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Ataxia with Vitamin E Deficiency

Synonyms: Ataxia with Isolated Vitamin E Deficiency, AVED, Familial Isolated Vitamin E Deficiency, Friedreich-Like Ataxia
, MD
Department of Neuropediatrics
Charité & NeuroCure Clinical Research Center
Charité - Universitätsmedizin Berlin
Berlin, Germany

Initial Posting: ; Last Update: October 13, 2016.

Summary

Clinical characteristics.

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.

Diagnosis/testing.

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.

Management.

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.

Prevention of primary manifestations: Vitamin E therapy in presymptomatic children with biallelic TTPA pathogenic variants prevents development of symptoms.

Surveillance: Monitor plasma vitamin E concentration every six months, particularly in children.

Agents/circumstances to avoid: Smoking; occupations requiring quick responses or good balance.

Evaluation of relatives at risk: Evaluation for vitamin E deficiency, especially in younger sibs of a proband.

Other: Before attempting to drive a car, assessment to determine if the affected individual can drive safely.

Genetic counseling.

AVED is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and carry one pathogenic variant; heterozygotes are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

Ataxia with vitamin E deficiency (AVED) should be suspected in individuals who typically present at the beginning of puberty with the following:

Clinical features

  • Progressive ataxia
  • Clumsiness of the hands
  • Loss of proprioception (especially distal joint position and vibration sense)
  • Areflexia
  • Dysdiadochokinesia
  • Positive Romberg sign
  • Head titubation
  • Decreased visual acuity
  • Positive Babinski sign
  • Macular atrophy, retinitis pigmentosa

Laboratory findings

  • Normal lipid and lipoprotein profile
  • Very low plasma vitamin E (α-tocopherol) concentration
    Note: (1) There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. In Finckh et al [1995], the normal range lies between 9.0 and 29.8 µmol/L (mean ± 2 SD). In El Euch-Fayache et al [2014] the normal range is given as 16.3-34.9 µmol/L, while individuals with AVED had vitamin E levels between 0.00 and 3.76 µmol/L (mean 0.95 µmol/L, SD 1.79 µmol/L; n=132). In individuals with AVED, the plasma vitamin E concentration is generally lower than 4.0 µmol/L (<1.7 mg/L) [Cavalier et al 1998, Mariotti et al 2004]. (2) Because oxidation of α-tocopherol by air may invalidate test results, the following precautions should be taken:
    • Centrifugation of the EDTA blood soon after venipuncture
    • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen
    • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen)
    • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube
    • Shipment of the sample to the test laboratory in dry ice

Electrophysiologic findings

  • In a large study of 132 individuals with AVED from North Africa, 45 individuals were investigated neurophysiologically (e.g., median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential) [El Euch-Fayache et al 2014].
    • 9% had normal findings.
    • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]).
    • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN).
    • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response).
    • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%).
  • Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20), increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [Schuelke et al 1999].

Note: No electrophysiologic findings are specific to or diagnostic of AVED; even a severe neuropathy does not exclude AVED.

Neuroimaging

  • Cerebellar atrophy [Mariotti et al 2004]; present in approximately half of reported individuals
  • Small T2 high-intensity spots in the periventricular region and the deep white matter [Usuki & Maruyama 2000]; inconsistent finding in some individuals

Note: No radiologic findings are specific to or diagnostic of AVED.

Histopathology findings [Larnaout et al 1997, Yokota et al 2000, El Euch-Fayache et al 2014, Ulatowski et al 2014]

  • Spinal sensory demyelination with neuronal atrophy and axonal spheroids
  • Dying back-type degeneration of the posterior columns
  • Neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root ganglia
  • Fiber type grouping of the peroneus brevis muscle
  • Mild loss of Purkinje cells

Establishing the Diagnosis

Presently no consensus diagnostic criteria for ataxia with vitamin E deficiency (AVED) exist.

