Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Marcello Scala; Saskia B. Wortmann; Namik Kaya; Menno D. Stellingwerff; Angela Pistorio; Emma Glamuzina; Clara D. van Karnebeek; Cristina Skrypnyk; Katarzyna Iwanicka-Pronicka; Dorota Piekutowska-Abramczuk; Elżbieta Ciara; Frederic Tort; Beth Sheidley; Annapurna Poduri; Parul Jayakar; Anuj Jayakar; Jariya Upadia; Nicolette Walano; Tobias B. Haack; Holger Prokisch; Hesham Aldhalaan; Ehsan G. Karimiani; Yilmaz Yildiz; Ahmet C. Ceylan; Teresa Santiago-Sim; Amy Dameron; Hui Yang; Mehran B. Toosi; Farah Ashrafzadeh; Javad Akhondian; Shima Imannezhad; Hanieh S. Mirzadeh; Shazia Maqbool; Aisha Farid; Mohamed A. Al-Muhaizea; Meznah O. Alshwameen; Lama Aldowsari; Maysoon Alsagob; Ashwaq Alyousef; Rawan AlMass; Aljouhra AlHargan; Ali H. Alwadei; Maha M. AlRasheed; Dilek Colak; Hanan Alqudairy; Sameena Khan; Matthew A. Lines; M. Ángeles García Cazorla; Antonia Ribes; Eva Morava; Farah Bibi; Shahzad Haider; Matteo P. Ferla; Jenny C. Taylor; Hessa S. Alsaif; Abdulwahab Firdous; Mais Hashem; Chingiz Shashkin; Kairgali Koneev; Rauan Kaiyrzhanov; Stephanie Efthymiou; Queen Square Genomics; Thomas Schmitt-Mechelke; Andreas Ziegler; Mahmoud Y. Issa; Hasnaa M. Elbendary; Pasquale Striano; Fowzan S. Alkuraya; Maha S. Zaki; Joseph G. Gleeson; Tahsin Stefan Barakat; Jorgen Bierau; Marjo S. van der Knaap; Reza Maroofian; Henry Houlden

doi:10.1002/humu.24326

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Marcello Scala, Saskia B. Wortmann, Namik Kaya, Menno D. Stellingwerff, Angela Pistorio, Emma Glamuzina, Clara D. van Karnebeek, Cristina Skrypnyk, Katarzyna Iwanicka-Pronicka, Dorota Piekutowska-Abramczuk, Elżbieta Ciara, Frederic Tort, Beth Sheidley, Annapurna Poduri, Parul Jayakar, Anuj Jayakar, Jariya Upadia, Nicolette Walano, Tobias B. Haack, Holger ProkischHesham Aldhalaan, Ehsan G. Karimiani, Yilmaz Yildiz, Ahmet C. Ceylan, Teresa Santiago-Sim, Amy Dameron, Hui Yang, Mehran B. Toosi, Farah Ashrafzadeh, Javad Akhondian, Shima Imannezhad, Hanieh S. Mirzadeh, Shazia Maqbool, Aisha Farid, Mohamed A. Al-Muhaizea, Meznah O. Alshwameen, Lama Aldowsari, Maysoon Alsagob, Ashwaq Alyousef, Rawan AlMass, Aljouhra AlHargan, Ali H. Alwadei, Maha M. AlRasheed, Dilek Colak, Hanan Alqudairy, Sameena Khan, Matthew A. Lines, M. Ángeles García Cazorla, Antonia Ribes, Eva Morava, Farah Bibi, Shahzad Haider, Matteo P. Ferla, Jenny C. Taylor, Hessa S. Alsaif, Abdulwahab Firdous, Mais Hashem, Chingiz Shashkin, Kairgali Koneev, Rauan Kaiyrzhanov, Stephanie Efthymiou, Queen Square Genomics, Thomas Schmitt-Mechelke, Andreas Ziegler, Mahmoud Y. Issa, Hasnaa M. Elbendary, Pasquale Striano, Fowzan S. Alkuraya, Maha S. Zaki, Joseph G. Gleeson, Tahsin Stefan Barakat, Jorgen Bierau, Marjo S. van der Knaap, Reza Maroofian^*, Henry Houlden

