<i>HSD17B4</i> -Related Disorder

Objectives: 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. Methods: 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. Results: 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. Discussion: 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.