The diagnosis of AVED is established in a proband with all of the following:

  • Markedly reduced plasma vitamin E (α-tocopherol) concentration
  • Normal lipoprotein profile
  • Exclusion of diseases that cause fat malabsorption

Identification of biallelic TTPA pathogenic variants on molecular genetic testing (see Table 1) establishes the diagnosis if clinical and laboratory features are inconclusive and confirms the diagnosis in individuals with the above features.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of TTPA is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Targeted analysis for TTPA pathogenic variant c.744delA can be performed first in individuals of Mediterranean or North African ancestry.
  • A multigene panel that includes TTPA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of AVED. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Ataxia with Vitamin E Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
TTPASequence analysis 3>90% 4, 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Ouahchi et al [1995], Hentati et al [1996], Cavalier et al [1998], Schuelke [personal observation]. Sequence analysis identified at least one abnormal allele in 46 of 51 individuals with the AVED phenotype, who had clearly reduced plasma vitamin E concentration [Schuelke, personal observation]. In 132 Tunisian individuals with AVED, 91.7% were homozygous for the c.744delA pathogenic variant; 8.3% of individuals were homozygous for other pathogenic variants (c.205-1G>T, c.400C>T, c.552+2T>A) [El Euch-Fayache et al 2014]. Sequence analysis of cDNA was used to confirm a synonymous pathogenic variant resulting in loss of splice site [Schuelke et al 1999] (see Molecular Genetics).

5.

Most individuals are homozygous or compound heterozygous for one of the known pathogenic variants.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available. A single whole-gene deletion has been reported [Kara et al 2008].

Clinical Characteristics

Clinical Description

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].

AVED generally manifests in late childhood or early teens between ages five and 15 years, however, the range may be from age two to 37 years as reported in a series of 132 North African individuals [El Euch-Fayache et al 2014]. The first symptoms include progressive ataxia, clumsiness of the hands, and loss of proprioception, especially of vibration and joint position sense. Handwriting deteriorates. In rare individuals, school performance declines secondary to loss of intellectual capacities. Tendon reflexes of the lower extremities are generally absent and the plantar reflexes increase in intensity. Affected individuals have difficulty walking in the dark and often have a positive Romberg sign. A high percentage of affected individuals (e.g., 8/11 individuals in one series) experience decreased visual acuity [Benomar et al 2002].

In many individuals, cerebellar signs such as dysdiadochokinesia and dysarthria with a scanning speech pattern are present. One third of individuals have a characteristic head tremor (head titubation). In some persons, psychotic episodes, intellectual decline, and dystonic episodes have been described. Rarely, AVED may manifest as arm or cervical dystonia [Becker et al 2016].

Most untreated individuals become wheelchair dependent as a result of ataxia and/or leg weakness between ages 11 and 50 years [Harding et al 1985, Ouahchi et al 1995, Hentati et al 1996, Cavalier et al 1998, Gabsi et al 2001, Benomar et al 2002, Mariotti et al 2004].

According to a large study on 132 individuals from North Africa [El Euch-Fayache et al 2014], the signs and symptoms include (in decreasing order of frequency):

  • Areflexia (94.7%)
  • Gait impairment (93.4%)
  • Positive Babinski sign (85.5%)
  • Deep sensory disturbances (67.1%)
  • Dysarthria (61.8%)
  • Head tremor (40.8%)
  • Urinary urgency (22.4%)
  • Nystagmus (5.3%)
  • Urinary incontinence (4.0%)
  • Retinitis pigmentosa (2.3%)
  • Cardiomyopathy (1.5%)

Genotype-Phenotype Correlations

To date, only two pathogenic variants have shown clear-cut genotype-phenotype correlations:

  • p.His101Gln is associated with late-onset disease (age >30 years), a mild course, and increased risk for pigmentary retinopathy. This variant is primarily reported in individuals of Japanese descent.
  • c.744delA is associated with early onset, a severe course, and slightly increased risk for cardiomyopathy. This variant is mainly observed in individuals of Mediterranean or North African descent. However, disease severity may vary considerably, and even in persons from the same family the onset of symptoms may vary between ages three and 12 years [Cavalier et al 1998, Marzouki et al 2005].

