Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Manuela Wiessner; Reza Maroofian; Meng-Yuan Ni; Andrea Pedroni; Juliane S. Muller; Rolf Stucka; Christian Beetz; Stephanie Efthymiou; Filippo M. Santorelli; Ahmed A. Alfares; Changlian Zhu; Anna Uhrova Meszarosova; Elham Alehabib; Somayeh Bakhtiari; Andreas R. Janecke; Maria Gabriela Otero; Jin Yun Helen Chen; James T. Peterson; Tim M. Strom; Peter De Jonghe; Tine Deconinck; Willem De Ridder; Jonathan De Winter; Rossella Pasquariello; Ivana Ricca; Majid Alfadhel; Bart P. van de Warrenburg; Ruben Portier; Carsten Bergmann; Saghar Ghasemi Firouzabadi; Sheng Chih Jin; Kaya Bilguvar; Sherifa Hamed; Mohammed Abdelhameed; Nourelhoda A. Haridy; Shazia Maqbool; Fatima Rahman; Najwa Anwar; Jenny Carmichael; Alistair Pagnamenta; Nick W. Wood; Frederic Tran Mau-Them; Tobias Haack; Maja Di Rocco; Isabella Ceccherini; Michele Iacomino; Federico Zara; Vincenzo Salpietro; Marcello Scala; Marta Rusmini; Yiran Xu; Yinghong Wang; Yasuhiro Suzuki; Kishin Koh; Haitian Nan; Hiroyuki Ishiura; Shoji Tsuji; Laetitia Lambert; Emmanuelle Schmitt; Elodie Lacaze; Hanna Kupper; David Dredge; Cara Skraban; Amy Goldstein; Mary J. H. Willis; Katheryn Grand; John M. Graham; Richard A. Lewis; Francisca Millan; Ozgur Duman; Nihal Dundar; Gokhan Uyanik; Ludger Schols; Peter Nurnberg; Gudrun Nurnberg; Andrea Catala Bordes; Pavel Seeman; Martin Kuchar; Hossein Darvish; Adriana Rebelo; Filipa Boucanova; Jean-Jacques Medard; Roman Chrast; Michaela Auer-Grumbach; Fowzan S. Alkuraya; Hanan Shamseldin; Saeed Al Tala; Jamileh Rezazadeh Varaghchi; Maryam Najafi; Selina Deschner; Dieter Glaser; Wolfgang Huttel; Michael C. Kruer; Erik-Jan Kamsteeg; Yoshihisa Takiyama; Stephan Zuchner; Jonathan Baets; Matthis Synofzik; Rebecca Schuele; Rita Horvath; Henry Houlden; Luca Bartesaghi; Hwei-Jen Lee; Konstantinos Ampatzis; Tyler Mark Pierson; Jan Senderek

doi:10.1093/brain/awab041

Back

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Journal article

Open access

Peer reviewed

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Manuela Wiessner, Reza Maroofian, Meng-Yuan Ni, Andrea Pedroni, Juliane S. Muller, Rolf Stucka, Christian Beetz, Stephanie Efthymiou, Filippo M. Santorelli, Ahmed A. Alfares, …

Brain (London, England : 1878), Vol.144(5), pp.1422-1434

22/06/2021

DOI: https://doi.org/10.1093/brain/awab041

Abstract

Clinical Neurology

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Files and links (1)

