Correspondence

Retinitis Pigmentosa and Ataxia Caused by a Mutation in the Gene for the α-Tocopherol–Transfer Protein

N Engl J Med 1996; 335:1770-1771December 5, 1996

Article

To the Editor:

The α-tocopherol–transfer protein (α-TTP) is presumed to function in the intracellular transport of α-tocopherol, the most biologically active form of vitamin E. We described a patient with adult-onset Friedreich's ataxia in whom a mutation of the α-TTP gene causing the substitution of glutamine for histidine in the protein resulted in vitamin E deficiency (Nov. 16, 1995, issue).1 Experiments in animals have shown that diets deficient in vitamin E cause retinitis pigmentosa.2 We therefore studied the α-TTP genes of two unrelated patients, a 60-year-old woman and a 47-year-old man, who had autosomal recessive retinitis pigmentosa and low serum vitamin E concentrations (0.9 and 1.5 μg per milliliter, respectively; normal, >5.7) and found the same mutation in both patients. The initial visual symptoms were night blindness in Patient 1, which began at the age of 43 years, and loss of peripheral vision in Patient 2, which began at the age of 45. Each patient also had mild ataxia, decreased vibration sense, and hyporeflexia. In each, ophthalmoscopy showed the typical changes of retinitis pigmentosa (Figure 1Figure 1Photograph of the Retina of Patient 1 Showing Black Pigmentation, Attenuation of the Retinal Arteries, and Pallor of the Optic Disk., below), Goldmann perimetry revealed a ring scotoma, and electroretinography revealed no light-evoked electrical responses. Visual acuity was markedly diminished in Patient 1 but was normal in Patient 2. A third, previously described patient (Patient 3) had had night blindness for 10 years when ataxia was noticed.1 He also had a ring scotoma and an attenuated response on electroretinography. Oral administration of α-tocopheryl acetate (400 to 900 mg per day) raised serum vitamin E concentrations to normal in all three patients, and none of them have had worsening of their visual and neurologic symptoms since treatment with vitamin E was begun 4, 1, and 10 years ago.

Vitamin E, which prevents lipid oxidation in membranes, is normally present in high concentrations in the photoreceptors of the outer segments in the retina.3 Because the outer-segment membranes contain an unusually high percentage of polyunsaturated fatty acids, they are very susceptible to damage by oxidation. Retinal changes similar to those of retinitis pigmentosa have been reported in patients with vitamin E deficiency due to fat malabsorption4 and in experiments in animals. It is not surprising, therefore, that our patients with severe long-term vitamin E deficiency had retinitis pigmentosa.

These results identify abnormalities of the α-TTP gene as a cause of retinitis pigmentosa. In patients with these mutations vitamin E therapy appears to stop or slow the progression of retinitis pigmentosa.

Takanori Yokota, M.D.
Toshiaki Shiojiri, M.D.
Tokyo Medical and Dental University

Takanari Gotoda, M.D.
Hiroyuki Arai, Ph.D.
Tokyo University, Tokyo 113, Japan

4 References

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   Maret G. Traber. (2007) Vitamin E Regulatory Mechanisms. Annual Review of Nutrition 27:1, 347-362
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   ACHIM STOCKER. (2004) Molecular Mechanisms of Vitamin E Transport. Annals of the New York Academy of Sciences 1031:1, 44-59
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    Achim Stocker, Angelo Azzi. (2000) Tocopherol-Binding Proteins: Their Function and Physiological Significance. Antioxidants & Redox Signaling 2:3, 397-404
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    Amir Rattner, Hui Sun, Jeremy Nathans. (1999) M OLECULAR G ENETICS OF H UMAN R ETINAL D ISEASE. Annual Review of Genetics 33:1, 89-131
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    M.O McCarron, A.J.C Russell, R.A Metcalfe, R deysilva. (1999) Chronic vitamin E deficiency causing spinocerebellar degeneration, peripheral neuropathy, and centro-cecal scotomata. Nutrition 15:3, 217-219
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    N. Delanty, M. A. Dichter. (1998) Oxidative injury in the nervous system. Acta Neurologica Scandinavica 98:3, 145-153
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