Analysis of clinical pedigree characteristics in Chinese patients with ataxia with vitamin E deficiency.

The clinical and genetic features of ataxia with isolated vitamin E deficiency (AVED) patients in Chinese are remain not well understood. We enrolled 120 unrelated probands with clinically suspected autosomal recessive cerebellar ataxia (ARCA) at the Department of Neurology, China-Japan Friendship Hospital between 2014 and 2024. all probands underwent Whole-exome sequencing (WES), with candidate variants validated by Sanger sequencing and family cosegregation analysis. In silico pathogenicity analysis, including protein structure homology modeling and multispecies conservation analysis, was performed for novel variants. Plasma vitamin E levels were measured using high-performance liquid chromatography with diode array detection(HPLC-DAD). We identified 4 probands with biallelic TTPA variants, accounting for 3.33% of the ARCA cohort. Three probands were from consanguineous families, and 1 was from non- consanguineous family. The median age at onset was 15years (range 14-23years), with gait instability/ataxia as the universal initial symptom. Core clinical features included cerebellar ataxia (4/4), dysarthria (4/4), areflexia (2/4), scoliosis (4/4), foot deformity (3/4), and head titubation (3/4). Brain MRI revealed cerebellar atrophy in 3 patients, and all had markedly reduced serum vitamin E levels. We identified 2 novel missense variants (c.265C>A(p.P89T) and c.790A>G(p.M264V)). All patients received high-dose vitamin E supplementation, with 3/4 improved ataxia symptoms at 2-years follow-up. Our findings expand the clinical and genetic spectrum of AVED in China and support early evaluation of plasma vitamin E status and TTPA variants in patients with unexplained sporadic or recessive ataxia, as well as proactive screening of siblings and other at-risk relatives, even before symptom onset.