Journal http://jcn.sagepub.com/ of Child Neurology
A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern Romina Romaniello, Claudio Zucca, Erika Tenderini, Filippo Arrigoni, Francesca Ragona, Giovanna Zorzi, Maria Teresa Bassi and Renato Borgatti J Child Neurol published online 29 October 2013 DOI: 10.1177/0883073813506936 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2013/10/29/0883073813506936 A more recent version of this article was published on - Jan 15, 2014
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
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Brief Communication
A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern
Journal of Child Neurology 00(0) 1-5 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813506936 jcn.sagepub.com
Romina Romaniello, MD1, Claudio Zucca, MD2, Erika Tenderini, BS3, Filippo Arrigoni, MD4, Francesca Ragona, MD5, Giovanna Zorzi, MD5, Maria Teresa Bassi, PhD3, and Renato Borgatti, MD1
Abstract Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-yearold boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of ‘‘STXBP1-related encephalopathy’’ suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects. Keywords epilepsy, epileptic encephalopathy, Ohtahara syndrome, STXBP1 gene, vigabatrin therapy Received May 22, 2013. Received revised July 11, 2013. Accepted for publication September 03, 2013.
Epileptic encephalopathies have been described as progressive conditions, characterized by recurrent clinical seizures in which epileptic activity itself can contribute to worsen cognitive and behavioral impairments.1 Age at onset, seizure types, ictal, and interictal electroencephalographic (EEG) pattern contribute as a whole to address the diagnosis. Main genetic causes of epileptic encephalopathies include mutations in ARX, CDKL5, SCN1A, and PCDH19 genes that have been associated with specific clinical and EEG patterns.2-5 Moreover, mutations in the STXBP1 (Syntaxin-binding Protein 1) gene have recently been described in Ohtahara syndrome6-8 and in several types of early-onset epileptic encephalopathies.2,3,5,8-11 A 3-year-old boy carrying a novel de novo mutation in the STXBP1 gene is described. Clinical and EEG features appear to be different from cases reported so far, thus broadening the spectrum of STXBP1-related encephalopathies.
Case Summary The patient was born at term after an uneventful pregnancy with Apgar score, weight, length, and head circumference in normal range. The neonatal period was unremarkable and followed by normal development milestones. Focal motor
seizures characterized by unresponsiveness, deviation of the head and eyes indifferently to the left or the right side, cyanosis, with secondary generalization, occurred in clusters since age 8 months. No response to phenobarbital treatment was observed. In the months following, seizures became more frequent; however despite crisis, neurologic examination and developmental quotient at 13 months of age were still normal
1
Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 2 Neurophysiopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 3 Laboratory of Molecular Biology, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 4 Neuroimaging Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 5 Child Neurology Department, Foundation IRCCS Istituto ‘‘Carlo Besta,’’ Milan, Italy Corresponding Author: Renato Borgatti, MD, Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea Via D. L. Monza 20, Bosisio Parini, Lecco 23842, Italy. Email: [email protected]
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
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Figure 1. Migrating epileptic foci at onset. Epileptiform abnormalities with prevalence over the frontotemporal regions, more often asynchronous on the 2 hemispheres with varying side prevalence. Ictal electroencephalographic (EEG) patterns have been described as multifocal. Seizures were demonstrated, on several recordings, to start from both the left and right hemispheres (seizures could start either from the left or right hemisphere).
