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.
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.
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.
REVIEW OF THE LITERATURE
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).
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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