url

https://doi.org/10.1093/brain/awab041View

Published (Version of record) Open

Metrics

1 Record Views

See more details

Details

Title: Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
Creators - without role: Manuela Wiessner - Friedrich Baur Stiftung
Reza Maroofian - University College London
Meng-Yuan Ni - National Defense Medical Center
Andrea Pedroni - Karolinska Institutet
Juliane S. Muller - University of Cambridge
Rolf Stucka - Friedrich Baur Stiftung
Christian Beetz - University of Cambridge
Stephanie Efthymiou - University College London
Filippo M. Santorelli - Fondazione Stella Maris
Ahmed A. Alfares - Qassim University
Changlian Zhu - University of Gothenburg
Anna Uhrova Meszarosova - Charles University
Elham Alehabib - Shahid Beheshti University of Medical Sciences
Somayeh Bakhtiari - Barrow Neurological Institute
Andreas R. Janecke - Universität Innsbruck
Maria Gabriela Otero - Cedars-Sinai Medical Center
Jin Yun Helen Chen - Boston University
James T. Peterson - Children's Hospital of Philadelphia
Tim M. Strom - Institute of Human Genetics
Peter De Jonghe - Antwerp University Hospital
Tine Deconinck - University of Antwerp
Willem De Ridder - Antwerp University Hospital
Jonathan De Winter - Antwerp University Hospital
Rossella Pasquariello - Fondazione Stella Maris
Ivana Ricca - Fondazione Stella Maris
Majid Alfadhel - King Abdulaziz Medical City
Bart P. van de Warrenburg - Radboud University Nijmegen
Ruben Portier - Medisch Spectrum Twente
Carsten Bergmann - University Medical Center Freiburg
Saghar Ghasemi Firouzabadi - University of Social Welfare and Rehabilitation Sciences
Sheng Chih Jin - Washington University in St. Louis
Kaya Bilguvar - University of New Haven
Sherifa Hamed - Assiut University
Mohammed Abdelhameed - Assiut University
Nourelhoda A. Haridy - Assiut University
Shazia Maqbool - Development and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Fatima Rahman - Development and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Najwa Anwar - Development and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan
Jenny Carmichael - Northampton General Hospital
Alistair Pagnamenta - University of Oxford
Nick W. Wood - National Hospital for Neurology and Neurosurgery
Frederic Tran Mau-Them - Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France
Tobias Haack - University of Tübingen
Maja Di Rocco - Istituto Giannina Gaslini
Isabella Ceccherini - Istituto Giannina Gaslini
Michele Iacomino - Istituto Giannina Gaslini
Federico Zara - University of Genoa
Vincenzo Salpietro - Istituto Giannina Gaslini
Marcello Scala - Istituto Giannina Gaslini
Marta Rusmini - Istituto Giannina Gaslini
Yiran Xu - Third Affiliated Hospital of Zhengzhou University
Yinghong Wang - First Affiliated Hospital of Henan University
Yasuhiro Suzuki - Osaka Women's and Children's Hospital
Kishin Koh - University of Yamanashi
Haitian Nan - University of Yamanashi
Hiroyuki Ishiura - The University of Tokyo
Shoji Tsuji - International University of Health and Welfare
Laetitia Lambert - Inserm
Emmanuelle Schmitt - Centre Hospitalier Universitaire de Nancy
Elodie Lacaze - Université Le Havre Normandie
Hanna Kupper - University Children's Hospital Tübingen
David Dredge - Boston University
Cara Skraban - University of Pennsylvania
Amy Goldstein - University of Pennsylvania
Mary J. H. Willis - Naval Medical Center San Diego
Katheryn Grand - Cedars-Sinai Medical Center
John M. Graham - Cedars-Sinai Medical Center
Richard A. Lewis - Cedars-Sinai Medical Center
Francisca Millan - GeneDx, Gaithersburg, USA
Ozgur Duman - Akdeniz University Hospital
Nihal Dundar - Izmir Kâtip Çelebi University
Gokhan Uyanik - Sigmund Freud University Vienna
Ludger Schols - University of Tübingen
Peter Nurnberg - University of Cologne
Gudrun Nurnberg - University of Cologne
Andrea Catala Bordes - Charles University
