PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum

Katrine M. Johannesen; Elena Gardella; Cathrine E. Gjerulfsen; Allan Bayat; Rob P.W. Rouhl; Margot Reijnders; Sandra Whalen; Boris Keren; Julien Buratti; Thomas Courtin; Klaas J. Wierenga; Bertrand Isidor; Amélie Piton; Laurence Faivre; Aurore Garde; Sébastien Moutton; Frédéric Tran-Mau-Them; Anne Sophie Denommé-Pichon; Christine Coubes; Austin Larson; Michael J. Esser; Juan Pablo Appendino; Walla Al-Hertani; Beatriz Gamboni; Alejandra Mampel; Lía Mayorga; Alessandro Orsini; Alice Bonuccelli; Agnese Suppiej; Julien Van-Gils; Julie Vogt; Simona Damioli; Lucio Giordano; Stephanie Moortgat; Elaine Wirrell; Sarah Hicks; Usha Kini; Nathan Noble; Helen Stewart; Shailesh Asakar; Julie S. Cohen; Sakku Bai R. Naidu; Ashley Collier; Eva H. Brilstra; Mindy H. Li; Casey Brew; Stefania Bigoni; Davide Ognibene; Elisa Ballardini; Claudia Ruivenkamp; Raffaella Faggioli; Alexandra Afenjar; Diana Rodriguez; David Bick; Devorah Segal; David Coman; Boudewijn Gunning; Orrin Devinsky; Laurie A. Demmer; Theresa Grebe; Dario Pruna; Ida Cursio; Lynn Greenhalgh; Claudio Graziano; Rahul Raman Singh; Gaetano Cantalupo; Marjolaine Willems; Sangeetha Yoganathan; Fernanda Góes; Richard J. Leventer; Davide Colavito; Sara Olivotto; Barbara Scelsa; Andrea V. Andrade; Kelly Ratke; Farha Tokarz; Atiya S. Khan; Clothilde Ormieres; William Benko; Karen Keough; Sotirios Keros; Shanawaz Hussain; Ashlea Franques; Felicia Varsalone; Sabine Grønborg; Cyril Mignot; Delphine Heron; Caroline Nava; Arnaud Isapof; Felippe Borlot; Robyn Whitney; Anne Ronan; Nicola Foulds; Marta Somorai; John Brandsema; Katherine L. Helbig; Ingo Helbig; Xilma R. Ortiz-González; Holly Dubbs; Antonio Vitobello; Mel Anderson; Dominic Spadafore; David Hunt; Rikke S. Møller; Guido Rubboli

doi:10.1212/NXG.0000000000000613

PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum

Katrine M. Johannesen, Elena Gardella, Cathrine E. Gjerulfsen, Allan Bayat, Rob P.W. Rouhl, Margot Reijnders, Sandra Whalen, Boris Keren, Julien Buratti, Thomas Courtin, Klaas J. Wierenga, Bertrand Isidor, Amélie Piton, Laurence Faivre, Aurore Garde, Sébastien Moutton, Frédéric Tran-Mau-Them, Anne Sophie Denommé-Pichon, Christine Coubes, Austin LarsonMichael J. Esser, Juan Pablo Appendino, Walla Al-Hertani, Beatriz Gamboni, Alejandra Mampel, Lía Mayorga, Alessandro Orsini, Alice Bonuccelli, Agnese Suppiej, Julien Van-Gils, Julie Vogt, Simona Damioli, Lucio Giordano, Stephanie Moortgat, Elaine Wirrell, Sarah Hicks, Usha Kini, Nathan Noble, Helen Stewart, Shailesh Asakar, Julie S. Cohen, Sakku Bai R. Naidu, Ashley Collier, Eva H. Brilstra, Mindy H. Li, Casey Brew, Stefania Bigoni, Davide Ognibene, Elisa Ballardini, Claudia Ruivenkamp, Raffaella Faggioli, Alexandra Afenjar, Diana Rodriguez, David Bick, Devorah Segal, David Coman, Boudewijn Gunning, Orrin Devinsky, Laurie A. Demmer, Theresa Grebe, Dario Pruna, Ida Cursio, Lynn Greenhalgh, Claudio Graziano, Rahul Raman Singh, Gaetano Cantalupo, Marjolaine Willems, Sangeetha Yoganathan, Fernanda Góes, Richard J. Leventer, Davide Colavito, Sara Olivotto, Barbara Scelsa, Andrea V. Andrade, Kelly Ratke, Farha Tokarz, Atiya S. Khan, Clothilde Ormieres, William Benko, Karen Keough, Sotirios Keros, Shanawaz Hussain, Ashlea Franques, Felicia Varsalone, Sabine Grønborg, Cyril Mignot, Delphine Heron, Caroline Nava, Arnaud Isapof, Felippe Borlot, Robyn Whitney, Anne Ronan, Nicola Foulds, Marta Somorai, John Brandsema, Katherine L. Helbig, Ingo Helbig, Xilma R. Ortiz-González, Holly Dubbs, Antonio Vitobello, Mel Anderson, Dominic Spadafore, David Hunt, Rikke S. Møller, Guido Rubboli

