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Shobbir Hussain - One of the best experts on this subject based on the ideXlab platform.
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developing a ppi inhibitor based therapy for stxbp1 haploinsufficiency associated epileptic disorders
Frontiers in Molecular Neuroscience, 2014Co-Authors: Shobbir HussainAbstract:STXBP1 HAPLOINSUFFICIENCY IN EARLY ONSET EPILEPTIC ENCEPHALOPATHY Early onset epileptic encephalopathies that occur in very early childhood are rare but particularly catastrophic forms of epilepsy that are invariably associated with significant neurological morbidity (Nordli, 2012). Mutations in the Syntaxin Binding Protein 1 (STXBP1) gene have been linked with two distinct but related forms of the disorder including early onset epileptic encephalopathy with suppression-bursts (EESB) associated with Ohtahara Syndrome, and more recently with infantile spasms (IS) associated with West Syndrome (Barcia et al., 2013). Mutations in patients are not inherited but rather found to occur de novo in a single copy of the STXBP1 gene. Ohtahara Syndrome is the earliest appearing age-related epileptic encephalopathy with seizures first presenting as early as the neonatal period and is diagnosed with a characteristic burstsuppression pattern on EEG (Yamatogi and Ohtahara, 2002). It is an extremely debilitating neurological disorder, involving intractable frequent daily seizures and severe intellectual disability. Patients often do not survive beyond early childhood. West Syndrome can present with frequent daily IS-type seizures within the first few weeks but more typically within the first few months of life and is diagnosed by a characteristic hypsarrhythmia pattern on EEG (Wong and Trevethan, 2001). The majority of patients have some degree of developmental delay and go on to have mild to severe intellectual disability. Later in life, symptoms of Ohtahara Syndrome patients can sometimes evolve into those usually associated with West Syndrome, where the seizure-types become more reminiscent of IS and the burstsuppression pattern on EEG evolves into hypsarrhythmia. There is currently no cure for Ohtahara Syndrome or West Syndrome and current therapy, which consists of generic anticonvulsant medication, is largely unsatisfactory due to the refractory nature of the seizures. To date, STXBP1 mutations have been reported in 27 cases of EESB and 7 cases of IS not preceded by EESB/Ohtahara Syndrome (Barcia et al., 2013). Whereas most genes associated with epileptic disorders encode ion channels or neurotransmitter receptor subunits, STXBP1 is the first epilepsy-associated gene with a direct role in the neurotransmitter release process (Poduri and Lowenstein, 2011). The presence of STXBP1 protein is necessary for neurotransmitter release in probably all neuron types in the brain (Verhage et al., 2000). However, it may be likely that impaired neurotransmitter release in inhibitory GABAergic interneurons throughout the brain results in uncontrolled synchronous firing of excitatory neurons in regions, resulting in epileptic foci. Indeed, a patient with an STXBP1 mutation was recently reported to have responded well to Vigabatrin (Romaniello et al., 2013), a drug which works specifically by inhibiting the gamma-aminobutyric acid transaminase enzyme responsible for the breakdown of GABA. In this article a potential route toward the development of a targeted anticonvulsant medication for STXBP1-associated epilepsy will be presented. The proposal is based on the refined model of neurotransmitter release suggested by recent findings in the Josep Rizo laboratory (Ma et al., 2013) and also the huge potential held in the field of protein-protein interaction (PPI) inhibitor therapeutic drug design.