A less clear genotype-phenotype correlation can be seen for the following pathogenic variants if they occur in homozygous form. Manifestation of disease:

  • Before age ten years. p.Arg59Trp, p.Arg134Ter, p.Glu141Lys, c.486delT, c.513_514insTT, c.530-531AG>GTAAGT (see Table 3)
  • After age ten years. p.Arg221Trp, p.Ala120Thr (see Table 3) [Cavalier et al 1998]

Penetrance

AVED shows nearly complete penetrance in individuals who are homozygous or compound heterozygous for a TTPA pathogenic variant.

Nomenclature

AVED was first called “Friedreich ataxia phenotype with selective vitamin E deficiency” [Ben Hamida et al 1993].

Prevalence

Several restricted population-based studies have been performed.

Gotoda et al [1995] found one TTPA pathogenic variant (p.His101Gln) in 21 of 801 randomly selected inhabitants of a Japanese island on which one individual had previously been diagnosed with AVED. This would amount to a calculated prevalence of one homozygous individual per 1500 inhabitants. This pathogenic variant was not detected in 150 unrelated individuals from Tokyo.

In a Moroccan study, AVED was diagnosed in 20% of individuals with a Friedreich ataxia-like phenotype [Benomar, personal communication].

In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia was found to have AVED, suggesting a prevalence of 0.6:1,000,000 [Elkamil et al 2015].

Anheim et al [2010] 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.

Zortea et al [2004] performed an epidemiologic study of inherited ataxias in the Italian province of Padua and found a prevalence of 3.5:1,000,000 for AVED.

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.

Differential Diagnosis

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].

Certain clinical signs also help distinguish the two disorders (Table 2); however, the distinction cannot be made on clinical grounds alone.

Table 2.

Clinical Signs that Help Distinguish FRDA from AVED

Clinical SignFRDAAVED
Cavus foot+Rare
Peripheral neuropathy+Mild
Diabetes mellitus type I+(+)
Head titubation (tremor)Rare+
Amyotrophy+
Babinski sign+(+)
Dystonia+
Retinitis pigmentosa(+)
Reduced visual acuityRare+
Cardiac conduction disorder+Rare
Cardiomyopathy+(+)
Muscle weakness+
Diabetes mellitus+
+

= generally present

(+) = present only with certain pathogenic variants

– = generally absent

FRDA can be diagnosed based on molecular genetic testing and AVED based on plasma α-tocopherol concentration and molecular genetic testing of TTPA. Inheritance is autosomal recessive.

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 (OMIM 200100) is caused by pathogenic variants in MTP, which encodes microsomal triglyceride transfer protein large subunit. Hypobetalipoproteinemia (OMIM 615558, 605019) is caused by pathogenic variants in APOB (encoding apolipoprotein B-100) or ANGPTL3 (encoding angiopoietin-related protein 3). 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.

Refsum disease. Findings are early-onset retinitis pigmentosa, chronic polyneuropathy, deafness, and cerebellar ataxia. Many individuals have cardiac conduction disorders and ichthyosis. In Refsum disease, the degradation of phytanic acid is impeded because of pathogenic variants in the gene encoding phytanoyl-CoA hydroxylase (PHYH) or the gene encoding the PTS2 receptor (PEX7). High serum concentration of phytanic acid differentiates Refsum disease from AVED. Inheritance is autosomal recessive.

Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Findings are sensorimotor neuropathy with areflexia, cavus foot, and muscle wasting and weakness, especially in the lower legs and of the interdigital muscles. Neuropathy can be verified by presence of reduced NCVs (<38 m/s). CMT1A is caused by duplication of PMP22, the gene encoding peripheral myelin protein 22. The plasma vitamin E concentrations in CMT1A are normal. Inheritance is autosomal dominant. See CMT Overview.

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.

