{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:37:48Z","timestamp":1790779068700,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002738","name":"Assistance Publique - H\u00f4pitaux de Paris","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015822","name":"Fondazione Roma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015822","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Intern Med"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by <jats:italic>ABCC6<\/jats:italic> pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of <jats:italic>ABCC6<\/jats:italic>, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the <jats:italic>ABCC6<\/jats:italic>\u2010negative patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, family\u2010based exome sequencing was performed, in one <jats:italic>ABCC6\u2010<\/jats:italic>negative PXE patient with additional neurological features, and her relatives. <jats:italic>CYP2U1,<\/jats:italic> involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, <jats:italic>CYP2U1<\/jats:italic> sequencing was performed in a retrospective series of 46 additional <jats:italic>ABCC6<\/jats:italic>\u2010negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>6.4% of <jats:italic>ABCC6<\/jats:italic>\u2010negative PXE patients (<jats:italic>n\u00a0<\/jats:italic>=\u00a03) harboured biallelic pathogenic variants in <jats:italic>CYP2U1<\/jats:italic>. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. <jats:italic>CYP2U1<\/jats:italic> missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>CYP2U1<\/jats:italic> pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of <jats:italic>ABCC6<\/jats:italic> and <jats:italic>CYP2U1<\/jats:italic> should be explored to explain their respective role and potential interaction in ectopic mineralization.<\/jats:p><\/jats:sec>","DOI":"10.1111\/joim.13193","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T15:07:40Z","timestamp":1603811260000},"page":"709-725","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5703-3493","authenticated-orcid":false,"given":"A.","family":"Legrand","sequence":"first","affiliation":[{"name":"From the Universit\u00e9 de Paris, PARCC, INSERM Paris France"},{"name":"Centre de R\u00e9f\u00e9rence des Maladies Vasculaires Rares, AP\u2010HP, H\u00f4pital europ\u00e9en Georges Pompidou Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Pujol","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. M.","family":"Durand","sequence":"additional","affiliation":[{"name":"Inserm, U1211, Laboratoire Maladies Rares: G\u00e9n\u00e9tique et M\u00e9tabolisme, Univ. 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