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Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency.

ABSTRACT: OBJECTIVE:To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families. METHODS:The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the intersection of the regions. Exome sequencing was performed on 1 affected patient with variant filtering and prioritization undertaken using these intersected regions. RESULTS:Using a combination of sequencing technologies, we identified compound heterozygous mutations in HSD17B4 in all 5 affected patients. In all 3 families, peroxisomal D-bifunctional protein (DBP) deficiency was caused by compound heterozygosity for 1 nonsense/deletion mutation and 1 missense mutation. CONCLUSIONS:We describe 5 patients with juvenile DBP deficiency from 3 different families, bringing the total number of reported patients to 14, from 8 families. This report broadens and consolidates the phenotype associated with juvenile DBP deficiency.

SUBMITTER: Amor DJ

PROVIDER: S-EPMC5070413 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Heterozygous mutations in <i>HSD17B4</i> cause juvenile peroxisomal D-bifunctional protein deficiency.

Amor David J DJ Marsh Ashley P L AP Storey Elsdon E Tankard Rick R Gillies Greta G Delatycki Martin B MB Pope Kate K Bromhead Catherine C Leventer Richard J RJ Bahlo Melanie M Lockhart Paul J PJ

Neurology. Genetics 20161018 6

<h4>Objective</h4>To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families.<h4>Methods</h4>The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the intersection o ...[more]

PMID: 27790638

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Project description: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.

Dataset Information

Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency.

Publications

Heterozygous mutations in <i>HSD17B4</i> cause juvenile peroxisomal D-bifunctional protein deficiency.

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