Ataxia with Vitamin E Deficiency (AVED)

Autosomal recessive spinocerebellar ataxia caused by biallelic variants in TTPA, with very low plasma vitamin E, normal lipids and response to lifelong high-dose oral supplementation; differential diagnosis with Friedreich ataxia, the genetic hypobetalipoproteinaemias and acquired vitamin E deficiencies.

Literature and regulatory information update: 17 October 2026.

0. Initial Reference Table

The entities of the differential diagnosis covered in this article are summarised in the following table.

1. Introduction

1.1. Definition and limits of the concept

Ataxia with vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease within the hereditary cerebellar ataxias, defined by the association of progressive spinocerebellar ataxia, loss of proprioception and areflexia with a marked deficiency of vitamin E in plasma [5]. The defect lies in the liver: dietary vitamin E is absorbed normally in the intestine, but the hepatocyte does not re-export it into very low density lipoproteins (VLDL), because the alpha-tocopherol transfer protein (α-TTP), encoded by TTPA, is missing [1, 3, 30]. From this comes the feature that separates AVED from the other genetic causes of vitamin E deficiency: plasma alpha-tocopherol is reduced to a fraction of normal with a normal lipid and lipoprotein profile and without fat malabsorption [1, 31]. The diagnosis is confirmed by identifying biallelic pathogenic or likely pathogenic variants in TTPA [1].

The clinical interest of AVED comes from the combination of two facts. The first is its resemblance to Friedreich ataxia (FRDA), which makes clinical distinction alone unreliable and led to many misdiagnoses over the years [1, 12, 32, 33]. The second is the existence of a cheap oral treatment: lifelong supplementation with high-dose alpha-tocopherol prevents manifestations when started before symptoms, halts progression in symptomatic patients and may reverse part of the deficits when started early [1, 14, 34]. Reference texts in clinical genetics therefore insist on measuring vitamin E in any child or adult with Friedreich-type ataxia, especially when molecular testing for FRDA is negative [35, 36].

1.2. Historical overview

The first description of a patient with neuromyopathy and low serum vitamin E was published in 1981 by Burck and colleagues: a 12-year-old boy, the child of a consanguineous marriage, with ataxia, sensory neuropathy and generalised muscle wasting, in whose family two relatives had died of a similar picture in late adolescence; biopsy showed autofluorescent lysosomal lipopigments in muscle fibres and Schwann cells, similar to those of abetalipoproteinaemia [37]. The patient diagnosed at the age of 12 at the Hamburg centre was followed to the age of 52 and remained free of neurological progression during 36 years of individualised supplementation [38]; Traber reports in 2024 that the person identified in 1981 with low alpha-tocopherol and peripheral neuropathy was followed for more than 40 years [39]. The abstracts consulted suggest, from the age and the centre, that this is the same patient, without stating it explicitly.

In 1985, Harding and colleagues described a young woman with spinocerebellar degeneration attributed to a selective defect of vitamin E absorption, without fat malabsorption: the picture of ataxia, areflexia and marked loss of proprioception had begun at the age of 13, serum vitamin E was undetectable at 23 years and the neurological state improved with supplementation [2, 40]. The same patient had hypercholesterolaemia, xanthelasmas and Achilles tendon xanthomas, interpreted as coincidental familial hypercholesterolaemia, also present in her mother; these skin and lipid items persist in the old OMIM clinical synopsis and are not part of the AVED phenotype [2]. Other descriptions of isolated vitamin E deficiency without malabsorption followed, among them that of Kohlschütter and colleagues in 1988, who spoke of a familial neuromyopathy treatable with increased vitamin E intake [41], and the series by Sokol and colleagues, also from 1988, with four young adults (three siblings) with normal intestinal absorption, lipoprotein transport, apoB and adipose tissue fatty acids, in whom oral vitamin E (400–1200 IU/day) normalised levels and improved the neurological state of two patients; the authors postulated an inherited defect of hepatocyte secretion of vitamin E into lipoproteins [2, 31].

Kinetic demonstration of that defect came in 1990. Traber and colleagues gave about 15 mg of deuterium-labelled RRR-alpha-tocopheryl acetate to four patients and six controls: the concentration in chylomicrons was similar, but in the patients the labelled tocopherol rose in plasma only during chylomicron catabolism and disappeared more quickly from VLDL, LDL and HDL, which indicated a lack of hepatic secretion in VLDL and a defective "hepatic tocopherol-binding protein" [30]. In 1993, the same group showed with labelled stereoisomers (natural RRR and synthetic SRR) that three of seven patients did not discriminate between the two isomers and that the degree of discrimination correlated with the age at onset of neurological disability (r² = 0.64; P < 0.03) [42].

Genetics advanced in the same period. Ben Hamida and colleagues showed in 1993, in two large consanguineous Tunisian families, a Friedreich ataxia phenotype without linkage to the FRDA locus at 9q13–q21.1 and with very low serum vitamin E in the patients, the first proof of non-allelic heterogeneity of the Friedreich phenotype [43]. In the same year, by homozygosity mapping in consanguineous Tunisian families, they localised the locus to proximal 8q, with a maximum lod score of 17.9 at θ = 0 for the D8S260–D8S510 haplotype, in one of the first applications of homozygosity mapping as a primary linkage analysis [44]. Doerflinger and colleagues narrowed the interval in 1995 to about 1 cM and showed genetic homogeneity with a predominant mutation in North African populations [2, 45]. Also in 1995, Arita and colleagues cloned the complementary DNA of human α-TTP and localised the gene to 8q13.1–13.3 [4], and Ouahchi and colleagues identified the first TTPA variants in patients, among them the 744delA deletion, which accounted for 68% of the mutant alleles in 17 families [46]. Gotoda and colleagues described in the same year an adult-onset form, due to p.His101Gln, on a Japanese island [11]. In 1996, Hentati and colleagues described the structure of the gene (five exons) and the first variants in North American families [47], and in 1998 Cavalier and colleagues published 13 variants in 27 families and the first analysis of phenotypic variability [12].

1.3. Nomenclature and reclassifications

The name "ataxia with vitamin E deficiency" (AVED) is the one used by GeneReviews, OMIM and Orphanet; the alternative OMIM titles include "Friedreich-like ataxia with selective vitamin E deficiency" and "vitamin E deficiency, familial isolated; VED" [1, 2]. The cytogenetic location of the gene appears as 8q13 in the publications of the 1990s and in recent articles that follow them, and as 8q12.3 in current databases (OMIM, GeneReviews); the difference reflects the mapping of the time and not a distinct locus [2, 4, 48]. The historical nomenclature of the variants (744delA, 513insTT, 486delT, R134X) predates the current rules of the HGVS (Human Genome Variation Society), and the correspondence with the MANE (Matched Annotation from NCBI and EMBL-EBI) Select transcript NM_000370.3 is described in section 2.

There is also a discussion about the term "vitamin E" itself. The Institute of Medicine (IOM) defined in 2000 vitamin E activity for the purposes of human requirements as that of the four 2R stereoisomers of alpha-tocopherol (RRR, RSR, RRS and RSS), excluding the 2S stereoisomers, the other tocopherols and the tocotrienols, because they are not retained by α-TTP [49]. Azzi and colleagues proposed in 2023 restricting the term to RRR-alpha-tocopherol [50], and Eggersdorfer and colleagues replied that α-TTP binds all 2R forms and that AVED has been treated successfully with forms other than RRR [51]; a 2026 review signed by a consortium of 31 authors maintains AVED as the human proof of the essentiality of alpha-tocopherol and records that the definitional controversy persists [52]. The question has practical consequences for the choice of formulation, dealt with in section 7.

1.4. Entities covered and related entities

This article treats AVED as the main entity and includes, as differential diagnoses with their own subsections, the genetic causes of vitamin E deficiency treatable with replacement — abetalipoproteinaemia (MTTP), APOB-related familial hypobetalipoproteinaemia in its biallelic and heterozygous forms, chylomicron retention disease (SAR1B) and combined hypolipidaemia due to ANGPTL3 — and the acquired deficiencies [1, 6]. Friedreich ataxia and the syndromic approach to early-onset ataxias, including common symptomatic management, form part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The TTPA gene and the α-TTP protein

TTPA has five exons and encodes a cytosolic protein of 278 amino acids and 31,749 Da, with 94% similarity to rat α-TTP and structural homology with cellular retinaldehyde-binding protein (CRALBP) and with yeast Sec14, of the CRAL-TRIO domain family [4, 47]. The three-helix N-terminal domain (residues about 11–83, CRAL_TRIO_N) takes part in binding alpha-tocopherol and the diphosphate phosphatidylinositols (PIP) that form, with the protein, the ternary complex needed for vectorial transport of alpha-tocopherol in the hepatocyte [48]. Expression is mainly hepatic; it has also been described in the cerebellum (GeneReviews and the case of Baso and colleagues speak of "cerebellar pyramidal cells", a term that does not identify a classical cerebellar cell type) and in the placenta, in the trophoblast, in the endothelium of the fetal capillaries and in the amniotic epithelium [1, 48, 53].

