First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

Abstract

Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes β-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.

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

“…It is consistent with the literature reports that most patients with early onset had craniofacial deformities (1,(18)(19)(20). The infant had severe neonatal hypotonia and convulsions, without primitive reflex elicited on the 1st day after birth, which was consistent with the literature reports that convulsive seizures occurred within a few days after birth, generally starting on the 2nd day after birth (1,3,(18)(19)(20)(21). After the patient's family signed the informed consent form for antiepileptic drugs, a combination of antiepileptic drugs, including levetiracetam tablets, topiramate tablets, and sodium valproate oral solution, was administered successively and at the maximum dose within the safety range, but the patient still had more frequent convulsive seizures of more than 10 times a day.…”

“…In this case report, the patient showed typical clinical abnormalities including cosmetic deformities (long head deformity, high forehead, wide eye distance, high palatal arch, and talipes varus). It is consistent with the literature reports that most patients with early onset had craniofacial deformities (1,(18)(19)(20). The infant had severe neonatal hypotonia and convulsions, without primitive reflex elicited on the 1st day after birth, which was consistent with the literature reports that convulsive seizures occurred within a few days after birth, generally starting on the 2nd day after birth (1,3,(18)(19)(20)(21).…”

“…It has been reported in the literature that cranial MRI in adulthood revealed cerebellar atrophy and ataxia (23), while neonatal cranial MRI revealed no significant brain atrophy (24). Our patient's cranial MRI showed shallow sulci, local widening and deepening of the lateral fissure cistern of the right cerebral hemisphere, extensive hyperintense white matter changes in the cerebral hemisphere on T2WI, and dysplasia of the corpus callosum, which were similar to the clinical report that MRI in children with D-BDP showed different severities of lateral fissure, peripheral multiple microgyria, and delayed myelination (3,18,21).…”

“…Therefore, the lack of D-BP will indirectly lead to DHA deficiency, ultimately affecting brain and retinal development. Bae et al (18) reported that although DHA supplementation in patients could increase DHA levels, it still could not improve clinical outcomes in patients with DHA deficiency. And patients showed progressive visual impairment and brain deterioration despite early DHA supplementation (within a month) (18).…”

“…Bae et al (18) reported that although DHA supplementation in patients could increase DHA levels, it still could not improve clinical outcomes in patients with DHA deficiency. And patients showed progressive visual impairment and brain deterioration despite early DHA supplementation (within a month) (18). In addition, the disease often causes abnormal BAEP and even leads to deafness.…”