{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:26:41Z","timestamp":1779190001170,"version":"3.51.4"},"reference-count":72,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GJC21131"],"award-info":[{"award-number":["GJC21131"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The human 4\u2010hydroxyphenylpyruvate dioxygenase\u2010like protein (HPDL) has been linked to hereditary spastic paraplegia (HSP) with potential roles in neurogenesis and energy metabolism. However, the prevalence of\n                      <jats:italic>HPDL<\/jats:italic>\n                      variants in childhood\u2010onset motor impairments remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This study set out to characterize new patients with biallelic\n                      <jats:italic>HPDL<\/jats:italic>\n                      variants, and to explore the role of this protein both in vitro and in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Exome sequencing was performed on 210 patients with HSP, diplegic cerebral palsy (CP), or moderate\/severe neurodevelopmental disorders. To understand the role of HPDL, we performed functional studies in patient\u2010derived fibroblasts and crispant (\n                      <jats:italic>hpdl<\/jats:italic>\n                      \u2010F0) zebrafish larvae.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 14 patients who exhibited reduced HPDL protein expression in cultured skin fibroblasts. Children with\n                      <jats:italic>HPDL<\/jats:italic>\n                      variants had elevated plasma glial fibrillary acidic protein levels, and serum metabolomics revealed reduced levels of 4\u2010hydroxybenzeneacetic acid, a precursor of 4\u2010hydroxymandelic acid (4HMA) and 4\u2010hydroxybenzoic acid (4HB), with disruptions in metabolic pathways, including the Krebs cycle. The involvement of HPDL in energy metabolism was supported by altered mitochondrial respiration and increased cytosolic reactive oxygen species in human cells. Investigations into\n                      <jats:italic>hpdl\u2010<\/jats:italic>\n                      F0 revealed neurodevelopmental abnormalities and epilepsy\u2010like behavior, likely due to mitochondrial dysfunction, mirroring the phenotypes observed in children. Bypass therapy with 4HMA rescued the disease phenotypes in cells and\n                      <jats:italic>hpdl\u2010<\/jats:italic>\n                      F0 crispant, while 4HB did so only partially in fish.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>HPDL<\/jats:italic>\n                      variants are responsible for CP\u2010like spastic paraparesis in children. Loss of HPDL function disrupts cellular oxidative metabolism, highlighting its role in neurodevelopment and energy homeostasis, both in vitro and in vivo. \u00a9 2025 International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.30296","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T09:24:35Z","timestamp":1753694675000},"page":"2085-2101","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>HPDL<\/scp>\n                    Biallelic Variants in Cerebral Palsy and Childhood\u2010Onset Hereditary Spastic Paraplegia: Human and Zebrafish Insights"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-6990","authenticated-orcid":false,"given":"Serena","family":"Mero","sequence":"first","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris  Pisa 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