2.2. Physiology of vitamin E transport

Of the eight natural forms of vitamin E, only alpha-tocopherol is maintained in human plasma, and within it only the 2R forms (natural RRR and the three synthetic 2R stereoisomers) [49]. Selection is performed by hepatic α-TTP: the relative affinities measured by competition are 100% for RRR-alpha-tocopherol, 38% for RRR-beta-tocopherol, 9% for gamma-tocopherol, 2% for delta-tocopherol, 11% for SRR-alpha-tocopherol and 12% for alpha-tocotrienol; the acetate ester has an affinity of 2%, because the protein binds free tocopherol after intestinal hydrolysis [49]. After absorption, alpha-tocopherol reaches the liver in chylomicron remnants; α-TTP incorporates it into nascent VLDL, which return it to the circulation, and the unbound forms are metabolised and excreted [1, 30]. This resecretion process replaces almost all circulating RRR-alpha-tocopherol daily: in controls, the half-life of RRR-alpha-tocopherol is longer than that of SRR, whereas in three patients with AVED the half-lives of the two stereoisomers were about 13 hours, equal to that of SRR in controls [42, 49].

In the absence of functional α-TTP, the absorbed vitamin E is not re-exported by the liver and is lost rapidly, partly as urinary metabolites [1, 54]. Plasma receives alpha-tocopherol only during chylomicron catabolism, by non-specific transfer to lipoproteins [30]. Traber summarises the therapeutic consequence: with large supplements, of the order of 1000 mg/day, this non-specific entry makes hepatic α-TTP unnecessary for maintaining normal plasma levels [39]. Stopping supplementation, even after years of treatment, causes plasma alpha-tocopherol to fall within 2–3 days [1, 38, 55].

2.3. Cellular and tissue mechanism

α-TTP has two functions that can be tested separately: stereoselective binding of the 2R-alpha-tocopherols and transfer of alpha-tocopherol between membranes [1]. In the hepatocyte, the protein directs the traffic of vitamin E from the endocytic compartment into transport vesicles to the plasma membrane. In cells expressing the p.Arg59Trp, p.Arg221Trp or p.Ala120Thr variants, vitamin E is retained in lysosomes and does not reach the membrane; the substitutions make the protein unstable, and the degree of impairment of secretion corresponded to the clinical severity associated with each variant [56]. The p.His101Gln protein, expressed in COS-7 cells, retains about 11% of the transfer activity of the wild type [11]. Some variants abolish stereoselectivity: patients no longer discriminate RRR from SRR-alpha-tocopherol and, when supplemented with all-rac-alpha-tocopherol, also incorporate non-2R stereoisomers [1, 42].

The most vulnerable tissue is the nervous system. Alpha-tocopherol acts mainly as an antioxidant that interrupts lipid peroxidation chains [49], and the neurological damage of human vitamin E deficiency is a neuropathy with degeneration of the large-calibre axons of sensory neurons [49]. The only published post mortem study of a patient with TTPA disease (missense variant, ataxia and retinitis pigmentosa) showed retinal atrophy, severe dying back degeneration of the posterior columns, massive accumulation of lipofuscin in neurons, including the dorsal root ganglia, and mild loss of Purkinje cells; α-TTP was expressed in the cerebellum and liver, and cerebellar tissue vitamin E remained low after oral supplementation, whereas in the dorsal root ganglia, without α-TTP expression, the concentration had normalised [57]. Comparative neurophysiology points to a distal central axonopathy in AVED, different from the sensory neuronopathy of FRDA [58].

Animal models confirm the causal relationship. The Ttpa−/− mouse develops ataxia and retinal degeneration after one year of age, with cerebral alpha-tocopherol completely depleted, a more severe phenotype on an alpha-tocopherol-poor diet and increased lipid peroxidation mainly in degenerating neurons; supplementation suppressed peroxidation and almost completely prevented the symptoms [59]. In another study, supplementation normalised plasma but increased alpha-tocopherol only modestly in the cerebellum and prefrontal cortex, and the deficient mice had cerebellar oxidative stress (protein nitrosylation), atrophy and reduced dendritic branching of Purkinje cells; the motor and cognitive deficits normalised with supplementation [60]. These data, both preclinical, help to explain why supplementation halts the disease without repairing all established deficits.

2.4. Inheritance, penetrance and heterozygosity

AVED is autosomal recessive, due to loss of function of both alleles [1]. Biochemical penetrance is complete in untreated biallelic carriers, and clinical expressivity varies: the age at onset and the course are more uniform within a family, but severity may differ between siblings with the same genotype [1, 61]; in the same family with c.744del, onset ranged from 3 to 12 years [1, 62]. Heterozygotes are asymptomatic and have no risk of disease [1]. On the Japanese island studied by Gotoda, the 21 p.His101Gln heterozygotes had serum vitamin E on average 25% lower than non-carriers (7.5 ± 2.2 vs. 10.1 ± 2.8 µg/mL; 17.4 ± 5.1 vs. 23.4 ± 6.5 µmol/L; P = 0.002) [11], and in the case of Baso and colleagues the carrier parents had normal values (11.16 and 8.35 mg/L; reference 5.6–14.8 mg/L) [48]. This overlap explains why vitamin E cannot be used to detect carriers [1].

2.5. Variant spectrum and nomenclature

ClinVar lists about 130 pathogenic or likely pathogenic records in TTPA, mainly truncating and splice site variants, and includes large copy number variations (CNV) of chromosome 8 [63]. Sequencing detects more than 97% of the pathogenic variants described; only one whole-gene deletion has been published, in a Turkish patient with AVED and deafness [1, 64]. This proportion refers to the known variants detectable by the method and is not a clinical sensitivity of the test. The following table presents the variants cited in the sources, normalised in VariantValidator for the GRCh38 genome and the MANE Select transcript NM_000370.3 / NP_000361.1, with the ClinVar classification consulted on 17 October 2026 [63, 65]. GeneReviews uses the earlier version NM_000370.2.

The p.(Asp64Gly), p.(Leu183Pro) and p.(Lys177SerfsTer3) variants come from the GeneReviews table and were not submitted to VariantValidator by the data collection; the c. notation in this table follows GeneReviews, whose numbering coincides between NM_000370.2 and NM_000370.3 for the variants that validated [1, 65]. The descriptions "c.706del (p.His236fs)" and "c.798delT", published in case reports, were not normalised. The c.58dup p.(His20fs) variant, from an Indian case with dystonia, is recorded in ClinVar as VCV002002112 [74].

2.6. Genotype-phenotype correlations

Truncating variants in homozygosity and substitutions of highly conserved amino acids are associated with early onset, around the age of 10 or before, and with a more severe course: p.Arg59Trp, p.Asp64Gly, p.Arg134Ter, p.Glu141Lys, p.Leu183Pro, p.Arg221Trp, c.487del, c.513_514insTT and c.530_531delAGinsGTAAGT [1, 12, 47]. Substitutions at poorly or semi-conserved amino acids (p.His101Gln, p.Ala120Thr, p.Arg192His, p.Gly246Arg) give mild forms with later onset: after the age of 20 with p.Ala120Thr, after the age of 30 with p.His101Gln, which is also associated with a greater risk of pigmentary retinopathy [1, 11, 67]. The c.744del variant alters only the C-terminal tenth of the protein and nevertheless correlates with a severe phenotype [46]. In Norway, the three known patients had c.400C>T; the only homozygote was the most severely affected, and the two compound heterozygotes (with c.358G>A or c.513_514insTT) had milder forms [8]. In the case of Baso and colleagues, the missense allele p.Leu53Pro in trans with a truncating variant was associated with adult onset [48]. In compound heterozygosity, and especially in homozygosity for rare variants, the correlation is less clear-cut [1].

2.7. Allelic disorders, heterogeneity and modifiers

There are no known allelic disorders of TTPA; retinopathy is a manifestation of AVED itself [1]. There are, however, families with ataxia and isolated vitamin E deficiency without TTPA variants: one of the Japanese siblings described by Aoki in 1990 was restudied and the gene was excluded [2, 75]. Patients have been described with ataxia and vitamin E deficiency associated with a variant of PLTP, the gene for a phospholipid transfer protein [76], and with variants of VLDLR, with vitamin E deficiency considered secondary [77]; these are isolated reports, without an established gene-disease relationship in the sources consulted.

