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Ataxia with Vitamin E Deficiency

Synonyms: AVED, Ataxia with Isolated Vitamin E Deficiency, 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: June 27, 2013.

Summary

Disease characteristics. Most individuals with ataxia with vitamin E deficiency (AVED) present at puberty; common characteristics of the disease include progressive ataxia, clumsiness of the hands, loss of proprioception (especially of vibration and joint position sense), and areflexia. Other features often observed are dysdiadochokinesia, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The phenotype and disease severity vary widely among families with different mutations; 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 in the absence of known causes of malabsorption. In most cases, molecular analysis of TTPA, the gene encoding α-tocopherol transfer protein and the only gene in which mutations are known to cause AVED, allows confirmation of 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 homozygous TTPA mutations prevents development of symptoms. Individuals heterozygous for TTPA mutations (carriers) do not need vitamin E supplementation and do not manifest neurologic symptoms.

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

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

Other: Before learning to drive a car, assessment to determine if abnormal position sense in the extremities presents a danger.

Genetic counseling. AVED is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and carry one mutant allele; 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier detection for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

Presently no consensus diagnostic criteria for ataxia with vitamin E deficiency (AVED) exist; the principal criterion for diagnosis is the presence of a Friedreich ataxia-like neurologic phenotype associated with markedly reduced plasma vitamin E (α-tocopherol) concentration in the absence of known causes of malabsorption. In most cases, molecular analysis of TTPA allows confirmation of the diagnosis by demonstrating the presence of pathogenic mutations.

Characteristic clinical findings. Most individuals present at the beginning of puberty with the following [Burck et al 1981, Harding et al 1985]:

  • Progressive ataxia
  • Early loss of proprioception (especially distal joint position and vibration sense)
  • Areflexia
  • Dysdiadochokinesia
  • Positive Romberg sign
  • Head titubation
  • Decreased visual acuity
  • Positive Babinski sign

Electrophysiologic findings [Zouari et al 1998, Schuelke et al 1999, Gabsi et al 2001]

  • Normal motor conduction velocity (MCV), normal muscle action potential (MAP) amplitude
  • Normal sensory conduction velocity (SCV), decreased sensory action potential (SAP)
  • Somatosensory evoked potentials (SSEP): 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.

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

Testing

Characteristic laboratory findings

  • Normal lipid and lipoprotein profile
  • Very low plasma α-tocopherol concentration

Note: (1) No universal normal range of plasma vitamin E concentration can be given as it depends on the specific method used 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 individuals with AVED, the plasma α-tocopherol concentrations are 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
  • Shipment of the sample to the test laboratory in dry ice

Heterozygotes. Although the plasma vitamin E concentration is generally within the normal range [Harding et al 1985, Amiel et al 1995], it is on average 25% lower than normal in heterozygotes [Gotoda et al 1995].

Molecular Genetic Testing

Gene. TTPA, the gene encoding the α-tocopherol transfer protein, is the only gene in which mutations are known to cause AVED [Arita et al 1995].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Ataxia with Vitamin E Deficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TTPASequence analysis 4Sequence variants>90% 5, 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. 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 out of 51 individuals with the AVED phenotype, who had clearly reduced plasma vitamin E concentration [Schuelke, personal observation]. Among affected individuals of Mediterranean or North African descent, approximately 80% have the c.744delA pathogenic allele. Sequence analysis of cDNA was used to confirm a synonymous mutation resulting in loss of splice site [Schuelke et al 1999]; see Molecular Genetics.

6. Most individuals are homozygous or compound heterozygous for one of the known mutations.

Testing Strategy

To confirm/establish the diagnosis in a proband, the following sequence of evaluations is indicated:

1.

Clinical examination with attention to symptoms described in Table 2

2.

Measurement of serum vitamin E concentration and the lipoprotein profile

3.

Molecular genetic testing of TTPA by sequence analysis

4.

Exclusion of diseases that cause fat malabsorption

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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. First symptoms include progressive ataxia, clumsiness of the hands, and loss of proprioception, especially of vibration and joint position sense. Handwriting deteriorates. In rare cases, 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 a 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.

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].