Other ataxias. Because AVED typically presents with ataxia or clumsiness in late childhood, AVED should be included in the differential diagnosis of all ataxias with the same age of onset (see Hereditary Ataxia Overview), including the following:

  • Ataxia-telangiectasia. Findings are cerebellar ataxia, seizures, nystagmus, conjunctival telangiectasias, hypogonadism, immunodeficiency, frequent pulmonary infections, and neoplasia. Plasma vitamin E levels are normal [Anheim et al 2010]. Ataxia-telangiectasia is caused by pathogenic variants in ATM; inheritance is autosomal recessive.
  • Marinesco-Sjögren syndrome. Findings are cerebellar ataxia, intellectual disability, dysarthria, cataracts, short stature, and hypergonadotropic hypogonadism. Marinesco-Sjögren syndrome is caused by pathogenic variants in SIL1; inheritance is autosomal recessive.
  • Chylomicron retention disease (Anderson disease) (OMIM 246700). Clinical findings are infantile-onset malabsorption of fat and fat-soluble vitamins, diarrhea, and neurologic deficits (peripheral neuropathy, absent tendon reflexes, diminished vibratory sense). The disease is caused by pathogenic variants in SAR1B that cause the absence of chylomicrons due to a defect of chylomicron secretion [Aguglia et al 2000]. Inheritance is autosomal recessive.
  • Congenital cataracts, facial dysmorphism, neuropathy. Clinical findings are congenital cataracts, cerebellar ataxia, cavus foot deformity, facial dysmorphisms, delayed motor development, and pyramidal signs. The affected individuals are of Roma/Gypsy origin and are all homozygous for the same pathogenic variant in intron 6 of CTDP1. Inheritance is autosomal recessive.
  • Pyruvate dehydrogenase E1 alpha deficiency (OMIM 312170). Findings are episodic ataxia, intellectual disability, hypotonia, cerebellar atrophy, dystonia, and lactic acidosis. The disease is caused by pathogenic variants in PDHA1; inheritance is X-linked. A high proportion of heterozygous females manifest severe symptoms.
  • Sideroblastic anemia and ataxia. Findings are early-onset non-progressive cerebellar ataxia, hyperreflexia, tremor, dysdiadochokinesia, and hypochromic microcytic anemia. The disease is caused by pathogenic variants in ABCB7; inheritance is X-linked.
  • Cayman-type cerebellar ataxia (OMIM 601238). Findings are cerebellar ataxia with wide-based gait, psychomotor retardation, intention tremor, and dysarthria. The disease is caused by pathogenic variants in ATCAY; inheritance is autosomal recessive.
  • SYNE1-related autosomal recessive cerebellar ataxia (also known as autosomal recessive spinocerebellar ataxia [SCAR8] and autosomal recessive cerebellar ataxia type 1 [ARCA1]). Findings are adult-onset cerebellar ataxia and/or dysarthria. Dysmetria, brisk lower-extremity tendon reflexes, and minor abnormalities in ocular saccades and pursuit can be seen. ARCA1 has not been observed outside of Quebec, Canada.
  • Joubert syndrome. Findings are truncal ataxia, developmental delays, episodic hyperpnea or apnea, and atypical eye movements. Cognitive abilities range from severe intellectual disability to normal. Variable features include retinal dystrophy, renal disease, ocular coloboma, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. The characteristic finding on MRI is the "molar tooth sign" in which hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities resemble a tooth. More than twenty genes are associated with Joubert syndrome (pathogenic variants in which appear to account for only about 50% of cases). Inheritance is autosomal recessive.
  • Cerebrotendinous xanthomatosis. Clinical features include xanthomas of the Achilles and other tendons, cerebellar ataxia beginning after puberty, juvenile cataracts, early atherosclerosis, and progressive dementia. The disease is caused by pathogenic variants in CYP27A1 (encoding sterol 27-hydroxylase, mitochondrial). Inheritance is autosomal recessive.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia with vitamin E deficiency (AVED), the following evaluations are recommended:

  • Clinical neurologic examination – particularly reflex status, vibratory and position sense, gait, Babinski sign, tremor, dysarthria
  • Ophthalmologic examination for evidence of macular degeneration or retinitis pigmentosa and decreased visual acuity; electroretinogram (ERG)
  • Cardiac examination; echocardiography and ECG to assess for cardiomyopathy
  • Neurophysiologic examination; nerve conduction velocity (NCV) and somatosensory potentials (especially the central conduction time [Schuelke et al 1999]), which are good objective measures of neurologic improvement after vitamin E supplementation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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.