(91 at Griffiths Mental Developmental Scale). Treatments with valproic acid, carbamazepine, levetiracetam, and pyridoxine were started without efficacy. Episodes of status epilepticus also occurred. EEG recordings, since the clinical history was recorded, showed epileptiform abnormalities with prevalence over the frontotemporal regions, which were more often asynchronous on the 2 hemispheres, with varying side prevalence. Ictal EEG patterns have been described as multifocal. As shown in Figure 1, seizures were demonstrated on several recordings, starting from both the left and right hemisphere. Video EEG recordings showed a clear correlation between the topography of the EEG ictal discharges and the clinical features. At 20 months of age, a severe regression of psychomotor development was observed with loss of walking, language, and interaction skills (developmental quotient A) de novo mutation, leading to a p.Ala251Thr substitution, in exon 9 (Figure 3). The change is not present in the Single Nucleotide Polymorphism database or in the 1000Genome
databases and is highly evolutionary conserved. In addition, different software used predicted deleterious effects for this missense mutation (Figure 3), which falls within the domain 3a of the protein. This domain along with domain 1 forms a cavity providing the binding surface for Syntaxin 1a. After diagnosis, in accordance with literature data,2 treatment with vigabatrin was attempted and the patient became immediately seizure free. Both awake and sleep EEG dramatically improved (Figure 2B) as well as clinical performance (he restarted to walk and showed minimal cognitive and behavioral abilities previously loss). After 4 months, few seizures relapsed only during sleep. Carbamazepine was added to vigabatrin, and a reduction of seizures frequency was observed.
Discussion Heterozygous mutations in the STXBP1 gene have been recently identified in patients with different types of infantile epileptic encephalopathies predominantly with early onset (first days or weeks of life).2,3,6-10,12 The present case adds to the few cases of epileptic encephalopathies so far reported that were caused by STXBP1 gene mutations or deletions with onset in the first year of life without the typical characteristics of West syndrome. Like most epilepsy-related genes, the phenotypic spectrum of STXBP1 gene mutations is broader than 1 specific epileptic syndrome; it’s thus more appropriate to talk about ‘‘STXBP1 encephalopathy.’’5 Deprez et al2 summarized the pattern of symptoms observed in the majority of patients with a STXBP1 gene mutation as follows: epilepsy onset before 9 months, several seizure types variably associated with spasms, variable severity of epilepsy from few controlled seizures to intractable epilepsy, invariable development of severe mental retardation and behavioral disturbances, and severely compromised ambulation. EEG most frequently shows focalized,
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
Romaniello et al
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Figure 2. Electroencephalographic (EEG) recordings before and after vigabatrin treatment. (A) EEG is characterized during wakefulness by an abnormal background with an excess of slow activity mainly localized over the anterior regions and the left hemisphere. During sleep, epileptiform abnormalities are present on the frontotemporal regions with prevalence over the left hemisphere. Background activity during sleep is irregular: phasic elements are rare, low-voltage, and often asynchronous. (B) EEG recording confirm irregular organization and slowing of the background activity both during wakefulness and sleep. Slow and epileptiform abnormalities are present over the frontal and frontotemporal areas often asynchronous with a slight prevalence on the right.
lateralized, or multifocal epileptic activity in association with abnormal background activity. Response to treatments is variable: a combination therapy including vigabatrin is recommended, and in some cases, patients become seizure-free.2,3,5,8 The case described presents some features overlapping with the pattern summarized by Deprez et al2: seizures onset before 9 months of age, severe mental retardation after seizures onset, normal brain MRI, and good response to vigabatrin. Nevertheless, the atypical electroclinical pattern observed (Figure 1), characterized by a multifocal interictal and itcal EEG features and a variable EEG focus with recorded seizures, starting both from the left and the right hemisphere has not been previously described. STXBP1 gene, also called MUNC18-1, encodes the syntaxinbinding protein 1, a neuron-specific protein of the SEC1 family of membrane-trafficking proteins. It plays 3 important functions: binds the closed form of syntaxin 1A, thereby (1) hindering or (2) promoting formation of Soluble NSF Attachment Protein Receptor complex, and (3) docking large dense-core vesicles to the plasma membrane.13 It is expressed throughout the brain and is a key component for calcium-dependent neurotransmitter release.14 In addition, it has an essential role in synaptic vesicle release at both glutamatergic and GABAergic synapses and in synaptic transmission.15-17