^*Corresponding author for this work

Integrative Neurophysiology

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Original language	English
Pages (from-to)	403-419
Number of pages	17
Journal	Human Mutation
Volume	43
Issue number	3
Early online date	6 Jan 2022
DOIs	https://doi.org/10.1002/humu.24326
Publication status	Published - Mar 2022

Bibliographical note

Funding Information:
We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co-funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigaci?n Biom?dica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovaci?n, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium f?r Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C)

Funding Information:
We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co‐funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium für Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C)

Publisher Copyright:
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

Funding

We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co-funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigaci?n Biom?dica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovaci?n, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium f?r Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C) We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co‐funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium für Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C)

Funders	Funder number
Centro de Investigación Biomédica en Red de Enfermedades Raras
Wellcome Trust Core	203141/Z/16/Z
ZonMw Veni	91617021
Muscular Dystrophy Association
Eunice Kennedy Shriver National Institute of Child Health and Human Development	P50HD105351
Muscular Dystrophy UK
Multiple System Atrophy Trust
Brain Research UK
Medical Research Council	MR/S01165X/1, G0601943, MR/S005021/1
National Institute for Health and Care Research
Ataxia UK
Oxford University
Rosetrees Trust
Bundesministerium für Bildung und Forschung	01KU2016A, 01GM1113C
Generalitat de Catalunya	SLT002/16/00174
Agència de Gestió d'Ajuts Universitaris i de Recerca	SGR 1428
Erasmus Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Instituto de Salud Carlos III	PI19/01310
Ministerio de Ciencia e Innovación
European Regional Development Fund
UCLH Biomedical Research Centre

Keywords

congenital microcephaly
developmental and epileptic encephalopathy 35
heart disease
ITPA
ITPase
white matter abnormalities

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/humu.24326

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Cite this

Scala, M., Wortmann, S. B., Kaya, N., Stellingwerff, M. D., Pistorio, A., Glamuzina, E., van Karnebeek, C. D., Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T. B., ... Houlden, H. (2022). Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. Human Mutation, 43(3), 403-419. https://doi.org/10.1002/humu.24326

@article{f1895b2e8f944932a37a30cbfce24676,

title = "Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency",

abstract = "Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.",

keywords = "congenital microcephaly, developmental and epileptic encephalopathy 35, heart disease, ITPA, ITPase, white matter abnormalities",

author = "Marcello Scala and Wortmann, {Saskia B.} and Namik Kaya and Stellingwerff, {Menno D.} and Angela Pistorio and Emma Glamuzina and {van Karnebeek}, {Clara D.} and Cristina Skrypnyk and Katarzyna Iwanicka-Pronicka and Dorota Piekutowska-Abramczuk and El{\.z}bieta Ciara and Frederic Tort and Beth Sheidley and Annapurna Poduri and Parul Jayakar and Anuj Jayakar and Jariya Upadia and Nicolette Walano and Haack, {Tobias B.} and Holger Prokisch and Hesham Aldhalaan and Karimiani, {Ehsan G.} and Yilmaz Yildiz and Ceylan, {Ahmet C.} and Teresa Santiago-Sim and Amy Dameron and Hui Yang and Toosi, {Mehran B.} and Farah Ashrafzadeh and Javad Akhondian and Shima Imannezhad and Mirzadeh, {Hanieh S.} and Shazia Maqbool and Aisha Farid and Al-Muhaizea, {Mohamed A.} and Alshwameen, {Meznah O.} and Lama Aldowsari and Maysoon Alsagob and Ashwaq Alyousef and Rawan AlMass and Aljouhra AlHargan and Alwadei, {Ali H.} and AlRasheed, {Maha M.} and Dilek Colak and Hanan Alqudairy and Sameena Khan and Lines, {Matthew A.} and {Garc{\'i}a Cazorla}, {M. {\'A}ngeles} and Antonia Ribes and Eva Morava and Farah Bibi and Shahzad Haider and Ferla, {Matteo P.} and Taylor, {Jenny C.} and Alsaif, {Hessa S.} and Abdulwahab Firdous and Mais Hashem and Chingiz Shashkin and Kairgali Koneev and Rauan Kaiyrzhanov and Stephanie Efthymiou and Genomics, {Queen Square} and Thomas Schmitt-Mechelke and Andreas Ziegler and Issa, {Mahmoud Y.} and Elbendary, {Hasnaa M.} and Pasquale Striano and Alkuraya, {Fowzan S.} and Zaki, {Maha S.} and Gleeson, {Joseph G.} and Barakat, {Tahsin Stefan} and Jorgen Bierau and {van der Knaap}, {Marjo S.} and Reza Maroofian and Henry Houlden",

