J Korean Med Sci.  2020 Oct;35(39):e357. 10.3346/jkms.2020.35.e357.

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

• Bae EY
• Yi Y
• Lim HH
• Lee JM
• Lee B
• Kim SY
• Kim YM

• KMID: 2507612
• DOI: http://doi.org/10.3346/jkms.2020.35.e357

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.

Keyword

Neonate; Hypotonia; Peroxisomal Disorder; HSD17B4

Figure

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  Fig. 1 Clinical photographs of patient. Patient showed (A) typical box-shaped face, (B) large fontanelle, (C) midfacial hypoplasia, and (D) club foot. The figures are published with agreement of parents.

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  Fig. 2 Partial genomic DNA sequences of HSD17B4 (NM_000414.3) of patients and parents. The result showed compound heterozygote mutation of (A) c.350A>T (p.Asp117Val) and (B) c.836T>C (p.Phe279Ser), and each mutation was inherited from subject parents. (C) Pedigree of patients with D-bifunctional protein deficiency and (D) the locus of two variants representative of 3-hydroxyacyl-CoA dehydrogenase deficiency.

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  Fig. 3 Brain MRI of the patient. (A, B) Axial T2-image showing bilateral frontal and sylvian polymicrogyria. (C, D) Follow-up images of brain MRI of the patient showing diffuse increased T2 signal intensity and the atrophy of the brain. The patient's parents provided written informed consent for publication of the patient and family information.MRI = magnetic resonance imaging.

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