The coexistence of other genetic defects modifies the picture. Cellini and colleagues described a patient with progressive ataxia from the age of 7, wheelchair-bound at 17, with cerebellar atrophy, compound heterozygosity for two TTPA variants and a CTA/CAG expansion suggestive of spinocerebellar ataxia type 8 (SCA8), who did not improve with vitamin E; the authors attributed the lack of response to the neurodegenerative process of the expansion [2, 78]. Maalej and colleagues described a patient with c.744del and mitochondrial DNA variants, including m.10044A>G in MT-TG [79]. In a highly consanguineous Tunisian family, Bouhlal and colleagues identified three causes of recessive ataxia in 11 patients: seven homozygotes for c.744del with low vitamin E, two homozygotes for an FXN variant and two with SACS variants, as well as an asymptomatic relative who was a compound heterozygote for TTPA and FXN [2, 80]. In a Spanish patient who was a compound heterozygote c.227_229delinsATT/c.744del, apoA1 and apoB were also reduced and supplementation normalised vitamin E and apoA1, but not apoB [71].

3. Clinical Spectrum and Manifestations by System

3.1. Age at onset and first manifestations

Without treatment, the disease usually begins in late childhood or early adolescence, between the ages of 5 and 15 [1]. In the largest published cohort, 132 Tunisian patients studied by El Euch-Fayache and colleagues, the age at onset was 13.2 ± 5.9 years, with a range of 2 to 37 years [10]. The mild forms linked to missense variants begin later, after the age of 20 or 30, and the Japanese patient homozygous for p.His101Gln had his first symptoms in the sixth decade [1, 11]. In a 2026 Chinese cohort of four patients, the median age at onset was 15 years (14–23) [72]. Younger siblings treated before symptoms do not develop the disease, which removes these individuals from natural history series [1, 34].

The first manifestations are progressive gait ataxia, clumsiness of the hands and loss of proprioception, especially vibration and position sense [1]. The patient has difficulty walking in the dark, the Romberg sign is positive, handwriting deteriorates and dysdiadochokinesia and dysarthria with scanning speech appear [1]. The tendon reflexes in the lower limbs are generally abolished and the Babinski sign appears with increasing intensity, the same pattern of areflexia with extensor plantar response found in FRDA [1, 35].

3.2. Frequency of manifestations without treatment

The following table reproduces the frequency of signs in the 132 untreated North African patients of the Tunisian cohort, the only series with a denominator of this size [1, 10]. This is a population with 91.7% homozygotes for the severe founder variant c.744del, which limits extrapolation to populations with other variants.

The abstract of the same study reports head tremor in 40% and frequent skeletal deformities [10]; the difference from the 33% titubation in the GeneReviews table may reflect different definitions of tremor and titubation, and the sources consulted do not explain it. In the multicentre series by Cavalier and colleagues, with 43 patients with a documented variant, from families of various origins, head titubation was recorded in 28%, dystonia in a further 13% and cardiomyopathy in 19% [12]. In the Chinese cohort, all had ataxia, dysarthria and scoliosis, three of four had foot deformity and head titubation, and two of four areflexia [72].

3.3. Peripheral nervous system and neurophysiology

The neurophysiological study of 45 of the 132 Tunisian patients, with motor conduction of the median and peroneal nerves and amplitudes of the motor and sensory potentials of the median and saphenous nerves, showed a normal examination in 9%, mild neuropathy (at least one parameter between 70% and 100% of the lower limit of normal) in 47%, moderate (30–70%) in 27% and severe (< 30% or absent response) in 17%; the neuropathy was purely sensory in 34%, purely motor in 24% and mixed in 42% [1, 10]. In the cohort as a whole, neuropathy was absent or mild in more than half of the patients [10]. Comparison of 15 patients with FRDA and 15 with an FRDA phenotype and selective vitamin E deficiency, of similar age and phenotype, showed normal motor conduction in both groups; in FRDA there was early and severe axonal sensory neuronopathy, with marked reduction of the sensory potentials and loss of large myelinated fibres without regeneration, whereas in vitamin E deficiency the axonal sensory neuropathy was mild to moderate, with normal to moderately reduced large fibre density and substantial regeneration; somatosensory evoked potentials (SSEP) were markedly abnormal in both [58].

3.4. Pyramidal signs and movement disorders

Pyramidal syndrome is frequent (Babinski sign in 85.5%) and spasticity may appear or worsen even during treatment, as observed in some Italian patients [1, 67]. Head titubation is a characteristic feature, which textbooks of metabolic diseases highlight as a pointer to vitamin E deficiency [1, 81]. There are reports of isolated head tremor as the initial presentation [82]. Dystonia, cervical, of the arm or cervicobrachial, is described as rare in GeneReviews but occurs in 13% of the Cavalier series and may be the dominant or initial manifestation [1, 12, 74, 83, 84]. Angelini and colleagues described a young man with isolated myoclonic dystonia for six years before the ataxia, with marked improvement of both on vitamin E [85]. In an Iranian series of three girls with AVED, all three had dystonia [86]. The syndromes of adult movement disorders and of peripheral neuropathy of metabolic cause include vitamin E deficiency alongside abetalipoproteinaemia [87].

3.5. Vision and retina

Reduced visual acuity is frequent in some series (8 of 11 patients in a Moroccan series) and is due to macular degeneration or pigmentary retinopathy [1, 88]. In the Tunisian cohort, pigmentary retinopathy was rare (2.3%) [1]. Retinopathy is more frequent with p.His101Gln: three of four unrelated Japanese patients developed retinitis pigmentosa after the ataxia [66]. Retinitis pigmentosa with progressive macular degeneration associated with c.717del has been described [70] and, in two consanguineous siblings, an atypical retinopathy with nummular, multifocal, hyperautofluorescent retinal atrophic plaques, stable on vitamin E, which the authors interpret as retinitis pigmentosa arrested by early supplementation [89]. Retinopathy may appear during treatment [67]. Nystagmus and oculomotor apraxia feature in the lists of ocular signs associated with vitamin E deficiency [81].

3.6. Heart

Cardiomyopathy is less frequent than in FRDA: 19% in the Cavalier series, 1.5% in the Tunisian cohort [1, 12]. Ben Hamida had noted in 1993 that Friedreich-type cardiomyopathy had not been described in patients with isolated vitamin E deficiency [2]. GeneReviews associates the c.744del variant with a slightly increased risk of cardiomyopathy [1], and there are family reports with possible cardiac involvement [90]. Marzouki and colleagues raised the hypothesis that vitamin E has a role in preventing cardiomyopathy, based on observations in Moroccan patients [62].

3.7. Cognition, behaviour and other manifestations

Psychotic episodes and intellectual decline have been described in some patients; rarely, the first manifestation is a fall in school performance due to loss of intellectual abilities [1]. Schuelke and colleagues treated a 14-year-old boy, homozygous for c.552G>A, with ataxia and organic mental syndrome: with high-dose alpha-tocopherol the mental syndrome disappeared and cognition improved rapidly, whereas neurological recovery was slow and incomplete [68]. There are isolated reports of epilepsy [91] and of deafness, the latter in the patient with a whole-gene deletion [64]. In Moroccan patients, features suggestive of a role of vitamin E in hypothalamic-pituitary regulation have been described, as a hypothesis of the authors [62]. Spermatogenesis and sperm function were normal in a man with AVED [92].

3.8. Natural history without treatment and treated disease

Without treatment, most patients become wheelchair-dependent, because of ataxia and/or lower limb weakness, between the ages of 11 and 50 [1]. Data on hereditary ataxias in general, such as the use of walking aids 5–10 years after onset, do not apply to treated AVED and should not be transposed [6]. Treated disease has a different course, with three patterns that depend on when supplementation starts [1]: in presymptomatic individuals, the manifestations do not appear; in symptomatic patients treated early, some manifestations (ataxia, intellectual deterioration) may regress; in older patients, progression may stop, but the proprioceptive deficits and gait instability persist. The cohort data supporting these patterns are in section 7.10 and the long-term prognosis in section 11.

4. Clinical Recognition and Warning Signs

4.1. When to suspect it

AVED should be considered in any progressive Friedreich-type ataxia, in children, adolescents or adults. GeneReviews brings together the suggestive findings: onset between the ages of 5 and 15; progressive cerebellar signs (gait ataxia, manual clumsiness, dysdiadochokinesia, positive Romberg sign, head titubation) with loss of proprioception, especially distal joint position sense and vibration; areflexia; Babinski sign; reduced visual acuity from macular degeneration or pigmentary retinopathy; normal lipid and lipoprotein profile with very low plasma alpha-tocopherol; and a family history compatible with recessive inheritance (affected siblings or consanguinity), the absence of which does not exclude the diagnosis [1]. Many adult patients had a previous diagnosis of FRDA, made in childhood before molecular testing, and discovered AVED only when testing for the GAA expansion came back negative [32, 33, 79, 93].

By age, the typical presentation is a school-age child with unsteadiness, falls and deteriorating handwriting; in adolescents and young adults, sensory and cerebellar ataxia with areflexia and Babinski sign; in adults, the late-onset forms due to mild variants, which may appear after the age of 30 and be associated with retinopathy [1, 11]. Autosomal recessive cerebellar ataxia with onset between childhood and young adulthood is the commonest type of ataxia, and treatable causes, with vitamin E deficiency foremost, should be considered first [81].

