Epilepsy in a patient with ataxia caused by vitamin E deficiency

Abstract

Ataxia due to vitamin E deficiency is important because disease progression can be stopped by supplementary therapy. A limited number of studies and case series suggest that the disease is mainly confined to the cerebellum and spinal cord tract and seems to be more common in North African countries. We report a patient from North Norway with progressive ataxia from the age of 5, bilateral dropfoot, Babinski’s sign, dysarthria and early epilepsy. Two mutations, 513insTT and p.Arg134x, were detected. When treatment was initiated 25 years after onset of symptoms, the patient was bound to the wheel chair. No further progression of pareses, ataxia or epileptic seizures has been observed in a 3-year follow-up period. This case indicates that cerebral involvement may be present in patients with a lack of vitamin E. If this observation is confirmed, a further exploration of clinical presentation, anatomic involvement and geographic distribution of the disease is warranted.

Background

Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive disorder phenotypically resembling Friedreich’s ataxia.^{1 2} The clinical manifestations of the disorder with low serum levels of vitamin E typically include progressive ataxia, dysarthria, areflexia, dorsal column and corticospinal tract signs with limb weakness and Babinski’s sign.^{1 3} Other less common clinical features are pes cavus, kyphoscoliosis and abnormal eye movements.^{1 3} Although AVED resembles Friedreich’s ataxia clinically, head titubation and retinopathy are more common findings, while cardiomyopathy occurs less frequently.¹ The disease is caused by different mutations of the α-tocopherol transport protein gene located on chromosome 8q13 and is treated with vitamin E substitution.^{3 4}

The first patients with AVED were described by Burck, Goebel and Kuhlendahl in 1981.⁵ In 1993, AVED was localised to chromosome 8, and 25 different mutations of the α-tocopherol transport protein gene are found till now.^{4 6} Most cases with the two most common mutations are found in North Africa (744delA mutation) and Europe (513insTT).^{7 8} Several cases have been detected in Italy.^{7 8} Two subjects with R134x mutations are reported from Canada, and the only previously detected case in Norway had combined A120T and R134x mutations.^{7 9} As the first case, we report a woman with AVED caused by 513insTT and R134x mutations of the α-tocopherol transport protein gene, who developed epilepsy at an early age. Early onset of epileptic discharges in this patient questions whether cerebral involvement may be present in subgroups of the patients.

Case presentation

The patient’s symptoms began with a lumping and unsteady gait at the age of 5. She progressively developed ataxic gait, limb ataxia, dysarthria and difficulties in writing. Two EEGs analysed when she was 11 showed widespread epileptogenic discharges. At age 14, she presented with ataxic gait, positive Romberg’s test, dysarthria, bilateral dropfoot, slight head titubation, decreased vibration and proprioception in her lower extremities, areflexia and decreased tempo, especially in her upper extremities. Babinski’s sign was silent on both sides. She had bilateral pes cavus and developed right thoracic scoliosis. Neurographic investigations revealed slight sensorimotor polyneuropathy in the lower extremities, and although brain CT and MRI were normal, she had widespread epileptic activity on EEG.

At age 15, she presented with her first generalised tonic clonic attack. The epilepsy was treated with carbamazepine, but she experienced side effects, and did not become free from generalised seizures until the treatment was changed to lamotrigine 10 years later. Friedreich’s ataxia was suggested, but due to normal eye movements and additional pes cavus, polyneuropathy and distal muscle weakness, Roussy–Levy’s syndrome (a hereditary autosomal dominant primary motor sensory neuropathy/Charcot-Marie-Tooth type 1 disorder) was diagnosed. No neurological diseases among parents, two siblings (one girl and one boy), grandparents and 25 cousins were found after a careful survey of the patient’s family history. Her neurological condition progressed further, and at age 17 she was walking on crutches. At age 26, she was bound to the wheel chair.

Genetic analyses of PMP-22 to screen for Charcot-Marie-Tooth disease, GAA repeats in the frataxin gene to screen for Friedreich’s ataxia, screening for spinocerebellar ataxias type 1, 2, 3 and 6 and Refsum’s disease (phytanic acid), spinal fluid analyses and cholesterol measurements revealed normal results. Vitamin E was found to be low (5 µmol/l), but supplementation was not initiated. No signs of malnutrition were observed.

She was 30 years old when the genetic diagnosis revealed 513insTT and R134x mutations of the α-tocopherol transport protein gene. Treatment with vitamin E was subsequently initiated with 350 mg daily. At this time she presented with prominent ataxia, areflexia, bilateral dropfoot, dysarthria, bilateral Babinski’s sign and epilepsy.

Differential diagnosis

The most important differential diagnoses are Friedreich’s ataxia, abetalipoproteinaemia, acquired vitamin E deficiency states, spinocerebellar ataxias, Charcot-Marie-Tooth disease and Refsum’s disease.

Treatment

Vitamin E supplementation in the diet leads to stagnation in disease progression and stabilisation in most patients.

