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Ataxia With Isolated Vitamin E Deficiency: Case Report and Review of the Literature

Aparicio, Juan Manuel*; Bélanger-Quintana, Amaya*; Suárez, Lucrecia*; Mayo, David; Benítez, Javier; Díaz, Manuela; Escobar, Héctor*

Journal of Pediatric Gastroenterology and Nutrition: August 2001 - Volume 33 - Issue 2 - p 206-210
Case Reports

Departments of *Pediatrics and †Biochemistry, Hospital Ramón y Cajal, Universidad de Alcalá de Henares, and ‡Department of Genetics, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain

Received March 30, 2000; accepted March 23, 2001.

Address correspondence and reprint requests to Dr. Amaya Bélanger-Quintana, Servicio de Pediatría, Hospital Ramón y Cajal, Crta de Colmenar Km 9,1 s/n, Madrid 28034, Spain (e-mail:

The differential diagnosis of progressive ataxia in childhood includes Friedreich ataxia, ataxia telangiectasia, toxic or metabolic diseases, Refsum disease, and several neuropathies and neurologic syndromes secondary to vitamin E deficiency.

Vitamin E is the term for a group of tocopherols and tocotrienols, of which α-tocopherol has the highest biologic activity. First thought only to be of importance for reproduction (1), in the past decades, α-tocopherol has proved to be one of the most important lipid-soluble antioxidants (2–4). It provides protective effects against free radical damage, which fosters chronic diseases, and it has been suggested that it may prevent ischemic heart disease, atherosclerosis, diabetes, cataracts, and Parkinson and Alzheimer diseases. It may also play a role in cancer, the immune system, and natriuresis. In all these cases, supplementation is thought to have beneficial effects (2–5).

The neurologic complications of severe vitamin E deficiency are rare but devastating: hyporeflexia, ataxia, strabismus, muscle weakness, and visual field contrition to complete blindness, dementia, and cardiac arrhythmias. These symptoms are progressive and are easily mistaken with those of other neurologic syndromes (6–10). Figure 1 summarizes the neurologic symptoms related to vitamin E deficiency (6). These symptoms are the consequence of a dying-back neuropathy in sensory neurons and the cerebellum resulting from the loss of the protective effect of vitamin E against several neurotoxic agents (11,12). Muscle fibers are also affected (13,14). Adequate vitamin replacement stops progression and can even ameliorate some of the symptoms, but the more advanced the deficit, the more limited the response to therapy.

FIG. 1.

FIG. 1.

Vitamin E is widely available. Edible vegetable oils are the richest dietary sources. Nutritional requirements are not high, so a deficiency severe enough to produce neurologic symptoms rarely is the result of diet alone. Most cases of vitamin E deficiency are secondary to fat malabsorption. In these cases, there is also a deficit of other liposoluble vitamins and substances. Only a small number of patients have isolated low levels of vitamin E. Patients with ataxia with isolated vitamin E deficiency have normal gastrointestinal absorption of lipids but impaired ability to incorporate α-tocopherol into very low-density lipoproteins secreted by the liver, and therefore these patients have a higher elimination rate of the vitamin.

We describe the first case of progressive spinocerebellar syndrome resulting from isolated vitamin E deficiency studied in Spain. It is a representative case of the problems encountered in the diagnosis and treatment of these patients.

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Our patient is a 7-year-old boy, the first of two siblings of a healthy and nonconsanguineous couple of Spanish descent. Pregnancy and delivery were normal, and until he was 3 years old his psychomotor development was adequate. At this age, gait difficulties began, demonstrated by unsteadiness, constant head titubation, tremor of the hands, and dysarthria. These symptoms were progressive. On examination, he had bilateral pes cavus and moderate scoliosis. His mental abilities were normal, but he had intentional tremor with dysmetria, dysarthria, ataxia, patellar and aquiline areflexia, bilateral positive Babinski, positive Romberg sign, loss of profound sensitivity, and slight generalized hypotonia. His height and weight were normal and he had no gastrointestinal symptoms. His maternal great-grandfather, granduncle, and aunt had pes cavus and gait instability.

