{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:13:21Z","timestamp":1774635201357,"version":"3.50.1"},"reference-count":23,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Recently, a mitochondrial encephalopathy due to biallelic <jats:italic>HPDL<\/jats:italic> variants was described, associated with a broad range of clinical manifestations ranging from severe, infantile\u2010onset neurodegeneration to adolescence\u2010onset hereditary spastic paraplegia. HPDL converts 4\u2010hydroxyphenylpyruvate acid (4\u2010HPPA) into 4\u2010hydroxymandelate (4\u2010HMA), necessary for the synthesis of the mitochondrial electron transporter CoQ10. This suggests a possible bypass of the metabolic block by 4\u2010HMA treatment; however, genotype\u2013phenotype correlations are lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010binding sites or the C\u2010terminus, which had more severe phenotypes. In addition, p.Met1? variants were also correlated with more severe phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study demonstrates the correlation of age of onset and disease severity with genotype for <jats:italic>HPDL\u2010<\/jats:italic>related conditions. Patients with truncating variants and specific missense variants correlated with severe, early\u2010onset features, whereas the presence of at least one missense variant located outside of the iron\u2010binding sites correlated with milder presentations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>Clinicaltrials.gov HPDL registry: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05848271\">https:\/\/clinicaltrials.gov\/study\/NCT05848271<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70047","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T21:04:19Z","timestamp":1747256659000},"page":"1360-1367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>HPDL<\/i> Variant Type Correlates With Clinical Disease Onset and Severity"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8903-8528","authenticated-orcid":false,"given":"Eun Hye","family":"Lee","sequence":"first","affiliation":[{"name":"Rady Children's Institute for Genomic Medicine  San Diego California USA"},{"name":"Department of Pediatrics, College of Medicine Kyung Hee University  Seoul Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4785-7795","authenticated-orcid":false,"given":"Olivia","family":"Kim\u2010Mcmanus","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Pediatrics University of California  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer H.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Pediatrics University of California  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Haas","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Pediatrics University of California  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha S.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Human Genetics and Genome Research Division, Clinical Genetics Department National Research Centre  Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghada M. H.","family":"Abdel\u2010Salam","sequence":"additional","affiliation":[{"name":"Human Genetics and Genome Research Division, Clinical Genetics Department National Research Centre  Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Rady Children's Institute for Genomic Medicine  San Diego California USA"},{"name":"Department of Neurosciences and Pediatrics University of California  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed S.","family":"Abdel\u2010Hamind","sequence":"additional","affiliation":[{"name":"Human Genetics and Genome Research Division, Medical Molecular Genetic Department National Research Centre  Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi\u2010Fakhari","sequence":"additional","affiliation":[{"name":"Department of Neurology, F.M. 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