Given the multiple roles of syntaxin-binding protein 1, in relation to the involvement of different domains of the gene, a wide spectrum of epileptic syndromes can be observed.13 In the present case, the novel de novo mutation identified falls within the domain 3a, which together with domain 1 is involved in the first type of binding of MUNC18 to the syntaxin-1. Although residue A251 is not located in any of the contact points identified, the predictions indicate that the mutation could determine loss of activity of the close catalytic residue M252, thereby affecting the protein’s ability to bind syntaxin 1.13 This could compromise the entire process of membrane fusion/exocytosis with dramatic effects in phasic neurotransmitter release from neurons, thereby increasing the cortex’s excitability. In conclusion, our findings contribute to further expanding the clinical spectrum of STXBP1-related encephalopathy, suggesting that STXBP1 gene could play a key role in a large spectrum of epilepsies of unknown origin as previously demonstrated for other genes associated with epileptic encephalopathies.18 For this reason, in the near future, a more systematic approach (such as whole exome or a epilepsy gene panel for targeted resequencing) to search for genetic causes in earlyonset epileptic seizures is recommendable in subjects with associated mental retardation of unknown etiology.19,20
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
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Journal of Child Neurology 00(0)
Figure 3. STXBP1 mutation. Electropherograms of the mutant and control sequence are shown at the top, with a box indicating the mutant nucleotide. In the middle, mutation prediction analysis of pathogenicity is shown. *With regard to Mutpred (*), scores with g > 0.75 and P < .05 are referred to as confident hypothesis. In this case, the prediction indicates that the A251 change observed in the patient likely leads to loss of catalytic activity at M252 residue. At the bottom, partial multiple sequence alignment of STXBP1 homologues from different species indicates the high evolutionary conservation of the A251 residue.
As already described in the literature,2 as well as in our patient, only vigabatrin has allowed a period of complete seizure control. This data confirm that vigabatrin probably has an action on the pathophysiological mechanisms of
epilepsy caused by STXBP1 mutation, thereby confirming the hypothesis suggested by Deprez et al2 that a trial of vigabatrin is justified in patients with a STXBP1 gene mutation.
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
Romaniello et al
5
Acknowledgments The authors are grateful to the parents of the patient for their kind cooperation.
6.
Author Contributions RR collected the data and drafted the manuscript. CZ acquired and interpreted the neurophysiological data and drafted the manuscript. ET carried out the molecular genetic studies. FA performed neuroradiological study and was involved in drafting the manuscript. FR and GZ collected the data and helped draft the manuscript. MTB performed interpretation of genetic data and was involved in drafting the manuscript. RB conceived the study, participated in its design and drafting, in revising it critically, and in acquisition of funding. All authors read and approved the final manuscript. Each author had full access to all the data supporting the publication.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
7.
8.
9.
10.
11.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partially supported by Italian National Institute of Health research funding (Ministero della Sanita`) grant to RB (RC/01/03/2012), CZ (RC/04/03/2012) and MTB (5X MILLE).
12.
13.
Ethical Approval Ethical approval was provided by the Institutional Review Board of Scientific Institute Eugenio Medea (016/11/CE). Patient’s parents have given informed consent to the research and to publication of the results.
14.
References
15.
1. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005– 2009. Epilepsia 2010;51:676-85. 2. Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology. 2010;75:1159-1165. 3. Mignot C, Moutard ML, Trouillard O, et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia. 2011;52:1820-1827. 4. Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012;46:24-31. 5. Weckhuysen S, Holmgren P, Hendrickx R, et al. Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1
16.
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18. 19.
