STXBP1 encephalopathy A neurodevelopmental disorder including epilepsy

被引：235

作者：

Stamberger, Hannah ^{[1
,3
,4
]}

Nikanorova, Marina ^{[5
]}

Willemsen, Marjolein H. ^{[6
]}

Accorsi, Patrizia ^{[8
]}

Angriman, Marco ^{[9
]}

Baier, Hartmut ^{[10
]}

Benkel-Herrenbrueck, Ira ^{[11
,12
]}

Benoit, Valerie ^{[13
]}

Budetta, Mauro ^{[14
]}

Caliebe, Almuth ^{[15
,16
]}

Cantalupo, Gaetano ^{[17
]}

Capovilla, Giuseppe ^{[18
]}

Casara, Gianluca ^{[9
,17
]}

Courage, Carolina ^{[19
]}

Deprez, Marie ^{[13
]}

Destree, Anne ^{[13
]}

Dilena, Robertino ^{[20
]}

Erasmus, Corrie E. ^{[7
]}

Fannemel, Madeleine ^{[21
]}

Fjaer, Roar ^{[21
,22
]}

Giordano, Lucio ^{[8
]}

Helbig, Katherine L. ^{[23
]}

Heyne, Henrike O. ^{[24
]}

Klepper, Joerg ^{[26
]}

Kluger, Gerhard J. ^{[27
,28
]}

Lederer, Damien ^{[13
]}

Lodi, Monica ^{[29
,30
]}

Maier, Oliver ^{[31
]}

Merkenschlager, Andreas ^{[25
]}

Michelberger, Nina ^{[10
]}

Minetti, Carlo ^{[32
]}

Muhle, Hiltrud ^{[34
,35
]}

Phalin, Judith ^{[36
]}

Ramsey, Keri ^{[37
]}

Romeo, Antonino ^{[29
,30
]}

Schallner, Jens ^{[38
]}

Schanze, Ina ^{[39
]}

Shinawi, Marwan ^{[40
]}

Sleegers, Kristel ^{[2
,3
]}

Sterbova, Katalin ^{[41
]}

Syrbe, Steffen ^{[25
]}

Traverso, Monica ^{[33
]}

Tzschach, Andreas ^{[42
,43
]}

Uldall, Peter ^{[5
,45
]}

Van Coster, Rudy ^{[46
]}

Verhelst, Helene ^{[46
]}

Viri, Maurizio ^{[29
,30
]}

Winter, Susan ^{[36
]}

Wolff, Markus ^{[44
]}

Zenker, Martin ^{[39
]}

机构：

[1] VIB, Dept Mol Genet, Neurogenet Grp, Antwerp, Belgium

[2] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[3] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium

[4] Univ Antwerp, Univ Antwerp Hosp, Dept Neurol, Antwerp, Belgium

[5] Danish Epilepsy Ctr, Dianalund, Denmark

[6] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Pediat Neurol, NL-6525 ED Nijmegen, Netherlands

[8] Spedali Civili Brescia, Div Child Neurol, Brescia, Italy

[9] Cent Hosp Bolzano, Dept Pediat, Child Neurol & Neurorehabil Unit, Bolzano, Italy

[10] Sinova Kliniken ZfP Sudwrttemberg, Dept Epileptol, Ravensburg Klin Kinderneurol, Ravensburg, Germany

[11] Sana Kliniken Dusseldorf, Klin Kinderneurol, Dusseldorf, Germany

[12] Sana Kliniken Dusseldorf, Kinderneurolog Zentrum, Dusseldorf, Germany

[13] Inst Pathol & Genet, Ctr Genet Humaine, Charleroi, Gosselies, Belgium

[14] Univ Specialist Neurol Pediat, Presidio Osped Cava Tirreni, Salerno, Italy

[15] Christian Albrechts Univ Kiel, Inst Human Genet, Campus Kiel, Kiel, Germany

[16] Univ Hosp Schleswig Holstein, Campus Kiel, Kiel, Germany

[17] Univ Verona, Dept Life & Reprod Sci, Child Neuropsychiat Unit, I-37100 Verona, Italy