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developing a ppi inhibitor based therapy for stxbp1 haploinsufficiency associated epileptic disorders
Frontiers in Molecular Neuroscience, 2014Co-Authors: Shobbir HussainAbstract:STXBP1 HAPLOINSUFFICIENCY IN EARLY ONSET EPILEPTIC ENCEPHALOPATHY Early onset epileptic encephalopathies that occur in very early childhood are rare but particularly catastrophic forms of epilepsy that are invariably associated with significant neurological morbidity (Nordli, 2012). Mutations in the Syntaxin Binding Protein 1 (STXBP1) gene have been linked with two distinct but related forms of the disorder including early onset epileptic encephalopathy with suppression-bursts (EESB) associated with Ohtahara Syndrome, and more recently with infantile spasms (IS) associated with West Syndrome (Barcia et al., 2013). Mutations in patients are not inherited but rather found to occur de novo in a single copy of the STXBP1 gene. Ohtahara Syndrome is the earliest appearing age-related epileptic encephalopathy with seizures first presenting as early as the neonatal period and is diagnosed with a characteristic burstsuppression pattern on EEG (Yamatogi and Ohtahara, 2002). It is an extremely debilitating neurological disorder, involving intractable frequent daily seizures and severe intellectual disability. Patients often do not survive beyond early childhood. West Syndrome can present with frequent daily IS-type seizures within the first few weeks but more typically within the first few months of life and is diagnosed by a characteristic hypsarrhythmia pattern on EEG (Wong and Trevethan, 2001). The majority of patients have some degree of developmental delay and go on to have mild to severe intellectual disability. Later in life, symptoms of Ohtahara Syndrome patients can sometimes evolve into those usually associated with West Syndrome, where the seizure-types become more reminiscent of IS and the burstsuppression pattern on EEG evolves into hypsarrhythmia. There is currently no cure for Ohtahara Syndrome or West Syndrome and current therapy, which consists of generic anticonvulsant medication, is largely unsatisfactory due to the refractory nature of the seizures. To date, STXBP1 mutations have been reported in 27 cases of EESB and 7 cases of IS not preceded by EESB/Ohtahara Syndrome (Barcia et al., 2013). Whereas most genes associated with epileptic disorders encode ion channels or neurotransmitter receptor subunits, STXBP1 is the first epilepsy-associated gene with a direct role in the neurotransmitter release process (Poduri and Lowenstein, 2011). The presence of STXBP1 protein is necessary for neurotransmitter release in probably all neuron types in the brain (Verhage et al., 2000). However, it may be likely that impaired neurotransmitter release in inhibitory GABAergic interneurons throughout the brain results in uncontrolled synchronous firing of excitatory neurons in regions, resulting in epileptic foci. Indeed, a patient with an STXBP1 mutation was recently reported to have responded well to Vigabatrin (Romaniello et al., 2013), a drug which works specifically by inhibiting the gamma-aminobutyric acid transaminase enzyme responsible for the breakdown of GABA. In this article a potential route toward the development of a targeted anticonvulsant medication for STXBP1-associated epilepsy will be presented. The proposal is based on the refined model of neurotransmitter release suggested by recent findings in the Josep Rizo laboratory (Ma et al., 2013) and also the huge potential held in the field of protein-protein interaction (PPI) inhibitor therapeutic drug design.
Mitsuhiro Kato - One of the best experts on this subject based on the ideXlab platform.
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De novo GABRA1 mutations in Ohtahara and West Syndromes
Epilepsia, 2016Co-Authors: Hirofumi Kodera, Mitsuhiro Kato, Chihiro Ohba, Toshiyuki Maeda, Kaoru Araki, Daisuke Tajima, Muneaki Matsuo, Naomi Hino-fukuyo, Kosuke Kohashi, Akihiko IshiyamaAbstract:SummaryObjective GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet Syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. Methods In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. Results We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West Syndrome and a patient with Ohtahara Syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. Significance Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara Syndrome and West Syndrome.