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encephalopathy and clinical description of six novel mutation carriers. Epilepsia. 2013;54:e74-e80. Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782-788. Saitsu H, Kato M, Okada I, et al. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. Epilepsia. 2010;51:2397-2405. Milh M, Villeneuve N, Chouchane M, et al. Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations. Epilepsia. 2011;52: 1828-1834. Otsuka M, Oguni H, Liang JS, et al. STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—result of Japanese cohort study. Epilepsia. 2010;51:2449-2452. Hamdan FF, Piton A, Gauthier J, et al. De novo STXBP1 mutations in mental retardation and non syndromic epilepsy. Ann Neurol. 2009;65:748-753. Mastrangelo M, Peron A, Spaccini L, et al. Neonatal suppressionburst without epileptic seizures: expanding the electroclinical phenotype of STXBP1-related, early-onset encephalopathy. Epileptic Disord. 2013;15:55-61. Vatta M, Tennison MB, Aylsworth AS, et al. A novel STXBP1 mutation causes focal seizures with neonatal onset. J Child Neurol. 2012;27:811-814. Han GA, Malintan NT, Collins BM, Meunier FA, Sugita S. Munc18-1 as a key regulator of neurosecretion. J Neurochem. 2010;115:1-10. Rickman C, Medine CN, Bergmann A, Duncan RR. Functionally and spatially distinct modes of munc18-syntaxin 1 interaction. J Biol Chem. 2007;282:12097-12103. Toonen RF, Wierda K, Sons MS, et al. Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size. Proc Natl Acad Sci U S A. 2006;103:18332-18337. Gerber SH, Rah JC, Min SW, et al. Conformational switch of syntaxin-1 controls synaptic vesicle fusion. Science. 2008;321: 1507-1510. Verhage M, Maia AS, Plomp JJ, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287:864-869. Cross JH, Guerrini R. The epileptic encephalopathies. Handb Clin Neurol. 2013;111:619-626. Veeramah KR, Johnstone L, Karafet TM, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54:1270-1281. Nabbout R, Dulac O. Genetics of early-onset epilepsy with encephalopathy. Nat Rev Neurol. 2012;31;8:129-130.
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A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern Romina Romaniello, Claudio Zucca, Erika Tenderini, Filippo Arrigoni, Francesca Ragona, Giovanna Zorzi, Maria Teresa Bassi and Renato Borgatti J Child Neurol published online 29 October 2013 DOI: 10.1177/0883073813506936 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2013/10/29/0883073813506936 A more recent version of this article was published on - Jan 15, 2014
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Jan 15, 2014 >> OnlineFirst Version of Record - Oct 29, 2013 What is This?
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
Brief Communication
A Novel Mutation in STXBP1 Gene in a Child With Epileptic Encephalopathy and an Atypical Electroclinical Pattern
Journal of Child Neurology 00(0) 1-5 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813506936 jcn.sagepub.com
Romina Romaniello, MD1, Claudio Zucca, MD2, Erika Tenderini, BS3, Filippo Arrigoni, MD4, Francesca Ragona, MD5, Giovanna Zorzi, MD5, Maria Teresa Bassi, PhD3, and Renato Borgatti, MD1
Abstract Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-yearold boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of ‘‘STXBP1-related encephalopathy’’ suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects. Keywords epilepsy, epileptic encephalopathy, Ohtahara syndrome, STXBP1 gene, vigabatrin therapy Received May 22, 2013. Received revised July 11, 2013. Accepted for publication September 03, 2013.
Epileptic encephalopathies have been described as progressive conditions, characterized by recurrent clinical seizures in which epileptic activity itself can contribute to worsen cognitive and behavioral impairments.1 Age at onset, seizure types, ictal, and interictal electroencephalographic (EEG) pattern contribute as a whole to address the diagnosis. Main genetic causes of epileptic encephalopathies include mutations in ARX, CDKL5, SCN1A, and PCDH19 genes that have been associated with specific clinical and EEG patterns.2-5 Moreover, mutations in the STXBP1 (Syntaxin-binding Protein 1) gene have recently been described in Ohtahara syndrome6-8 and in several types of early-onset epileptic encephalopathies.2,3,5,8-11 A 3-year-old boy carrying a novel de novo mutation in the STXBP1 gene is described. Clinical and EEG features appear to be different from cases reported so far, thus broadening the spectrum of STXBP1-related encephalopathies.
Case Summary The patient was born at term after an uneventful pregnancy with Apgar score, weight, length, and head circumference in normal range. The neonatal period was unremarkable and followed by normal development milestones. Focal motor
seizures characterized by unresponsiveness, deviation of the head and eyes indifferently to the left or the right side, cyanosis, with secondary generalization, occurred in clusters since age 8 months. No response to phenobarbital treatment was observed. In the months following, seizures became more frequent; however despite crisis, neurologic examination and developmental quotient at 13 months of age were still normal
1
Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 2 Neurophysiopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 3 Laboratory of Molecular Biology, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 4 Neuroimaging Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 5 Child Neurology Department, Foundation IRCCS Istituto ‘‘Carlo Besta,’’ Milan, Italy Corresponding Author: Renato Borgatti, MD, Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea Via D. L. Monza 20, Bosisio Parini, Lecco 23842, Italy. Email: [email protected]
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
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Figure 1. Migrating epileptic foci at onset. Epileptiform abnormalities with prevalence over the frontotemporal regions, more often asynchronous on the 2 hemispheres with varying side prevalence. Ictal electroencephalographic (EEG) patterns have been described as multifocal. Seizures were demonstrated, on several recordings, to start from both the left and right hemispheres (seizures could start either from the left or right hemisphere).
