Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens between ages five and 15 years. The first symptoms include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The phenotype and disease severity vary widely among families with different pathogenic variants; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.
Presently, no consensus diagnostic criteria for AVED exist; the principal criterion for diagnosis is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration and a normal lipoprotein profile in the absence of known causes of malabsorption. Identification of biallelic TTPA pathogenic variants on molecular genetic testing confirms the diagnosis.
Treatment of manifestations: Lifelong high-dose oral vitamin E supplementation to bring plasma vitamin E concentrations into the high-normal range; treatment early in the disease process may to some extent reverse ataxia and mental deterioration.
The phenotype and disease severity of ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, symptoms and disease severity can vary among sibs [Shorer et al 1996].
Anheim et al  evaluated102 individuals with suspected autosomal recessive cerebellar ataxia; in 57 individuals (56%) a molecular diagnosis could be established. Of these, 36 had Friedreich ataxia (FRDA), seven had ataxia with oculomotor apraxia type 2 (AOA2), four had ataxia-telangiectasia (AT), three had Marinesco-Sjögren syndrome (MSS), three had ataxia with oculomotor apraxia type 1 (AOA1), two had AR spastic ataxia of Charlevoix-Saguenay (ARSACS), one had AR cerebellar ataxia (ARCA2), and one had ataxia with vitamin E deficiency (AVED). From their findings, the authors infer a prevalence for AVED in the Alsace region of France of approximately 1:1,800,000.
It also appears to be of interest that TTPA knockout mice are resistant to cerebral malaria and that this resistance can be abrogated by supplementation with vitamin E [Herbas et al 2010a, Herbas et al 2010b]. This may add TTPA pathogenic variants to several inherited alterations that confer protection against malaria [López et al 2010] and could explain the comparatively high prevalence of such pathogenic variants around the Mediterranean Sea.
Friedreich ataxia(FRDA). The age of onset is similar in ataxia with vitamin E deficiency (AVED) and FRDA; however, only in AVED are plasma vitamin E concentrations low [Benomar et al 2002].
Abetalipoproteinemia (Bassen-Kornzweig) and hypobetalipoproteinemia. Features include retinitis pigmentosa, progressive ataxia, steatorrhea, demyelinating neuropathy, dystonia, extrapyramidal signs, spastic paraparesis (rare), and acanthocytosis together with vitamin E deficiency, which is secondary to defective intestinal absorption of lipids. The serum cholesterol concentration is very low, and serum β-lipoproteins are absent. Low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) cannot be synthesized properly. Abetalipoproteinemia is caused by pathogenic variants in MTP, which encodes microsomal triglyceride transfer protein large subunit. Hypobetalipoproteinemia is caused by pathogenic variants in APOB, encoding apolipoprotein B-100 (see APOB-Related Familial Hypobetalipoproteinemia) or ANGPTL3, encoding angiopoietin-related protein 3 (OMIM 605019). Inheritance is autosomal recessive.
Malnutrition/reduced vitamin E uptake. To become vitamin E deficient, healthy individuals have to consume a diet depleted in vitamin E over months. This is sometimes seen in individuals, especially children, who eat a highly unbalanced diet (e.g., Zen macrobiotic diet), but is most often observed in chronic diseases that impede the resorption of fat-soluble vitamins in the distal ileum (e.g., cholestatic liver disease, short bowel syndrome, cystic fibrosis, Crohn's disease). The symptoms are similar to AVED. Although such individuals should be supplemented with oral preparations of vitamin E, they do not need the high doses necessary for treatment of AVED.
Ataxia with oculomotor apraxia type 1(AOA1). Findings are oculomotor apraxia, cerebellar ataxia, peripheral neuropathy, and choreoathetosis. Hypoalbuminemia and hypercholesterolemia may occur. AOA1 neurologically mimics ataxia-telangiectasia, but without telangiectasias or immunodeficiency. Plasma vitamin E levels are normal [Anheim et al 2010]. AOA1 is caused by pathogenic variants in the gene encoding aprataxin (APTX). Inheritance is autosomal recessive.