In presymptomatic individuals, the manifestations of AVED can be prevented if vitamin E supplementation is initiated early [El Euch-Fayache et al 2014].

No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes.

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].

One of the following vitamin E preparations is used:

  • The chemically manufactured racemic form, all-rac-α-tocopherol acetate
  • The naturally occurring form, RRR-α-tocopherol

It is currently unknown whether affected individuals should be treated with all-rac-α-tocopherol acetate or with RRR-α-tocopherol. It is known that alpha-TTP (αTPP) stereoselectively binds and transports 2R-α-tocopherols [Weiser et al 1996, Hosomi et al 1997, Leonard et al 2002]. For some TTPA pathogenic variants, this stereoselective binding capacity is lost and affected individuals cannot discriminate between RRR- and SRR-α-tocopherol [Traber et al 1993, Cavalier et al 1998]. In this instance, affected individuals would also be able to incorporate non-2R-α-tocopherol stereoisomers into their bodies if they were supplemented with all-rac-α-tocopherol. Since potential adverse effects of the synthetic stereoisomers have not been studied in detail, it seems appropriate to treat with RRR-α-tocopherol, despite the higher cost.

Prevention of Primary Manifestations

If vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), the symptoms of AVED do not develop [Amiel et al 1995, El Euch-Fayache et al 2014].

Surveillance

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].

Agents/Circumstances to Avoid

Individuals with AVED should avoid:

  • Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [Sharpe et al 1996];
  • Occupations requiring quick responses or good balance.

Evaluation of Relatives at Risk

Predictive testing should be offered to all sibs of a proband, as timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

  • All relatives at risk, especially younger sibs of a proband, should be evaluated for vitamin E deficiency.
  • If plasma vitamin E concentration is low, the person should be tested for presence of the TTPA pathogenic variants found in the proband so that individuals with biallelic pathogenic variants can be treated promptly with vitamin E supplementation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Because of abnormal position sense in the extremities, individuals with AVED may have difficulty riding a bicycle or driving a car. Before attempting to drive a car, affected individuals need to be tested by a physician to determine whether they can drive safely.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Ataxia with vitamin E deficiency (AVED) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one TTPA pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with AVED are obligate heterozygotes (carriers) for a pathogenic variant in TTPA.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in TTPA.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the TTPA pathogenic variants in the family.

The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between heterozygous carriers and non-carriers.

Related Genetic Counseling Issues

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.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TTPA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for AVED are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Organization for Rare Disorders (NORD)
    Phone: 203-744-0100
    Fax: 203-263-9938
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Ataxia with Vitamin E Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TTPA8q12​.3Alpha-tocopherol transfer proteinTTPA databaseTTPATTPA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Ataxia with Vitamin E Deficiency (View All in OMIM)

277460VITAMIN E, FAMILIAL ISOLATED DEFICIENCY OF; VED
600415TOCOPHEROL TRANSFER PROTEIN, ALPHA; TTPA

Gene structure. TTPA consists of five uniformly spliced exons (ENST00000260116) with an open reading frame of 834 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants of TTPA comprise nonsense, missense, and splice site variants as well as small deletions, insertions, and indels (i.e., simultaneous deletion and insertion) (see Table 3). Most affected individuals have private pathogenic variants. Only the c.744delA and the c.513_514insTT pathogenic variants occur more often, especially in individuals of Mediterranean or North African descent. In a study of 33 individuals with AVED, the c.744delA pathogenic variant was found on both alleles in 11 individuals and on one allele in one individual [Cavalier et al 1998]. Putative splice defects can be investigated experimentally by analysis of cDNA from Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines [Schuelke et al 1999].

For more information, see Table A.

Table 3.