note = "Funding Information: We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co-funded by European Regional Development Fund {"}A way to make Europe{"}), the Centro de Investigaci?n Biom?dica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovaci?n, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium f?r Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C) Funding Information: We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co‐funded by European Regional Development Fund {"}A way to make Europe{"}), the Centro de Investigaci{\'o}n Biom{\'e}dica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovaci{\'o}n, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium f{\"u}r Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C) Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",

year = "2022",

month = mar,

doi = "10.1002/humu.24326",

language = "English",

volume = "43",

pages = "403--419",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "3",

}

Scala, M, Wortmann, SB, Kaya, N, Stellingwerff, MD, Pistorio, A, Glamuzina, E, van Karnebeek, CD, Skrypnyk, C, Iwanicka-Pronicka, K, Piekutowska-Abramczuk, D, Ciara, E, Tort, F, Sheidley, B, Poduri, A, Jayakar, P, Jayakar, A, Upadia, J, Walano, N, Haack, TB, Prokisch, H, Aldhalaan, H, Karimiani, EG, Yildiz, Y, Ceylan, AC, Santiago-Sim, T, Dameron, A, Yang, H, Toosi, MB, Ashrafzadeh, F, Akhondian, J, Imannezhad, S, Mirzadeh, HS, Maqbool, S, Farid, A, Al-Muhaizea, MA, Alshwameen, MO, Aldowsari, L, Alsagob, M, Alyousef, A, AlMass, R, AlHargan, A, Alwadei, AH, AlRasheed, MM, Colak, D, Alqudairy, H, Khan, S, Lines, MA, García Cazorla, MÁ, Ribes, A, Morava, E, Bibi, F, Haider, S, Ferla, MP, Taylor, JC, Alsaif, HS, Firdous, A, Hashem, M, Shashkin, C, Koneev, K, Kaiyrzhanov, R, Efthymiou, S, Genomics, QS, Schmitt-Mechelke, T, Ziegler, A, Issa, MY, Elbendary, HM, Striano, P, Alkuraya, FS, Zaki, MS, Gleeson, JG, Barakat, TS, Bierau, J, van der Knaap, MS, Maroofian, R & Houlden, H 2022, 'Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency', Human Mutation, vol. 43, no. 3, pp. 403-419. https://doi.org/10.1002/humu.24326

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency. / Scala, Marcello; Wortmann, Saskia B.; Kaya, Namik et al.
In: Human Mutation, Vol. 43, No. 3, 03.2022, p. 403-419.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

AU - Scala, Marcello

AU - Wortmann, Saskia B.

AU - Kaya, Namik

AU - Stellingwerff, Menno D.

AU - Pistorio, Angela

AU - Glamuzina, Emma

AU - van Karnebeek, Clara D.