(91 at Griffiths Mental Developmental Scale). Treatments with valproic acid, carbamazepine, levetiracetam, and pyridoxine were started without efficacy. Episodes of status epilepticus also occurred. EEG recordings, since the clinical history was recorded, showed epileptiform abnormalities with prevalence over the frontotemporal regions, which were more often asynchronous on the 2 hemispheres, with varying side prevalence. Ictal EEG patterns have been described as multifocal. As shown in Figure 1, seizures were demonstrated on several recordings, starting from both the left and right hemisphere. Video EEG recordings showed a clear correlation between the topography of the EEG ictal discharges and the clinical features. At 20 months of age, a severe regression of psychomotor development was observed with loss of walking, language, and interaction skills (developmental quotient A) de novo mutation, leading to a p.Ala251Thr substitution, in exon 9 (Figure 3). The change is not present in the Single Nucleotide Polymorphism database or in the 1000Genome
databases and is highly evolutionary conserved. In addition, different software used predicted deleterious effects for this missense mutation (Figure 3), which falls within the domain 3a of the protein. This domain along with domain 1 forms a cavity providing the binding surface for Syntaxin 1a. After diagnosis, in accordance with literature data,2 treatment with vigabatrin was attempted and the patient became immediately seizure free. Both awake and sleep EEG dramatically improved (Figure 2B) as well as clinical performance (he restarted to walk and showed minimal cognitive and behavioral abilities previously loss). After 4 months, few seizures relapsed only during sleep. Carbamazepine was added to vigabatrin, and a reduction of seizures frequency was observed.
Discussion Heterozygous mutations in the STXBP1 gene have been recently identified in patients with different types of infantile epileptic encephalopathies predominantly with early onset (first days or weeks of life).2,3,6-10,12 The present case adds to the few cases of epileptic encephalopathies so far reported that were caused by STXBP1 gene mutations or deletions with onset in the first year of life without the typical characteristics of West syndrome. Like most epilepsy-related genes, the phenotypic spectrum of STXBP1 gene mutations is broader than 1 specific epileptic syndrome; it’s thus more appropriate to talk about ‘‘STXBP1 encephalopathy.’’5 Deprez et al2 summarized the pattern of symptoms observed in the majority of patients with a STXBP1 gene mutation as follows: epilepsy onset before 9 months, several seizure types variably associated with spasms, variable severity of epilepsy from few controlled seizures to intractable epilepsy, invariable development of severe mental retardation and behavioral disturbances, and severely compromised ambulation. EEG most frequently shows focalized,
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
Romaniello et al
3
Figure 2. Electroencephalographic (EEG) recordings before and after vigabatrin treatment. (A) EEG is characterized during wakefulness by an abnormal background with an excess of slow activity mainly localized over the anterior regions and the left hemisphere. During sleep, epileptiform abnormalities are present on the frontotemporal regions with prevalence over the left hemisphere. Background activity during sleep is irregular: phasic elements are rare, low-voltage, and often asynchronous. (B) EEG recording confirm irregular organization and slowing of the background activity both during wakefulness and sleep. Slow and epileptiform abnormalities are present over the frontal and frontotemporal areas often asynchronous with a slight prevalence on the right.