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Genes Responsible for Epileptic Syndromes
Brain and nerve = Shinkei kenkyu no shinpo, 2016Co-Authors: Mitsuhiro KatoAbstract:The first causative gene for epileptic Syndrome was revealed 20 years ago. Since then, many genes responsible for epileptic Syndrome, particularly sporadic epileptic encephalopathies, such as Ohtahara Syndrome, West Syndrome, and focal cortical dysplasia, have been identified. Although epilepsy was recognized as a channelopathy in the beginning stages of gene discovery, other molecular mechanisms for epileptic Syndromes, such as interneuronopathy, synaptic vesicle release, and mTOR signal transduction, are emerging. A new technique for gene analysis using the next-generation sequencer is now available for clinical purpose abroad and precision medicine based on the molecular mechanisms has started. Infrastructural development of the official framework, from molecular diagnosis to personalized therapy, is urgently required in Japan.
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Clinical spectrum of SCN2A mutations expanding to Ohtahara Syndrome
Neurology, 2013Co-Authors: Kazuyuki Nakamura, Mitsuhiro Kato, Sumimasa Yamashita, Hitoshi Osaka, Eiji Nakagawa, Kazuhiro Haginoya, Jun Tohyama, Mitsuko Okuda, Takahito Wada, Shuichi ShimakawaAbstract:Objective: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). Methods: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara Syndrome (OS) and 150 with West Syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. Results: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West Syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. Conclusions: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.
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Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation.
Epilepsia, 2013Co-Authors: Mitsuhiro Kato, Sumimasa Yamashita, Takanori Yamagata, Masaya Kubota, Hiroshi Arai, Taku Nakagawa, Takanari Fujii, Kenji Sugai, Kaoru Imai, Tami UsterAbstract:Summary 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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CASK aberrations in male patients with Ohtahara Syndrome and cerebellar hypoplasia.
Epilepsia, 2012Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Yoshinori Tsurusaki, Hitoshi Osaka, Nobuko Moriyama, Hideki Horita, Kiyomi Nishiyama, Yuriko Yoneda, Yukiko Kondo, Hiroshi DoiAbstract:Summary Purpose: Ohtahara Syndrome (OS) is one of the most severe and earliest forms of epilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In this study, we aimed to identify new genes involved in OS by copy number analysis and whole exome sequencing. Methods: Copy number analysis and whole exome sequencing were performed in 34 and 12 patients with OS, respectively. Fluorescence in situ hybridization, quantitative polymerase chain reaction (PCR), and breakpoint-specific and reverse-transcriptase PCR analyses were performed to characterize a deletion. Immunoblotting using lymphoblastoid cells was done to examine expression of CASK protein. Key Findings: Genomic microarray analysis revealed a 111-kb deletion involving exon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his mother, who was somatic mosaic for the deletion. Sequencing of the mutant transcript expressed in lymphoblastoid cell lines derived from the patient confirmed the deletion of exon 2 in the mutant transcript with a premature stop codon. Whole exome sequencing identified another male patient who was harboring a c.1A>G mutation in CASK, which occurred de novo. Both patients showed severe cerebellar hypoplasia along with other congenital anomalies such as micrognathia, a high arched palate, and finger anomalies. No CASK protein was detected by immunoblotting in lymphoblastoid cells derived from two patients. Significance: The detected mutations are highly likely to cause the loss of function of the CASK protein in male individuals. CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG Syndrome. Our data expand the clinical spectrum of CASK mutations to include OS with cerebellar hypoplasia and congenital anomalies at the most severe end.
Naomichi Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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Compound heterozygous BRAT1 mutations cause familial Ohtahara Syndrome with hypertonia and microcephaly
Journal of Human Genetics, 2014Co-Authors: Hirotomo Saitsu, Sumimasa Yamashita, Yukichi Tanaka, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Naomichi MatsumotoAbstract:Homozygous frameshift BRAT1 mutations were found in patients with lethal neonatal rigidity and multifocal seizure Syndrome (MIM# 614498). Here, we report on two siblings with compound heterozygous mutations in BRAT1 . They had intractable seizures from neonatal period, dysmorphic features and hypertonia. Progressive microcephaly was also observed. Initial electroencephalogram showed a suppression-burst pattern, leading to a diagnosis of Ohtahara Syndrome. They both died from pneumonia at 1 year and 3 months, respectively. Whole-exome sequencing of one patient revealed a compound heterozygous BRAT1 mutations (c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321Profs*81)). We are unable to obtain DNA from another patient. The p.Leu59Pro mutation occurred at an evolutionarily conserved amino acid in a CIDE-N (N-terminal of an cell death-inducing DFF45-like effector) domain, which has a regulatory role in the DNA fragmentation pathway of apoptosis. Our results further support that mutations of BRAT1 could lead to epileptic encephalopathy.