The results of the patient's routine blood chemistries, electrocardiography, echocardiography, ophthalmologic exploration, brain magnetic resonance, visual evoked potentials, and troncular evoked auditory potentials had no pathologic alterations. Somatosensorial evoked potentials showed alteration of the sensory pathways in the spinal cord.

Our first diagnostic choice would have been Friedreich ataxia, but we also asked for liposoluble vitamin levels. Vitamin A level was low (18 μg/dL; normal values, 25–80 μg/dL) and vitamin E level was undetectable. A malabsorptive cause for this finding needed to be discarded. Triglyceride (117 mg/dL) and cholesterol (155 mg/dL) counts were normal. Creatine kinase, apolipoprotein A1 (172 mg/dL) and B (69 mg/dL), high-density lipoproteins (54.2 mg/dL), and low-density lipoproteins (103.2 mg/dL) were also within normal values. These tests have been repeated on several occasions with normal results. A 72-hour fecal fat determination and a jejunal biopsy were performed, and the results of both were normal.

On follow-up, we noted that vitamin A levels varied between 13 and 22 μg/dL, with no relation to vitamin E levels. We have no clear explanation as to why our patient had low vitamin A levels. All malabsorption tests have been normal. Treatment with 50,000 IU/72 h orally has raised its value to normal levels. The patient has no symptomatology related to the deficiency of this vitamin.

Genetic studies were negative for Friedreich ataxia but revealed a 744delA mutation of the α-tocopherol transfer protein in one of the patient's genes. It was amplified by PCR with the following primers: D, GAC ATT CTT CCT CTG GAA TAT G; R, GAT ATT CTT CAG ACT TCA TTA TAA A. His father shared the same mutation. The mother's gene did not have the same mutation, and investigations are under way to find the alteration responsible for the disease. Different mutations reported to date have proven negative. Interestingly, the mother also had low vitamin E levels (482 μg/dL; normal values, 570–1670 μg/dL), but no neurologic symptoms.

Figure 2 shows the evolution of vitamin E levels and the changes made in the dose and the method of administration. The brand we used for both oral and intramuscular administration contained exclusively α-tocopherol acetate. Parenteral administration has been necessary to maintain normal values. In high doses, exclusive oral therapy did not achieve this objective. Most importantly, neurologic symptoms, which improve when levels are normal, to our distress reappear when values of vitamin E drop. It does seem that over time the requirements of parenteral vitamin are lessening, and in the future, we hope to use only oral supplements. Treatment now consists on 3,000 mg/d orally of vitamin E. Neurologic symptoms are slowly disappearing. He has less gait instability, his walk is almost normal (he joined a soccer team and danced at the end-of-school party), head titubation is less frequent, and his talk is fluent. Manual abilities have improved but are not yet normal. Sensory evoked potentials, repeated 7 months after treatment started, confirmed these clinical findings: in the lower limbs, potential P37, not found in the previous study, was starting to reappear.

FIG. 2.

FIG. 2.

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Vitamin E deficiency most often occurs secondary to enteropathies. Rarely, vitamin E levels are lower than normal, but gastrointestinal, liver, and lipoprotein abnormalities are absent. First named “isolated vitamin E deficiency” (FIVE), it was a rare sporadic or familial disease of which several cases were described in the 1981 to 1993 period. Isolated vitamin E deficiency had great phenotypic variability, ranging from severe Friedreichlike ataxia to mild neurologic impairment and very late onset (14–22).

In 1993, the description of eight affected individuals from two large Tunisian families led to the identification of more patients of a condition renamed “ataxia with vitamin E deficiency”(23). It is now known to be an autosomal recessive disease. The defective gene is in chromosome 8q13 and codes for the α-tocopherol transfer protein present in the liver (24–26). The lack or malfunction of this protein results in an impaired ability to select preferentially α-tocopherol and to incorporate it into very low-density lipoproteins. Efficient plasma vitamin E recycling is impossible, and patients have an excessive elimination of circulating vitamin (27–30). The other various tocopherols absorbed do not have enough biologic activity to avoid symptoms.