TTPA Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.175C>Tp.Arg59TrpNM_000370​.2
NP_000361​.1
c.191A>Gp.Asp64Gly
c.303T>Gp.His101Gln
c.358G>Ap.Ala120Thr
c.400C>Tp.Arg134Ter
c.421G>Ap.Glu141Lys
c.486delTp.Trp163GlyfsTer13
c.513_514insTTp.Thr172LeufsTer5
c.530-531AG>GTAAGTp.Lys177SerfsTer3
c.548T>Cp.Leu183Pro
c.575G>Ap.Arg192His
c.661C>Tp.Arg221Trp
c.736G>Cp.Gly246Arg
c.744delAp.Glu249AsnfsTer15

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The transcript encodes the 278-amino acid protein, α-tocopherol transfer protein (αTTP). This cytosolic 31.7-kd protein is mainly expressed in liver cells [Sato et al 1993] but also in the pyramidal cells of the cerebellum [Hosomi et al 1998, Copp et al 1999] and in the placenta [Kaempf-Rotzoll et al 2003, Müller-Schmehl et al 2004].

Liver-αTPP incorporates the α-tocopherol from the chylomicrons into VLDLs, which are then secreted into the circulation [Traber et al 1990] – a stereoselective process that favors 2R-α-tocopherols [Weiser et al 1996, Leonard et al 2002]. In the absence of αTPP, α-tocopherol is rapidly lost into the urine [Schuelke et al 2000a]. Alpha TTP appears to have two functions that can be tested separately: (1) the stereoselective binding of 2R-α-tocopherols and (2) the transfer of α-tocopherol between membranes [Gotoda et al 1995, Morley et al 2004]. In the hepatocytes, αTPP appears to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane. In the presence of TTPA pathogenic variants (p.Arg59Trp, p.Arg221Trp, p.Ala120Thr), vitamin E did not travel to the plasma membrane and remained trapped in the lysosomes. The authors also reported that the impact of the pathogenic variant on protein stability appears to be directly related to the clinical phenotype [Qian et al 2006].

Alpha-TTP has two CRAL-TRIO domains (AA 11-83 and 89-275). These domains were first described in the cellular retinaldehyde-binding protein (CRALBP) and the trifunctional protein (TRIO) [Crabb et al 1988, Debant et al 1996]. Other proteins of this family include a phosphatidyl inositol/phosphatidyl choline transfer protein (Sec14p) of yeast [Sha et al 1998] and the tocopherol-associated protein (TAP or SEC14 like 2) [Zimmer et al 2000]. Pathogenic variants in caytaxin, another CRAL-TRIO protein, cause ataxia in humans (Cayman ataxia) as well [Bomar et al 2003].

Abnormal gene product. Fourteen of 26 known pathogenic variants in TTPA predict a truncated protein through missplicing or generation of a premature termination codon. Pathogenic missense variants that cause substitutions in non- or semi-conserved amino acids (e.g., p.His101Gln, p.Ala120Thr, p.Arg192His, or p.Gly246Arg) cause a mild phenotype, whereas substitutions in highly conserved amino acids are associated with early onset and severe symptoms (e.g., p.Arg59Trp, p.Asp64Gly, p.Glu141Lys, p.Leu183Pro, p.Arg221Trp).

Through the x-ray crystallographic structure of αTPP [Meier et al 2003, Min et al 2003], the impact of some pathogenic variants on the protein structure and function may be explained. Of ten pathogenic missense variants, only one (p.Leu183Pro) is located in the α-tocopherol binding pouch. There is a highly positively charged arginine cluster on the surface of the protein, where αTPP probably interacts with other binding partners. Pathogenic variants of these conserved amino acids, Arg59 and Arg221 cause a severe AVED phenotype.

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].

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Suggested Reading

  • Christopher Min K. Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. Vitam Horm. 2007;76:23–43. [PubMed: 17628170]
  • Koenig M. Friedreich ataxia and AVED. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 232.
  • Manor D, Morley S. The alpha-tocopherol transfer protein. Vitam Horm. 2007;76:45–65. [PubMed: 17628171]

Chapter Notes

Revision History

  • 13 October 2016 (sw) Comprehensive update posted live
  • 2 November 2010 (me) Comprehensive update posted live
  • 4 September 2007 (me) Comprehensive update posted live
  • 20 May 2005 (me) Review posted live
  • 4 October 2004 (ms) Original submission
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