HSD17B4-Related Disorder: Defining the Phenotype in Adult-Onset Patients

Biallelic variants in HSD17B4 cause D-bifunctional protein (DBP) deficiency, a disorder of peroxisomal fatty acid β-oxidation initially associated with a neonatal phenotype and early lethality. Recently, thanks to advances in genetic analyses, the clinical spectrum has expanded to include a slowly progressive adult-onset ataxic syndrome with additional features. Our aim was to describe 5 additional affected adults and to highlight the characteristic phenotype.

Five affected individuals (4 from one family; 1 from a second family) were examined in our tertiary neurogenetics referral center. The core clinical manifestations consisted of a slowly progressive cerebellar ataxia, with subclinical evidence of sensorineural hearing loss and hypergonadotropic hypogonadism leading to premature ovarian failure in affected women. Genetic analysis was performed using a custom-targeted sequencing panel for genes associated with hereditary ataxias. Causative variants were confirmed by Sanger sequencing and segregated within the families. Peroxisomal investigations were performed on blood specimens.

In family A, the affected siblings born from consanguineous parents carried a novel homozygous HSD17B4 variant, c.557A>T (p.Asn186Ile), whereas in the proband from the other family, 2 novel compound heterozygous variants, c.652G>T (p.Val218Leu) and c.2116C>T (p.Gln706), were identified. The peroxisomal profiles were normal.

Our case series expand the phenotypic-genotypic spectrum of DBP deficiency and provide long-term follow-up data. While no disease-modifying treatments currently exist, diagnosis has implications for genetic counseling, particularly for reproductive planning in affected women.