Ataxia with oculomotor apraxia type 2(AOA2). Findings are spinocerebellar ataxia and, rarely, oculomotor apraxia. Serum concentrations of creatine kinase, γ-globulin, and α-fetoprotein (AFP) are increased. AOA2 is caused by pathogenic variants in SETX, the gene encoding probable helicase senataxin. Plasma vitamin E levels are normal [Anheim et al 2010]. Inheritance is autosomal recessive.
The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. Some symptoms (e.g., ataxia and intellectual deterioration) can be reversed if treatment is initiated early in the disease process [Schuelke et al 1999]. In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [Gabsi et al 2001, Mariotti et al 2004, El Euch-Fayache et al 2014]. With treatment, plasma vitamin E concentrations can become normal.
The reported vitamin E dose ranges from 800 mg to 1500 mg (or 40 mg/kg body weight in children) [Burck et al 1981, Harding et al 1985, Amiel et al 1995, Cavalier et al 1998, Schuelke et al 1999, Schuelke et al 2000b, Gabsi et al 2001, Mariotti et al 2004].
During vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high normal range.
Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [Schuelke et al 1999]. Discontinuation of vitamin E supplementation, even temporarily, leads to a drop in plasma vitamin E concentration within two to three days and to a prolonged drop in TRAP, even after reinitiating vitamin E supplementation [Kohlschütter et al 1997, Schuelke et al 2000b].
Reduced vitamin E levels are associated with low fertility and embryo resorption in mice [Traber & Manor 2012] and α-tocopherol transfer protein is highly expressed in the human placenta [Müller-Schmehl et al 2004]; therefore, it is advisable to keep vitamin E levels in the high normal range during pregnancy.
Predictive testing of at-risk family members. Because vitamin E treatment initiated in presymptomatic individuals can prevent the findings of AVED [Amiel et al 1995], predictive testing of at-risk family members (particularly younger sibs of the proband) is appropriate. See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Biochemical investigations of the in vitro capacity of αTPP to bind and to transfer α-tocopherol revealed a reduction in both functions for the p.Arg59Trp, p.Glu141Lys, and p.Arg221Trp pathogenic variants. In contrast, the pathogenic variants associated with the mild AVED phenotype (p.His101Gln, p.Ala120Thr) do not have a pronounced effect on αTPP in vitro function. It has been hypothesized that the pathology of these pathogenic variants may derive from other as-yet-unknown αTPP functions [Morley et al 2004]. Both types of pathogenic variants may impair the ability of αTPP to facilitate the secretion of vitamin E from cells where it remains trapped in lysosomes [Qian et al 2006]. On the other hand, binding of vitamin E to αTPP prevents its ubiquinylation and its subsequent proteolytic degradation through the proteasome [Thakur et al 2010].
Vitamin E comes in 8 different forms, all of which can be absorbed in the small intestine. However, alpha-tocopherol is the only form that the liver can metabolize, and the remaining forms are excreted. This activity reviews the causes, pathophysiology, and presentation of vitamin E deficiency and highlights the role of the interprofessional team in its management.
Objectives:Identify the etiology of vitamin E deficiency.Outline the presentation of a patient with vitamin E deficiency.Review the treatment options for vitamin E deficiency.Explain the importance of improving coordination among the interprofessional team to enhance the delivery of care for patients affected by vitamin E deficiency. Access free multiple choice questions on this topic.
Vitamin E is all the following eight compounds alpha, beta, gamma, and delta-tocopherol and alpha, beta, gamma, and delta-tocotrienol. Alpha-tocopherol is the only compound of the eight that are known to meet human dietary needs. All of the vitamin E forms are absorbed in the small intestine, and then the liver metabolizes only alpha-tocopherol. The liver then removes and excretes the remaining vitamin E forms.
Vitamin E deficiency is extremely rare in humans as it is unlikely caused by a diet consisting of low vitamin E. Rather, it tends to be caused by irregularities in dietary fat absorption or metabolism. Vitamin E is a lipid-soluble nutrient. Vitamin E may have a role in reducing atherosclerosis and lowering rates of ischemic heart disease. Premature infants have low vitamin E reserves due to vitamin E only able to cross the placenta in small amounts. 153554b96e