Research output: Contribution to journal › Article › peer-review

Abstract

Background and Objectives Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. Discussion The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Original language	English (US)
Article number	e613
Journal	Neurology: Genetics
Volume	7
Issue number	6
DOIs	https://doi.org/10.1212/NXG.0000000000000613
State	Published - Dec 15 2021

ASJC Scopus subject areas

Clinical Neurology
Genetics(clinical)

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Johannesen, K. M., Gardella, E., Gjerulfsen, C. E., Bayat, A., Rouhl, R. P. W., Reijnders, M., Whalen, S., Keren, B., Buratti, J., Courtin, T., Wierenga, K. J., Isidor, B., Piton, A., Faivre, L., Garde, A., Moutton, S., Tran-Mau-Them, F., Denommé-Pichon, A. S., Coubes, C., ... Rubboli, G. (2021). PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum. Neurology: Genetics, 7(6), Article e613. https://doi.org/10.1212/NXG.0000000000000613

Johannesen, KM, Gardella, E, Gjerulfsen, CE, Bayat, A, Rouhl, RPW, Reijnders, M, Whalen, S, Keren, B, Buratti, J, Courtin, T, Wierenga, KJ, Isidor, B, Piton, A, Faivre, L, Garde, A, Moutton, S, Tran-Mau-Them, F, Denommé-Pichon, AS, Coubes, C, Larson, A, Esser, MJ, Appendino, JP, Al-Hertani, W, Gamboni, B, Mampel, A, Mayorga, L, Orsini, A, Bonuccelli, A, Suppiej, A, Van-Gils, J, Vogt, J, Damioli, S, Giordano, L, Moortgat, S, Wirrell, E, Hicks, S, Kini, U, Noble, N, Stewart, H, Asakar, S, Cohen, JS , Naidu, SBR, Collier, A, Brilstra, EH, Li, MH, Brew, C, Bigoni, S, Ognibene, D, Ballardini, E, Ruivenkamp, C, Faggioli, R, Afenjar, A, Rodriguez, D, Bick, D, Segal, D, Coman, D, Gunning, B, Devinsky, O, Demmer, LA, Grebe, T, Pruna, D, Cursio, I, Greenhalgh, L, Graziano, C, Singh, RR, Cantalupo, G, Willems, M, Yoganathan, S, Góes, F, Leventer, RJ, Colavito, D, Olivotto, S, Scelsa, B, Andrade, AV, Ratke, K, Tokarz, F, Khan, AS, Ormieres, C, Benko, W, Keough, K, Keros, S, Hussain, S, Franques, A, Varsalone, F, Grønborg, S, Mignot, C, Heron, D, Nava, C, Isapof, A, Borlot, F, Whitney, R, Ronan, A, Foulds, N, Somorai, M, Brandsema, J, Helbig, KL, Helbig, I, Ortiz-González, XR, Dubbs, H, Vitobello, A, Anderson, M, Spadafore, D, Hunt, D, Møller, RS & Rubboli, G 2021, 'PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum', Neurology: Genetics, vol. 7, no. 6, e613. https://doi.org/10.1212/NXG.0000000000000613

