Ataxia with vitamin E deficiency (AVED) is a type of autosomal recessive cerebellar ataxia. Clinical manifestations include progressive cerebellar ataxia and movement disorders. TTPA gene mutations cause the disease.

We report the case of a 32-year-old woman who presented with progressive cerebellar ataxia, dysarthria, dystonic tremors and a remarkably decreased serum vitamin E concentration. Brain magnetic resonance images showed that her brainstem and cerebellum were within normal limits. Acquired causes of ataxia were excluded. Whole exome sequencing subsequently identified a novel homozygous variant (c.473T>C, p.F158S) of the TPPA gene. Bioinformatic analysis predicted that F185S is harmful to protein function. After supplementing the patient with vitamin E 400 mg three times per day for 2 years, her symptoms remained stable.

We identified an AVED patient caused by novel mutation in TTPA gene. Our findings widen the known TTPA gene mutation spectrum.

Ataxia with vitamin E deficiency (AVED) is a type of autosomal recessive cerebellar ataxia (ARCA). The most prominent symptoms include cerebellar ataxia, areflexia, peripheral neuropathy and movement disorder[1,2]. AVED patients may also exhibit retinitis pigmentosa, cardiomyopathy and scoliosis[3,4]. AVED is caused by mutations in the TTPA gene, which encodes the α-tocopherol transfer protein, which in turn binds α-tocopherol and transports vitamin E from hepatocytes to circulating lipoproteins[5]. Vitamin E supplementation may prevent the worsening of the condition of patients with AVED.

To date, the known incidence rate of AVED in China has been low[6]. Here, we report the clinical, biochemical and genetic investigation of a Chinese patient with AVED due to homozygous mutations in the TTPA gene. This patient exhibited progressive cerebellar ataxia, dysarthria and head titubation with markedly low levels of serum vitamin E. After treatment with vitamin E 400 mg three times per day for 2 years, the patient’s neurological symptoms were stabilized.

The final diagnosis of the presented case was AVED due to TTPA homozygous missense mutation (c.473C>T, p.Phe185Ser) (GRCh37/hg19).

After we detected decreased plasma levels of total vitamin E, supplementation with vitamin E 400 mg three times per day was immediately administered. The patient also kept physical exercises for rehabilitation therapy.

After 2 years of vitamin E supplementation therapy, the symptoms of this patient showed neither improvement nor deterioration. On her last follow-up visit, her SARA score was 11 [gait 2, stance 2, sitting 0, speech 1, finger chase 1.5 (left 2, right 1), nose-finger test 1.5 (left 2, right 1), fast alternating hand movements 1.0 (left 1, right 1) and heel-shin slide 2.0 (left 2, right 2)].

By WES we identified homozygous mutations of TTPA gene (c.473C>T, p.Phe185Ser) in a Chinese family with ARCA and we have excluded common causes of ataxia. AVED was first reported by Burck et al[8]. It usually manifests as a mild disease course and is rarely reported in China. The presentation of AVED is highly heterogeneous with onset usually in childhood[9] but some cases have manifested in infancy and in adulthood[1]. Clinical phenotypes include progressive gait ataxia, movement disorders, areflexia, dysarthria, epilepsy, pyramidal signs, impaired proprioception and vibration sense and sensory neuropathy[9-11]. Apart from cerebellar ataxia, our patient exhibited obvious head tremor. Head titubation, seen in 37% to 73% of patients, and cervical dystonia are distinguishing motor features of AVED[1,3,12]. Non-neurological symptoms, such as retinitis pigmentosa, macular degeneration and cardiomyopathy[13,14] were not found in our patient. Laboratory examination often reveals markedly low serum vitamin E concentration in AVED[1]. The patient’s MRI showed no obvious cerebellar atrophy in our patient and absence of cerebellar atrophy is common in AVED patients[15].

To date, various mutations of the TTPA gene have been reported[16]. The genotype-phenotype correlations were not found to be strong in AVED and c.744delA was the most frequent mutation, often originating in the Mediterranean region[9]. Moreover, 744delA could increase the risk of early age onset, severe disease course and cardiomyopathy[17]. c.473C>T(p.F185S), which was detected in our patient, has not been reported previously. Her symptoms began in adolescence and she is still able to walk 18 years after the onset of disease. F185S is located in CRAL_TRIO domain and its predicted function is to combine with α-tocopherol[18]. Bioinformatic analysis predicted this novel mutation would lead to the damage of protein function.

AVED is a treatable form of hereditary ataxia and early and sustained vitamin E supplementation could result in a remarkable clinical response or stabilization in AVED patients[1,19,20]. In patients with ataxia, a prompt investigation for vitamin E deficiency is recommended[19,20]. AVED patients require lifelong vitamin E supplementation at 300-2400 mg/d to maintain adequate plasma levels of vitamin E[1,8,14]. Our patient received 1200 mg/d of vitamin E for 2 years and her symptoms showed no deterioration.

We identified a Chinese AVED female patient caused by a novel mutation in the TTPA gene. This finding widens the known TTPA gene mutation spectrum.

We thank the patient who participated in our study and her family members.