Outcome and follow-up

On a follow-up consultation after 6 months, vitamin E supplementation in the diet was increased to 350 mg two times daily, and during 3 years follow-up no further epileptic seizures or progression of ataxia and pareses was observed. After 3 years, she was hospitalised for follow-up investigations. Generalised seizures had not occurred for many years, and EEG was normal. We therefore decided to taper off lamotrigine.

The EMG and neurographic evaluations were unchanged from the previous ones, showing slight sensorimotor polyneuropathy. There were no abnormalities on echocardiography, but an eye examination showed retinitis pigmentosa.

Discussion

Vitamin E is a fat-soluble antioxidant. In AVED, mutations in the α-tocopherol transfer protein gene lead to inability for incorporation of vitamin E into very low density lipoproteins. Consequently, the low serum level reduces delivery of vitamin E to the nervous system. A previous study found that α-tocopherol are synthesised in the brain, although in much lower levels than in the liver.¹⁰ The way shortage of vitamin E damages the nervous system is not well understood. One common hypothesis is that by these mechanisms, the reduced delivery of vitamin E to the central nervous system causes neurodegeneration, probably by increased oxidative stress.^{1 3}

Autopsy studies of the pathological changes in the nervous system caused by vitamin E deficiency states are sparce.^{11 12} A few studies with vitamin E deficiency in rats, rhesus monkeys and humans found lesions in the dorsal root ganglion, posterior medullary tracts, cerebellar cortex, spinocerebellar tracts, anterior horn cells and peripheral nerves with different extent of damage.^11–13 These findings match the clinical presentation of sensory and motor polyneuropathy, dysarthria and ataxia in our patient, as well as in other patients with AVED. Other conditions with low levels of vitamin E such as abetalipoproteinaemia (Bassen-Kornzweig syndrome), and conditions with acquired low vitamin E levels such as disorders with acquired fat malabsorption give similar neurological pictures as AVED.^{13 14} The neurological similarity between these disorders is probably a result of chronic vitamin E deficiency. Low serum vitamin E level in abetalipoproteinaemia is due to inborn defects in the fat metabolism, leading to fat malabsorption through the intestines. Symptoms and signs of fat malabsorption-like stool abnormalities, protruded abdomen and low cholesterol values also distinguish acquired vitamin E deficiency from AVED.¹ Retinitis pigmentosa is more common in both abetalipoproteinaemia and AVED than in Friedreich’s ataxia.¹ Among 20 patients with low levels of vitamin E after gastrectomy, 6 had peripheral neuropathy, 4 had dizziness and 3 presented with limb or trunk ataxia.¹⁴ These findings support a cause relationship between vitamin E deficiency and clinical symptoms regardless of the underlying mechanism. However, different genotypes may give rise to the same phenotype, while the same genetic mutation can show different clinical presentations. Cortical lesions correlating with epileptic discharges are not reported previously, but coexistence of AVED with other central nervous system disorders are reported.¹⁵

Vitamin E deficiency have previously been associated with seizures.^{13 16} A 22-year-old man with a 6-year history of epilepsy who developed spinocerebellar ataxia and sensorimotor demyelinating neuropathy had low vitamin E values.¹³ The neuropathy improved after vitamin E substitution, but the disease was not genetically verified.¹³ In our patient, the distal weakness remained unchanged after vitamin E treatment. Moderate neurophysiological findings and Babinski’s sign suggest that both central and peripheral nerve affection contribute to the distal muscle weakness. A study comparing 100 children with generalised seizures with 100 healthy controls revealed statistically significant lower serum values of vitamin E in the epilepsy group.¹⁶ On this background, we hypothesise a possible relationship between vitamin E and epilepsy in our patient.

Adequate vitamin E supplementation in the diet started at an early stage in AVED and other syndromes with vitamin E deficiency often leads to stagnation in disease progression and sometimes to recovery.³ To prevent diagnostic delay and misdiagnoses, it is important to measure vitamin E in patients with undetermined ataxias or other neurological symptoms associated with these syndromes. Among 16 patients with AVED, the diagnoses from the onset of the first symptom varied from 2 to 32 years, suggesting that the disease is often misdiagnosed, and also underdiagnosed.⁸ It took 25 years from the onset of the first symptom to the final diagnosis and onset of vitamin E supplementation in this patient. This confirms the importance of analysing vitamin E in patients with ataxia, especially in younger patients.

Learning points.

• ▶Progression of neurological symptoms caused by vitamin E deficiency can be stopped by supplementation of vitamin E in the diet.
• ▶Vitamin E should be measured in patients with ataxia of unknown origin.
• ▶Our case shows the importance of early treatment and the result of diagnostic delay and misdiagnosis of patients with ataxias caused by vitamin E deficiency.
• ▶It is important to be aware of possible cerebral involvement in vitamin E deficiency states.
• ▶Low levels of vitamin E may be associated with epilepsy.