Joshua Mould
Joshua Mould, a 21-year-old studying computer science and statistics at Villanova University in Pennsylvania, had suffered from mysterious balance issues and tightness, called spasticity, in his leg muscles since junior high. When Mould was in eighth grade, these symptoms began interfering with his passion for baseball, and eventually sidelined him.
“I wasn't very flexible,” Mould said. “I also wasn't getting stronger, and I wasn’t gaining any velocity on my fastball even though I was lifting weights and working out at least three times a week.”
Pitchers generate power through their legs, with the arm simply following through. “I didn’t have the flexibility to take a very long stride toward the plate, or the leg strength or stability to create much momentum,” Mould said.
After a lackluster sophomore year, Mould trained throughout the offseason, even working with coaches from a top sports performance center in hope of making progress. “But the next spring, we checked the velocity on my fastball, and it had dropped about 10 miles per hour,” he said.
His trainer suggested he see a doctor, and a local neurologist ordered a genetic screening test that identified variations in both copies of his human 4-hydroxyphenylpiruvate dioxygenase-like (HPDL) gene, a gene that had never before been associated with disease. The neurologist connected him with Tyler Pierson, MD, PhD, assistant professor of Pediatrics and Neurology at Cedars-Sinai and lead pediatrician at the center.
Over the years, Pierson had seen a few other patients with symptoms and a genetic variation similar to Mould’s.
“At the time, very little was known about this gene,” Pierson said, “so further research was needed to determine whether the variation was causing Josh’s symptoms.”
Pierson and collaborators put together a study involving nearly 50 institutions in the U.S. and abroad, looking at the cases of Mould and 30 others with the HPDL variation, and were able to describe a new disorder called HPDL deficiency (also called SPG83) and provide Mould and the others with a diagnosis.
Pierson said the diagnosis has value, even though HPDL deficiency doesn’t yet have a cure, because it lets families know the symptoms came from a condition over which they had no control. It also gives the patient the opportunity to pursue genetic counseling before having children, and to seek information within the community of fellow patients.
“It allows them to look for other people with the same diagnosis, whether that’s a family research group or even just a Facebook group,” said Pierson. “They can connect and perhaps gain insight from other families.”
Pierson continues to work to better understand HPDL deficiency in the hope of one day finding a therapy that halts or even reverses the progression of symptoms. And Mould takes medications to reduce the tightness in his legs, which he said is helping improve his balance.
“Early in high school, it was really hard to deal with,” Mould said of his condition. “The diagnosis gives me a reason why my muscles aren’t listening to me, and that it’s not just my failure to work as hard as other people. And it’s been really important to me to know that.”
Pediatric patients referred to the center are diagnosed most often with genetic conditions. Adult patients are more likely to have conditions that arose later in life, and they often have been to multiple specialists who haven't been able to explain their symptoms or test results.
https://www.newswise.com/articles/medical-mysteries-are-their-specialty
Sun Y, Wei X, Fang F, Shen Y, Wei H, Li J, Ye X, Zhan Y, Ye X, Liu X, Yang W, Li Y, Geng X, Huang X, Ruan Y, Qin Z, Yi S, Lyu J, Fang H, Yu Y. HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration. J Genet Genomics. 2021 Aug 20;48(8):727-736. doi: 10.1016/j.jgg.2021.01.009. Epub 2021 Jun 17. PMID: 34334354.
Abstract
Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.
