ArticleAmerican journal of human genetics2020
Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 51 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
- 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
- Neurodevelopmental Disorder with Progressive Spasticity and Brain White Matter Abnormalities (NEDSWMA).Indian journal of pediatrics · 2025Article
- 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
- 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
- Functional genomics and small molecules in mitochondrial neurodevelopmental disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Primary Coenzyme Q10 Deficiency: An Update.Antioxidants (Basel, Switzerland) · 2023Review
- Neuroimaging in Primary Coenzyme-QAntioxidants (Basel, Switzerland) · 2023Review
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Authors and funding
46 authors at 20 institutions in 9 countries.
Ralf A HusainDepartment of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany.
Mona GrimmelInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Matias WagnerInstitute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
J Christopher HenningsInstitute of Human Genetics, Jena University Hospital, 07747 Jena, Germany.
Christian MarxLeibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany.
René G FeichtingerUniversity Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
Abdelkrim SaadiDepartment of Neurology, Ben Aknoun Hospital, Benyoucef Benkhedda University, 16028 Algiers, Algeria.
Kevin RostásyDepartment of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany.
Florentine RadelfahrDepartment of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
Andrea BevotDepartment of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.
Marion Döbler-NeumannDepartment of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.
Hans HartmannClinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
Laurence ColleauxINSERM UMR1163, Developmental Brain Disorders Laboratory, Imagine Institute, Paris-Descartes University, Paris, France.
Isabell CordtsDepartment of Neurology, Technische Universität München, School of Medicine, 81675 Munich, Germany.
Xenia KobelevaDepartment of Neurology, University of Bonn, 53127 Bonn, Germany.
Hossein DarvishCancer Research Center and Department of Medical Genetics, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
Somayeh BakhtiariBarrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
Michael C KruerBarrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
Arnaud BesseDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Andy Cheuk-Him NgDivision of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Diana ChiangDivision of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Francois BolducDivision of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Abbas TafakhoriIranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Shrikant ManeYale Center for Genome Analysis, Yale University School of Medicine, West Haven, CT 06516, USA.
Saghar Ghasemi FirouzabadiGenetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Antje K HuebnerInstitute of Human Genetics, Jena University Hospital, 07747 Jena, Germany.
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Stefanie Beck-WoedlInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Amelie J MüllerInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Lucia LaugwitzInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.
Thomas NägeleDepartment of Neuroradiology, University Hospital Tuebingen, 72072 Tübingen, Germany.
Zhao-Qi WangLeibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany; Faculty of Biological Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany.
Tim M StromInstitute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Marc SturmInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
Thomas MeitingerInstitute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Thomas KlockgetherDepartment of Neurology, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
Olaf RiessInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
Thomas KlopstockDepartment of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Ulrich BrandlDepartment of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany.
Christian A HübnerInstitute of Human Genetics, Jena University Hospital, 07747 Jena, Germany.
Marcus DeschauerDepartment of Neurology, Technische Universität München, School of Medicine, 81675 Munich, Germany.
Johannes A MayrUniversity Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
Penelope E BonnenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ingeborg Krägeloh-MannDepartment of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.
Saskia B WortmannInstitute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, 6525 GA Nijmegen, the Netherlands.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address: tobias.haack@med.uni-tuebingen.de.
University of Tübingen · DEJena University Hospital · DEUniversity Children's Hospital Tübingen · DEHelmholtz Zentrum München · DEUniversity of Alberta · CABarrow Neurological Institute · USBaylor College of Medicine · USGerman Center for Neurodegenerative Diseases · DELeibniz Institute on Aging - Fritz Lipmann Institute (FLI) · DEParacelsus Medical University · ATTechnical University of Munich · DEUniversity of Bonn · DEInserm · FRMedizinische Hochschule Hannover · DERadboud University Nijmegen · NLSemnan University of Medical Sciences · IRTehran University of Medical Sciences · IRUniversity of Algiers Benyoucef Benkhedda · DZUniversity of Social Welfare and Rehabilitation Sciences · IRWitten/Herdecke University · DE
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MPersonalized Functional Genomics for Mitochondrial Encephalopathy Gene DiscoveryR01NS083726 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BONNEN, PENELOPE E · 2014 to 2025
$6.1MNCATS NIH HHS UL1 TR001863NINDS NIH HHS R01 NS083726
Abstract
We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
Indexed as
AdolescentAdultAllelesAmino Acid SequenceBrain DiseasesChildFemaleHumansMaleMitochondriaMitochondrial ProteinsNeurodegenerative DiseasesPedigreePhenotypeSpastic Paraplegia, HereditaryYoung AdultMitochondrial Proteinsdevelopmental delayencephalopathyexome sequencinghereditary spastic paraplegiaHPDLLeigh-like syndromemitochondrial metabolismmovement disorder
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