy revealed that the baclofen had been washed out to blood circulation more rapidly than is typically observed. We considered two possible causes for this; obstruction of the cerebrospinal space due to kyphosis and excessive washout of celebrospinal fluid through the ventriculoperitoneal shunt. The catheter was moved to a more caudal site surgically, and his spasticity improved. The use of radioisotopic scintigraphy to identify the distribution of baclofen is an effective technique for investigation of baclofen pump system malfunction.
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September 2015

Analysis of a child who developed abnormal neuropsychiatric symptoms after administration of oseltamivir: a case report.

BMC Neurol 2015 Aug 5;15:130. Epub 2015 Aug 5.

Division of Neurology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: Neuropsychiatric side effects of oseltamivir occur occasionally, especially in infants and young patients, but nothing is known about possible contributory factors.

Case Presentation: We report a case of a 15-year-old Japanese female with influenza infection who developed abnormal psychiatric symptoms after administration of standard doses of oseltamivir. She had no history of neurological illness, had never previously taken oseltamivir, and had not developed psychiatric reactions during previous influenza infection. Her delirium-like symptoms, including insomnia, visual hallucinations, and a long-term memory deficit, disappeared after cessation of oseltamivir and administration of benzodiazepine. Detailed assessment was performed, including neurological examination (electroencephalogram, brain magnetic resonance imaging, single photon emission computed tomography with 99mTc-ethyl cysteinate dimer and with (123)I-iomazenil, cerebrospinal fluid analysis and glutamate receptor autoantibodies), drug level determination and simulation, and genetic assessment (OAT1, OAT3, CES1, Neu2).

Conclusions: Abnormal slowing in the electroencephalogram, which is characteristic of influenza-associated encephalopathy, was not observed in repeated recordings. The serum level determination of active metabolite Ro 64-0802 determined at 154 h after final dosing of oseltamivir was higher than the expected value, suggesting delayed elimination of Ro 64-0802. Thus, abnormal exposure to Ro 64-0802 might have contributed, at least in part, to the development of neuropsychiatric symptoms in this patient. The score on Naranjo's adverse drug reaction probability scale was 6. Mutation of c.122G > A (R41Q) in the sialidase Neu2 gene, increased CSF glutamate receptor autoantibodies, and limbic GABAergic dysfunction indicated by SPECT with (123)I-iomazenil were found as possible contributory factors to the CNS side effects.
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http://dx.doi.org/10.1186/s12883-015-0393-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526296PMC
August 2015

Nationwide survey of Cockayne syndrome in Japan: Incidence, clinical course and prognosis.

Pediatr Int 2015 Jun;57(3):339-47

Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo.

In the first nationwide survey of Cockayne syndrome (CS) in Japan, the incidence of CS was estimated to be 2.77 per million births (95%CI: 2.19-3.11) and the prevalence was approximately 1 in 2,500,000. A total of 47 CS patients (24 surviving and 23 deceased) were identified. Based on clinical course, these 47 patients were classified into CS type 1 (n = 41; 21 surviving, 20 deceased), CS type 2 (n = 2; all deceased), CS type 3 (n = 3; all surviving), and CS/xeroderma pigmentosum type D (n = 1, deceased). In the 41 CS type 1 patients, seven findings (i.e. failure to thrive; photosensitivity; deafness; characteristic facial appearance of CS [sunken eyes]; foot joint contracture; intellectual disability; and basal ganglia calcification on computed tomography [CT]) were observed in >90% of patients. Of these, failure to thrive, photosensitivity, and intellectual disability (language delays) developed before 2 or 3 years of age, whereas deafness, sunken eyes, and basal ganglia calcification on CT occurred later. Features such as bodyweight and height stagnation, language delay, abnormal nutritional pathways (tube feeding), and renal failure were more prominent in the 20 deceased CS type 1 patients than in the 21 surviving CS type 1 patients. Of the 20 deceased CS type 1 patients, nine developed severe renal failure during the terminal stages of their condition. The present findings suggest that the clinical course of CS includes a diverse range of symptoms, but each type has characteristic symptoms. In addition, the management of renal failure and nutrition are very important for ensuring good quality of life throughout the long-term course of CS.
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http://dx.doi.org/10.1111/ped.12635DOI Listing
June 2015

Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3.

Neurogenetics 2014 Aug 8;15(3):193-200. Epub 2014 Jun 8.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Recessive mutations in genes of the glycosylphosphatidylinositol (GPI)-anchor synthesis pathway have been demonstrated as causative of GPI deficiency disorders associated with intellectual disability, seizures, and diverse congenital anomalies. We performed whole exome sequencing in a patient with progressive encephalopathies and multiple dysmorphism with hypophosphatasia and identified novel compound heterozygous mutations, c.250G>T (p. Glu84*) and c.1342C>T (p. Arg488Trp), in PIGT encoding a subunit of the GPI transamidase complex. The surface expression of GPI-anchored proteins (GPI-APs) on patient granulocytes was lower than that of healthy controls. Transfection of the Arg488Trp mutant PIGT construct, but not the Glu84* mutant, into PIGT-deficient cells partially restored the expression of GPI-APs DAF and CD59. These results indicate that PIGT mutations caused neurological impairment and multiple congenital anomalies in this patient.
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http://dx.doi.org/10.1007/s10048-014-0408-yDOI Listing
August 2014

[Diagnostic value of brain biopsy in a pediatric multiple sclerosis mimicking brain stem glioma].

Nihon Rinsho Meneki Gakkai Kaishi 2013 ;36(3):175-9

Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development.

Diagnosis of multiple sclerosis (MS) is difficult when the lesion mimics glioma or cerebral enchephalitis. We report a case of pediatric MS initially suspected as brain stem glioma. An 11-year-old boy developed left foot joint pain followed by progressive symptoms such as left arm and leg weakness, dysarthria, paraplegia, and decreased level of consciousness. He subsequently developed respiratory distress requiring endotracheal intubation and mechanical ventilation. Magnetic resonance imaging showed a mass measuring 2 cm in the medulla oblongata. Although this mass was initially suspected as a glioma, the patient's acutely progressive disease course was not consistent with this diagnosis. Open biopsy revealed inflammation and demyelination, but no malignant cells were detected. He was treated with steroid pulse therapy, which showed dramatic effects. Nine months later, he developed another episode characterized by several neurological symptoms, and the diagnosis of MS was clinically confirmed. Open brain stem biopsy is technically demanding, but this case demonstrates that appropriate neurosurgical evaluation can play an important role in diagnosis by ruling out glioma and confirming MS.
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http://dx.doi.org/10.2177/jsci.36.175DOI Listing
February 2014

Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation.

Epilepsia 2013 Jul 26;54(7):1282-7. Epub 2013 Apr 26.

Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.

Purpose: KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation.

Methods: A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high-resolution melting (HRM) analysis or whole-exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation.

Key Findings: A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression-burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate-to-profound intellectual disability was found in all except one patient who died at 3 months.

Significance: De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression-burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.
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http://dx.doi.org/10.1111/epi.12200DOI Listing
July 2013