Ataxia with vitamin E deficiency

Patients who lack the hepatic tocopherol transfer protein (Section 4.2) and suffer from what has been called AVED (ataxia with vitamin E deficiency) are unable to export a-tocopherol from the liver in VLDL. 

Disorders associated with vitamin E deficiency (ataxia with vitamin E deficiency (AVED), chronic cholestatic liver disease, cystic fibrosis, chronic pancreatitis, short bowel syndrome, progressive systemic sclerosis,... 

Copp, R.P., Wisniewski, T., Hentati, E, Larnaout, A., Ben Hamida, M., and Kayden, H.J., Localization of alpha-tocopherol transfer protein in the brains of patients with ataxia with vitamin E deficiency and other oxidative stress related neurodegenerative disorders. Brain. Res. 822 (1-2), 80-87, 1999. 

Vitamin E deficiency is seen rarely in humans. However, there may be a risk of vitamin E deficiency in premature infants because the placenta does not transfer a-tocopherol to the fetus in adequate amounts. When it occurs in older children and adults, it is usually a result of lipoprotein deficiencies or a lipid malabsorption syndrome. These include patients with abetalipoproteinemia or homozygous hypobeta-lipoproteinemia, those with cholestatic disease, and patients receiving total parenteral nutrition. There is also an extremely rare disorder in which primary vitamin E deficiency occurs in the absence of lipid malabsorption. This disorder is a rare autosomal recessive neurodegenerative disease caused by mutations in the gene for a-TTP. This disorder is known as ataxia with vitamin E deficiency (AVED). Patients with AVED have extraordinary low plasma vitamin E concentrations (<5pgml ) and have an onset between 4 and 18 years, with progressive development of peripheral neuropathy,... 

Vitamin E deficiency occurs due to genetic defects in the formation of hepatic a-tocopherol transfer protein. This transport protein plays a central role in the liver and one of its functions is to facilitate incorporation of a-tocopherol into nascent very low density lipoproteins (VLDLs). Since there are no specific transport proteins for vitamin E in plasma, the delivery of vitamin E to the tissues is primarily mediated by VLDL-LDL transport mechanisms (Chapter 20). Thus, deficiency of hepatic a-tocopherol transport protein causes low plasma levels of vitamin E with impairment of delivery to the tissues. Patients with the transport protein deficiency exhibit peripheral neuropathy and ataxia. Early and vigorous vitamin E supplementation in patients with neurological symptoms and with low plas-mal levels of vitamin E has yielded therapeutic benefits. 

Federico, A., Ataxia with isolated vitamin E deficiency a treatable neurologic disorder resembling Friedreich s ataxia, Neurol. Sci. 25 (3), 119-121, 2004. 

Liver secretion of very low density lipoproteins contributed to the daily turnover of plasma RRR-a-tocopherol. Patients with the autosomal recessive neurodegenerative disease called ataxia with isolated vitamin E deficiency have an impaired ability to incorporate a-tocopherol into very low density lipoproteins secreted by the liver, because of mutations in the gene encoding the tocopherol transfer protein. 

The hepatic 31 kDa a-TTP is a cytosolic protein that has been purified and found to exist as two charge isoforms (Kuhlenkamp et al, 1993). The primary structures of a-TTP from rat liver (Sato et al, 1993) and human liver (Arita et al, 1995) have been determined and found to have a structural homology with retinaldehyde-binding protein (Sato et al, 1993). It is now known that a defect in a-TTP is the cause of ataxia (a nervous disorder characterized by the inability to coordinate muscular movement) associated with familial isolated vitamin E deficiency (Traber etal, 1990c Schuelke etal, 1999). Recent work also indicates that a-TTP is very important for the normal development of placental labyrinthine trophoblasts the placenta of female mice deficient in a-TTP was found to be extremely impaired and the embryos died at mid-gestation (Jishage et al, 2001). 

Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Aral H, Inoue K, Mandel JL, and Koenig M (1995) Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nature Genetics 9 141-145. 

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