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

Ralf Husain 1 Mona Grimmel 2 Matias Wagner 3 J. Christopher Hennings 1 Christian Marx 4 René Feichtinger 5 Abdelkrim Saadi 6 Kevin Rostásy 7 Florentine Radelfahr 8 Andrea Bevot 9 Marion Döbler-Neumann 9 Hans Hartmann 10 Laurence Colleaux 11 Isabell Cordts 12 Xenia Kobeleva 13 Hossein Darvish 14 Somayeh Bakhtiari 15 Michael Kruer 15 Arnaud Besse 16 Andy Cheuk-Him Ng 17 Diana Chiang 17 Francois Bolduc 17 Abbas Tafakhori 18 Shrikant Mane 19 Saghar Ghasemi Firouzabadi 20 Antje Huebner 1 Rebecca Buchert 2 Stefanie Beck-Woedl 2 Amelie Müller 2 Lucia Laugwitz 9 Thomas Nägele 21 Zhao-Qi Wang 22 Tim Strom 3 Marc Sturm 2 Thomas Meitinger 23 Thomas Klockgether 8 Olaf Riess 2 Thomas Klopstock 23 Ulrich Brandl 1 Christian Hübner 1 Marcus Deschauer 12 Johannes Mayr 5 Penelope Bonnen 16 Ingeborg Krägeloh-Mann 9 Saskia Wortmann 24 Tobias Haack 2 
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.
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Submitted on : Monday, October 18, 2021 - 2:12:09 PM
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Ralf Husain, Mona Grimmel, Matias Wagner, J. Christopher Hennings, Christian Marx, et al.. Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (2), pp.364-373. ⟨10.1016/j.ajhg.2020.06.015⟩. ⟨hal-03366376⟩



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