The 744delA mutation is the most frequent, with a founder effect originating in North Africa (31). Therefore, it is the one shared by most patients from Mediterranean countries. To our knowledge, ours is the first case found in Spain. Sixteen other mutations of the α-tocopherol transfer protein gene have been described (31,32). In many cases, the mutation has not been identified (33–37). It seems there is a correlation between the severity of the disease and the type of mutation. It appears to depend on the greater or lesser loss of the capacity to incorporate the α-tocopherol stereoisomer into very low-density lipoproteins (31). A complete loss of this capacity (missense and severe truncating mutations, including 744delA, 513insTT, 485delT, G552A) is associated with severe, early onset of the disease (38–42). Patients heterozygous for a 513insTT or an Arg192His mutation exhibit mild ataxia (40). Mutation H101Q, found in Japanese patients, is associated with retinitis but also with a mild phenotype and very late onset (43–45). Other mutations may also entail visual impairment (32–34).

The administration of vitamin E supplements has resulted in cessation of the progression of the neurologic symptoms and signs in most patients and in amelioration of established neurologic abnormalities in some of them. In other cases, there has been no improvement (41). The extent of recovery clearly is related to when the therapy is begun: the more advanced the deficit, the more limited the response to therapy. The type of mutation may also correlate with the response to supplementation treatment (41). Therefore, accurate molecular diagnosis in ataxia with vitamin E deficiency is crucial for predicting the prognosis and the response to treatment.

Unlike when the cause is malabsorptive, ataxia with vitamin E deficiency responds to oral supplements. Suggested doses range from 800 to 3,500 IU per day (1,5). Vitamin E supplements are marketed as mixed tocopherols (in which case the amount of α-tocopherol needs to be calculated), α-tocopherol, or α-tocopherol esters (acetate, nicotinate, or succinate) (4). It is important to remember that even in healthy individuals, up to 45% of the vitamin ingested is not absorbed. Several studies suggest that loading tests are important to adjustment of dosage and timing of vitamin E administration to the dynamic pattern of each patient. Vitamin E supplementation, even in large doses, has few adverse effects. Patients with low levels of vitamin K have a higher risk of bleeding (79). It has also been suggested that vitamin E interferes with the absorption of vitamin A (46,47).

Physical rehabilitation by postural biofeedback has also been described to be of help in teaching patients how to control their slowly regained strength and therefore to optimize the response to vitamin supplementation (48).

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Vitamin E deficiency is not a well-known disease, especially in its isolated form. Some patients had been diagnosed previously with Friedreich ataxia, and most suffered for many years without a diagnosis. The severity of the neurologic disorder, its marked clinical heterogeneity, and the ease with which symptoms can be prevented with supplemental vitamin make measurement of plasma vitamin E necessary in all patients with ataxia or neurologic symptoms of unknown origin. It is possible that the full spectrum of neurologic symptoms resulting from vitamin E deficiency is not yet known.

In patients with ataxia with vitamin E deficiency, an accurate molecular diagnosis is necessary to evaluate the prognosis. The heterogeneity of the disease not only affects its clinical presentation but also its response to treatment. These differences seem to correlate with the different mutations. New mutations are still being documented. Our patient has a 744delA mutation in one of his genes, but the mutation of the maternal gene is yet to be determined. Our patient may carry an unknown mutation. As mentioned previously, the mother had no neurologic symptoms but her vitamin E levels were suboptimal. She may have a mild mutation or be heterozygous for a truncating mutation in which at least one of her genes produces enough α-tocopherol transfer protein to retain some of the absorbed vitamin. It is possible that once determined, the kind of mutation may explain why, in our patient, oral replacement therapy has not been totally effective in maintaining normal vitamin E values.