Neuroimaging

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

Pathogenic findings [Larnaout et al 1997, Yokota et al 2000]

  • 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
  • Retinal atrophy
  • Mild loss of Purkinje cells

Genotype-Phenotype Correlations

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

  • p.His101Gln. Late-onset disease (age >30 years), mild course, increased risk for pigmentary retinopathy; mainly described in individuals of Japanese descent
  • c.744delA. Early-onset, severe course, increased risk for cardiomyopathy; 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 mutations 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 4)
  • After age ten years. p.Arg221Trp, p.Ala120Thr (see Table 4) [Cavalier et al 1998]

Penetrance

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

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 mutant allele of TTPA (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 mutation 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]

Anheim et al [2010] published a prospective study in which they performed an epidemiologic survey with molecular analysis in 102 persons with the leading symptom of “autosomal cerebellar recessive ataxia” before age 60 years; in 57/102 (56%) a molecular diagnosis could be established. Of these, 36 were affected with Friedreich ataxia (FRDA), seven with ataxia-oculomotor apraxia type 2 (AOA2), four with ataxia telangiectasia (AT), three with Marinesco-Sjögren syndrome (MSS), three with ataxia-oculomotor apraxia type 1 (AOA1), two with AR spastic ataxia of Charlevoix-Saguenay (ARSACS), one with AR cerebellar ataxia (ARCA2), and one with 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 AVED of 3.5:1,000,000.

It also appears to be of interest that TTPA knockout mice are resistant against cerebral malaria and that this resistance can be abrogated by resupplementation of vitamin E [Herbas et al 2010a, Herbas et al 2010b]. This may add TTPA mutations to several inherited alterations that confer protection against malaria [López et al 2010] and could explain the comparatively high prevalence of such mutations around the Mediterranean Sea.

Differential Diagnosis

Friedreich ataxia. The age of onset is similar in ataxia with vitamin E deficiency (AVED) and Friedreich ataxia (FRDA); however, only in AVED are plasma vitamin E concentrations low [Benomar et al 2002].

Certain clinical signs 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 titubationRare+
Amyotrophy+
Babinski sign+(+)
Retinitis pigmentosa(+)
Reduced visual acuityRare+
Cardiac conduction disorder+Rare
Cardiomyopathy+(+)
Muscle weakness+

+ = symptom generally present

(+) = symptom present only with certain mutations

– = symptom 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.

Abetalipoproteinemia (Bassen-Kornzweig) and hypobetalipoproteinemia (OMIM 200100). 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 mutations in MTP, which encodes microsomal triglyceride transfer protein. Hypobetalipoproteinemia is caused by mutations in APOB, which encodes the protein apolipoprotein B.

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 [Harding et al 1982, Weder et al 1984]. 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 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 mutations in the gene encoding phytanoyl-CoA hydroxylase (PHYH) or the gene encoding peroxin 7 (PEX7). High serum concentration of phytanic acid differentiates Refsum disease from AVED.

Charcot-Marie-Tooth disease 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.

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 mutations 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 mutations in SETX, the gene encoding 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, Palau & Espinos [2006]), 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]. Inheritance is autosomal recessive and caused by mutations in ATM.
  • Marinesco-Sjögren syndrome. Findings are cerebellar ataxia, intellectual disability, dysarthria, cataracts, short stature, and hypergonadotropic hypogonadism. It may be caused by mutations in SIL1 or SARA2; inheritance is autosomal recessive. Note: Vitamin E levels may be low in Marinesco-Sjögren syndrome as a result of chylomicron retention [Aguglia et al 2000]
  • Congenital cataracts, facial dysmorphism, neuropathy (CCFDN). 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 share the same mutation in intron 1 of CTDP1.
  • Pyruvate dehydrogenase deficiency (OMIM 312170). Findings are episodic ataxia, intellectual disability, hypotonia, cerebellar atrophy, dystonia, and lactic acidosis. The disease is caused by mutations 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 mutations in ABCB7 and inheritance is X-linked.
  • Cayman-type cerebellar ataxia (OMIM 601238). Findings are cerebellar ataxia with wide-based gait, psychomotor retardation, intention tremor, and dysarthria. Inheritance is autosomal recessive through mutations in ATCAY.
  • 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 (JBTS). Findings are truncal ataxia, developmental delays, and episodic hyperpnea or apnea and/or atypical eye movements. Cognitive abilities range from severe intellectual disability to normal. Variable features include retinal dystrophy, renal disease, ocular colobomas, 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. Eighteen associated genes (mutations in which appear to account for only a fraction of cases of Joubert syndrome) are INPP5E, TMEM216, AHI1, NPHP1, CEP290 , TMEM67, RPGRIP1L, ARL13B, CC2D2A, C5orf42, CEP41, INPP5E, KIF7, OFD1, TCTN1, TCTN2, TMEM138, TTC21B. The other associated genes are unknown. Inheritance is autosomal recessive.
  • Cerebrotendineous 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 mutations in CYP27A1, the gene encoding sterol 27-hydroxylase.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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 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
  • Medical genetics consultation

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. 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]. With treatment, plasma vitamin E concentrations can become normal.

