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Dive into the research topics where Hitoshi Osaka is active.

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Featured researches published by Hitoshi Osaka.


European Journal of Human Genetics | 2016

Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay

Hirotomo Saitsu; Ryoko Fukai; Bruria Ben-Zeev; Yasunari Sakai; Masakazu Mimaki; Nobuhiko Okamoto; Yasuhiro Suzuki; Yukifumi Monden; Hiroshi Saito; Barak Tziperman; Michiko Torio; Satoshi Akamine; Nagahisa Takahashi; Hitoshi Osaka; Takanori Yamagata; Kazuyuki Nakamura; Yoshinori Tsurusaki; Mitsuko Nakashima; Noriko Miyake; Masaaki Shiina; Kazuhiro Ogata; Naomichi Matsumoto

De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.


Journal of Neurology | 2015

Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene

Masayuki Sasaki; Chihiro Ohba; Mizue Iai; Shinichi Hirabayashi; Hitoshi Osaka; Takuya Hiraide; Hirotomo Saitsu; Naomichi Matsumoto

Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of ITPR1 are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous ITPR1 missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy. ITPR1 missense mutations cause infantile-onset cerebellar ataxia. ITPR1-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29.


Journal of The American Society of Nephrology | 2016

Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage

Takehiro Suzuki; Hiroaki Yamaguchi; Motoi Kikusato; Osamu Hashizume; Satoru Nagatoishi; Akihiro Matsuo; Takeya Sato; Tai Kudo; Tetsuro Matsuhashi; Kazutaka Murayama; Yuki Ohba; Shun Watanabe; Shin-ichiro Kanno; Daichi Minaki; Hiroko Shinbo; Nobuyoshi Mori; Akinori Yuri; Miyuki Yokoro; Eikan Mishima; Hisato Shima; Yasutoshi Akiyama; Yoichi Takeuchi; Koichi Kikuchi; Takafumi Toyohara; Chitose Suzuki; Takaharu Ichimura; Jun-ichi Anzai; Masahiro Kohzuki; Nariyasu Mano; Shigeo Kure

Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.


Tohoku Journal of Experimental Medicine | 2015

Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases

Takehiro Suzuki; Hiroaki Yamaguchi; Motoi Kikusato; Tetsuro Matsuhashi; Akihiro Matsuo; Takeya Sato; Yuki Oba; Shun Watanabe; Daichi Minaki; Hiroko Shimbo; Nobuyoshi Mori; Eikan Mishima; Hisato Shima; Yasutoshi Akiyama; Yoichi Takeuchi; Akinori Yuri; Koichi Kikuchi; Takafumi Toyohara; Chitose Suzuki; Masahiro Kohzuki; Jun-ichi Anzai; Nariyasu Mano; Shigeo Kure; Teruyuki Yanagisawa; Yoshihisa Tomioka; Masaaki Toyomizu; Sadayoshi Ito; Hitoshi Osaka; Ken-ichiro Hayashi; Takaaki Abe

Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Lebers hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.


Brain & Development | 2017

A case of severe movement disorder with GNAO1 mutation responsive to topiramate.

Saori Sakamoto; Yukifumi Monden; Ryoko Fukai; Noriko Miyake; Hiroshi Saito; Akihiko Miyauchi; Ayumi Matsumoto; Masako Nagashima; Hitoshi Osaka; Naomichi Matsumoto; Takanori Yamagata

We report the case of a 19-year-old female patient who had progressive chorea associated with a GNAO1 mutation. Chorea was refractory to multiple anticonvulsants, and the patient suffered from tiapride-induced neuroleptic malignant syndrome. After identification of a GNAO1 missense mutation at the age of 18years, topiramate treatment was initiated and the frequency of chorea decreased dramatically. The efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated Ca2+ channels. Given the side effects and complications associated with neuroleptics and deep brain stimulation, respectively, topiramate is recommended for the first-line management of severe chorea associated with a GNAO1 mutation.


Cell Reports | 2018

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Atsushi Takata; Noriko Miyake; Yoshinori Tsurusaki; Ryoko Fukai; Satoko Miyatake; Eriko Koshimizu; Itaru Kushima; Takashi Okada; Mako Morikawa; Yota Uno; Kanako Ishizuka; Kazuhiko Nakamura; Masatsugu Tsujii; Takeo Yoshikawa; Tomoko Toyota; Nobuhiko Okamoto; Yoko Hiraki; Ryota Hashimoto; Yuka Yasuda; Shinji Saitoh; Kei Ohashi; Yasunari Sakai; Shouichi Ohga; Toshiro Hara; Mitsuhiro Kato; Kazuyuki Nakamura; Aiko Ito; Chizuru Seiwa; Emi Shirahata; Hitoshi Osaka

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the de novo paradigm of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.