With this case report, we try to emphasize the importance of monitoring vitamin E levels frequently. The dose and timing of vitamin E supplementation should be personalized for each patient. If oral therapy seems to fail, the dose of vitamin may need to be raised. Sometimes an error in estimating the dose received by the patient is the result of the percentage of α-tocopherol contained in the brand of marketed vitamin used. Parenteral administration may also be useful in the early stages of treatment.

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1. Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science. 1922; 56:650–1.
2. Brigelius-Flohe R, Traber MG. Vitamin E: function and metabolism. FASEB J. 1999; 13:1145–55.
3. Traber MG, Sies H. Vitamin E in humans: demand and delivery. Annu Rev Nutr. 1996; 16:321–47.
4. Meydani M. Vitamin E. Lancet. 1995; 345:170–5.
5. Vatassery GT, Bauer T, Dysken M. High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. Am J Clin Nutr. 1999; 70:793–801.
6. Mahlon MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Phys. 1997; 55:197–202.
7. Kohlschütter A. Vitamin E and neurological problems in childhood: a curable neurodegenerative process. Develop Med Child Neurol. 1993; 35:642–6.
8. Sokol RJ. Vitamin E and neurological deficits. Adv Pediatr. 1990; 37:119–48.
9. Carpenter D. Vitamin E deficiency. Semin Neurol. 1985; 5:283–7.
10. Muller DP, Lloyd JK, Wolff OH. Vitamin E and neurological function. Lancet. 1983; 1:225–8.
11. Schmidt RE, Coleman BD, Nelson JS. Differential effect of chronic vitamin E deficiency on the development of neuroaxonal dystrophy in rat gracile/cuneate nuclei and prevertebral sympathetic ganglia. Neurosci Lett. 1991; 123:102–6.
12. Muller DPR, Goss-Sampson MA. Neurochemical, neurophysiological, and neuropathological studies in vitamin E deficiency. Crit Rev Neurobiol. 1990; 5:239–63.
13. Neville JK, Ringel SP, Guggenheim MA, et al. Ultrastructural and histochemical abnormalities of skeletal muscle in patients with chronic vitamin E deficiency. Neurology. 1983; 33:483–8.
14. Burk U, Goebel HH, Kuhlendahl HD, et al. Neuropathy and vitamin E deficiency in man. Neuropediatrics. 1981; 12:267–78.
15. Laplante P, Vanasse M, Michaud J, et al. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Can J Neurol Sci. 1984; 11:561–4.
16. Harding AE, Mathews S, Jones S, et al. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med. 1985; 313:32–5.
17. Krendel DA, Gilchrist JM, Johnson AO, et al. Isolated deficiency of vitamin E with progressive neurologic deterioration. Neurology. 1987; 37:538–40.
18. Stumpf DA, Sokol RJ, Bettis DB, et al. Friedreich's disease. A variant form with vitamin E deficiency and normal fat absorption. Neurology. 1987; 37:68–74.
19. Yokota T, Wada Y, Furukawa T, et al. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann Neurol. 1987; 22:84–7.
20. Kohlschütter A, Hubner C, Jansen W, et al. A treatable familial neuropathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inherit Metab Dis. 1988; 11:149–52.
21. Sokol RJ, Kayden HJ, Bettis DB, et al. Isolated vitamin E deficiency in the absence of fat malabsorption-familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med. 1988; 11:548–59.
22. Rayner RJ, Doran R, Roussounis SH. Isolated vitamin E deficiency and progressive ataxia. Arch Dis Child. 1993; 69:602–3.
23. Ben Hamida M, Belal S, Sirugo G, et al. Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology. 1993; 43:2179–83.
24. Ben Hamida C, Doerflinger N, Belal S, et al. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet. 1993; 5:195–200.
