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.

Barrow Neurological Institute Phoenix Children's Hospital and University of Arizona College of Medicine Phoenix USA

Board of Governors Regenerative Medicine Institute Cedars Sinai Medical Center Los Angeles USA

Center for Brain Repair and Rehabilitation Institute of Neuroscience and Physiology University of Gothenburg Göteborg Sweden

Center for Medical Genetics Hanusch Hospital Vienna Austria

Center for the Undiagnosed Patient Cedars Sinai Medical Center Los Angeles USA

Center of Medical Genetics University of Antwerp and Antwerp University Hospital Antwerpen Belgium

Cologne Center for Genomics Faculty of Medicine and Cologne University Hospital University of Cologne Cologne Germany

Department of Biochemistry National Defense Medical Center Neihu Taipei Taiwan

Department of Clinical Genetics CHRU Nancy UMR_S INSERM N GERE 1256 Université de Lorraine Faculté de Médecine Nancy France

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Genetics Washington University School of Medicine St Louis USA

Department of Genetics Yale University School of Medicine New Haven USA

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

Department of Medical Genetics Le Havre Hospital Le Havre France

Department of Medicine Nephrology University Hospital Freiburg Germany

Department of Neurology and Psychiatry Assiut University Hospital Assiut Egypt

Department of Neurology Cedars Sinai Medical Center Los Angeles USA

Department of Neurology Donders Institute for Brain Cognition and Behavior Radboud University Medical Centre Nijmegen The Netherlands

Department of Neurology Graduate School of Medical Sciences University of Yamanashi Yamanashi Japan

Department of Neurology Graduate School of Medicine The University of Tokyo Tokyo Japan

Department of Neuromuscular Disorders Institute of Neurology University College London London UK

Department of Neuroradiology CHRU Nancy Nancy France

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Genoa Italy

Department of Orthopaedics and Traumatology Medical University of Vienna Vienna Austria

Department of Paediatric Neurology Liberec Hospital Liberec Czech Republic

Department of Pediatric Neurology Akdeniz University Hospital Antalya Turkey

Department of Pediatric Neurology Izmir Katip Celebi University Izmir Turkey

Department of Pediatric Neurology Osaka Women's and Children's Hospital Osaka Japan

Department of Pediatric Neurology University Children's Hospital Tübingen Tübingen Germany

Department of Pediatrics 1 Medical University of Innsbruck Innsbruck Austria

Department of Pediatrics Cedars Sinai Medical Center Los Angeles USA

Department of Pediatrics College of Medicine Qassim University Qassim Saudi Arabia

Department of Pediatrics Genetic Unit Armed Forces Hospital Khamis Mushayt Saudi Arabia

Department of Pediatrics Medical Genetics Cedars Sinai Medical Center Los Angeles USA

Department of Pediatrics Naval Medical Center San Diego San Diego USA

Department of Pediatrics Perelman School of Medicine University of Pennsylvania Philadelphia USA

Department of Pediatrics The 1st Affiliated Hospital of Henan University of Chinese Medicine Zhengzhou China

Department of Translational Genomics Center for Genomic Medicine King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia

Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Development and Behavioural Paediatrics Department Institute of Child Health and The Children Hospital Lahore Pakistan

Division of Human Genetics Medical University of Innsbruck Innsbruck Austria

DNA Laboratory Department of Paediatric Neurology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Dr John T Macdonald Foundation Department of Human Genetics John P Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami USA

Friedrich Baur Institute Department of Neurology LMU Munich Munich Germany

GeneDx Gaithersburg USA

Genetics and Genomics of Rare Diseases Unit IRCCS Istituto Giannina Gaslini Genoa Italy

Genetics Division Department of Pediatrics King Abdullah International Medical Research Center Riyadh Saudi Arabia

Genetics Research Center University of Social Welfare and Rehabilitation Sciences Tehran Iran

genetikum Center for Human Genetics Neu Ulm Germany

German Center for Neurodegenerative Diseases University of Tübingen Tübingen Germany

Hasti Genetic Counseling Center of Welfare Organization of Southern Khorasan Birjand Iran

Henan Key Laboratory of Child Brain Injury Institute of Neuroscience and 3rd Affliated Hospital of Zhengzhou University Zhengzhou China

Hertie Institute for Clinical Brain Research Center of Neurology University of Tübingen Tübingen Germany

Institut für Pharmazeutische Wissenschaften Albert Ludwigs Universität Freiburg Freibug Germany

Institute of Human Genetics Technische Universität Mänchen Munich Germany

Institute of Medical Genetics and Applied Genomics University of Tübingen Tübingen Germany

Institute of Medical Genomics International University of Health and Welfare Chiba Japan

Laboratory of Neuromuscular Pathology Institute Born Bunge University of Antwerp Antwerpen Belgium

Medical Genetics Unit IRCCS Istituto Giannina Gaslini Genoa Italy

Medical School Sigmund Freud Private University Vienna Austria

Medizinische Genetik Mainz Limbach Genetics Mainz Germany

Mitochondrial Medicine Frontier Program Children's Hospital of Philadelphia Philadelphia USA

Molecular Medicine Unit IRCCS Fondazione Stella Maris Pisa Italy

Neurology Department Massachusetts General Hospital Boston USA

Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital Antwerpen Belgium

Neuroscience Research Center Faculty of Medicine Golestan University of Medical Sciences Gorgan Iran

NIHR Oxford BRC Wellcome Centre for Human Genetics University of Oxford Oxford UK

Oxford Regional Clinical Genetics Service Northampton General Hospital Northampton UK

Pediatric Neurology and Neuromuscular Diseases Unit IRCCS Istituto Giannina Gaslini Genoa Italy

Polikliniek Neurologie Enschede Medisch Spectrum Twente Enschede The Netherlands

Rare Diseases Unit IRCCS Istituto Giannina Gaslini Genoa Italy

Roberts Individualized Medical Genetics Center Division of Human Genetics Children's Hospital of Philadelphia Philadelphia USA

Student Research Committee School of Medicine Shahid Beheshti University of Medical Sciences Tehran Iran

The National Hospital for Neurology and Neurosurgery London UK

Translational Neurosciences Faculty of Medicine and Health Sciences University of Antwerp Antwerpen Belgium

Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares Pôle de Biologie CHU Dijon Bourgogne Dijon France

Yale Center for Genome Analysis Yale University New Haven USA

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Brain. 2021 Sep 4;144(8):e70. doi: 10.1093/brain/awab193. PubMed

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