Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia

Abstract

ObjectiveTo determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.MethodsHomozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.ResultsWe identified a homozygous mutation as causative of middle age–onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.ConclusionsThis is the report of middle age–onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

Two Novel HSD17B4 Heterozygous Mutations in Association With D-Bifunctional Protein Deficiency: A Case Report and Literature Review

“…It has been reported in the literature that cranial MRI in adulthood revealed cerebellar atrophy and ataxia (23), while neonatal cranial MRI revealed no significant brain atrophy (24). Our patient's cranial MRI showed shallow sulci, local widening and deepening of the lateral fissure cistern of the right cerebral hemisphere, extensive hyperintense white matter changes in the cerebral hemisphere on T2WI, and dysplasia of the corpus callosum, which were similar to the clinical report that MRI in children with D-BDP showed different severities of lateral fissure, peripheral multiple microgyria, and delayed myelination (3,18,21).…”