From Neonatal Encephalopathy to Adult Survival: Revisiting the Natural History of D-Bifunctional Protein Deficiency...

D-bifunctional protein deficiency (DBP-D) is a rare autosomal recessive peroxisomal disorder caused by biallelic pathogenic HSD17B4 variants. Its clinical spectrum ranges from severe neonatal-onset encephalopathy to milder, juvenile-onset forms, but comprehensive data on long-term outcomes remain limited. We conducted a retrospective, multicentre review of 26 DBP-D 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 days of life with neonatal seizures and hypotonia. Mortality was high: 77% died before the age of 2 years and 20% between ages two and five. Notably, three patients survived beyond 5 years, including one with neonatal-onset now aged 19. Two others had infantile-juvenile presentations with hearing loss, ataxia, and cerebellar atrophy. While 68% of patients had elevated very long-chain fatty acids (VLCFAs), 32% had normal or mildly raised levels; all of these survived beyond 2 years. Pathogenic variants were distributed across all three HSD17B4 domains, with 14 novel alleles identified. Neuroimaging findings varied with severity: polymicrogyria and cysts predominated in neonatal-onset cases, while cerebellar atrophy was typical in later-onset survivors. This study expands the clinical and genetic landscape of DBP-D, 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-term care.