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Hirotomo Saitsu - One of the best experts on this subject based on the ideXlab platform.
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mislocalization of syntaxin 1 and impaired neurite growth observed in a human ipsc model for STXBP1 related epileptic encephalopathy
Epilepsia, 2016Co-Authors: Satoshi Yamashita, Tomohiro Chiyonobu, Michiko Yoshida, Hiroshi Maeda, Masashi Zuiki, Satoshi Kidowaki, Kenichi Isoda, Masafumi Morimoto, Mitsuhiro Kato, Hirotomo SaitsuAbstract:Summary Syntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of control-derived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy.
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paternal mosaicism of an STXBP1 mutation in os
Clinical Genetics, 2011Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Hideki Hoshino, Masaya Kubota, Kiyomi Nishiyama, Yuriko Yoneda, Yoshinori Tsurusaki, Noriko Miyake, Kiyoshi HayasakaAbstract:Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, Tsurusaki Y, Doi H, Miyake N, Kubota M, Hayasaka K, Matsumoto N. Paternal mosaicism of an STXBP1 mutation in OS. Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.
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STXBP1 mutations in early infantile epileptic encephalopathy with suppression burst pattern
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Kenji E Orii, Tsukasa Higuchi, Hideki Hoshino, Masaya Kubota, Hiroshi Arai, Tetsuzo Tagawa, Shigeru KimuraAbstract:Summary Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
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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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STXBP1 mutations in early infantile epileptic encephalopathy with suppression‐burst pattern
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Kenji E Orii, Tsukasa Higuchi, Hideki Hoshino, Masaya Kubota, Hiroshi Arai, Tetsuzo Tagawa, Shigeru KimuraAbstract:Summary Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
Mitsuhiro Kato - One of the best experts on this subject based on the ideXlab platform.
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mislocalization of syntaxin 1 and impaired neurite growth observed in a human ipsc model for STXBP1 related epileptic encephalopathy
Epilepsia, 2016Co-Authors: Satoshi Yamashita, Tomohiro Chiyonobu, Michiko Yoshida, Hiroshi Maeda, Masashi Zuiki, Satoshi Kidowaki, Kenichi Isoda, Masafumi Morimoto, Mitsuhiro Kato, Hirotomo SaitsuAbstract:Summary Syntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of control-derived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy.
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paternal mosaicism of an STXBP1 mutation in os
Clinical Genetics, 2011Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Hideki Hoshino, Masaya Kubota, Kiyomi Nishiyama, Yuriko Yoneda, Yoshinori Tsurusaki, Noriko Miyake, Kiyoshi HayasakaAbstract:Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, Tsurusaki Y, Doi H, Miyake N, Kubota M, Hayasaka K, Matsumoto N. Paternal mosaicism of an STXBP1 mutation in OS. Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.
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STXBP1 mutations in early infantile epileptic encephalopathy with suppression burst pattern
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Kenji E Orii, Tsukasa Higuchi, Hideki Hoshino, Masaya Kubota, Hiroshi Arai, Tetsuzo Tagawa, Shigeru KimuraAbstract:Summary Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
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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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STXBP1 mutations in early infantile epileptic encephalopathy with suppression‐burst pattern
Epilepsia, 2010Co-Authors: Hirotomo Saitsu, Mitsuhiro Kato, Ippei Okada, Kenji E Orii, Tsukasa Higuchi, Hideki Hoshino, Masaya Kubota, Hiroshi Arai, Tetsuzo Tagawa, Shigeru KimuraAbstract:Summary Purpose: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. Methods: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. Results: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. Discussion: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
Sarah Weckhuysen - One of the best experts on this subject based on the ideXlab platform.
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STXBP1 encephalopathy connecting neurodevelopmental disorders with α synucleinopathies
Neurology, 2019Co-Authors: Vanessa Lanoue, Sarah Weckhuysen, Ye Jin Chai, Julie Z Brouillet, Elizabeth E Palmer, Brett M Collins, Frederic A MeunierAbstract:De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.
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STXBP1 as a therapeutic target for epileptic encephalopathy
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Hannah Stamberger, Sarah Weckhuysen, Peter De JongheAbstract:Introduction: STXBP1 is an essential protein for presynaptic vesicle release. Mutations in STXBP1 have been associated with a series of (epileptic) neurodevelopmental disorders collectively referre...
