Vitamin E, Familial Isolated Deficiency Of

A number sign (#) is used with this entry because of evidence that ataxia with vitamin E deficiency (AVED) is caused by homozygous or compound heterozygous mutation in the TTPA gene (600415) on chromosome 8q12.

Clinical Features

Harding et al. (1985) described a young woman with spinocerebellar degeneration thought to be due to a selective defect in vitamin E absorption. There was no evidence of fat malabsorption. Binder et al. (1967) suggested a relationship between neurologic dysfunction and vitamin E deficiency in patients with chronic steatorrhea. This was subsequently confirmed in patients with abetalipoproteinemia (200100), the most severe state of vitamin E deficiency known. When studied at age 23, the proband had no vitamin E in the serum. A progressive neurologic disorder comprising ataxia, areflexia and marked loss of proprioception developed at age 13. She also had increased serum concentrations of cholesterol, triglyceride and beta-lipoprotein and showed xanthelasmata and xanthomas of the Achilles tendon. Improvement in the neurologic disease accompanied administration of vitamin E. The proband's mother had tendinous xanthomas and elevated serum cholesterol. Both parents and 4 brothers had low or low-normal serum vitamin E levels consistent with the heterozygous state of a disorder for which the proband was homozygous. The lipid disturbance in the proband and her mother was thought to be familial hypercholesterolemia. Evidence was cited that the mechanism of absorption of vitamin E may be different from that for the other fat-soluble vitamins. A progressive development of ataxia and areflexia with a 'dying back' of the peripheral nerves, along with spinocerebellar degeneration, are characteristic of vitamin E deficiency. Several patients have been described who, like the patient of Harding et al. (1985), had neurologic abnormalities similar to those of vitamin E deficiency but had no evidence of fat malabsorption (Burck et al., 1981; Kohlschutter et al., 1988; Laplante et al., 1984; Krendel et al., 1987; Yokota et al., 1987; Sokol et al., 1988). Sokol et al. (1988) studied 2 affected sisters, a brother, and an isolated case in another family. No consanguinity was observed, but no other affected persons were demonstrated by studies in these families. These patients all had normal lipid absorption, gastrointestinal, pancreatic, and intestinal function, and lipoproteins, but when consuming a normal diet, they had exquisitely low plasma vitamin E levels and developed neurologic abnormalities characteristic of vitamin E deficiency. With the addition of daily vitamin E supplements (400-1,200 IU) to the diet, normal plasma vitamin E levels could be maintained and in several patients improvement in neurologic function was reported. When vitamin E supplementation was interrupted, plasma tocopherol fell sharply to suboptimal levels.

Selective vitamin E deficiency shows clinical features very similar, and in some cases identical, to those of Friedreich ataxia (FRDA; 229300). Ben Hamida et al. (1993) pointed out that cardiomyopathy like that in Friedreich ataxia had not been reported in patients with isolated vitamin E deficiency.

Mapping

During a search for recombinants between the 9q13-q21 markers and the disease locus in FRDA families, Ben Hamida et al. (1993, 1993) found 5 with apparent recombinations that turned out, in fact, to be segregating a Friedreich-like disease associated with selective vitamin E deficiency. Since 3 such families of Tunisian origin were large and highly inbred, they were used to search for the defective locus by a combination of homozygosity mapping and sib comparisons. Linkage was found to 2 microsatellite markers located about 400 kb apart on proximal 8q. The other 2 families, one Tunisian and one Italian, also showed homozygosity and linkage with these markers, as did a sixth family of Albanese origin for which serum vitamin E levels could not be obtained. By combining all 6 families and by computing the consanguinity loops, a maximum lod score of 17.9 was obtained at theta = 0.0 for a haplotype combining the 2 microsatellite marker loci. The lod-1 confidence interval was 2.4 cM on either side of these markers. Doerflinger et al. (1995) performed linkage studies in 6 new and 2 previously described families and demonstrated genetic homogeneity despite significant clinical variability. They refined the AVED position to a 1-cM interval on 8q. Haplotype analysis using tightly linked microsatellite markers demonstrated a predominant, although not unique, mutation as responsible for the disorder in North African populations, where this condition is unusually frequent. Doerflinger et al. (1995) also constructed a YAC contig over this interval to facilitate the search for the AVED gene.

Molecular Genetics

The tocopherol-binding protein is also known as alpha-tocopherol transfer protein and TTP1. In patients with familial isolated vitamin E deficiency, Traber et al. (1990) demonstrated a defect in the incorporation of alpha-tocopherol into lipoproteins secreted by the liver. They suggested that these patients are lacking or have a defective liver tocopherol-binding protein that incorporates alpha-tocopherol into nascent very-low-density lipoprotein.

The implication of TTP1 in ataxia with isolated vitamin E deficiency was established by the identification of frameshift mutations in the TTPA gene. A 744delA mutation (600415.0001) accounted for 68% of the mutant alleles in 17 families analyzed by Ouahchi et al. (1995) and appeared to have spread in North Africa and Italy. Although only the C-terminal tenth of the protein was altered, this mutation correlated with a severe phenotype. Two other mutations were found in single families. Hentati et al. (1996) described the structure of the TTPA gene and identified several TTPA mutations that were associated with familial vitamin E deficiency.

Schuelke et al. (1999) described a 14-year-old male with ataxia and mental symptoms who was found to be homozygous for a 552G-A mutation in the TTPA gene (600415.0007). After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete.

Aoki et al. (1990) reported 2 sibs who had an atypical spinocerebellar syndrome with isolated vitamin E deficiency. On restudy of one of these patients, mutation in the TTPA gene was excluded, suggesting the existence of another gene for familial isolated vitamin E deficiency (Shiojiri et al., 1999).

Cellini et al. (2002) reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 (608768) and also had compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. Cellini et al. (2002) suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit.

Heterogeneity

Bouhlal et al. (2008) reported an unusual, highly consanguineous Tunisian family in which 11 individuals had autosomal recessive ataxia caused by 3 distinct gene defects. Seven patients who also had low vitamin E levels were all homozygous for the common 744delA mutation in the TTPA gene (600415.0001), consistent with a diagnosis of AVED. Two patients with normal vitamin E levels were homozygous for a mutation in the FXN gene (606829.0001), consistent with a diagnosis of FRDA (229300). The final 2 patients with normal vitamin E levels carried a mutation in the SACS gene (604490), consistent with a diagnosis of ARSACS (270550). The clinical phenotype was relatively homogeneous, although the 2 patients with SACS mutations had hyperreflexia of the knee. One asymptomatic family member was compound heterozygous for the TTPA and FXN mutations. Bouhlal et al. (2008) emphasized the difficulty of genetic counseling in deeply consanguineous families.