ATAXIA, FRIEDREICH-LIKE, WITH SELECTIVE VITAMIN E DEFICIENCY
VED
AVED
Ataxia with isolated vitamin E deficiency
friedreich-like ataxia
Isolated vitamin E deficiency
Familial isolated vitamin E deficiency
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 ... 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.
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. ... 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.
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....
DiagnosisClinical DiagnosisPresently 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 ataxiaEarly loss of proprioception (especially distal joint position and vibration sense)AreflexiaDysdiadochokinesiaPositive Romberg signHead titubationDecreased visual acuityPositive Babinski signElectrophysiologic findings [Zouari et al 1998, Schuelke et al 1999, Gabsi et al 2001]Normal motor conduction velocity (MCV), normal muscle action potential (MAP) amplitudeNormal 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.TestingCharacteristic laboratory findingsNormal lipid and lipoprotein profileVery low plasma α-tocopherol concentrationNote: (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 venipunctureQuick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogenFilling 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 foilShipment of the sample to the test laboratory in dry iceHeterozygotes. 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 TestingGene. TTPA, the gene encoding the α-tocopherol transfer protein, is the only gene known to be associated with AVED [Arita et al 1995].Clinical testingSequence analysis. Sequencing the five exons and flanking intron sequences of TTPA genomic DNA detects mutations in more than 90% of individuals with AVED [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 pathologic allele. Sometimes mutations in intron sequences create a cryptic splice site that can cause abnormal splicing, leading to abnormal RNA transcripts and thus abnormal proteins. These kinds of splice-site mutations may be overlooked if sequencing is only done on the exon and flanking intron sequences on the genomic DNA level. Sequencing can be done on cDNA from EBV immortalized lymphoblastoid cells to detect splicing errors [Schuelke et al 1999]. Most individuals are homozygous or compound heterozygous for one of the known mutations. See Table 3 (pdf).Table 1. Summary of Molecular Genetic Testing Used in Ataxia with Vitamin E DeficiencyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTTPASequence analysisSequence variants 2>90% Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband, the following sequence of evaluations is indicated:1.Clinical examination with attention to symptoms described in Table 22.Measurement of serum vitamin E concentration and the lipoprotein profile3.Molecular genetic testing of TTPA by direct sequence analysis4.Exclusion of diseases that cause fat malabsorptionCarrier 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TTPA.
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]....
Natural HistoryThe 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].NeuroimagingCerebellar atrophy [Aoki et al 1990, Gabsi et al 2001, Mariotti et al 2004]; present in approximately half of reported individualsDilatation of the cisterna magna [Shimohata et al 1998]; single case reportSmall T2 high-intensity spots in the periventricular region and the deep white matter [Amiel et al 1995, Usuki & Maruyama 2000]; inconsistent finding in some individualsNote: No radiologic findings are specific to or diagnostic of AVED.Pathologic findings [Larnaout et al 1997, Yokota et al 2000]Spinal sensory demyelination with neuronal atrophy and axonal spheroidsDying back-type degeneration of the posterior columnsNeuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, spinal horns, and posterior root gangliaRetinal atrophyMild loss of Purkinje cells
Except for the following two mutations, no clear-cut genotype-phenotype correlations have been identified:...
Genotype-Phenotype CorrelationsExcept for the following two mutations, no clear-cut genotype-phenotype correlations have been identified:p.His101Gln. Late-onset disease (age >30 years), mild course, increased risk for pigmentary retinopathy; mainly described in individuals of Japanese descentc.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 relation can be seen for the following mutations if they occur in homozygous form. Manifestation of disease:Before age ten years. p.Arg59Trp, p.Arg134X, 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]
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]....
Differential DiagnosisFriedreich 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 AVEDView in own windowClinical SignFRDAAVEDCavus foot+RarePeripheral neuropathy+MildDiabetes mellitus type I+(+)Head titubationRare+Amyotrophy+–Babinski sign+(+)Retinitis pigmentosa–(+)Reduced visual acuityRare+Cardiac conduction disorder+RareCardiomyopathy+(+)Muscle weakness+–+ symptom generally present (+) symptom present only with certain mutations – symptom generally absentFRDA 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 the gene encoding peripheral myelin protein 22 (PMP22). The plasma vitamin E concentrations in CMT1A are normal. Inheritance is autosomal dominant.Ataxia-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-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 the gene encoding senataxin (SETX). 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. Ten associated genes (mutations in which appear to account for only a fraction of cases of Joubert syndrome) are INPP5E, TMEM216, AHI1, NPHP1, CEP290 (NPHP6), TMEM67, RPGRIP1L, ARL13B, CC2D2A, and CXORF5. 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.
To establish the extent of disease in an individual diagnosed with ataxia with vitamin E deficiency (AVED), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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, dysarthriaOphthalmologic examination for evidence of retinitis pigmentosa and decreased visual acuity; electroretinogram (ERG)Cardiac examination; echocardiography and ECG to assess for cardiomyopathyNeurophysiologic 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 supplementationTreatment of ManifestationsThe 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 ORThe naturally occurring form, RRR-α-tocopherolIt 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 ManifestationsIf 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].SurveillanceDuring 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 AvoidIndividuals 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 RiskPredictive 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 InvestigationSearch 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.OtherBecause 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTTPA8q12.3Alpha-tocopherol transfer proteinTTPA homepage - Mendelian genesTTPAData 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) View in own window 277460VITAMIN E, FAMILIAL ISOLATED DEFICIENCY OF; VED 600415TOCOPHEROL TRANSFER PROTEIN, ALPHA; TTPANormal allelic variants. TTPA consists of five uniformly spliced exons (ENST00000260116) with an open reading frame of 834 bp.Pathologic 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 [pdf] 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].For more information, see Table A.Table 4. Selected TTPA Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.175C>Tp.Arg59TrpNM_000370.2 NP_000361.1c.303T>Gp.His101Glnc.358G>Ap.Ala120Thrc.400C>Tp.Arg134Xc.421G>Ap.Glu141Lysc.486delTp.Trp163Glyfs*13c.513_514insTTp.Thr172Leufs*5c.530-531AG>GTAAGT p.K177Sfs*3c.548T>Cp.Leu183Proc.575G>Ap.Arg192Hisc.661C>Tp.Arg221Trpc.744delAp.Glu249Asnfs*15See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).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 seems 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. Twelve out of 24 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 or p.Arg192His) cause a mild phenotype, whereas substitutions in highly conserved amino acids are associated with early onset and severe symptoms (e.g., p.Arg59Trp, p.Glu141Lys, 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, 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].