25. Doerflinger N, Linder C, Ouahchi K, et al. Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families. Am J Med Genet. 1995; 56:1116–24.
26. Arita M, Sato Y, Miyata A, et al. Human α-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem J. 1995; 306:437–43.
27. Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-α-tocopherol. Proc Natl Acad Sci U S A. 1994; 91:10005–8.
28. Kayden HJ, Traber MG. Absorption, lipoprotein transport and regulation of plasma concentrations of vitamin E in humans. J Lipid Res. 1993; 34:343–58.
29. Traber MG, Sokol RJ, Kohlschütter A, et al. Impaired discrimination between stereoisomers of α-tocopherol in patients with familial isolated vitamin E deficiency. J Lipid Res. 1993; 34:201–10.
30. Traber MG, Sokol RJ, Burton GW, et al. Impaired ability of patients with familial isolated vitamin E deficiency to incorporate α-tocopherol into lipoproteins secreted by the liver. J Clin Invest. 1990; 85:397–407.
31. Cavalier L, Ouahchi K, Kayden HJ, et al. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998; 62:301–10.
32. Hoshino M, Masuda N, Ito Y, et al. Ataxia with isolated vitamin E deficiency: a Japanese family carrying a novel mutation in the α-tocopherol transfer protein gene. Ann Neurol. 1999; 45:809–12.
33. Amiel J, Maziere JC, Beucler I, et al. Familial isolated vitamin E deficiency. Extensive study of a large family with a 5-year therapeutic follow-up. J Inher Metab Dis. 1995; 18:333–40.
34. Shorer Z, Parvati R, Bril G, et al. Ataxia with isolated vitamin E deficiency in four siblings. Pediatr Neurol. 1996; 15:340–3.
35. Jackson CE, Amato AA, Barohn RJ. Isolated vitamin E deficiency. Muscle Nerve. 1996; 19:1161–5.
36. Hammans SR, Kennedy CR. Ataxia with isolated vitamin E deficiency presenting as mutation negative Friedreich's ataxia. J Neurol Neurosurg Psychiatry. 1998; 64:368–70.
37. Martinello F, Fardin P, Ottina M, et al. Supplemental therapy in isolated vitamin E deficiency improves peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci. 1998; 156:177–9.
38. Ouahchi K, Arita M, Kayden H, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the α-tocopherol transfer protein. Nat Genet. 1995; 9:141–5.
39. Gotoda T, Arita M, Arai H, et al. Adult-onset espinocerebellar disfunction caused by a mutation in a gene for α-tocopherol transfer protein. N Engl J Med. 1995; 333:1313–8.
40. Hentati A, Deng HX, Hung WY, et al. Human α-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol. 1996; 39:295–300.
41. Tamaru Y, Hirano M, Kusaka H, et al. α-Tocopherol transfer protein gene: exon skipping of all transcripts causes ataxia. Neurology. 1997; 49:584–8.
42. Shuelke M, Mayatepek E, Inter M, et al. Treatment of ataxia in isolated vitamin E deficiency caused by α-tocopherol transfer protein deficiency. J Pediatr. 1999; 134:240–4.
43. Yokota T, Shiojiri T, Gotoda T, et al. Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol transfer protein. N Engl J Med. 1996; 335:1770–1.
44. Yokota T, Shiojiri T, Gotoda T, et al. Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alpha-tocopherol transfer protein gene. Ann Neurol. 1997; 41:826–32.
45. Shimohata T, Date H, Ishiguro H, et al. Ataxia with isolated vitamin E deficiency and retinitis pigmentosa. Ann Neurol. 1998; 43:273.
46. Diplock AT. Safety of antioxidant vitamins and β carotene. Am J Clin Nutr. 1995; 62(suppl):1510S–6S.
47. Meydani SN, Meydani M, Blumberg JB, et al. Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. Am J Clin Nutr. 1998; 68:311–8.
48. Battisti C, Toffola ED, Verri AP, et al. Clinical and stabilometric monitoring in a case of cerebellar atrophy with vitamin E deficiency. Brain Develop. 1998; 20:253–7.
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