Wiessner M, Maroofian R, Ni MY, Pedroni A, Müller JS, Stucka R, Beetz C, Efthymiou S, Santorelli FM, Alfares AA, Zhu C, Uhrova Meszarosova A, Alehabib E, Bakhtiari S, Janecke AR, Otero MG, Chen JYH, Peterson JT, Strom TM, De Jonghe P, Deconinck T, De Ridder W, De Winter J, Pasquariello R, Ricca I, Alfadhel M, van de Warrenburg BP, Portier R, Bergmann C, Ghasemi Firouzabadi S, Jin SC, Bilguvar K, Hamed S, Abdelhameed M, Haridy NA, Maqbool S, Rahman F, Anwar N, Carmichael J, Pagnamenta A, Wood NW, Tran Mau-Them F, Haack T; Genomics England Research Consortium, PREPARE network; Di Rocco M, Ceccherini I, Iacomino M, Zara F, Salpietro V, Scala M, Rusmini M, Xu Y, Wang Y, Suzuki Y, Koh K, Nan H, Ishiura H, Tsuji S, Lambert L, Schmitt E, Lacaze E, Küpper H, Dredge D, Skraban C, Goldstein A, Willis MJH, Grand K, Graham JM, Lewis RA, Millan F, Duman Ö, Dündar N, Uyanik G, Schöls L, Nürnberg P, Nürnberg G, Catala Bordes A, Seeman P, Kuchar M, Darvish H, Rebelo A, Bouçanova F, Medard JJ, Chrast R, Auer-Grumbach M, Alkuraya FS, Shamseldin H, Al Tala S, Rezazadeh Varaghchi J, Najafi M, Deschner S, Gläser D, Hüttel W, Kruer MC, Kamsteeg EJ, Takiyama Y, Züchner S, Baets J, Synofzik M, Schüle R, Horvath R, Houlden H, Bartesaghi L, Lee HJ, Ampatzis K, Pierson TM, Senderek J. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain. 2021 Jun 22;144(5):1422-1434. doi: 10.1093/brain/awab041. Erratum in: Brain. 2021 Sep 4;144(8):e70. doi: 10.1093/brain/awab193. PMID: 33970200; PMCID: PMC8219359.
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.
Lee EH, Kim-Mcmanus O, Yang JH, Haas R, Zaki MS, Abdel-Salam GMH, Nakamura Y, Abdel-Hamind MS, Ebrahimi-Fakhari D, Alecu JE, Brunetti-Pierri N, Srinivasan VM, Gowda VK, Gross S, Alanay Y, Najarzadeh Totbati P, Yadavilli M, Friedman L, Ojeda NM, Gleeson JG. HPDL Variant Type Correlates With Clinical Disease Onset and Severity. Ann Clin Transl Neurol. 2025 Jul;12(7):1360-1367. doi: 10.1002/acn3.70047. Epub 2025 May 14. Erratum in: Ann Clin Transl Neurol. 2026 Jan;13(1):212. doi: 10.1002/acn3.70084. PMID: 40368591; PMCID: PMC12257120.
Abstract
Objective: Recently, a mitochondrial encephalopathy due to biallelic HPDL variants was described, associated with a broad range of clinical manifestations ranging from severe, infantile-onset neurodegeneration to adolescence-onset hereditary spastic paraplegia. HPDL converts 4-hydroxyphenylpyruvate acid (4-HPPA) into 4-hydroxymandelate (4-HMA), necessary for the synthesis of the mitochondrial electron transporter CoQ10. This suggests a possible bypass of the metabolic block by 4-HMA treatment; however, genotype-phenotype correlations are lacking.
Methods: We established an HPDL Patient Registry to prepare for a future clinical trial. Here we report the clinical features of 13 enrolled participants and compare them with 86 previously reported patients. We establish three major clinical classes: severe, intermediate, and mild, presenting onset in early infancy, childhood, and adolescence, respectively. The biallelic genotypes were classified into truncating/truncating, truncating/missense, and missense/missense variants, mapped onto the predicted 3D protein structure, and correlated with severity.
Results: Patients with biallelic truncating variants presented with severe phenotypes and earlier ages of onset. Missense variants were often associated with milder phenotypes, except those with variants predominantly located in or near the VOC2 domain containing iron-binding sites or the C-terminus, which had more severe phenotypes. In addition, p.Met1? variants were also correlated with more severe phenotypes.
Interpretation: This study demonstrates the correlation of age of onset and disease severity with genotype for HPDL-related conditions. Patients with truncating variants and specific missense variants correlated with severe, early-onset features, whereas the presence of at least one missense variant located outside of the iron-binding sites correlated with milder presentations.