[18] Azienda Osped Carlo Poma, Neuropsichiatria Infantile, Dipartimento Maternoinfantile, Manotva, Italy

[19] Univ Bern, Dept Pediat, Inselspital, Div Human Genet, CH-3012 Bern, Switzerland

[20] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Serv Epilettol & Neuro Fisiopatol Pediat, Neurofisiopatol, Milan, Italy

[21] Oslo Univ Hosp, Dept Med Genet, N-0450 Oslo, Norway

[22] Univ Oslo, N-0316 Oslo, Norway

[23] Ambry Genet, Div Clin Genom, Aliso Viejo, CA USA

[24] Univ Leipzig, Inst Human Genet, D-04109 Leipzig, Germany

[25] Univ Leipzig, Dept Women & Child Hlth, Hosp Children & Adolescents, D-04109 Leipzig, Germany

[26] Hasenkopf, Childrens Hosp Aschaffenburg, Aschaffenburg, Germany

[27] Schon Klin Vogtareuth, Epilepsy Ctr Children & Adolescents, Neuropediat Clin & Clin Neurorehabilitat, Vogtareuth, Germany

[28] PMU Salzburg, Salzburg, Austria

[29] Pediat Neurol Unit, Milan, Italy

[30] Fatebenefratelli & Oftalm Hosp, Epilepsy Ctr, Milan, Italy

[31] Childrens Hosp Eastern Switzerland, Dept Child Neurol Develop & Rehabil, KER Zentrum, St Gallen, Switzerland

[32] Univ Genoa, Pediat Neurol & Muscular Dis Unit, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16126 Genoa, Italy

[33] G Gaslini Inst Children, Dept Neurosci, Neurogenet Lab, Genoa, Italy

[34] Christian Albrechts Univ Kiel, Dept Neuropediatr, Campus Kiel, Kiel, Germany

[35] Univ Hosp Schleswig Holstein, Campus Kiel, Kiel, Germany

[36] Valley Childrens Hosp, Dept Med Genet & Metab, Madera, CA USA

[37] Translat Genom Res Inst, Ctr Rare Childhood Disorders, Phoenix, AZ USA

[38] Univ Clin Carl Gustav Carus, Dept Neuropediat, Dresden, Germany

[39] Univ Hosp, Inst Human Genet, Magdeburg, Germany

[40] Washington Univ, Div Genet & Genom Med, Sch Med, Dept Pediat, St Louis, MO USA

[41] Charles Univ Prague, Motol Hosp, Fac Med 2, Dept Child Neurol, Prague, Czech Republic

[42] Tech Univ Dresden, Inst Clin Genet, Dresden, Germany

[43] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany

[44] Univ Tubingen, Dept Neuropediat, Tubingen, Germany

[45] Univ Copenhagen, Rigshosp, Child & Adolescence Dept, DK-1168 Copenhagen, Denmark

[46] Ghent Univ Hosp, Div Pediat Neurol & Metab, Dept Pediat, Ghent, Belgium

[47] Childrens Hosp, Div Neurol, Philadelphia, PA 19104 USA

[48] Univ Southern Denmark, Inst Reg Hlth Serv, Odense, Denmark

[49] Univ Paris 06, Ctr Natl Rech Sci, UMR 7225, INSERM 1127, Paris, France

[50] Sorbonne Univ, UMR S 1127, Inst Cerveau & Moelle Epiniere, Paris, France

来源：

NEUROLOGY | 2016年 / 86卷 / 10期

关键词：

DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; INFANTILE SPASMS; SUPPRESSION-BURST; OHTAHARA SYNDROME; GENE; FEATURES; DELETIONS; SEIZURES; SPECTRUM;

D O I：

10.1212/WNL.0000000000002457

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective:To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients.Methods:We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients.Results:We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features.Conclusion:De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

引用

页码：954 / 962

页数：9

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