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Paternal germline mosaicism of a SCN2A mutation results in Ohtahara Syndrome in half siblings
European Journal of Paediatric Neurology, 2014Co-Authors: Ayelet Zerem, Naomichi Matsumoto, Dorit Lev, Lubov Blumkin, Hadassa Goldberg-stern, Yael Michaeli-yossef, Ayelet Halevy, Sara Kivity, Kazuyuki Nakamura, Esther Leshinsky-silverAbstract:Ohtahara Syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara Syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara Syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara Syndrome. This is the first report of familial Ohtahara Syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet Syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara Syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.
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haploinsufficiency of stxbp1 and Ohtahara Syndrome
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Naomichi MatsumotoAbstract:Ohtahara Syndrome (OS) is one of the most severe and earliest forms of epilepsy. De novo heterozygous mutations and a microdeletion of STXBP1 have been found in individuals with OS. STXBP1 encodes MUNC18-1, which is essential in synaptic vesicle release, highlighting aberration of synaptic vesicle release in pathogenesis of epilepsy. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press. (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).
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haploinsufficiency of stxbp1 and Ohtahara Syndrome
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Naomichi MatsumotoAbstract:Ohtahara Syndrome (OS) is one of the most severe and earliest forms of epilepsy. De novo heterozygous mutations and a microdeletion of STXBP1 have been found in individuals with OS. STXBP1 encodes MUNC18-1, which is essential in synaptic vesicle release, highlighting aberration of synaptic vesicle release in pathogenesis of epilepsy. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press. (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).
Sarah Weckhuysen - One of the best experts on this subject based on the ideXlab platform.
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reduction of seizure frequency after epilepsy surgery in a patient with stxbp1 encephalopathy and clinical description of six novel mutation carriers
Epilepsia, 2013Co-Authors: Sarah Weckhuysen, Philip Holmgren, Anna C Jansen, Rik Hendrickx, D Hasaerts, Charlotte Dielman, Julitta De Bellescize, Nadia Boutrykryza, Gaetan LescaAbstract:Mutations in STXBP1 have been identified in a subset of patients with early onset epileptic encephalopathy (EE), but the full phenotypic spectrum remains to be delineated. Therefore, we screened a cohort of 160 patients with an unexplained EE, including patients with early myoclonic encephalopathy (EME), Ohtahara Syndrome, West Syndrome, nonsyndromic EE with onset in the first year, and Lennox-Gastaut Syndrome (LGS). We found six de novo mutations in six patients presenting as Ohtahara Syndrome (2/6, 33%), West Syndrome (1/65, 2%), and nonsyndromic early onset EE (3/64, 5%). No mutations were found in LGS or EME. Only two of four mutation carriers with neonatal seizures had Ohtahara Syndrome. Epileptic spasms were present in five of six patients. One patient with normal magnetic resonance imaging (MRI) but focal seizures underwent epilepsy surgery and seizure frequency dropped drastically. Neuropathology showed a focal cortical dysplasia type 1a. There is a need for additional neuropathologic studies to explore whether STXBP1 mutations can lead to structural brain abnormalities.