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gabra1 and STXBP1 novel genetic causes of dravet syndrome
Neurology, 2014Co-Authors: Gemma L Carvill, Sarah Weckhuysen, Jacinta M Mcmahon, Corinna Hartmann, Rikke S Moller, Helle Hjalgrim, Joseph CookAbstract:Objective: To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing. Methods: We performed whole-exome sequencing in 13 SCN1A -negative patients with Dravet syndrome and targeted resequencing in 67 additional patients to identify new genes for this disorder. Results: We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1 in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ∼75% of cases. Conclusions: We show that GABRA1 and STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families.
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head stereotypies in STXBP1 encephalopathy
Developmental Medicine & Child Neurology, 2013Co-Authors: Christian M. Korff, Sarah Weckhuysen, Peter De Jonghe, Arvid Suls, Mel Michel G Villaluz, Ingrid E. SchefferAbstract:STXBP1 encephalopathy is associated with a range of movement disorders. We observed head stereotypies in three patients. These comprised a slow (<1Hz), high-amplitude, horizontal, ‘figure-of-eight’ pattern, beginning at age 4–6 years and resulting in neck muscle hypertrophy, in two males; a faster (2–3Hz), side-to-side, ‘no’ movement, starting at the age of 9 years 6 months was observed in one female. Upper limb and truncal stereotypies and vocalization occurred intermittently with the head movements. The stereotypies increased with excitement but settled with concentration and sleep. Head and upper limb stereotypies are valuable clinical clues to the diagnosis of STXBP1 encephalopathy in patients with profound impairments.
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Head stereotypies in STXBP1 encephalopathy.
Developmental Medicine & Child Neurology, 2013Co-Authors: Christian M. Korff, Sarah Weckhuysen, Peter De Jonghe, Arvid Suls, Mel Michel G Villaluz, Ingrid E. SchefferAbstract:STXBP1 encephalopathy is associated with a range of movement disorders. We observed head stereotypies in three patients. These comprised a slow (
Federico Zara - One of the best experts on this subject based on the ideXlab platform.
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homozygous STXBP1 variant causes encephalopathy and gain of function in synaptic transmission
Brain, 2020Co-Authors: Hanna C A Lammertse, Pasquale Striano, Annemiek A Van Berkel, Michele Iacomino, Ruud F Toonen, Antonio Gambardella, Matthijs Verhage, Federico ZaraAbstract:Heterozygous mutations in the STXBP1 gene encoding the presynaptic protein MUNC18-1 cause STXBP1 encephalopathy, characterized by developmental delay, intellectual disability and epilepsy. Impaired mutant protein stability leading to reduced synaptic transmission is considered the main underlying pathogenetic mechanism. Here, we report the first two cases carrying a homozygous STXBP1 mutation, where their heterozygous siblings and mother are asymptomatic. Both cases were diagnosed with Lennox-Gastaut syndrome. In Munc18-1 null mouse neurons, protein stability of the disease variant (L446F) is less dramatically affected than previously observed for heterozygous disease mutants. Neurons expressing Munc18L446F showed minor changes in morphology and synapse density. However, patch clamp recordings demonstrated that L446F causes a 2-fold increase in evoked synaptic transmission. Conversely, paired pulse plasticity was reduced and recovery after stimulus trains also. Spontaneous release frequency and amplitude, the readily releasable vesicle pool and the kinetics of short-term plasticity were all normal. Hence, the homozygous L446F mutation causes a gain-of-function phenotype regarding release probability and synaptic transmission while having less impact on protein levels than previously reported (heterozygous) mutations. These data show that STXBP1 mutations produce divergent cellular effects, resulting in different clinical features, while sharing the overarching encephalopathic phenotype (developmental delay, intellectual disability and epilepsy).