lateralized, or multifocal epileptic activity in association with abnormal background activity. Response to treatments is variable: a combination therapy including vigabatrin is recommended, and in some cases, patients become seizure-free.2,3,5,8 The case described presents some features overlapping with the pattern summarized by Deprez et al2: seizures onset before 9 months of age, severe mental retardation after seizures onset, normal brain MRI, and good response to vigabatrin. Nevertheless, the atypical electroclinical pattern observed (Figure 1), characterized by a multifocal interictal and itcal EEG features and a variable EEG focus with recorded seizures, starting both from the left and the right hemisphere has not been previously described. STXBP1 gene, also called MUNC18-1, encodes the syntaxinbinding protein 1, a neuron-specific protein of the SEC1 family of membrane-trafficking proteins. It plays 3 important functions: binds the closed form of syntaxin 1A, thereby (1) hindering or (2) promoting formation of Soluble NSF Attachment Protein Receptor complex, and (3) docking large dense-core vesicles to the plasma membrane.13 It is expressed throughout the brain and is a key component for calcium-dependent neurotransmitter release.14 In addition, it has an essential role in synaptic vesicle release at both glutamatergic and GABAergic synapses and in synaptic transmission.15-17
Given the multiple roles of syntaxin-binding protein 1, in relation to the involvement of different domains of the gene, a wide spectrum of epileptic syndromes can be observed.13 In the present case, the novel de novo mutation identified falls within the domain 3a, which together with domain 1 is involved in the first type of binding of MUNC18 to the syntaxin-1. Although residue A251 is not located in any of the contact points identified, the predictions indicate that the mutation could determine loss of activity of the close catalytic residue M252, thereby affecting the protein’s ability to bind syntaxin 1.13 This could compromise the entire process of membrane fusion/exocytosis with dramatic effects in phasic neurotransmitter release from neurons, thereby increasing the cortex’s excitability. In conclusion, our findings contribute to further expanding the clinical spectrum of STXBP1-related encephalopathy, suggesting that STXBP1 gene could play a key role in a large spectrum of epilepsies of unknown origin as previously demonstrated for other genes associated with epileptic encephalopathies.18 For this reason, in the near future, a more systematic approach (such as whole exome or a epilepsy gene panel for targeted resequencing) to search for genetic causes in earlyonset epileptic seizures is recommendable in subjects with associated mental retardation of unknown etiology.19,20
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
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Journal of Child Neurology 00(0)
Figure 3. STXBP1 mutation. Electropherograms of the mutant and control sequence are shown at the top, with a box indicating the mutant nucleotide. In the middle, mutation prediction analysis of pathogenicity is shown. *With regard to Mutpred (*), scores with g > 0.75 and P < .05 are referred to as confident hypothesis. In this case, the prediction indicates that the A251 change observed in the patient likely leads to loss of catalytic activity at M252 residue. At the bottom, partial multiple sequence alignment of STXBP1 homologues from different species indicates the high evolutionary conservation of the A251 residue.
As already described in the literature,2 as well as in our patient, only vigabatrin has allowed a period of complete seizure control. This data confirm that vigabatrin probably has an action on the pathophysiological mechanisms of
epilepsy caused by STXBP1 mutation, thereby confirming the hypothesis suggested by Deprez et al2 that a trial of vigabatrin is justified in patients with a STXBP1 gene mutation.
Downloaded from jcn.sagepub.com at Ondokuz Mayis Universitesi on November 11, 2014
Romaniello et al
5
Acknowledgments The authors are grateful to the parents of the patient for their kind cooperation.
6.
Author Contributions RR collected the data and drafted the manuscript. CZ acquired and interpreted the neurophysiological data and drafted the manuscript. ET carried out the molecular genetic studies. FA performed neuroradiological study and was involved in drafting the manuscript. FR and GZ collected the data and helped draft the manuscript. MTB performed interpretation of genetic data and was involved in drafting the manuscript. RB conceived the study, participated in its design and drafting, in revising it critically, and in acquisition of funding. All authors read and approved the final manuscript. Each author had full access to all the data supporting the publication.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
7.
8.
9.
10.
11.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partially supported by Italian National Institute of Health research funding (Ministero della Sanita`) grant to RB (RC/01/03/2012), CZ (RC/04/03/2012) and MTB (5X MILLE).
12.
13.
Ethical Approval Ethical approval was provided by the Institutional Review Board of Scientific Institute Eugenio Medea (016/11/CE). Patient’s parents have given informed consent to the research and to publication of the results.
14.
References
15.
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