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

• DOI: 10.1016/j.ajhg.2020.06.015
• Publication Date: 2020-07-23T14:42:18Z
• Authors: Ralf A. Husain; Mona Grimmel; Matias Wagner; J. Christopher He...; Christian Marx; René G. Feichtinger; Abdelkrim Saadi; Kevin Rostásy; Florentine Radelfahr; Andrea Bevot; Marion Döbler-Neu...; Hans Hartmann; Laurence Colleaux; Isabell Cordts; Xenia Kobeleva; Hossein Darvish; Somayeh Bakhtiari; Michael C. Kruer; Arnaud Besse; Andy Cheuk-Him Ng; Diana Chiang; Francois Bolduc; Abbas Tafakhori; Shrikant Mane; Saghar Ghasemi Fi...; Antje K. Huebner; Rebecca Buchert; Stefanie Beck-Woedl; Amelie J. Müller; Lucia Laugwitz; Thomas Nägele; Zhao-Qi Wang; Tim M. Strom; Marc Sturm; Thomas Meitinger; Thomas Klockgether; Olaf Riess; Thomas Klopstock; Ulrich Brandl; Christian A. Hübner; Marcus Deschauer; Johannes A. Mayr; Penelope E. Bonnen; Ingeborg Krägeloh...; Saskia B. Wortmann; Tobias B. Haack
• Keywords: Adult; Male; 0301 basic medicine; mitochondrial metabolism; Adolescent; [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics; Developmental Delay ; Encephalopathy ; Exome Sequencing ; Hereditary Spastic Paraplegia ; Hpdl ; Leigh-like Syndrome ; Mitochondrial Metabolism ; Movement Disorder; Leigh-like syndrome; Mitochondrial Proteins; Young Adult; 03 medical and health sciences; ddc:570; genetics [Spastic Paraplegia, Hereditary]; Humans; Amino Acid Sequence; hereditary spastic paraplegia; Child; Alleles; Brain Diseases; Spastic Paraplegia, Hereditary; genetics [Brain Diseases]; Neurodegenerative Diseases; HPDL; encephalopathy; Mitochondria; Pedigree; 3. Good health; developmental delay; Phenotype; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; genetics [Neurodegenerative Diseases]; genetics [Mitochondrial Proteins]; Female; movement disorder; genetics [Mitochondria]; exome sequencing

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.