Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.
Manuela WiessnerReza MaroofianMeng-Yuan NiAndrea PedroniJuliane S MüllerRolf StuckaChristian BeetzStephanie EfthymiouFilippo M SantorelliAhmed A AlfaresChanglian ZhuAnna Uhrova MeszarosovaElham AlehabibSomayeh BakhtiariAndreas R JaneckeMaria Gabriela OteroJin Yun Helen ChenJames T PetersonTim M StromPeter De JongheTine DeconinckWillem De RidderJonathan De WinterRossella PasquarielloIvana RiccaMajid AlfadhelBart P van de WarrenburgRuben PortierCarsten BergmannSaghar Ghasemi FirouzabadiSheng Chih JinKaya BilguvarSherifa HamedMohamed A AbdelhamedNourelhoda A HaridyShazia MaqboolFatima RahmanNajwa AnwarJenny CarmichaelAlistair T PagnamentaNick W WoodFrederic Tran Mau-ThemTobias Haacknull nullMaja Di RoccoIsabella CeccheriniMichele IacominoFederico ZaraVincenzo SalpietroMarcello ScalaMarta RusminiYiran XuYinghong WangYasuhiro SuzukiKishin KohHaitian NanHiroyuki IshiuraShoji TsujiLaëtitia LambertEmmanuelle SchmittElodie LacazeHanna KüpperDavid DredgeCara SkrabanAmy GoldsteinMary J H WillisKatheryn GrandJohn M GrahamRichard A LewisFrancisca MillanÖzgür DumanNihal DündarGökhan UyanikLudger SchölsPeter NürnbergGudrun NürnbergAndrea Catala BordesPavel SeemanMartin KucharHossein DarvishAdriana RebeloFilipa BouçanovaJean-Jacques MedardRoman ChrastMichaela Auer-GrumbachFowzan S AlkurayaHanan ShamseldinSaeed Al TalaJamileh Rezazadeh VaraghchiMaryam NajafiSelina DeschnerDieter GläserWolfgang HüttelMichael C KruerErik-Jan KamsteegYoshihisa TakiyamaStephan ZüchnerJonathan BaetsMatthis SynofzikRebecca SchüleRita HorvathHenry HouldenLuca BartesaghiHwei-Jen LeeKonstantinos AmpatzisTyler Mark PiersonJan SenderekPublished in: Brain : a journal of neurology (2021)
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.