@article{5de21d0ff5a34613b586dd1945b5d45c,

title = "PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum",

abstract = "Background and Objectives Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. Discussion The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.",

author = "Johannesen, {Katrine M.} and Elena Gardella and Gjerulfsen, {Cathrine E.} and Allan Bayat and Rouhl, {Rob P.W.} and Margot Reijnders and Sandra Whalen and Boris Keren and Julien Buratti and Thomas Courtin and Wierenga, {Klaas J.} and Bertrand Isidor and Am{\'e}lie Piton and Laurence Faivre and Aurore Garde and S{\'e}bastien Moutton and Fr{\'e}d{\'e}ric Tran-Mau-Them and Denomm{\'e}-Pichon, {Anne Sophie} and Christine Coubes and Austin Larson and Esser, {Michael J.} and Appendino, {Juan Pablo} and Walla Al-Hertani and Beatriz Gamboni and Alejandra Mampel and L{\'i}a Mayorga and Alessandro Orsini and Alice Bonuccelli and Agnese Suppiej and Julien Van-Gils and Julie Vogt and Simona Damioli and Lucio Giordano and Stephanie Moortgat and Elaine Wirrell and Sarah Hicks and Usha Kini and Nathan Noble and Helen Stewart and Shailesh Asakar and Cohen, {Julie S.} and Naidu, {Sakku Bai R.} and Ashley Collier and Brilstra, {Eva H.} and Li, {Mindy H.} and Casey Brew and Stefania Bigoni and Davide Ognibene and Elisa Ballardini and Claudia Ruivenkamp and Raffaella Faggioli and Alexandra Afenjar and Diana Rodriguez and David Bick and Devorah Segal and David Coman and Boudewijn Gunning and Orrin Devinsky and Demmer, {Laurie A.} and Theresa Grebe and Dario Pruna and Ida Cursio and Lynn Greenhalgh and Claudio Graziano and Singh, {Rahul Raman} and Gaetano Cantalupo and Marjolaine Willems and Sangeetha Yoganathan and Fernanda G{\'o}es and Leventer, {Richard J.} and Davide Colavito and Sara Olivotto and Barbara Scelsa and Andrade, {Andrea V.} and Kelly Ratke and Farha Tokarz and Khan, {Atiya S.} and Clothilde Ormieres and William Benko and Karen Keough and Sotirios Keros and Shanawaz Hussain and Ashlea Franques and Felicia Varsalone and Sabine Gr{\o}nborg and Cyril Mignot and Delphine Heron and Caroline Nava and Arnaud Isapof and Felippe Borlot and Robyn Whitney and Anne Ronan and Nicola Foulds and Marta Somorai and John Brandsema and Helbig, {Katherine L.} and Ingo Helbig and Ortiz-Gonz{\'a}lez, {Xilma R.} and Holly Dubbs and Antonio Vitobello and Mel Anderson and Dominic Spadafore and David Hunt and M{\o}ller, {Rikke S.} and Guido Rubboli",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2021",

month = dec,

day = "15",

doi = "10.1212/NXG.0000000000000613",

language = "English (US)",

volume = "7",

journal = "Neurology: Genetics",

issn = "2376-7839",

publisher = "Lippincott Williams and Wilkins",

number = "6",

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TY - JOUR

T1 - PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum

AU - Johannesen, Katrine M.

AU - Gardella, Elena

AU - Gjerulfsen, Cathrine E.

AU - Bayat, Allan

AU - Rouhl, Rob P.W.

