ArticleBrain : a journal of neurology2021
Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.
Erratum issuedOpen access · bronzeAbstract read
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Article in Brain : a journal of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 36 papers.
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36citing papers in PubMed
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Who cites it
36 citing papers in PubMed, 48 citations in OpenAlex.
- New insights into HPDL protein: identification of a novel Bi-allelic variant, docking simulation study, and literature review.BMC medical genomics · 2026Review
- Bypass Treatments for Primary Coenzyme Q10 Deficiency: An Update.International journal of molecular sciences · 2026Review
- A bioinorganic view on the potential chemical space of hydroxyphenylpyruvate dioxygenase-like (HPDL) enzymes.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2026Article
- Children with suspected hereditary spastic paraplegia clearly benefit from whole exome analysis.Human genomics · 2026Article
- Loss of function variants in HPDL impair human cortical development via alterations of mitochondrial function.Cell death & disease · 2026Article
- Mitochondrial Dysfunctions in Human Primary Coenzyme QBiomolecules · 2026Review
- Imaging patterns of paediatric CNS mitochondrial disorders.Neuroradiology · 2026Review
- Regulation of Histone Emulsification by HPDL via LDHA/LDHB Promotes EC Cell Proliferation.Oncology research · 2026Article
- Children with Genetically Confirmed Hereditary Spastic Paraplegia: A Single-Center Experience.Children (Basel, Switzerland) · 2025Article
- Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population.Movement disorders clinical practice · 2025Observational
- Article
- HPDL Variant Type Correlates With Clinical Disease Onset and Severity.Annals of clinical and translational neurology · 2025Observational
- Exotropia in a Patient With a Novel Homozygous 4-Hydroxyphenylpyruvate Dioxygenase-Like Protein (HPDL) Variant.Cureus · 2025Article
- Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Generation and Characterization of hiPS Lines from Three Patients Affected by Different Forms ofInternational journal of molecular sciences · 2024Article
- Acute Ophthalmoplegia with Wernicke-Like MRI Pattern in a Patient with HPDL-Related Disorder.Movement disorders clinical practice · 2024Article
- SCAR32: Functional characterization and expansion of the clinical-genetic spectrum.Annals of clinical and translational neurology · 2024Article
- A novel homozygous HPDL variant in Japanese siblings with autosomal recessive hereditary spastic paraplegia: case report and literature review.Neurogenetics · 2024Review
- Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
Corrections and comments
- Erratum issued
Authors and funding
107 authors at 20 institutions in 17 countries.
Manuela WiessnerFriedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany.
Reza MaroofianDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.
Meng-Yuan NiDepartment of Biochemistry, National Defense Medical Center, Neihu, Taipei, Taiwan.
Andrea PedroniDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Juliane S MüllerDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Rolf StuckaFriedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany.
Christian BeetzDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.
Filippo M SantorelliMolecular Medicine Unit, IRCCS Fondazione Stella Maris, Pisa, Italy.
Ahmed A AlfaresDepartment of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia.
Changlian ZhuHenan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affliated Hospital of Zhengzhou University, Zhengzhou, China.
Anna Uhrova MeszarosovaDNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Elham AlehabibStudent Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Somayeh BakhtiariBarrow Neurological Institute, Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, USA.
Andreas R JaneckeDepartment of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Maria Gabriela OteroBoard of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
Jin Yun Helen ChenNeurology Department, Massachusetts General Hospital, Boston, USA.
James T PetersonMitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, USA.ORCID 0000-0002-0480-5709
Tim M StromInstitute of Human Genetics, Technische Universität Mänchen, Munich, Germany.
Peter De JongheTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium.
Tine DeconinckCenter of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerpen, Belgium.
Willem De RidderTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium.
Jonathan De WinterTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium.
Rossella PasquarielloMolecular Medicine Unit, IRCCS Fondazione Stella Maris, Pisa, Italy.
Ivana RiccaMolecular Medicine Unit, IRCCS Fondazione Stella Maris, Pisa, Italy.
Majid AlfadhelGenetics Division, Department of Pediatrics, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
Bart P van de WarrenburgDepartment of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands.
Ruben PortierPolikliniek Neurologie Enschede, Medisch Spectrum Twente, Enschede, The Netherlands.ORCID 0000-0001-5897-3073
Carsten BergmannMedizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.
Saghar Ghasemi FirouzabadiGenetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Sheng Chih JinDepartment of Genetics, Washington University School of Medicine, St. Louis, USA.
Kaya BilguvarDepartment of Genetics, Yale University School of Medicine, New Haven, USA.
Sherifa HamedDepartment of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt.
Mohammed AbdelhameedDepartment of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt.ORCID 0000-0002-0514-7779
Nourelhoda A HaridyDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.ORCID 0000-0001-6045-3309
Shazia MaqboolDevelopment and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.
Fatima RahmanDevelopment and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.
Najwa AnwarDevelopment and Behavioural Paediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.
Jenny CarmichaelOxford Regional Clinical Genetics Service, Northampton General Hospital, Northampton, UK.
Alistair PagnamentaNIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.ORCID 0000-0001-7334-0602
Nick W WoodDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.
Frederic Tran Mau-ThemUnité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France.
Tobias HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Genomics England Research Consortium, PREPARE network
Maja Di RoccoRare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Isabella CeccheriniGenetics and Genomics of Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Michele IacominoMedical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Federico ZaraMedical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Vincenzo SalpietroDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
Marcello ScalaDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.ORCID 0000-0003-2194-7239
Marta RusminiGenetics and Genomics of Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Yiran XuHenan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affliated Hospital of Zhengzhou University, Zhengzhou, China.
