{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T23:12:01Z","timestamp":1790118721677,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania\u2019s first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.<\/jats:p>","DOI":"10.3390\/ijms25094924","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:30:49Z","timestamp":1714534249000},"page":"4924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["D-Bifunctional Protein Deficiency Diagnosis\u2014A Challenge in Low Resource Settings: Case Report and Review of the Literature"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-4218","authenticated-orcid":false,"given":"Maria Livia","family":"Ognean","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Lucian Blaga University, 550025 Sibiu, Romania"},{"name":"Neonatology Department, Clinical County Emergency Hospital, 550245 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana Bianca","family":"Mutic\u0103","sequence":"additional","affiliation":[{"name":"Neonatology Department, Clinical County Emergency Hospital, 550245 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Adriana","family":"Vi\u0219a","sequence":"additional","affiliation":[{"name":"Research and Telemedicine Center in Pediatric Neurology, Pediatric Clinical Hospital Sibiu, 550169 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciprian Radu","family":"\u0218ofariu","sequence":"additional","affiliation":[{"name":"Research and Telemedicine Center in Pediatric Neurology, Pediatric Clinical Hospital Sibiu, 550169 Sibiu, Romania"},{"name":"Pediatric Clinical Hospital Sibiu, 550169 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudiu","family":"Matei","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Lucian Blaga University, 550025 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2573-621X","authenticated-orcid":false,"given":"Bogdan","family":"Neam\u021bu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Lucian Blaga University, 550025 Sibiu, Romania"},{"name":"Research and Telemedicine Center in Pediatric Neurology, Pediatric Clinical Hospital Sibiu, 550169 Sibiu, Romania"},{"name":"Department of Computer Science and Electrical Engineering, Faculty of Engineering, Lucian Blaga University Sibiu, 550025 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-5433","authenticated-orcid":false,"given":"Manuela","family":"Cucerea","sequence":"additional","affiliation":[{"name":"Department of Neonatology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu","family":"Gali\u0219","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Clinical County Emergency Hospital Bihor, 410167 Oradea, Romania"},{"name":"Department of Neonatology, Poznan University Medical Sciences, 60-512 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Ariadna","family":"Coci\u0219iu","sequence":"additional","affiliation":[{"name":"Medical Laboratory, Military Emergency Hospital, 550024 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-0365","authenticated-orcid":false,"given":"Ioana Octavia","family":"M\u0103t\u0103cu\u021b\u0103-Bogdan","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Lucian Blaga University, 550025 Sibiu, Romania"},{"name":"Pediatric Clinical Hospital Sibiu, 550169 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0303-7207(00)00388-9","article-title":"Molecular basis of d-bifunctional protein deficiency","volume":"171","author":"Wanders","year":"2001","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1055\/s-0035-1557474","article-title":"D-bifunctional protein deficiency, a novel mutation","volume":"06","author":"Dib","year":"2008","journal-title":"J. Pediatr. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"679597","DOI":"10.3389\/fped.2021.679597","article-title":"Two Novel HSD17B4 Heterozygous Mutations in Association with D-Bifunctional Protein Deficiency: A Case Report and Literature Review","volume":"9","author":"Chen","year":"2021","journal-title":"Front. Pediatr."},{"key":"ref_4","first-page":"213","article-title":"Clinical and neuropathological picture of familial encephalopathy with bifunctional protein deficiency","volume":"45","author":"Paprocka","year":"2007","journal-title":"Folia Neuropathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1750-1172-7-90","article-title":"Specific combination of compound heterozygous mutations in 17\u03b2-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency","volume":"7","author":"McMillan","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.pediatrneurol.2015.01.007","article-title":"D-Bifunctional Protein Deficiency: A Cause of Neonatal Onset Seizures and Hypotonia","volume":"52","author":"Nascimento","year":"2015","journal-title":"Pediatr. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Meht\u00e4l\u00e4, M.L., Lensink, M.F., Pietik\u00e4inen, L.P., Hiltunen, J.K., and Glumoff, T. (2013). On the Molecular Basis of D-Bifunctional Protein Deficiency Type III. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053688"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.bbamcr.2015.12.005","article-title":"Peroxisomes in brain development and function","volume":"1863","author":"Berger","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1086\/498880","article-title":"Mutational Spectrum of d-Bifunctional Protein Deficiency and Structure-Based Genotype-Phenotype Analysis","volume":"78","author":"Ferdinandusse","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","unstructured":"MedlinePlus (2024, February 18). HSD17B4 Gene, Available online: https:\/\/medlineplus.gov\/genetics\/gene\/hsd17b4\/."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/ana.20702","article-title":"Clinical and biochemical spectrum of D-bifunctional protein deficiency","volume":"59","author":"Ferdinandusse","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e357","DOI":"10.3346\/jkms.2020.35.e357","article-title":"First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea","volume":"35","author":"Bae","year":"2020","journal-title":"J. Korean Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1172\/JCI113956","article-title":"Peroxisomal bifunctional enzyme deficiency","volume":"83","author":"Watkins","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.gene.2015.05.020","article-title":"Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia","volume":"568","author":"Chandoga","year":"2015","journal-title":"Gene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jns.2016.11.009","article-title":"Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing","volume":"372","author":"Matsukawa","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000433621","article-title":"Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care","volume":"6","author":"Khromykh","year":"2015","journal-title":"Mol. