Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency

Abstract

BackgroundD-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia.Case presentationAn adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10–13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation.ConclusionOur case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…Besides morphological abnormalities in mitochondria found in patients suffering from the adult form of X-ALD, adrenomyeloneuropathy (AMN) [130,131], additional evidence of mitochondrial abnormalities or dysfunction in peroxisomal disease have been reported in Zellweger syndrome [132,133]; in patients with mutations in the HSD17B4 gene, which encodes for the peroxisomal D-bifunctional enzyme [134]; and in patients suffering from the mistargeting of peroxisomal EHHADH (peroxisomal Lbifunctional enzyme). The latter enzyme disrupts mitochondrial metabolism (decreasing OXPHOS activities) by interacting with the mitochondrial trifunctional proteins involved in mitochondrial fatty acid β-oxidation, HADHA and HADHB (hydroxyacylCoA dehydrogenase-3-ketoacyl-CoA thiolase-enoyl-CoA hydratase A and B) [135].…”

Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3

“…Additional clinical features including spasticity, peripheral neuropathy, ataxia, and learning difficulty have also been described [2][3][4]. SNHL and limb spasticity may start in early life with gradual progression and variable severity leading to complete deafness and wheelchair dependency or inability to walk [5,6]. The infertility features, defined by impaired sex hormone profiles and premature menopause can only be detected after puberty [2,3].…”

“…PRLTS type-1 (PRLTS1, OMIM 233400) patients are characterized by hearing loss, ovarian dysgenesis leading to female infertility, and markedly reduced D-bifunctional protein (DBP) enzymatic activity causing male infertility, ataxia, and peripheral neuropathy [6,8,9]. Mutations in a gene on chromosome 5q23.1, encoding a multifunctional peroxisomal enzyme 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4, OMIM 601860) cause PRLTS1 [6,8,9].…”

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

“…RNF216 mutations are responsible for a uniform phenotype (dark red) with constant clinical signs [16]. Apart from severe D-bifunctional protein deficiency, the ataxia plus hypogonadism phenotype caused by HSD17B4 mutations is also rather homogeneous (dark blue) [108][109][110]. In contrast, PNPLA6 (orange) and STUB1 (light blue) have been shown to induce variable phenotypes, with no or few mandatory signs [13-15, 42, 43].…”