Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency

Abstract

BackgroundD-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa.Methods and resultsBiochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17β-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable.ConclusionsWe propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.

The important role of biochemical and functional studies in the diagnostics of peroxisomal disorders

“…In all DBP-deficient patients, DBP activity is markedly reduced. Remarkably, this is also the case in mild patients with normal peroxisomal parameters in blood and without VLCFA accumulation in fibroblasts (Ferdinandusse et al 2006a; McMillan et al 2012; Lines et al 2014). DBP activity measurement can also be performed in lymphocytes, allowing rapid screening for DBP deficiency in blood.…”

“…Several patients with DBP or ACOX1 deficiency or a ZSD have been reported with normal peroxisomal parameters in blood in whom diagnosis was only established or confirmed by studies in fibroblasts (Soorani-Lunsing et al 2005; Rosewich et al 2006; McMillan et al 2012; Lines et al 2014; Ratbi et al 2015). Especially in milder DBP patients the only identifiable defect in blood and fibroblasts can be DBP activity and expression (see Table 3, patient 5), which is a well-recognized diagnostic pitfall for this disorder.…”

A Novel Missense Mutation in the CLPP Gene Causing Perrault Syndrome Type 3 in a Turkish Family

“…PRLTS type 1 is caused by mutations in HSD17B4 gene at chromosome 5q23.1 (2) and PRLTS1 patients may present with hearing loss, ovarian dysgenesis leading to female infertility, male infertility, ataxia, and peripheral neuropathy (2,3,4). PRLTS type 2 is caused by mutations in HARS2 at chromosome 5q31.3 and is characterized by deafness in both males and females and gonadal dysgenesis in female patients only (5).…”

D-Bifunctional Protein Deficiency: A Cause of Neonatal Onset Seizures and Hypotonia

“…D-bifunctional protein deficiencies are classified into three types: type I -deficiency of 2-enoyl-CoA hydratase unit and 3-hydroxyacyl-CoA dehydrogenase unit, type II -isolated hydratase deficiency and type III -isolated dehydrogenase deficiency [2][3][4] . Recently, McMillan et al (2012) proposed a type IV phenotype, based on the presence of a missense mutation in each of enzyme domains resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP 5 .…”