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ajhg.2010.07.007","article-title":"Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome","volume":"87","author":"Pierce","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4103\/aian.AIAN_273_18","article-title":"D-bifunctional protein deficiency: A case report of a Turkish child","volume":"22","author":"Incecik","year":"2019","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100631","DOI":"10.1016\/j.ymgmr.2020.100631","article-title":"Four patients with D-bifunctional protein (DBP) deficiency: Expanding the phenotypic spectrum of a highly variable disease","volume":"25","author":"Landau","year":"2020","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/ajmg.a.62520","article-title":"D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia","volume":"188","author":"Werner","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1007\/s10545-005-0149-z","article-title":"Normal very-long-chain fatty acids in peroxisomal D-bifunctional protein deficiency: A diagnostic pitfall","volume":"28","author":"Wanders","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9851","DOI":"10.1073\/pnas.1302575110","article-title":"Clinical Genomic Database","volume":"110","author":"Solomon","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000371398","article-title":"Genomic Sequencing and the Impact of Molecular Diagnosis on Patient Care","volume":"6","author":"Solomon","year":"2015","journal-title":"Mol. Syndr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"154ra135","DOI":"10.1126\/scitranslmed.3004041","article-title":"Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units","volume":"4","author":"Saunders","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1056\/NEJMra1312543","article-title":"Diagnostic Clinical Genome and Exome Sequencing","volume":"370","author":"Biesecker","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1212\/WNL.0000000000000219","article-title":"Peroxisomal D-bifunctional protein deficiency","volume":"82","author":"Lines","year":"2014","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265ra168","DOI":"10.1126\/scitranslmed.3010076","article-title":"Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders","volume":"6","author":"Soden","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a005496","DOI":"10.1101\/mcs.a005496","article-title":"Rapid whole-genome sequencing identifies a homozygous novel variant, His540Arg, in HSD17B4 resulting in D-bifunctional protein deficiency disorder diagnosis","volume":"6","author":"Savage","year":"2020","journal-title":"Mol. Case Stud."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41525-018-0049-4","article-title":"Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization","volume":"3","author":"Farnaes","year":"2018","journal-title":"NPJ Genom. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1007\/s00246-019-02203-2","article-title":"Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors","volume":"40","author":"Bennett","year":"2019","journal-title":"Pediatric Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1212\/WNL.0b013e3181f07061","article-title":"Docosahexaenoic acid therapy in peroxisomal diseases","volume":"75","author":"Paker","year":"2010","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1093\/oxfordjournals.jbchem.a021458","article-title":"Purification and Properties of Human D-3-Hydroxyacyl-CoA Dehydratase: Medium-Chain Enoyl-CoA Hydratase Is D-3-Hydroxyacyl-CoA Dehydratase","volume":"120","author":"Jiang","year":"1996","journal-title":"J. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1086\/302180","article-title":"Peroxisomal Bifunctional Protein Deficiency Revisited: Resolution of Its True Enzymatic and Molecular Basis","volume":"64","author":"Mooijer","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1086\/301599","article-title":"d-3-Hydroxyacyl-CoA Dehydratase\/d-3-Hydroxyacyl-CoA Dehydrogenase Bifunctional Protein Deficiency: A Newly Identified Peroxisomal Disorder","volume":"61","author":"Suzuki","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1442-200X.2012.03562.x","article-title":"Mild case of d-bifunctional protein deficiency associated with novel gene mutations","volume":"54","author":"Mizumoto","year":"2012","journal-title":"Pediatr. Int."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wanders, R.J.A., Waterham, H.R., and Ferdinandusse, S. (2016). Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum. Front. Cell Dev. Biol., 3.","DOI":"10.3389\/fcell.2015.00083"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev.biochem.74.082803.133329","article-title":"Biochemistry of Mammalian Peroxisomes Revisited","volume":"75","author":"Wanders","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_38","unstructured":"National Center for Biotechnology Information (2024, February 18). ClinVar; [VCV000632859.1], [Last Updated 25 April 2022], Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/VCV000632859.1."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1177\/0883073811401399","article-title":"Clinical and Imaging Observations in Isolated Sulfite Oxidase Deficiency","volume":"26","author":"Bindu","year":"2011","journal-title":"J. Child Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s10545-017-0089-4","article-title":"Isolated sulfite oxidase deficiency","volume":"41","author":"Claerhout","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e396","DOI":"10.1212\/NXG.0000000000000396","article-title":"Biallelic mutation of HSD17B4 induces middle age\u2013onset spinocerebellar ataxia","volume":"6","author":"Matsuda","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e240097","DOI":"10.1001\/jamanetworkopen.2024.0097","article-title":"Enhancing Neonatal Intensive Care with Rapid Genome Sequencing","volume":"7","author":"Jiang","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e240146","DOI":"10.1001\/jamanetworkopen.2024.0146","article-title":"National Rapid Genome Sequencing in Neonatal Intensive Care","volume":"7","author":"Marom","year":"2024","journal-title":"JAMA Netw. Open"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:32Z","timestamp":1760107052000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094924"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094924","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}