No therapeutic studies have been performed on a large cohort to determine optimal dosage and evaluate outcomes.

Reported doses of vitamin E range 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].

The following vitamin E preparations are used:

  • The chemically manufactured racemic form, all-rac-α-tocopherol acetate
    OR
  • 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) stereo-selectively binds and transports 2R-α-tocopherols [Weiser et al 1996, Hosomi et al 1997, Leonard et al 2002]. For some TTPA mutations, this stereo-selective 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 siblings of an index case), symptoms of AVED do not develop [Amiel et al 1995].

Surveillance

During vitamin E therapy, plasma vitamin E concentration should be checked at regular intervals (e.g., every six months), especially in children. Ideally the plasma concentration of vitamin E 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 seems to be the best surrogate marker for clinical improvement [Schuelke et al 1999]. Discontinuation of vitamin E supplementation — even temporarily — leads to a fall of vitamin E plasma concentration within two to three days and to a prolonged fall of 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].

Individuals with AVED should avoid occupations requiring quick responses or good balance.

Evaluation of Relatives at Risk

Predictive testing should be offered to all sibs of an index patient, as timely treatment with vitamin E supplementation may completely avert the clinical manifestation 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 mutations found in the proband so that those with two disease-causing alleles can be treated promptly with vitamin E supplementation.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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, an individuals with AVED may have difficulty riding a bicycle or driving a car. Before attempting to drive a car, the individual needs to be tested by a physician to determine whether he/she 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 and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with AVED are obligate heterozygotes (carriers) for a disease-causing mutation in TTPA.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified 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

Presymptomatic testing of at-risk family members. Because vitamin E treatment initiated in presymptomatic individuals can prevent the findings of AVED [Amiel et al 1995], 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

If the disease-causing mutations have been identified in the family and both parents have been verified to be carriers, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • 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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TTPA8q12​.3Alpha-tocopherol transfer proteinTTPA databaseTTPA

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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 Symbol.

Pathogenic allelic variants. Disease-causing mutations of TTPA comprise nonsense, missense, and splice-site mutations as well as small deletions, insertions, and indels (i.e., simultaneous deletion and insertion) (see Table 3 and Table 4). Most affected individuals have private mutations. Only the c.744delA and the c.513_514insTT mutations occur more often, especially in individuals of Mediterranean or North African descent. In a study of 33 individuals with AVED, the c.744delA mutation 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 ChangeProtein Amino Acid 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>GTAAGT p.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 authors. 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 (www​.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, Muller-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]. This is a stereo-selective 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 stereo-selective 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 seems 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 mutations (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 mutation on protein stability seems 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 comprise 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]. Mutations in caytaxin, another CRAL-TRIO protein, cause ataxia in humans (Cayman ataxia) as well [Bomar et al 2003].

Abnormal gene product. Fourteen out of 26 known mutations in TTPA predict a truncated protein through missplicing or generation of a premature termination codon. Missense mutations 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 mutations on the protein structure and function may be explained. Of ten missense mutations, 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. Mutations 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 mutations. In contrast, the mutations 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 mutations may derive from other as-yet-unknown αTPP functions [Morley et al 2004]. Both types of mutations 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].

References

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Suggested Reading

  1. Koenig M. Friedreich ataxia and AVED. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 232. Available online. Accessed 5-21-14.
  2. Manor D, Morley S. The alpha-tocopherol transfer protein. Vitam Horm. 2007;76:45–65. [PubMed: 17628171]
  3. Min KC. Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED. Vitam Horm. 2007;76:23–43. [PubMed: 17628170]

Chapter Notes

Revision History

  • 27 June 2013 (me) Comprehensive update posted live
  • 2 November 2010 (me) Comprehensive update posted live
  • 4 September 2007 (me) Comprehensive update posted to live Web site
  • 20 May 2005 (me) Review posted to live Web site
  • 4 October 2004 (ms) Original submission
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