Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
Authors: Wiessner Manuela , Maroofian Reza , Ni Meng-Yuan , Pedroni Andrea , Müller Juliane S , Stucka Rolf , Beetz Christian , Efthymiou Stephanie , Santorelli Filippo M , Alfares Ahmed A , Zhu Changlian , Uhrova Meszarosova Anna , Alehabib Elham , Bakhtiari Somayeh , Janecke Andreas R , Otero Maria Gabriela , Chen Jin Yun Helen , Peterson James T , Strom Tim M , De Jonghe Peter , Deconinck Tine , De Ridder Willem , De Winter Jonathan , Pasquariello Rossella , Ricca Ivana , Alfadhel Majid , van de Warrenburg Bart P , Portier Ruben , Bergmann Carsten , Ghasemi Firouzabadi Saghar , Jin Sheng Chih , Bilguvar Kaya , Hamed Sherifa , Abdelhameed Mohammed , Haridy Nourelhoda A , Maqbool Shazia , Rahman Fatima , Anwar Najwa , Carmichael Jenny , Pagnamenta Alistair , Wood Nick W , Tran Mau-Them Frederic , Haack Tobias ,   Genomics England Research Consortium, PREPARE network, Di Rocco Maja , Ceccherini Isabella , Iacomino Michele , Zara Federico , Salpietro Vincenzo , Scala Marcello , Rusmini Marta , Xu Yiran , Wang Yinghong , Suzuki Yasuhiro , Koh Kishin , Nan Haitian , Ishiura Hiroyuki , Tsuji Shoji , Lambert Laëtitia , Schmitt Emmanuelle , Lacaze Elodie , Küpper Hanna , Dredge David , Skraban Cara , Goldstein Amy , Willis Mary J H , Grand Katheryn , Graham John M , Lewis Richard A , Millan Francisca , Duman Özgür , Dündar Nihal , Uyanik Gökhan , Schöls Ludger , Nürnberg Peter , Nürnberg Gudrun , Catala Bordes Andrea , Seeman Pavel , Kuchar Martin , Darvish Hossein , Rebelo Adriana , Bouçanova Filipa , Medard Jean-Jacques , Chrast Roman , Auer-Grumbach Michaela , Alkuraya Fowzan S , Shamseldin Hanan , Al Tala Saeed , Rezazadeh Varaghchi Jamileh , Najafi Maryam , Deschner Selina , Gläser Dieter , Hüttel Wolfgang , Kruer Michael C , Kamsteeg Erik-Jan , Takiyama Yoshihisa , Züchner Stephan , Baets Jonathan , Synofzik Matthis , Schüle Rebecca , Horvath Rita , Houlden Henry , Bartesaghi Luca , Lee Hwei-Jen , Ampatzis Konstantinos , Pierson Tyler Mark , Senderek Jan 
Published: February 2021

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.