{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:13:44Z","timestamp":1782184424541,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    D\u2010bifunctional protein deficiency (DBP\u2010D) is a rare autosomal recessive peroxisomal disorder caused by biallelic pathogenic\n                    <jats:italic>HSD17B4<\/jats:italic>\n                    variants. Its clinical spectrum ranges from severe neonatal\u2010onset encephalopathy to milder, juvenile\u2010onset forms, but comprehensive data on long\u2010term outcomes remain limited. We conducted a retrospective, multicentre review of 26 DBP\u2010D patients managed at seven centres in the United Kingdom and Spain from 1982 to 2024. Clinical, biochemical, neuroimaging, neurophysiological, and genetic data were systematically collected. A literature review was performed to contextualize our findings. Most patients (92%) presented within the first 5\u2009days of life with neonatal seizures and hypotonia. Mortality was high: 77% died before the age of 2\u2009years and 20% between ages two and five. Notably, three patients survived beyond 5\u2009years, including one with neonatal\u2010onset now aged 19. Two others had infantile\u2010juvenile presentations with hearing loss, ataxia, and cerebellar atrophy. While 68% of patients had elevated very long\u2010chain fatty acids (VLCFAs), 32% had normal or mildly raised levels; all of these survived beyond 2\u2009years. Pathogenic variants were distributed across all three\n                    <jats:italic>HSD17B4<\/jats:italic>\n                    domains, with 14 novel alleles identified. Neuroimaging findings varied with severity: polymicrogyria and cysts predominated in neonatal\u2010onset cases, while cerebellar atrophy was typical in later\u2010onset survivors. This study expands the clinical and genetic landscape of DBP\u2010D, demonstrating that survival into adulthood is possible and that normal or mildly elevated VLCFA levels are associated with milder phenotypes. Early molecular testing is essential in all suspected cases, even with normal VLCFAs, to guide diagnosis, prognosis, and long\u2010term care.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70118","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T07:13:56Z","timestamp":1765350836000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Neonatal Encephalopathy to Adult Survival: Revisiting the Natural History of D\u2010Bifunctional Protein Deficiency in a Multicentre International Case Series"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9040-3142","authenticated-orcid":false,"given":"U.","family":"Diaz\u2010Moreno","sequence":"first","affiliation":[{"name":"Department of Paediatric Inherited Metabolic Medicine Great Ormond Street Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7365-7940","authenticated-orcid":false,"given":"S. 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