Epilepsia | 2016

De novo DNM1 mutations in two cases of epileptic encephalopathy

Mitsuko Nakashima; Takeshi Kouga; Charles Marques Lourenço; Masaaki Shiina; Tomohide Goto; Yoshinori Tsurusaki; Satoko Miyatake; Noriko Miyake; Hirotomo Saitsu; Kazuhiro Ogata; Hitoshi Osaka; Naomichi Matsumoto

Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin‐mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox‐Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.


Brain & Development | 2016

The magnetic resonance imaging spectrum of Pelizaeus–Merzbacher disease: A multicenter study of 19 patients

Kaoru Sumida; Ken Inoue; Jun-ichi Takanashi; Masayuki Sasaki; Kenji Watanabe; Motomasa Suzuki; Hirokazu Kurahashi; Taku Omata; Manabu Tanaka; Kenji Yokochi; Jun Iio; Kuniaki Iyoda; Toru Kurokawa; Muneaki Matsuo; Tamotu Sato; Akiko Iwaki; Hitoshi Osaka; Kenji Kurosawa; Toshiyuki Yamamoto; Naomichi Matsumoto; Hiroshi Matsuda; Noriko Sato

PURPOSEnWe retrospectively evaluated the imaging spectrum of Pelizaeus-Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality.nnnMETHODSnWe collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings.nnnRESULTSnThe clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age before birth on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were >u20094months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum.nnnCONCLUSIONnOur multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies.


Brain & Development | 2015

Effect of CYP2C19 polymorphisms on stiripentol administration in Japanese cases of Dravet syndrome

Takeshi Kouga; Hiroko Shimbo; Mizue Iai; Sumimasa Yamashita; Atsushi Ishii; Yukiko Ihara; Shinichi Hirose; Kazuhiro Yamakawa; Hitoshi Osaka

OBJECTIVEnThe objective of this study was to investigate stiripentol (STP) administration in cases of Dravet syndrome (DS) by comparing CYP2C19 allelic polymorphisms with the clinical effects of STP, including plasma concentrations of concomitant drugs and adverse effects of STP.nnnMATERIALS AND METHODSnEleven cases of DS cases were included. Demographic and clinical characteristics of the cases (age at the study period, body weight, mean dose and plasma concentration of valproate acid (VPA)/clobazam (CLB) off and on STP, mean plasma concentration of norclobazam (N-CLB) off and on STP, degree of seizure reduction, and adverse effects of STP) were examined with each CYP2C19 polymorphism.nnnRESULTSnThere were 3 cases of DS with wild type, 6 with intermediate type, and 2 with poor type of CYP2C19 polymorphisms. The N-CLB concentration/CLB dose ratio and N-CLB/CLB concentration ratio off STP were significantly higher in poor metabolizers. Three (37%) of 8 cases showed no effectiveness of STP regardless of the N-CLB concentration increase, and 1 (33%) of 3 cases showed effectiveness of STP regardless of N-CLB concentration decrease. In total, 6 (54%) of 11 cases with DS had >50% reduction in seizure frequency without significant differences in CYP2C19 polymorphisms.nnnCONCLUSIONnThis study demonstrated an effect of CYP2C19 polymorphisms on STP administration in Japanese cases of DS. There were cases of seizure reduction regardless of N-CLB concentration decrease on STP, which suggests a significant anti-convulsant action of STP. N-CLB concentration decrease on STP was observed in 1 case with ketogenic diet and 2 cases with (∗)3 allelic polymorphisms of CYP2C19.


Clinical Genetics | 2018

Novel biallelic SZT2 mutations in three cases of early-onset epileptic encephalopathy

Naomi Tshuchida; Mitsuko Nakashima; Akihiko Miyauchi; Shinsaku Yoshitomi; Tomokazu Kimizu; Vigneswari Ganesan; Keng Wee Teik; Ch'ng Gaik-Siew; Mitsuhiro Kato; Takeshi Mizuguchi; Atsushi Takata; Satoko Miyatake; Noriko Miyake; Hitoshi Osaka; Takanori Yamagata; Nakajima Hideaki; Hirotomo Saitsu; Naomichi Matsumoto

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non‐syndromic intellectual disabilities. In this study, we identified by whole‐exome sequencing compound heterozygous SZT2 mutations in 3 patients with early‐onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice‐site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.

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Noriko Miyake

Yokohama City University

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Eriko F. Jimbo

Jichi Medical University

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Takahiro Ikeda

Jichi Medical University

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Mizue Iai

Children's Medical Center of Dallas

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