Pavel Seeman - Charles University
Martin Kuchar - Krajská Nemocnice Liberec
Hossein Darvish - Golestan University of Medical Sciences
Adriana Rebelo - University of Miami
Filipa Boucanova - Karolinska Institutet
Jean-Jacques Medard - Karolinska Institutet
Roman Chrast - Karolinska Institutet
Michaela Auer-Grumbach - Medical University of Vienna
Fowzan S. Alkuraya - King Faisal Specialist Hospital & Research Centre
Hanan Shamseldin - King Faisal Specialist Hospital & Research Centre
Saeed Al Tala - Armed Forces Hospital
Jamileh Rezazadeh Varaghchi - Center for Human Genetics
Maryam Najafi - Radboud University Nijmegen
Selina Deschner - Genetikum
Dieter Glaser - Genetikum
Wolfgang Huttel - University of Freiburg
Michael C. Kruer - Barrow Neurological Institute
Erik-Jan Kamsteeg - Radboud University Nijmegen
Yoshihisa Takiyama - University of Yamanashi
Stephan Zuchner - Dr. John T. Macdonald Foundation
Jonathan Baets - Antwerp University Hospital
Matthis Synofzik - Hertie Institute for Clinical Brain Research
Rebecca Schuele - University of Tübingen
Rita Horvath - University of Cambridge
Henry Houlden - UCL, Inst Neurol, Dept Neuromuscular Disorders, London, England
Luca Bartesaghi - Karolinska Institutet
Hwei-Jen Lee - College Station Medical Center
Konstantinos Ampatzis - Karolinska Institutet
Tyler Mark Pierson - MED Institute
Jan Senderek - Ludwig Maximilians Univ Munchen, Dept Neurol, Friedrich Baur Inst, Ziemssenstr 1, D-80336 Munich, Germany
Publication Details: Brain (London, England : 1878), Vol.144(5), pp.1422-1434
Publisher: Oxford Univ Press
Number of pages: 13
Grant note: Wellcome Trust; European Commission Hersenstichting 01GM1905 / Federal Ministry of Education and Research, Germany, through the TreatHSP network 779257 / EU; European Commission AZV NU20-04-00279; DRO 00064203 / Ministry of Health, Czech Republic; Czech Republic Government ZonMW; Netherlands Organization for Health Research and Development RF-2016-02361610 / Italian Ministry of Health; Ministry of Health, Italy MR/N025431/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission WT093205 MA; WT104033AIA / SYNaPS Study Group MAB-108-070 / National Defense Medical Bureau, Taiwan JP18K07495 / Ministry of Health, Labor and Welfare, Japan; Ministry of Health, Labour and Welfare, Japan 109915/Z/15/Z / Wellcome Trust; European Commission 1805016N / Research Foundation Flanders; FWO 2018-02667 / Swedish Research Council; European Commission 825575 (441409627) / Ministry of Health, Italy, through the PROSPAX consortium MOST 107-2320-B-016-014 / Ministry of Science and Technology, Taiwan uniQure Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program Research Committee for Ataxic Disease German Research Foundation; German Research Foundation (DFG) R01NS072248 / National Institute of Neurological Diseases and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 19ek0109279h0003 / Japan Agency for Medical Research and Development; Japan Agency for Medical Research and Development (AMED) Cedars-Sinai institutional funding program Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases 10.15.1.021MN / Fritz-Thyssen-Stiftung Tom-Wahlig-Stiftung Ministry of Education, Culture, Sports, Science, and Technology, Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Gossweiler Foundation ALFGBG-717791 / Swedish governmental grants 171100310200 / Henan Province Major Science and Technology Project 01GM1607 / Federal Ministry of Education and Research, Germany, through the E-Rare-3 network PREPARE 01GM1511 / Federal Ministry of Education and Research, Germany, through the CMT-NET network Radboud UMC MR/N027302/1 / Newton Fund
Identifiers: 9920483808331
Academic Unit: King Saud Bin Abdulaziz University for Health Sciences; King Abdulaziz University; King Faisal University; Qassim University
Language: English
Resource Type: Journal article