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clinical spectrum of early onset epileptic encephalopathies associated with stxbp1 mutations
Neurology, 2010Co-Authors: L Deprez, Philip Holmgren, T Van Dyck, Dirk Goossens, Jurgen Delfavero, Anna C Jansen, K Verhaert, Arvid Suls, Sarah Weckhuysen, Lieven LagaeAbstract:OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara Syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara Syndrome. One patient was diagnosed with West Syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy Syndrome. Three of these patients later evolved to West Syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara Syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West Syndrome and rarely in typical West Syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.
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o2 5 the clinical spectrum of stxbp1 mutations in early onset epileptic encephalpathy between Ohtahara Syndrome and west Syndrome
European Journal of Paediatric Neurology, 2009Co-Authors: B Ceulemans, L Deprez, K Verhaert, Sarah Weckhuysen, Lieven Lagae, Anne Holmgren, A J M Janssen, W Van Paesschen, Albena Jordanova, P De JongheAbstract:O2-5 The clinical spectrum of STXBP1 mutations in early onset epileptic encephalpathy: between Ohtahara-Syndrome and West Syndrome? B. Ceulemans1,2,3 *, S. Weckhuysen4,5,6, K. Verhaert1, L. Deprez7,8,9, A. Holmgren7,8,9, A. Janssen10, W. Van Paesschen11, A. Jordanova4,5,12, L. Lagae3,13, P. De Jonghe4,5,14. 1Child Neurology, University Hospital of Antwerp, Antwerp, Belgium; 2Child Neurology, University of Antwerp, Antwerp, Belgium; 3Child Neurology, Epilepsy Centre Pulderbos, Pulderbos, Belgium; 4Neurology, University of Antwerp, Antwerp, Belgium; 5Neurology, Department of Molecular Genetics, VIB, Antwerp, Belgium; 6Neurology, Epilepsy Centre Kempenhaeghe, Oosterhout, The Netherlands; 7Biochemistry, University of Antwerp, Antwerp, Belgium; 8Biochemistry, Department of Molecular Genetics, VIB, Antwerp, Belgium; 9Biochemistry, Institute Born-Bunge, Antwerp, Belgium; 10Child Neurology, University Hospital of Brussels, Brussels, Belgium; 11Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium; 12Neurology, Institute Born-Bunge, Antwerp, Belgium; 13Child Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium; 14Neurology, University Hospital of Antwerp, Antwerp, Belgium
Jesús Eirís-puñal - One of the best experts on this subject based on the ideXlab platform.
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Ohtahara Syndrome and respiratory chain complex I deficiency
Brain & development, 2010Co-Authors: Manuel Castro-gago, Jesús Eirís-puñalAbstract:Sir, We read with great interest the recent contribution by Seo et al. in the Brain and Development [1]. They report a female infant with Ohtahara Syndrome (OS) and complex I deficiency of themitochondrial respiratory chain (MRC), and good response to ketogenic diet associated with mitochondrial cocktail supplementation. The authors affirm in the introduction and in the discussion than this observation is the first case of OS with proven cause of MRC I defect. In this sense, in 2009, we published also in Brain and Development [2] a male infant with OS and complex I deficiency of MRC, and untreatable epilepsy. This child died at age 18 months from multiorgan failure in the course of a respiratory infection. We concluded that despite the few cases reported, in our view OS should be considered as one of the rare forms of presentation of mitochondrial dysfunction. At this moment we think that our observation is the first case of OS withMRC I defect.
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Respiratory chain complex I deficiency in an infant with Ohtahara Syndrome
Brain & development, 2008Co-Authors: Manuel Castro-gago, Manuel Oscar Blanco-barca, Carmen Gómez-lado, Jesús Eirís-puñal, Yolanda Campos-gonzález, Joaquín Arenas-barberoAbstract:We report an infant with complex I deficiency of the mitochondrial respiratory chain whose most conspicuous symptom at presentation was an Ohtahara Syndrome. Review of the literature suggest that association of these two conditions is extremely rare. Despite the few cases reported, in our view Ohtahara Syndrome should be considered as one of the forms of presentation of mitochondrial dysfunction.