4.2. Pointers and warning signs

The signs that most point to AVED are the combination of ataxia with areflexia, Babinski sign and proprioceptive loss in a patient without an FXN GAA expansion; head titubation; cervical or cervicobrachial dystonia in a young person with ataxia; pigmentary retinopathy associated with ataxia; North African, Mediterranean or consanguineous community origin; and a sibling with "Friedreich" ataxia without molecular confirmation [1, 10, 81, 83]. In the Tunisian cohort, absent or mild neuropathy in a patient with a recessive ataxia phenotype and abolished reflexes was enough for the authors to propose direct testing for the c.744del variant, even before measuring vitamin E, in the Tunisian setting [10]. The absence of malabsorption, diarrhoea and acanthocytosis rules out the hypobetalipoproteinaemias and points to AVED when vitamin E is low [1, 19].

4.3. Situations requiring prompt action

The sources consulted do not describe acute emergencies specific to AVED. The clinical situation that requires prompt action is interruption of supplementation: plasma alpha-tocopherol falls within 2–3 days and the total antioxidant capacity of plasma decreases for a prolonged period, even after restarting [1, 55]. Identifying a patient entails studying the siblings as early as possible, because treatment started before symptoms prevents the disease [1, 34].

4.4. Newborn screening

AVED is not part of the biochemical newborn screening panels described in the sources. It has been included in genomic newborn screening research programmes: the Baby Detect study (NCT05687474, University Hospital Centre of Liège, Belgium; 126 treatable diseases in 361 genes; 6824 newborns; completed on 2 June 2025, with no results published in the registry) and the Early Check programme (NCT03655223, RTI International, North Carolina; active, not recruiting, with completion expected on 31 December 2026) [94]. The yield of these panels for AVED has not been published in the sources consulted.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no published consensus clinical criteria for AVED [1]. The diagnosis is established in a proband with suggestive findings (section 4.1) and biallelic pathogenic or likely pathogenic variants in TTPA; the two classes have the same clinical value, according to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [1]. Identification of two variants of uncertain significance (VUS), or of one pathogenic variant and one VUS, neither establishes nor excludes the diagnosis [1].

5.2. Measurement of plasma vitamin E

Measurement of plasma alpha-tocopherol is the first and most informative test. Ataxia UK includes lipid- and lipoprotein-adjusted vitamin E among the first-line tests for any progressive adult ataxia in secondary care [13], and the ERN-RND flowcharts for adult and early-onset ataxias include vitamin E in the biochemical panel, alongside alpha-fetoprotein, albumin, cholesterol, lactate, caeruloplasmin, phytanic acid, very long-chain fatty acids and creatine kinase [15, 95]. Since alpha-tocopherol circulates in lipoproteins, the result is read together with the lipid profile: in AVED, vitamin E is very low with normal cholesterol, triglycerides and lipoproteins, whereas in the hypobetalipoproteinaemias the deficiency accompanies the absence or reduction of apoB-containing lipoproteins [1, 19, 96].

There is no universal reference range, because values depend on the method and the laboratory [1]. The following table brings together the published values, with conversion between units using the molar mass of alpha-tocopherol (1000 mg correspond to 2326 µmol, that is, 1 mg/L ≈ 2.33 µmol/L) [49].

Sampling requires pre-analytical care, because oxidation of alpha-tocopherol by air invalidates the result: centrifuge the blood collected in EDTA immediately after sampling, separate the plasma quickly and freeze it in liquid nitrogen, fill the headspace above the plasma with an inert gas (argon or nitrogen), protect the sample from light with aluminium foil or an opaque tube and send it on dry ice [1].

5.3. Neurophysiology, imaging and ophthalmology

No neurophysiological finding is specific. Motor conduction velocities, motor potential amplitudes and sensory potentials may be normal or show neuropathy of any degree, and severe neuropathy does not exclude AVED [1, 10]. SSEP show an increased central conduction time between C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of N20 (median nerve) and P40 (tibial nerve), which may be absent [1, 68]. The comparison with FRDA is in section 3.3: in FRDA, sensory potentials are absent and motor conduction velocities reduced but above 40 m/s, whereas in AVED the sensory neuropathy is as a rule mild to moderate [35, 58].

Brain magnetic resonance imaging (MRI) shows cerebellar atrophy in about half of the patients described and, inconsistently, small T2-hyperintense foci in periventricular and deep white matter; none of these findings is specific [1, 67, 99]. MRI may be normal, as in the two siblings of Baso and colleagues and the three Iranian patients of Ashrafi and colleagues [48, 86]. Ophthalmological examination, with fundoscopy and, when available, optical coherence tomography (OCT), looks for pigmentary retinopathy and macular degeneration [1, 13].

5.4. Diagnostic algorithms

The ERN-RND flowchart for adult ataxias (published on 11 February 2019 and revised in September 2024) begins by excluding acquired causes, among them vitamin deficiencies, checks for the presence of sensory neuropathy or neuronopathy and the MRI findings and, in recessive inheritance, tests first for FRDA and for cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS, RFC1); if these are negative, it proceeds to an NGS (next-generation sequencing) panel, exome or genome, with the biochemical panel that includes vitamin E when NGS is not available or to help interpret its results [15]. The ERN-RND flowchart for early-onset ataxias (agreed in July 2020) is based on the algorithm of the European paediatric neurology group of Brandsma and colleagues, with clinical scales, MRI, neurophysiology, laboratory tests and an NGS panel, exome or genome [95, 100]. The 2014 EFNS/ENS (European Federation of Neurological Societies / European Neurological Society) consensus, read in abstract, recommends a stepwise recessive work-up that includes AVED, complete in patients with onset before the age of 45 [101].

Ataxia UK places lipid-adjusted vitamin E among the first-line tests, alongside alpha-fetoprotein, blood film, caeruloplasmin and copper, coeliac disease screening, CK, genetic testing for FRDA, spinocerebellar ataxias (SCA) 1, 2, 3, 6 and 7 and fragile X-associated tremor/ataxia syndrome (FXTAS), lactate, brain and cervical MRI and paraneoplastic and anti-GAD antibodies, and reserves for the second line cholestanol, oxysterols, coenzyme Q10, very long-chain fatty acids, phytanic acid, leukocyte enzymes and NGS [13]. In the ataxic child, the Oxford Desk Reference includes in the biochemical screen vitamin E, cholesterol, albumin, apoB-containing lipoproteins, alpha-fetoprotein, very long-chain fatty acids and phytanic acid, leukocyte enzymes and transferrin isoelectric focusing [35]; in adults, vitamin E, alpha-fetoprotein, cholesterol and albumin [36]. The metabolic approach of Saudubray adds the blood film for acanthocytes, triglycerides and, in plasma, vitamin E together with sterols, caeruloplasmin, peroxisomal studies and coenzyme Q10 [81]. The practical sequence that follows from these sources is: vitamin E and lipid profile in a Friedreich-type ataxia; if vitamin E is low with normal lipids and without malabsorption, molecular testing of TTPA; if it is low with markedly reduced lipids or apoB, investigation of the hypobetalipoproteinaemias (section 6.2); testing for the FXN GAA expansion is done in parallel, because NGS does not detect it [1, 6, 15].

5.5. Molecular testing

GeneReviews proposes two options: a multigene ataxia panel that includes TTPA, which limits VUS and findings in genes unrelated to the phenotype, or an exome (the most used option) or genome; the genes, methods and sensitivity of panels vary between laboratories [1]. In Tunisia, where 91.7% of patients are homozygous for c.744del, targeted testing for this variant is the first option [10]. The yield of NGS varies with the setting: in Rio Grande do Sul, in patients with ataxia without a vertical family history followed between 2002 and 2020, the Sanger panel gave the diagnosis in 5 of 7 (71.4%), the exome in 9 of 17 (52.9%) and the genome in 1 of 7 (14%), with limited access within the Unified Health System [102]; in a Chinese cohort of 120 probands with suspected autosomal recessive cerebellar ataxia, all studied by exome, 4 (3.33%) had AVED [72].

The limitations of the tests shape interpretation. Sequencing detects point variants and small insertions and deletions, but as a rule does not detect exon or whole-gene deletions, which require targeted deletion and duplication analysis; apparent homozygosity may result from an undetected deletion on the other allele (false homozygosity) or from uniparental isodisomy, and studying the parents clarifies these situations [1]. Panels and exomes do not detect repeat expansions, so a negative NGS result does not exclude FRDA or CANVAS [6, 103]. Multinucleotide variants may be misinterpreted if adjacent substitutions are assessed separately: Zaki-Dizaji and Sarband described in 2026 a homozygous complex allele NM_000370.3:c.296G>A;299A>C, which the authors describe as p.Gly99_Tyr100delinsAspSer, with the phase confirmed by read inspection and by Sanger sequencing and carrier parents [73]. A negative NGS result does not exclude AVED when vitamin E is very low with normal lipids; in that case deletion and duplication analysis and review of intronic variants are considered, and the rare families with isolated deficiency without TTPA variants show that other causes exist (section 2.7) [1, 75].

