Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia PMID: 32707086

ADC Targets in Oncology

2026-04-10

Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Am J Hum Genet. 2020 Aug 6;107(2):364-373. doi: 10.1016/j.ajhg.2020.06.015.

Ralf A Husain ¹ , Mona Grimmel ² , Matias Wagner ³ , J Christopher Hennings ⁴ , Christian Marx ⁵ , René G Feichtinger ⁶ , Abdelkrim Saadi ⁷ , Kevin Rostásy ⁸ , Florentine Radelfahr ⁹ , Andrea Bevot ¹⁰ , Marion Döbler-Neumann ¹⁰ , Hans Hartmann ¹¹ , Laurence Colleaux ¹² , Isabell Cordts ¹³ , Xenia Kobeleva ¹⁴ , Hossein Darvish ¹⁵ , Somayeh Bakhtiari ¹⁶ , Michael C Kruer ¹⁶ , Arnaud Besse ¹⁷ , Andy Cheuk-Him Ng ¹⁸ , Diana Chiang ¹⁸ , Francois Bolduc ¹⁸ , Abbas Tafakhori ¹⁹ , Shrikant Mane ²⁰ , Saghar Ghasemi Firouzabadi ²¹ , Antje K Huebner ⁴ , Rebecca Buchert ² , Stefanie Beck-Woedl ² , Amelie J Müller ² , Lucia Laugwitz ²² , Thomas Nägele ²³ , Zhao-Qi Wang ²⁴ , Tim M Strom ²⁵ , Marc Sturm ² , Thomas Meitinger ²⁶ , Thomas Klockgether ²⁷ , Olaf Riess ²⁸ , Thomas Klopstock ²⁹ , Ulrich Brandl ¹ , Christian A Hübner ⁴ , Marcus Deschauer ¹³ , Johannes A Mayr ⁶ , Penelope E Bonnen ¹⁷ , Ingeborg Krägeloh-Mann ¹⁰ , Saskia B Wortmann ³⁰ , Tobias B Haack ³¹

Affiliations

1. Department of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany.
2. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
3. Institute 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.
4. Institute of Human Genetics, Jena University Hospital, 07747 Jena, Germany.
5. Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany.
6. University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
7. Department of Neurology, Ben Aknoun Hospital, Benyoucef Benkhedda University, 16028 Algiers, Algeria.
8. Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany.
9. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
10. Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tübingen, Germany.
11. Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.
12. INSERM UMR1163, Developmental Brain Disorders Laboratory, Imagine Institute, Paris-Descartes University, Paris, France.
13. Department of Neurology, Technische Universität München, School of Medicine, 81675 Munich, Germany.
14. Department of Neurology, University of Bonn, 53127 Bonn, Germany.
15. Cancer Research Center and Department of Medical Genetics, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
16. Barrow Neurological Institute, Phoenix Children's Hospital & University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
18. Division of Pediatric Neurology, Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
19. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
20. Yale Center for Genome Analysis, Yale University School of Medicine, West Haven, CT 06516, USA.
21. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
22. Institute 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.
23. Department of Neuroradiology, University Hospital Tuebingen, 72072 Tübingen, Germany.
24. Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745 Jena, Germany; Faculty of Biological Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany.
25. Institute of Human Genetics, Technical University of Munich (TUM), School of Medicine, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
26. Institute 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.
27. Department of Neurology, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
28. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
29. Department 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.
30. Institute 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.
31. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany. Electronic address: [email protected].

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.

Keywords

HPDL; Leigh-like syndrome; developmental delay; encephalopathy; exome sequencing; hereditary spastic paraplegia; mitochondrial metabolism; movement disorder.