Two Novel HSD17B4 Heterozygous Mutations in Association With D-Bifunctional Protein Deficiency: A Case Report and Literature Review

Abstract

Background: D-Bifunctional protein deficiency (D-BPD) is an autosomal recessive disorder caused by peroxisomal β-oxidation defects. According to the different activities of 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units, D-bifunctional protein defects can be divided into four types. The typical symptoms include hypotonia and seizures. The gene that encodes D-BP was HSD17B4, which is located in chromosome 5q23.1.Case Presentation: We report the first case of D-BPD in a Chinese patient with neonatal onset. Cosmetic malformations, severe hypotonia and seizures are prominent. The blood bile acid profile showed increased taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid. Very-long-chain fatty acids (VLCFAs) revealed significant increases in hexacosanoic acid (C26:0), tetracosanoic acid/docosanoic acid (C24:0/C22:0), and hexacosanoic acid/docosanoic acid (C26:0/C22:0). Cranial MRI revealed bilateral hemispheric and callosal dysplasia, with schizencephaly in the right hemisphere. EEG showed loss of sleep–wake cycle and epileptiform discharge. Other examinations include abnormal brainstem auditory evoked potentials (BAEPs) and temporal pigmented spots on the optic disc in the right eye. After analysis by whole-exome sequencing, heterozygous c.972+1G>T in the paternal allele and c.727T>A (p.W243R) in the maternal allele were discovered. He was treated with respiratory support, formula nasogastric feeding, and antiepileptic therapy during hospitalization and died at home due to food refusal and respiratory failure at the age of 5 months.Conclusions: Whole-exome sequencing should be performed in time to confirm the diagnosis when the newborn presents hypotonia, seizures, and associated cosmetic malformations. There is still a lack of effective radical treatment. Supportive care is the main treatment, aiming at controlling symptoms of central nervous system like seizures and improving nutrition and growth. The disease has a poor outcome, and infants often die of respiratory failure within 2 years of age. In addition, heterozygous deletion variant c.972+1G>T and missense mutations c.727T>A (p.W243R) are newly discovered pathogenic variants that deserve further study.

Shared genetics and causal associations between COVID‐19 and multiple sclerosis

“…On chromosome 5q23.1, HSD17B4 encodes a bifunctional enzyme that is involved in the peroxisomal beta‐oxidation pathway for both straight‐chain and 2‐methyl‐branched‐chain fatty acids. Mutations in this locus lead to a distinct neurological condition due to the inherent defect of beta‐oxidation 42 . While no specific studies of HSD17B4 have been reported in MS or COVID‐19 thus far, peroxisome pathways are disturbed in each of these two disorders 43,44 …”

“…Mutations in this locus lead to a distinct neurological condition due to the inherent defect of beta-oxidation. 42 While no specific studies of HSD17B4 have been reported in MS or COVID-19 thus far, peroxisome pathways are disturbed in each of these two disorders. 43,44 A total of 24 protein-coding genes were implicated by the analysis of molecular relationships within the reconstructed pathways mediating the synergistic link between MS and COVID-19.…”

A clinical case of a familial form of hereditary metabolic disease from the group of peroxisomal diseases (D-bifunctional protein deficiency) in the neonatal period

“…У человека идентифицированы две ацил-КоА-оксидазы с различной субстратной специфичностью На рубеже XX в. был описан новый фермент пероксисомального β-окисления, названный D-бифункциональным белком (D-ВР) с активностью еноил-КоА-гидратазы и 3-гидроксиацил-КоА-дегидрогеназы, в первую очередь реагирующий с α-метиловыми жирными кислотами, DBP представляет собой гомодимерный фермент с субъединицами 79 кДа и содержит три функциональных домена: 3-гидроксиацил-КоА-дегидрогеназу, 2-еноил-КоА-гидратазу и домен, подобный белку-носителю стерола 2. Три функциональные единицы DBP необходимы для разложения жирных кислот с очень длинной цепью (VLCFA), α-метильных жирных кислот с разветвлённой цепью и промежуточных продуктов желчных кислот, таких как DHCA и THCA [11].…”

“…Все три типа имеют сходную клиническую картину, однако различаются по степени тяжести. Так, пациенты с дефицитом I типа демонстрировали самые тяжёлые симптомы со средней продолжительностью жизни в 6,9 месяца, в то время как у пациентов со II и III типами продолжительность жизни составила 10,7 и 17,6 месяцев соответственно [11].…”

Therapierefraktäre zerebrale Anfälle bei einem Neugeborenen aufgrund einer D-bifunktionellen Protein-Defizienz (Pseudo-Zellweger-Syndrom) – Fallbericht

“…Diskussion Die D-bifunktionelle Protein-Defizienz ist eine seltene autosomal rezessive Erbkrankheit 4 5 . Analog zu unserem Fall sind typische Befunde eine Muskelhypotonie, zerebrale Anfälle und kraniofaziale Pathologien.5 Das klinische Bild variiert 6 7 8 9 . In der Literatur finden sich allerdings keine Berichte über Begleitthrombosen wie im vorgestellten Fall.…”