Urinary a -tocopherol metabolites in a -tocopherol transfer protein-deficient patients

Patients with a -tocopherol transfer protein ( a TTP) defects experience neurological symptoms characteristic of vitamin E deficiency and depend on continuous high a -tocopherol supplements. We investigated the excretion of 2,5,7,8-tetramethyl-2(2 9 -carboxyethyl)-6-hydroxychroman ( a -CEHC), a urinary metabolite of a -tocopherol, as a putative marker for the a -tocopherol status of a -TTP-deficient patients and control subjects. In three patients vitamin E supplementation was stopped for short periods of time, during which plasma a -tocopherol concentrations and urinary a -CEHC excretion were measured. In the patients, plasma a -tocopherol decreased below normal ( , 5 m mol/l) but a -CEHC excretion remained above the range of unsupplemented control subjects (0.118–0.306 mg/day, n 5 6). In healthy subjects, however, a -CEHC excretion was increased only after surpassing a plasma a -tocopherol threshold of 30–40 m mol/l. Such a threshold did not exist in patients. The general mechanism of a -tocopherol degradation did not appear to differ between patients and control subjects. The presumed mechanism of v and subsequent b -oxidation was supported by the detection of a CPHC, an a -CEHC homolog with a side chain longer by 3 carbon atoms, both in supplemented patients and in control subjects. — Schuelke, M., A. Elsner, B. Finckh, A. Kohlschütter, C. Hübner, and R. Brigelius-Flohé. Urinary a -tocopherol metabolites in a -tocopherol transfer protein-deficient patients . J. Lipid Res. 2000. 41: 1543–1551. Supplementary key words a -tocopherol • a -tocopherol metabolites • a -CEHC • a -tocopherol transfer protein • AVED patients Ataxia with isolated vitamin E deficiency (AVED) is a rare inherited disease characterized by a defect in the a tocopherol transfer protein ( a -TTP) (1, 2). a -TTP is primarily expressed in liver cytosol (3) and functions there as a sorting protein. It specifically selects a -tocopherol from all incoming tocopherols (4) for incorporation into very low density lipoprotein (VLDL) and subsequent release into the circulation (5). Apart from liver, a -TTP mRNA has been found in the Purkinje cell layer of the cerebellar cortex, in spleen, lung, and kidney from rodents (6). a -TTP protein has been detected in human cerebellar Purkinje cells but only in patients with diseases that are associated with oxidative stress or various vitamin E deficiency states (7). The specific enrichment of ( RRR )a -tocopherol in the fetal circulation points to the presence of a -TTP also in the placenta (8, 9), although this has not been directly demonstrated. Its role in these target tissues is unknown but it may be involved in appropriate vitamin E utilization. Functionally relevant mutations in the a -TTP gene lead to a severe neurological disorder characterized by spinocerebellar dysfunction with progressive ataxia (10), in some cases associated with retinitis pigmentosa (11, 12). So far, 27 affected families with 13 different mutations have been described. The most frequent 744delA frameshift mutation (2, 13) truncates the protein by 11% and leads to an early onset of AVED. Other truncation mutations, 513– 514insTT (14), 485delT (14), and 552G ➝ A (15, 16), have similar consequences. The result of a mutated a -TTP gene is a severe vitamin E deficiency syndrome despite normal intestinal absorption and chylomicron metabolism (17). The inability of mutant a -TTP to incorporate a -tocopherol into VLDL causes clinical symptoms that are similar to those observed in other vitamin E deficiency states such as abetalipoproteinemia (18, 19) or cholestatic liver disease (20). In line with the view that the clinical symptoms of AVED result from an impaired vitamin E supply, ataxia, dysmetria, dysarthria, increased daytime sleepiness, and mental symptoms can be ameliorated by supplementation with high doses of vitamin E up to 40 mg/ kg body weight (12, 16, 21). These high doses, 250to 350-fold the recommended daily allowance, normalize the plasma a -tocopherol levels to 30–40 m mol/l (16), Abbreviations: a -CEHC, 2,5,7,8-tetramethyl-2(2 9 -carboxyethyl)-6hydroxychroman; a -TPP, a -tocopherol transfer protein; AVED, ataxia with isolated vitamin E deficiency. 1 To whom correspondence should be addressed. by on A ril 7, 2008 w w w .j.org D ow nladed fom