Ataxia with vitamin E deficiency syndrome and a novel TTPA variant: a paired case report

Objectives: Ataxia with vitamin E deficiency (AVED) is a chronic progressive syndrome with low vitamin E levels, caused by biallelic pathogenic variants in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13.1. According to family segregation studies, we describe a novel putative variant in compound heterozygosity with a known pathogenic variant. Methods: Clinical and instrumental evaluations were performed at our Neuromuscular Unit. Results: Two siblings had been experiencing clumsiness, which later evolved into progressive gait unsteadiness, with falls and dysarthria. Brain MRI, EMG, and nerve conduction studies were inconclusive, but focused clinical exome sequencing revealed biallelic variants in the TTPA gene in both, the pathogenetic maternally inherited variant c.513_514insTT (p.Thr172Leufs*5) on exon 3 and the previously undescribed paternally inherited variant c.158T > C (p.Leu53Pro) on exon 1. Their plasma vitamin E levels were low (<1.7 mg/L). Their relatives carried 1 single variant each, with normal vitamin E levels. After 6 months of oral vitamin supplementation with a laboratory response, disease progression has stopped, although their neurologic examination has not clearly ameliorated. Discussion: Exome sequencing identified a new potentially pathogenic variant in AVED, an ultra-rare but treatable cause of inherited ataxia. We recommend prompt vitamin E supplementation in patients with AVED.