Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein

N Engl J Med. 1995 Nov 16;333(20):1313-8. doi: 10.1056/NEJM199511163332003.


Background: Patients with isolated vitamin E deficiency have an impaired ability to incorporate alpha-tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the alpha-tocopherol-transfer protein, which is presumed to function in the intracellular transport of alpha-tocopherol, is abnormal in these patients.

Methods: We studied a patient from an isolated Japanese island who began to have ataxia, dysarthria, and sensory disturbances in the sixth decade of life. His serum vitamin E concentration was low (1.2 micrograms per milliliter [2.8 mumol per liter]). Exons of his gene for the alpha-tocopherol-transfer protein were analyzed by DNA sequencing. We also screened an additional 801 inhabitants of the island for the mutation. Both the normal and mutant alpha-to-copherol-transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for alpha-tocopherol-transfer activity.

Results: The patient was homozygous for a point mutation that replaces histidine (CAT) with glutamine (CAG) at position 101 of the gene for the alpha-tocopherol-transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective alpha-tocopherol-transfer protein with approximately 11 percent of the transfer activity of the wild-type protein. Of the 801 island inhabitants examined, 21 were heterozygous for the His101Gln mutation. In all affected subjects, including the patient, this mutation cosegregated with an intron-sequence polymorphism. The heterozygotes were phenotypically normal and had serum vitamin E concentrations that were on average 25 percent lower than those of normal subjects (mean [+/- SD], 7.5 +/- 2.2 vs. 10.1 +/- 2.8 micrograms per milliliter [17.4 +/- 5.1 vs. 23.4 +/- 6.5 mumol per liter]; P = 0.002).

Conclusions: alpha-Tocopherol-transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Carrier Proteins / blood
  • Carrier Proteins / genetics*
  • Female
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Point Mutation*
  • Polymorphism, Genetic
  • Spinocerebellar Degenerations / blood
  • Spinocerebellar Degenerations / etiology
  • Spinocerebellar Degenerations / genetics*
  • Vitamin E / blood
  • Vitamin E Deficiency / complications
  • Vitamin E Deficiency / genetics


  • Carrier Proteins
  • alpha-tocopherol transfer protein
  • Vitamin E