5.6. Report, VUS and segregation

The 2026 ERN-RND consensus on NGS in rare neurological diseases, obtained by the Delphi method with 31 experts, recommends that reports state the composition and version of the panel, the method-specific limitations (repeat expansions, for example FRDA, not detected by NGS), the minimum quality parameters and the sharing of variant interpretations; there was consensus on 27 of 28 topics, with no consensus on who should request NGS [103]. For AVED, the report should state the gene, the transcript with version (NM_000370.3), the HGVS c. and p. nomenclature, the zygosity, the phase when there are two variants and the ACMG/AMP class [1, 103]. A VUS in trans with a pathogenic variant, in a patient with very low alpha-tocopherol and normal lipids, may be reassessed by family segregation and the biochemical phenotype, as in the case of Baso and colleagues, in which the novel p.Leu53Pro variant was associated with disease and low vitamin E only in a biallelic combination [48]. The authors acknowledge that pathogenicity was not demonstrated by a functional study [48].

5.7. Carriers and prenatal diagnosis

Vitamin E in heterozygotes overlaps with that of non-carriers, and carrier detection is exclusively molecular [1, 11]. Prenatal diagnosis and preimplantation genetic diagnosis are possible once the two familial variants have been identified (section 8) [1].

6. Differential Diagnosis

6.1. Comparative table

6.2. Friedreich ataxia

FRDA has a similar age at onset and the same core semiology of ataxia, areflexia, proprioceptive loss and Babinski sign, and the distinction cannot be made on clinical grounds alone; only in AVED is plasma vitamin E low [1, 88]. Benomar and colleagues compared AVED patients with c.744del and FRDA patients with the GAA expansion in 15 Moroccan families: of 29 patients with a Friedreich phenotype, 13 had AVED [1, 88]. The features that favour AVED are head titubation, dystonia, the lower frequency of cardiomyopathy and the less severe sensory neuropathy, with fibre regeneration on biopsy; those that favour FRDA are cardiomyopathy, absent sensory potentials, scoliosis and pes cavus [6, 12, 58]. Scoliosis and foot deformities also occur in AVED, especially in the Tunisian and Chinese cohorts, and do not discriminate by themselves [10, 72]. The Tunisian family of Bouhlal, with AVED, FRDA and ARSACS in the same extended sibship and a relatively homogeneous phenotype, shows that, in consanguineous populations, molecular confirmation is needed in each patient [2, 80].

6.3. Abetalipoproteinaemia

Abetalipoproteinaemia (Bassen-Kornzweig syndrome) is caused by biallelic variants in MTTP, which encodes microsomal triglyceride transfer protein, needed for the assembly of apoB-containing lipoproteins in the intestine and the liver; it is the most severe known vitamin E deficiency [2, 19]. It begins in infancy, in the classical form from birth, with failure to thrive, diarrhoea, vomiting, steatorrhoea and hepatomegaly; laboratory tests show acanthocytosis, anaemia, reticulocytosis and haemolysis, prolonged INR, total cholesterol about 1 mmol/L (about 40 mg/dL), LDL and apoB absent or extremely low, very low triglycerides, low to average HDL, transaminases 1–1.5 times the upper limit and low vitamins A, D, E and K [19]. Neuromuscular manifestations appear in the first or second decade (loss of reflexes, vibration sense and proprioception, weakness, dysarthria, broad-based ataxia and steppage gait in young adults), and the atypical retinal pigmentation, with loss of night and colour vision, appears in adulthood [19]. Ptosis and ophthalmoplegia are attributed to demyelination from vitamin E deficiency [19]. The Japanese entry criteria are LDL cholesterol < 15 mg/dL and/or apoB < 15 mg/dL, with total cholesterol typically 20–50 mg/dL, triglycerides < 10 mg/dL without a rise after a fat load and acanthocytes frequently above 50% of erythrocytes [104]. Obligate heterozygous parents have normal lipids [19, 21]. Before supplementation, typical survival did not extend beyond the third decade; with lifelong supplementation, survival to the seventh or eighth decade has been described [19, 104].

6.4. APOB-related familial hypobetalipoproteinaemia

FHBL1 is codominant. The biallelic form, rare (estimated at less than 1/1,000,000), presents from infancy to adulthood with total cholesterol, LDL and apoB below the 5th percentile for age and sex, acanthocytosis, raised liver enzymes, hyperbilirubinaemia, hepatomegaly, steatorrhoea and failure to thrive; without treatment, atypical retinopathy, loss of reflexes, vibration sense and proprioception, myalgias, weakness, dysarthria, ataxia, tremor and steatohepatitis appear, at times fibrosis and rarely cirrhosis [23]. Moderate hypolipidaemia in first-degree relatives distinguishes biallelic FHBL1 from abetalipoproteinaemia, in which the parents have normal lipids [19, 21, 24]. The heterozygous form due to truncating variants occurs in about 1 in 3000 people; it is usually asymptomatic, with mild hepatic dysfunction and steatosis, and 5–10% develop more severe non-alcoholic steatohepatitis, rarely cirrhosis [23]. Saudubray describes in heterozygosity, in addition, partial fat malabsorption in children or adults and gallstones in adults [20].

The sources differ on the treatment of the heterozygous form. GeneReviews states that heterozygotes generally need no treatment [23]; Saudubray indicates vitamin E to prevent adult-onset neuropathy [20]; and Ataxia UK, as a good practice point (GPP), recommends considering, in the moderate form of hypobetalipoproteinaemia, reducing the proportion of fat in the diet and supplementation with vitamin E [13]. None of the three sources presents outcome data to support its position. In practice, the decision depends on whether vitamin E is low and neurological signs are present, because the Ataxia UK recommendation is addressed to patients with ataxia.

6.5. Chylomicron retention disease

Chylomicron retention disease (CMRD), also called Anderson disease or type II abetalipoproteinaemia, results from biallelic variants in SAR1B, which encodes the Sar1b GTPase needed for the secretion of chylomicrons by enterocytes [20, 26, 81]. It begins in infancy with failure to thrive, diarrhoea, vomiting, abdominal distension, steatorrhoea proportional to the fat ingested and hepatomegaly; the neuromuscular manifestations, from vitamin E deficiency, appear in the first or second decade, bone mineralisation is deficient from vitamin D deficiency and the INR is prolonged from vitamin K deficiency [26]. Ophthalmological changes are mild (micronystagmus, slow dark adaptation, abnormal visual evoked potentials and scotopic electroretinogram), and a small proportion of adults have cardiomyopathy with reduced ejection fraction [26]. Laboratory tests show marked hypocholesterolaemia (reduction of more than 50%), low but present apoB, normal triglycerides, CK 1.5 to 5 times the upper limit, frequent macrovesicular steatosis, essential fatty acid deficiency and invariable vitamin E deficiency; endoscopy shows the duodenal "gelée blanche" appearance with fat-laden enterocytes [20, 26, 27]. Acanthocytosis is rare and hardly compatible with the diagnosis, and the pigmentary retinopathy typical of abetalipoproteinaemia is absent [19, 27]. About 40 patients have been described [26].

6.6. ANGPTL3-related familial combined hypolipidaemia

The GeneReviews overview of hereditary ataxias includes ANGPTL3, of autosomal recessive inheritance, among the genetic causes of vitamin E deficiency treatable with replacement, with neuropathy, retinopathy and acanthocytosis in addition to ataxia [6, 106, 107]. The sources consulted provide no cohort, frequency or dose data for this entity.

6.7. Acquired vitamin E deficiencies

A healthy individual becomes deficient in vitamin E only after months of a diet very poor in this vitamin; this has been seen in children on severely unbalanced diets, such as the Zen macrobiotic diet, but it occurs mainly in chronic diseases that prevent absorption of fat-soluble vitamins in the distal ileum: cholestatic liver disease, short bowel syndrome, cystic fibrosis and Crohn disease [1]. Coeliac disease with malabsorption may cause ataxia from vitamin E deficiency [29], and in cystic fibrosis neurological function relates to serum vitamin E [105]. In children with untreated chronic cholestatic disease, the combination of spinocerebellar ataxia, neuropathy and ophthalmoplegia becomes established by the end of the first decade, and progression is slower in cystic fibrosis and in abetalipoproteinaemia; the symptomatology of AVED is similar to that of these latter patients [49]. These patients should be supplemented orally but do not need the high doses used in AVED [1]. Gluten ataxia, vitamin B12 deficiency and autoimmune and paraneoplastic causes form part of the differential diagnosis of the treatable acquired ataxias of Ataxia UK [13].

