Neurology. Genetics · 2026
HSD17B4-Related Disorder: Defining the Phenotype in Adult-Onset Patients.
СтатьяНазвание и аннотация: Перевод в очереди
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Falcone Grazia Maria Igea, Tessa Alessandra, Rizzo Cristiano, Semeraro Michela, Barghigiani Melissa, Santorelli Filippo M, Musumeci Olimpia
Аннотация
OBJECTIVES: 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.
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: 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.
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.
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: 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.
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.