Yinghong WangDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
Yasuhiro SuzukiDepartment of Pediatric Neurology, Osaka Women's and Children's Hospital, Osaka, Japan.
Kishin KohDepartment of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.
Haitian NanDepartment of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.
Hiroyuki IshiuraDepartment of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Shoji TsujiInstitute of Medical Genomics, International University of Health and Welfare, Chiba, Japan.
Laëtitia LambertDepartment of Clinical Genetics, CHRU Nancy, UMR_S INSERM N-GERE 1256, Université de Lorraine - Faculté de Médecine, Nancy, France.
Emmanuelle SchmittDepartment of Neuroradiology, CHRU Nancy, Nancy, France.ORCID 0000-0002-6704-3158
Elodie LacazeDepartment of Medical Genetics, Le Havre Hospital, Le Havre, France.ORCID 0000-0003-3483-4663
Hanna KüpperDepartment of Pediatric Neurology, University Children's Hospital Tübingen, Tübingen, Germany.
David DredgeNeurology Department, Massachusetts General Hospital, Boston, USA.
Cara SkrabanRoberts Individualized Medical Genetics Center, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.
Amy GoldsteinMitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, USA.
Mary J H WillisDepartment of Pediatrics, Naval Medical Center San Diego, San Diego, USA.
Katheryn GrandDepartment of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, USA.
John M GrahamDepartment of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, USA.
Richard A LewisDepartment of Neurology, Cedars-Sinai Medical Center, Los Angeles, USA.
Francisca MillanGeneDx, Gaithersburg, USA.
Özgür DumanDepartment of Pediatric Neurology, Akdeniz University Hospital, Antalya, Turkey.
Nihal DündarDepartment of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey.
Gökhan UyanikCenter for Medical Genetics, Hanusch Hospital, Vienna, Austria.
Ludger SchölsHertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
Peter NürnbergCologne Center for Genomics, Faculty of Medicine and Cologne University Hospital, University of Cologne, Cologne, Germany.
Gudrun NürnbergCologne Center for Genomics, Faculty of Medicine and Cologne University Hospital, University of Cologne, Cologne, Germany.
Andrea Catala BordesDNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Pavel SeemanDNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Martin KucharDepartment of Paediatric Neurology, Liberec Hospital, Liberec, Czech Republic.
Hossein DarvishNeuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
Adriana RebeloDr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
Filipa BouçanovaDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jean-Jacques MedardDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Roman ChrastDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Michaela Auer-GrumbachDepartment of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hanan ShamseldinDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Saeed Al TalaDepartment of Pediatrics, Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia.
Jamileh Rezazadeh VaraghchiHasti Genetic Counseling Center of Welfare Organization of Southern Khorasan, Birjand, Iran.
Maryam NajafiDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Selina Deschnergenetikum, Center for Human Genetics, Neu-Ulm, Germany.
Dieter Gläsergenetikum, Center for Human Genetics, Neu-Ulm, Germany.
Wolfgang HüttelInstitut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freibug, Germany.
Michael C KruerBarrow Neurological Institute, Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, USA.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Yoshihisa TakiyamaDepartment of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.
Stephan ZüchnerDr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, USA.
Jonathan BaetsTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium.
Matthis SynofzikHertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
Rebecca SchüleHertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.
Rita HorvathDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Henry HouldenDepartment of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.ORCID 0000-0002-2866-7777
Luca BartesaghiDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Hwei-Jen LeeDepartment of Biochemistry, National Defense Medical Center, Neihu, Taipei, Taiwan.
Konstantinos AmpatzisDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0001-7998-6463
Tyler Mark PiersonBoard of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA.ORCID 0000-0003-1985-3671
Jan SenderekFriedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany.
Istituto Giannina Gaslini · ITKarolinska Institutet · SECedars-Sinai Medical Center · USUniversity of Antwerp · BEUniversity College London · GBCharles University · CZChildren's Hospital of Philadelphia · USFondazione Stella Maris · ITFriedrich Baur Stiftung · DEGerman Center for Neurodegenerative Diseases · DERadboud University Nijmegen · NLUniversity of Cambridge · GBUniversity of Yamanashi · JPAssiut University · EGBarrow Neurological Institute · USGenetikum · DEKing Faisal Specialist Hospital & Research Centre · SAMassachusetts General Hospital · USNational Defense Medical Center · TWUniversity of Cologne · DE
Funding
GENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA - beyond the exomeR01NS072248 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Stephan Zuchner · 2011 to 2026
$9.2MIntegrative Genomic Analysis of Congenital Heart DiseaseR00HL143036 · NHLBI · WASHINGTON UNIVERSITY · PI JIN, SHENG CHIH · 2020 to 2022
$730kMedical Research Council G1000848Medical Research Council MR/N010035/1Medical Research Council MR/N025431/1Medical Research Council MR/N025431/2Medical Research Council MR/V009346/1NHLBI NIH HHS R00 HL143036NINDS NIH HHS R01 NS072248Wellcome Trust
Abstract
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.
Indexed as
AnimalsFemaleHumansMaleMiceMutationOxygenasesPedigreeRatsSpastic Paraplegia, HereditaryZebrafishOxygenasesautosomal recessivehereditary spastic paraplegiaHPDLHSPmitochondrial disorder
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