6.8. Other ataxias with the same age at onset

Recessive ataxias with onset before the age of 20 include FRDA and ataxias with oculomotor apraxia types 1 and 2, and before the age of 5 ataxia-telangiectasia; alpha-fetoprotein and albumin point to these entities [6, 35]. ARSACS (SACS) should be considered when FRDA testing is negative, because of lower limb spasticity, mixed neuropathy and hypermyelinated retinal nerve fibres [35]. Among the ataxias amenable to specific treatment, Ataxia UK highlights, alongside AVED and abetalipoproteinaemia, coenzyme Q10 deficiency, cerebrotendinous xanthomatosis (chenodeoxycholic acid) and Niemann-Pick disease type C (miglustat), and in children GLUT1 glucose transporter deficiency, Hartnup disease and biotinidase deficiency [13].

7. Treatments and Risk Management Strategies

7.1. Principles and quality of the evidence

There are no clinical practice guidelines specific to AVED [1]. The only graded recommendation found is that of the Ataxia UK guideline on the diagnosis and management of the progressive ataxias (2016 edition, published in 2019 and still indicated as the most recent by the association): patients with AVED or abetalipoproteinaemia should be treated with vitamin E supplements, a grade C recommendation, with no dose stated [13, 108]. The treatment of choice is lifelong oral supplementation with high-dose alpha-tocopherol, with which plasma alpha-tocopherol may normalise [1]. No large-scale therapeutic studies have been performed to define the optimal dose or to assess outcomes, and there is no randomised trial [1, 38]. The doses and results that follow come from case series, observational cohorts and reviews, and are presented as such.

7.2. Formulations and units

The oral formulations used in AVED are all-rac-alpha-tocopherol (synthetic racemic, generally as the acetate, historically labelled "dl-alpha-tocopherol") and RRR-alpha-tocopherol (natural form, historically labelled "d-alpha-tocopherol") [1, 49]. The published doses are expressed sometimes in milligrams, sometimes in international units (IU), and the meaning of one unit depends on the form. The following table summarises the official equivalences of the IOM and of the Office of Dietary Supplements (ODS) of the United States National Institutes of Health [49, 109].

Before 1980, the United States Pharmacopeia (USP) defined 1 IU as 1 mg of all-rac-alpha-tocopheryl acetate; after 1980 the USP unit kept the same equivalence (1 mg of all-rac acetate, 0.67 mg of RRR-alpha-tocopherol or 0.74 mg of RRR acetate) [49]. The IOM, by restricting vitamin E activity to the 2R forms, considers that all-rac-alpha-tocopherol has half the activity of RRR, and the ODS summarises the practical rule: 1 mg of vitamin E corresponds to 1 mg of RRR-alpha-tocopherol or to 2 mg of all-rac-alpha-tocopherol [49, 109]. Tocofersolan (d-alpha-tocopheryl polyethylene glycol 1000 succinate) is a water-soluble prodrug that forms micelles and is hydrolysed in the intestinal lumen [110]. The AVED doses in milligrams quoted by GeneReviews and by the series do not, in most cases, specify the chemical form; Baso and colleagues, for example, do not state the form of the 800 mg/day they administered [1, 48].

7.3. Published doses

The recommended daily allowance (RDA) of alpha-tocopherol for the healthy population is 15 mg/day from the age of 14, 6 mg from 1 to 3 years, 7 mg from 4 to 8 years and 11 mg from 9 to 13 years, 15 mg in pregnancy and 19 mg in lactation [49, 109]; doses of 800–1500 mg/day correspond, in adults, to about 53 to 100 times the RDA, the range of 50–100 times mentioned by Fogel and colleagues [111]. In children, 40 mg/kg/day represent 400 mg/day at 10 kg and 1200 mg/day at 30 kg. The sources consulted do not define a maximum dose for AVED or a paediatric ceiling; Ashrafi and colleagues give the dose divided through the day [86]. Adjustment is made by plasma alpha-tocopherol, with the aim of keeping it in the normal-high range and with measurement every 6 months, especially in children [1]: in the first Hamburg patient, an individualised regimen kept levels moderately above normal for 36 years [38]. For the tocofersolan formulations, the summary of product characteristics (SmPC) of Vedrop® recommends monthly monitoring of the plasma level in the first months, within the authorised indication [110].

7.4. RRR- or all-rac-alpha-tocopherol

GeneReviews considers it unknown whether patients should be treated with all-rac-alpha-tocopheryl acetate or with RRR-alpha-tocopherol and, because α-TTP binds the 2R-alpha-tocopherols stereoselectively, because some variants lose that selectivity and because the adverse effects of the synthetic stereoisomers have not been studied in detail, concludes that it seems appropriate to treat with RRR-alpha-tocopherol, despite the higher cost [1]. Traber argues differently: in AVED, RRR- and SRR-alpha-tocopherol are absorbed and lost in the same way, without stereoisomeric discrimination, and both forms have been used successfully [39, 42]. Eggersdorfer and colleagues maintain that AVED has been treated successfully with forms other than RRR [51], and Azzi and colleagues that only RRR-alpha-tocopherol has been used medically against a deficiency disease and that prescribing other tocochromanols as vitamin E without testing may lead to ineffective treatment [50]. There are no comparative studies of the two forms in AVED. In abetalipoproteinaemia and CMRD, a crossover study in seven patients compared tocofersolan with alpha-tocopheryl acetate: bioavailability was very low in abetalipoproteinaemia (2.8% and 3.1%) and higher in CMRD (24.7% and 11.4%), with no difference in plasma alpha-tocopherol at 4 months [113]. The other tocopherols (beta, gamma, delta) and the tocotrienols do not substitute for alpha-tocopherol, because α-TTP binds them poorly and they are not maintained in plasma [49, 50].

7.5. Safety, tolerable upper intake level and interactions

The IOM tolerable upper intake level (UL) for the healthy population, applicable to all forms of supplemental alpha-tocopherol, is 200 mg/day from 1 to 3 years, 300 mg/day from 4 to 8 years, 600 mg/day from 9 to 13 years, 800 mg/day from 14 to 18 years and 1000 mg/day from the age of 19, including in pregnancy and lactation; it could not be established in infants [49, 109]. The adult value was derived from the haemorrhagic effect in rats: a lowest observed adverse effect level of 500 mg/kg/day, divided by an overall uncertainty factor of 36, gave 14 mg/kg/day, which multiplied by the reference weight of 68.5 kg results in 959 mg/day, rounded to 1000 mg/day (1500 IU of the natural form or 1100 IU of the synthetic form) [49, 109]. The paediatric values were extrapolated by body weight, because there are no reports of toxicity in children and adolescents [49]. The IOM itself specifies that the UL does not apply to people receiving vitamin E under medical supervision [49]. The doses used in AVED exceed the UL and are therefore a treatment to be prescribed and monitored by a physician, not an over-the-counter supplement to be used on one's own initiative [49, 109]. Human safety data come mainly from small groups with doses up to 3200 mg/day, as a rule below 2000 mg/day, over weeks to a few months, which calls for caution in extrapolating to use over several years [49].

The main risk is haemorrhagic. High-dose alpha-tocopherol inhibits platelet aggregation and antagonises the vitamin K-dependent clotting factors; with warfarin or antiplatelet agents, especially with low vitamin K intake, it increases the risk of bleeding, and the amounts with a clinical effect are unknown, probably above 400 IU/day [109]. The haemorrhagic effects in animals are corrected with vitamin K, and people with vitamin K deficiency are at greater risk of clotting disturbances [49]. The Vedrop® SmPC requires monitoring of prothrombin time and INR in patients with vitamin K deficiency or taking vitamin K antagonists [110]. In the general population, two trials associated alpha-tocopherol with more haemorrhagic strokes (ATBC, 50 mg/day in Finnish smokers; PHS II, 400 IU on alternate days), and the SELECT trial associated 400 IU/day of dl-alpha-tocopheryl acetate with more prostate cancer [109]; these trials tested prevention in adults without deficiency and do not inform directly about AVED. In preterm newborns weighing ≤ 1.5 kg, 200 mg/day of alpha-tocopheryl acetate was associated with more necrotising enterocolitis [49]. The ODS also reports that antioxidants blunt the rise in HDL cholesterol with simvastatin and niacin and advises caution during chemotherapy and radiotherapy [109].

The adverse effects described in the Vedrop® SmPC are diarrhoea (common), abdominal pain and, as uncommon, alopecia, pruritus, rash, asthenia, headache, changes in sodium and potassium and raised transaminases; the medicine inhibits P-glycoprotein and may increase the absorption of other fat-soluble vitamins and of lipophilic drugs (steroids, antibiotics, antihistamines, ciclosporin, tacrolimus), contains parabens (E219, E215) and 0.18 mmol (4.1 mg) of sodium per mL, and is contraindicated in preterm newborns; in renal disease or dehydration it is used with caution and monitoring of renal function, because polyethylene glycol may damage the kidney, and in liver disease with monitoring of liver function [110]. The sources consulted do not describe adverse effects specific to prolonged supplementation in the AVED cohorts.