AU - Reijnders, Margot

AU - Whalen, Sandra

AU - Keren, Boris

AU - Buratti, Julien

AU - Courtin, Thomas

AU - Wierenga, Klaas J.

AU - Isidor, Bertrand

AU - Piton, Amélie

AU - Faivre, Laurence

AU - Garde, Aurore

AU - Moutton, Sébastien

AU - Tran-Mau-Them, Frédéric

AU - Denommé-Pichon, Anne Sophie

AU - Coubes, Christine

AU - Larson, Austin

AU - Esser, Michael J.

AU - Appendino, Juan Pablo

AU - Al-Hertani, Walla

AU - Gamboni, Beatriz

AU - Mampel, Alejandra

AU - Mayorga, Lía

AU - Orsini, Alessandro

AU - Bonuccelli, Alice

AU - Suppiej, Agnese

AU - Van-Gils, Julien

AU - Vogt, Julie

AU - Damioli, Simona

AU - Giordano, Lucio

AU - Moortgat, Stephanie

AU - Wirrell, Elaine

AU - Hicks, Sarah

AU - Kini, Usha

AU - Noble, Nathan

AU - Stewart, Helen

AU - Asakar, Shailesh

AU - Cohen, Julie S.

AU - Naidu, Sakku Bai R.

AU - Collier, Ashley

AU - Brilstra, Eva H.

AU - Li, Mindy H.

AU - Brew, Casey

AU - Bigoni, Stefania

AU - Ognibene, Davide

AU - Ballardini, Elisa

AU - Ruivenkamp, Claudia

AU - Faggioli, Raffaella

AU - Afenjar, Alexandra

AU - Rodriguez, Diana

AU - Bick, David

AU - Segal, Devorah

AU - Coman, David

AU - Gunning, Boudewijn

AU - Devinsky, Orrin

AU - Demmer, Laurie A.

AU - Grebe, Theresa

AU - Pruna, Dario

AU - Cursio, Ida

AU - Greenhalgh, Lynn

AU - Graziano, Claudio

AU - Singh, Rahul Raman

AU - Cantalupo, Gaetano

AU - Willems, Marjolaine

AU - Yoganathan, Sangeetha

AU - Góes, Fernanda

AU - Leventer, Richard J.

AU - Colavito, Davide

AU - Olivotto, Sara

AU - Scelsa, Barbara

AU - Andrade, Andrea V.

AU - Ratke, Kelly

AU - Tokarz, Farha

AU - Khan, Atiya S.

AU - Ormieres, Clothilde

AU - Benko, William

AU - Keough, Karen

AU - Keros, Sotirios

AU - Hussain, Shanawaz

AU - Franques, Ashlea

AU - Varsalone, Felicia

AU - Grønborg, Sabine

AU - Mignot, Cyril

AU - Heron, Delphine

AU - Nava, Caroline

AU - Isapof, Arnaud

AU - Borlot, Felippe

AU - Whitney, Robyn

AU - Ronan, Anne

AU - Foulds, Nicola

AU - Somorai, Marta

AU - Brandsema, John

AU - Helbig, Katherine L.

AU - Helbig, Ingo

AU - Ortiz-González, Xilma R.

AU - Dubbs, Holly

AU - Vitobello, Antonio

AU - Anderson, Mel

AU - Spadafore, Dominic

AU - Hunt, David

AU - Møller, Rikke S.

AU - Rubboli, Guido

PY - 2021/12/15

Y1 - 2021/12/15

N2 - Background and Objectives Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. Discussion The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

AB - Background and Objectives Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. Discussion The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

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U2 - 10.1212/NXG.0000000000000613

DO - 10.1212/NXG.0000000000000613

M3 - Article

C2 - 34790866

AN - SCOPUS:85121913018

SN - 2376-7839

VL - 7

JO - Neurology: Genetics

JF - Neurology: Genetics

IS - 6

M1 - e613

ER -

PURA-Related Developmental and Epileptic Encephalopathy Phenotypic and Genotypic Spectrum

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