AU - Skrypnyk, Cristina

AU - Iwanicka-Pronicka, Katarzyna

AU - Piekutowska-Abramczuk, Dorota

AU - Ciara, Elżbieta

AU - Tort, Frederic

AU - Sheidley, Beth

AU - Poduri, Annapurna

AU - Jayakar, Parul

AU - Jayakar, Anuj

AU - Upadia, Jariya

AU - Walano, Nicolette

AU - Haack, Tobias B.

AU - Prokisch, Holger

AU - Aldhalaan, Hesham

AU - Karimiani, Ehsan G.

AU - Yildiz, Yilmaz

AU - Ceylan, Ahmet C.

AU - Santiago-Sim, Teresa

AU - Dameron, Amy

AU - Yang, Hui

AU - Toosi, Mehran B.

AU - Ashrafzadeh, Farah

AU - Akhondian, Javad

AU - Imannezhad, Shima

AU - Mirzadeh, Hanieh S.

AU - Maqbool, Shazia

AU - Farid, Aisha

AU - Al-Muhaizea, Mohamed A.

AU - Alshwameen, Meznah O.

AU - Aldowsari, Lama

AU - Alsagob, Maysoon

AU - Alyousef, Ashwaq

AU - AlMass, Rawan

AU - AlHargan, Aljouhra

AU - Alwadei, Ali H.

AU - AlRasheed, Maha M.

AU - Colak, Dilek

AU - Alqudairy, Hanan

AU - Khan, Sameena

AU - Lines, Matthew A.

AU - García Cazorla, M. Ángeles

AU - Ribes, Antonia

AU - Morava, Eva

AU - Bibi, Farah

AU - Haider, Shahzad

AU - Ferla, Matteo P.

AU - Taylor, Jenny C.

AU - Alsaif, Hessa S.

AU - Firdous, Abdulwahab

AU - Hashem, Mais

AU - Shashkin, Chingiz

AU - Koneev, Kairgali

AU - Kaiyrzhanov, Rauan

AU - Efthymiou, Stephanie

AU - Genomics, Queen Square

AU - Schmitt-Mechelke, Thomas

AU - Ziegler, Andreas

AU - Issa, Mahmoud Y.

AU - Elbendary, Hasnaa M.

AU - Striano, Pasquale

AU - Alkuraya, Fowzan S.

AU - Zaki, Maha S.

AU - Gleeson, Joseph G.

AU - Barakat, Tahsin Stefan

AU - Bierau, Jorgen

AU - van der Knaap, Marjo S.

AU - Maroofian, Reza

AU - Houlden, Henry

N1 - Funding Information: We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co-funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigaci?n Biom?dica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovaci?n, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium f?r Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C) Funding Information: We thank the patients and their families for their collaboration and consent to the publication of this paper. This study was funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), and also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, the Wellcome Trust Core award (203141/Z/16/Z), the Instituto de Salud Carlos III (PI19/01310) (Co‐funded by European Regional Development Fund "A way to make Europe"), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain), Generalitat de Catalunya (URDCAT project, SLT002/16/00174; (AGAUR 2017: SGR 1428), and the CERCA Programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. TSB's lab is supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021), an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by German Bundesministerium für Bildung und Forschung (BMBF) through the ERA PerMed project PerMiM (01KU2016A) and the German Network for Mitochondrial Disorders (mitoNET; 01GM1113C) Publisher Copyright: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

PY - 2022/3

Y1 - 2022/3

N2 - Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

AB - Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

KW - congenital microcephaly

KW - developmental and epileptic encephalopathy 35

KW - heart disease

KW - ITPA

KW - ITPase

KW - white matter abnormalities

UR - http://www.scopus.com/inward/record.url?scp=85122725382&partnerID=8YFLogxK

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U2 - 10.1002/humu.24326

DO - 10.1002/humu.24326

M3 - Article

C2 - 34989426

AN - SCOPUS:85122725382

SN - 1059-7794

VL - 43

SP - 403

EP - 419

JO - Human Mutation

JF - Human Mutation

IS - 3

ER -

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

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