7.6. Regulatory status

No vitamin E formulation has a marketing authorisation for AVED, in the United States or in the European Union; prescribing high-dose alpha-tocopherol in this disease is an off-label use [110, 114].

7.7. Therapeutic studies

These studies are case reports and uncontrolled series, with different scales and durations; they do not allow the effect to be estimated with confidence intervals, they have no comparison group and they do not permit indirect comparisons with one another. The 1-point fall in SARA at 6 months in the case of Baso occurred with associated physiotherapy and cannot be attributed to vitamin E alone [48]. The most consistent information is qualitative and is repeated in different populations: presymptomatic treatment prevents, early treatment halts and may improve, and late treatment stabilises without recovering the proprioceptive deficits and the reflexes [1, 14, 34, 69]. Fogel and colleagues describe long-term stabilisation without improvement of the cerebellar deficits [111]. There are reports of lack of response: the patient of Cellini with a concomitant SCA8 expansion did not improve [2, 78], and Agarwal and colleagues report, citing other authors, that variants causing exon skipping may be associated with resistance to vitamin E [112]. A search of ClinicalTrials.gov identified no interventional trials directed at AVED, and a negative search does not prove that no studies exist in other registries [94].

7.8. Adherence and interruption

Supplementation has to be lifelong. Short interruptions, from poor adherence, do not cause immediate symptoms but produce a prolonged fall in the total antioxidant capacity of plasma (TRAP, total radical-trapping antioxidant parameter), which is not compensated by urate or by sulfhydryl groups [55]. Plasma alpha-tocopherol falls within 2–3 days of interruption, even after years of massive supplementation [1, 38]. Educating the patient and family about these kinetics, and regular measurement, are the way to detect poor adherence [1, 55].

7.9. Symptomatic treatment and rehabilitation

Symptomatic management follows that of the hereditary ataxias: a team with neurology, occupational therapy, physiotherapy, physical and rehabilitation medicine, orthopaedics, nutrition, speech and language therapy, respiratory medicine and mental health [1, 6]. Physiotherapy includes balance and gait training and strengthening, with adaptive devices (sticks, walking frames, ramps, weighted utensils) and home adaptations; inpatient rehabilitation with occupational therapy and physiotherapy, of 4 weeks in the American Academy of Neurology (AAN) review, may improve ataxia and function [6, 117]. Spasticity is treated with baclofen, tizanidine or dantrolene; dysarthria with speech and language therapy and alternative communication; dysphagia with consistency modification and assessment by videofluoroscopy; scoliosis with orthopaedics and, if necessary, surgery [6]. Riluzole, 100 mg/day (with no age of application or maximum dose defined in the source), is the only drug with demonstrated improvement of symptoms in ataxias of mixed aetiology and requires monitoring of liver enzymes; the EFNS/ENS consensus assigns it level B and amantadine level C, regardless of aetiology, and the 2018 AAN systematic review, since withdrawn by the society, considered riluzole probably effective at 8 weeks and at 12 months in class I studies [6, 101, 117]. None of these studies specifically included patients with AVED. Cerebellar transcranial magnetic stimulation may improve motor signs after 21 daily sessions [6]. Neurogenic urinary and sexual symptoms, frequent in the ataxias (urinary urgency in 22.4% of the Tunisian cohort), follow the NEUROGED recommendations of the European Academy of Neurology, published by ERN-RND in a version for ataxias and hereditary spastic paraplegias [1, 118].

7.10. Agents and situations to avoid

Smoking should be avoided, because it considerably reduces TRAP and plasma vitamin E [1, 119]. Occupations that require rapid responses or good balance are to be avoided [1]. Combining high doses of alpha-tocopherol with warfarin, other vitamin K antagonists or antiplatelet agents requires monitoring of coagulation (section 7.5) [109, 110]. Tocochromanols other than alpha-tocopherol (tocotrienols, gamma-tocopherol, "tocopherol" mixtures) should not be substituted for alpha-tocopherol [49, 50].

7.11. Pregnancy, lactation, perioperative period and transition

Because reduced vitamin E levels are associated with low fertility and embryonic resorption in mice and α-TTP is highly expressed in the human placenta, GeneReviews advises keeping vitamin E at a normal-high level during pregnancy in women with AVED [1, 53, 120]. The sources consulted do not describe series of pregnancies in women with AVED. The Vedrop® SmPC has no clinical data in pregnancy and animal studies showed no harmful effects [110]. The UL of 1000 mg/day in pregnancy and lactation from the age of 19 refers to the healthy population and does not apply to supplementation under medical supervision [49]. There are no data on passage into breast milk of the therapeutic doses used in AVED in the sources consulted; the requirement in lactation in the general population is 19 mg/day [49]. A man with AVED had normal spermatogenesis and sperm function [92].

The sources consulted contain no perioperative recommendations for AVED. The applicable data are the fall in alpha-tocopherol within 2–3 days when supplementation is interrupted, relevant in prolonged fasting, and the haemorrhagic risk of high-dose alpha-tocopherol in the presence of vitamin K deficiency or anticoagulation [1, 49, 110]. Nor are there specific guidelines for the paediatric-to-adult transition; biochemical surveillance is closer in children (section 11), and the move to the adult clinic must ensure continuity of prescription and measurement [1].

7.12. Treatment in the lipoprotein differentials

The comparison shows a difference in pathophysiology: in abetalipoproteinaemia, despite doses of 100–300 IU/kg/day, the patient always has low vitamin E, because the lipoprotein route is missing, and the aim is prevention of neurological and retinal disease, not normalisation of the level [19, 104]; early treatment with vitamin E may delay or prevent neurological dysfunction and ophthalmoplegia [19, 122], and the combination of vitamins A and E started before the age of 2 markedly attenuates retinal degeneration [123, 124]. In CMRD, the oral route may prevent neurological complications despite chronically low serum levels, and erythrocyte alpha-tocopherol has been proposed as a biomarker of efficacy [27, 98]. In AVED, by contrast, absorption and lipoprotein transport are intact and the aim is normalisation of plasma alpha-tocopherol [1, 39].

7.13. Developments in the last 12 months

The window from October 2025 to October 2026 brought no clinical trials, regulatory applications or new treatments for AVED; the review by Fogel and colleagues on the recessive ataxias lists no investigational treatment for AVED, unlike other metabolic ataxias [94, 111]. The developments published are observational and diagnostic: the Chinese cohort of recessive ataxias with AVED in 3.33% and two novel variants [72]; the novel p.Leu53Pro variant in two Italian siblings [48]; the homozygous multinucleotide complex allele described with attention to phase [73]; the ataxia series from southern Brazil, Latvia and the Philippines [102, 125, 126]; the ERN-RND consensus on NGS reports [103]; the vitamin E centenary review [52]; and the publication by ERN-RND of the version of the NEUROGED recommendations for ataxias and spastic paraplegias, on 28 July 2026 [118]. In genomic newborn screening, the Baby Detect study, which includes AVED, ended in June 2025 without results in the registry, and Early Check remains active [94]. The most relevant preclinical evidence continues to be that of the Ttpa−/− model [59, 60].

7.14. Guideline recommendations and divergences

The sources diverge on three points. On the chemical form, GeneReviews prefers RRR-alpha-tocopherol, and Traber and Eggersdorfer consider all 2R forms adequate, including those of all-rac (section 7.4) [1, 39, 51]. On the dose, the sources give values from 800 mg/day to 1500 mg/day in adults (about 40 mg/kg/day in children), with no dose-response study and no maximum dose defined, and the effective dose is set by the plasma level and not by a fixed value [1, 14, 39]. On heterozygous FHBL1, GeneReviews, Saudubray and Ataxia UK give different answers (section 6.4) [13, 20, 23].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

AVED is transmitted in an autosomal recessive manner [1]. The parents of a patient are presumed heterozygotes, and molecular testing of the parents is recommended to confirm heterozygosity, calculate the recurrence risk and determine the phase of the variants [1]. If only one parent is a carrier, with confirmed parentage, the other variant may have arisen de novo in the proband or exist as post-zygotic mosaicism in one of the parents; apparent homozygosity may correspond to a deletion of one or more exons not detected by sequencing or to uniparental isodisomy [1]. Each sibling of a patient has a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of being a non-carrier; siblings with the same variants may have different severity [1, 61]. Heterozygotes are asymptomatic and at no risk of disease [1]. The children of a patient are obligate carriers, unless the other parent is affected or a carrier, and each sibling of the parents of a patient has a 50% risk of being a carrier [1].

8.2. Testing of siblings and cascade testing

The genetic status of all siblings should be clarified as early as possible, and predictive testing of siblings, including minors, is appropriate, because treatment started before symptoms prevents the manifestations [1, 34]. Testing of asymptomatic minors is justified here by the direct benefit: a positive result leads to preventive treatment. Lv and colleagues recommend proactive screening of siblings and at-risk relatives before symptoms [72], and Biglari and colleagues genetic screening in consanguineous communities, where c.219T>A has a possible founder effect [69]. Vitamin E does not identify carriers; cascade testing is molecular, using the familial variants [1, 11, 48]. In highly consanguineous families, the coexistence of other recessive ataxias, as in the Tunisian family with AVED, FRDA and ARSACS, makes counselling more difficult and requires molecular characterisation of each patient [2, 80].