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dramatic effect of levetiracetam in early onset epileptic encephalopathy due to STXBP1 mutation
Brain & Development, 2016Co-Authors: Robertino Dilena, Pasquale Striano, Monica Traverso, Maurizio Viri, Gloria Cristofori, Laura Tadini, S Barbieri, Antonino Romeo, Federico ZaraAbstract:Abstract Background Syntaxin Binding Protein 1 ( STXBP1 ) mutations determine a central neurotransmission dysfunction through impairment of the synaptic vesicle release, thus causing a spectrum of phenotypes varying from syndromic and non-syndromic epilepsy to intellectual disability of variable degree. Among the antiepileptic drugs, levetiracetam has a unique mechanism of action binding SV2A, a glycoprotein of the synaptic vesicle release machinery. Patient description We report a 1-month-old boy manifesting an epileptic encephalopathy with clonic seizures refractory to phenobarbital, pyridoxine and phenytoin that presented a dramatic response to levetiracetam with full epilepsy control and EEG normalization. Genetic analysis identified a novel de novo heterozygous mutation (c.[922A > T]p.[Lys308 ∗ ]) in the STXBP1 gene that severely affects the protein. Conclusions The observation of a dramatic efficacy of levetiracetam in a case of STXBP1 epileptic encephalopathy refractory to other antiepileptic drugs and considerations regarding the specific mechanism of action of levetiracetam modulating the same system affected by STXBP1 mutations support the hypothesis that this drug may be able to reverse specifically the disease epileptogenic abnormalities. Further clinical observations and laboratory studies are needed to confirm this hypothesis and eventually lead to consider levetiracetam as the first choice treatment of patients with suspected or confirmed STXBP1 -related epilepsies.
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OP12 – 2577: Targeted resequencing in epileptic encephalopathies: diagnostic implications and genotype–phenotype correlations
European Journal of Paediatric Neurology, 2015Co-Authors: Federico Zara, Elena Gennaro, S. Vari, Domenico Coviello, Pasquale StrianoAbstract:Objective To assess the diagnostic value of NGS target resequencing approach for epileptic encephalopathies. Methods The diagnostic tool allows the screening of 20 genes which have been consistently associated with early-onset epileptic encephalopathy (EE): ALDH7A1, PNP0, ARHGEF9, ARX, SLC25A22, PLCB1, TBC1D24, PNKP, KCNT1, KCNQ2, SCN2A, SCN8A, STXBP1, SCN1A, PCDH19, CDKL5, SPTAN1, SLC2A1, ST3GAL3, GRIN2A). NGS have been performed by Ampliseq/Ion Torrent technology of at least 120X. Patients have been classified into 5 phenotypic classes: 1) EEs with onset in the first year of life; 2) infantile spasms/West syndrome 3) Dravet Syndrome 4) CSWS/Landau-Kleffner Syndrome 5) EEs with onset after the first year of life. Results Fifty-four patients have been analyzed: class 1, n° 26; class 2, n° 10; class 3, n° 6; class 4, n° 4; class 5, n° 8. Pathogenetic effects of variants have been attributed according to i) segregation analysis (inherited vs transmitted; putative functional effect (damaging vs benign); state-of-art genotype-phenotype correlations. We identified a total of 23 unreported variants: – n° 13 variants were classified as likely pathogenetic (24%) on the following genes: STXBP1 (n°2), SCN1A (n°2), SCN2A (n°2), KCNQ2 N°2), CDKL5 (n°2), KCTN1 (n°1), GRIN2A (n°1), PNPO (n°1). – n° 6 variants were classified of uncertain significance (11%): PCDH19 (n°1); SCN1A (n°1), ARHGEF9 (n°1), KCNQ2 (n°1), SPTAN (n°1), STXBP1 (n°1). – n° 4 variants were classified likely benign (7%): ARHGEF9 (n°1), TBC1D24 (n°1), SCN1A (n°1), KCNQ2 (n°1). Conclusion In about 1/4 of the cases we were able to reach a definite diagnosis. Detailed clinical information is required to interprete genetic findings. The diagnostic yield is particularly high within the group of EEs with onset in the first year of life. SCN1A, SCN2A, STXBP1 and CDKL5 show multiple mutations, providing a further confirmation on their pivotal role in the etiology of epileptic encephalopathy.
Amy Crunk - One of the best experts on this subject based on the ideXlab platform.
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novel 9q34 11 gene deletions encompassing combinations of four mendelian disease genes STXBP1 sptan1 eng and tor1a
Genetics in Medicine, 2012Co-Authors: Ian M. Campbell, Patricia Hixson, Usha Dayal, Tyler Reimschisel, James W. Wheless, Svetlana A Yatsenko, Matthew J Thomas, William G Wilson, Amy CrunkAbstract:Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1 , SPTAN1 , ENG , and TOR1A
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Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A
Genetics in Medicine, 2012Co-Authors: Ian M. Campbell, Patricia Hixson, W. Wilson, Usha Dayal, Amy Crunk, Matthew Thomas, Tyler Reimschisel, James W. Wheless, Svetlana A Yatsenko, Cynthia CurryAbstract:PURPOSE: A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype-phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking. METHODS: We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content. RESULTS: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated. CONCLUSION: STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.