8.3. Family planning, carriers and partners

Genetic counselling should be offered before pregnancy to young adults who are affected, carriers or at risk of being carriers [1]. Carrier testing of the partner is relevant when one member of the couple is affected or a carrier, especially if both have the same ethnic origin or belong to the same community [1]. In founder populations, targeted testing for the local variant (c.744del in North Africa and the Mediterranean; c.303T>G p.His101Gln on the Japanese island studied) is the first option [10, 11]. The gnomAD frequencies (section 9.2) cannot be used to estimate carrier risk in these communities [127].

8.4. Prenatal and preimplantation diagnosis

Once the familial pathogenic variants have been identified, prenatal diagnosis and preimplantation genetic diagnosis are possible [1]. Views on the use of prenatal diagnosis vary between professionals and families, especially in a treatable disease, and the decision is personal [1]. The existence of an effective oral preventive treatment is part of the information to be given in counselling.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

These values are of different natures. Those from Padua, Norway and Alsace are European regional prevalence estimates; that from the Japanese island is a prevalence calculated in an isolated community with a founder effect; those from Morocco, Tunisia and China are proportions in clinical series and do not measure population prevalence [1, 3]. Any single value underestimates the risk in consanguineous or founder populations [3]. By 2014, more than 91 patients had been described worldwide, most of Mediterranean origin, and 22 variants [10].

9.2. Founder populations and allele frequencies

c.744del is the commonest variant in Tunisia and worldwide, with a Mediterranean and North African founder effect (Tunisia, Libya, Morocco, Algeria, Italy); in Morocco, 16 patients from seven families were all homozygous for it [1, 10, 62]. Doerflinger's haplotyping already indicated a predominant variant in North African populations, where the disease is unusually frequent [2]. In Italy, the commonest variants in 16 patients from 12 families were c.744del and c.513_514insTT [67]. In families of European and North American origin, c.513_514insTT, c.487del and c.400C>T predominate [12, 47]. In Japan, p.His101Gln was found in four unrelated patients, with a common haplotype [11, 66]. In Iran, c.219T>A has a possible founder effect [69].

In gnomAD v4 (about 1.6 million alleles), the commonest variants are c.513_514insTT (288 alleles; 1.78 × 10⁻⁴; 262 in non-Finnish Europeans), c.575G>A (130; 8.06 × 10⁻⁵), c.400C>T and c.358G>A (91 each; 5.64 × 10⁻⁵), c.487del (75; 4.65 × 10⁻⁵), c.661C>T (46) and c.744del (42; 2.87 × 10⁻⁵; 30 in non-Finnish Europeans and 8 in Latin Americans); c.303T>G p.His101Gln appears in 5 alleles, all in East Asians, and there are no homozygotes [127]. Because gnomAD under-represents North Africa and consanguineous populations, these frequencies do not estimate the carrier frequency in founder populations [127].

9.3. United States, Europe, Portugal and Brazil

In the United States, the sources consulted describe North American families with c.487del or 485delT, c.513_514insTT and c.575G>A [47], the Sokol series [31] and cases with cervical dystonia [83, 84], but no prevalence estimates. In Europe, besides the regional estimates, there are first national cases published in the Netherlands (woman of 36 years with a previous diagnosis of FRDA) and in Norway (woman of 45 years, compound heterozygote p.Ala120Thr/p.Arg134Ter) [32, 33], and cases in Spain [71, 90]. The sources consulted contain no epidemiological data on AVED in Portugal. In Brazil, the 20-year series of the Hospital de Clínicas de Porto Alegre in ataxias without a vertical family history (174 patients began investigation, 120 returned for the second consultation and 45 received a diagnosis) does not list AVED among the commonest diagnoses, which were FRDA, ataxia-telangiectasia, coenzyme Q10 deficiency, Niemann-Pick disease type C, ataxia with oculomotor apraxia type 2 and spinocerebellar ataxia type 2 [102]. Absence in the sources consulted does not demonstrate the absence of patients in these countries. Outside these regions there are cases and series in India [74, 112], Iran [69, 86], China [72], Turkey [64] and the Philippines, where a scoping review considers underdiagnosis likely because of limited access to testing [126, 128].

9.4. Special populations

In consanguineous communities, the frequency of AVED is higher and several recessive ataxias may coexist in the same family [69, 80]. In low-resource settings, measurement of vitamin E, a first-line test, identifies candidates for molecular testing and treatment [13, 126]; in Tunisia, targeted testing for c.744del serves the same purpose [10]. In children, biochemical surveillance is closer [1].

9.5. Reference networks and patient associations

The relevant European reference network is ERN-RND, whose group on ataxias and hereditary spastic paraplegias publishes the diagnostic flowcharts cited and the resources for patients (https://www.ern-rnd.eu/disease-knowledge-hub/ataxia/) [15, 95]; the case in section 10 was followed at a centre of ERN EURO-NMD, for neuromuscular diseases [48]. The patient associations include euro-ATAXIA (European Federation of Hereditary Ataxias), Ataxia UK, the National Ataxia Foundation of the United States (founded in 1957, based in Minneapolis, which organised an online seminar dedicated to AVED), NORD, APAHE in Portugal and ABAHE in Brazil; MedlinePlus Genetics has a page on AVED [1, 16–18, 129].

10. Illustrative Clinical Case

Baso and colleagues described in 2026 two siblings followed in the neuromuscular disease clinic of the Policlinico in Milan, a centre of ERN EURO-NMD, the children of non-consanguineous parents and with no other siblings [48]. Both had noticed in adulthood a clumsiness when playing sport, compared with their peers. The brother, aged 28, reported since the age of 20 progressive clumsiness of the arms, weakness of the lower limbs, falls and altered speech. The sister, aged 36, had since the age of 21 recurrent neck pain, followed by gait instability with loss of balance and falls during risky tasks, especially in the dark, and a nasal voice; there were no visual complaints [48].

Examination showed in both dysarthria with scanning speech, mild head titubation and dysdiadochokinesia. The brother had mild symmetrical weakness, proximal and distal, diffuse areflexia, distal loss of proprioception and bilateral Babinski sign, with ataxic gait especially in tandem walking and on the Unterberger test, but without walking aids; the SARA score was 13 out of 40. The sister had preserved strength, diffuse areflexia and loss of proprioception, without Babinski sign, with a positive Romberg sign, inability to maintain the tandem position without intermittent support and a SARA of 19 out of 40 [48]. Brain MRI and cerebellar volume were normal; sensory and motor potentials were preserved and electromyography showed a mild diffuse increase in the amplitude and/or duration of motor unit potentials; fundoscopy, visual acuity and sphincter function were normal, without OCT [48].

A clinical exome focused on the phenotype of central and peripheral ataxias identified in both the variants NM_000370.3:c.513_514insTT p.(Thr172LeufsTer5), in exon 3, inherited from the mother and classified as pathogenic (rs397515379), and c.158T>C p.(Leu53Pro), in exon 1, inherited from the father, novel, absent from population databases, with a PolyPhen-2 score of 1.00, confirmed by Sanger sequencing [48]. With a balanced diet, normal lipids and no ileal disease, plasma alpha-tocopherol was 1.36 mg/L in the brother and 1.26 mg/L in the sister (reference 5.6–14.8 mg/L); the parents, each a carrier of one variant, had a normal neurological examination and values of 11.16 mg/L (mother) and 8.35 mg/L (father) [48]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC13186537/figure/F1/) is the two-generation pedigree, with the two affected siblings marked as probands and the genotypes and pre-supplementation vitamin E levels of each member; Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC13186537/figure/F2/) is a structural model of α-TTP in which Leu53, in the N-terminal domain, lies next to the cluster of positively charged residues on the inner wall of the binding pocket for alpha-tocopherol and the PIP; the figure results from in silico modelling, without functional data [48].

Both started 800 mg/day of oral vitamin E. At 3 months, plasma alpha-tocopherol had risen to 6.35 mg/L in the brother and 14.4 mg/L in the sister; at 6 months of treatment combined with physiotherapy, the SARA fell by 1 point in both (12 and 18 out of 40), with subjective improvement, and repeat nerve conduction studies and electromyography were unchanged [48]. The authors propose that the missense allele attenuates the effect of the truncating variant, with onset in late adolescence or adulthood and gait preserved around the age of 30, and call for functional studies to define the pathogenicity of p.Leu53Pro [48].

The case shows three points of general value. The first is the adult onset, with neck pain as the first complaint in one of the siblings, outside the classical range of 5–15 years [1]. The second is the diagnostic sequence: MRI and neurophysiology did not point the way, and the diagnosis came from the exome, confirmed by measurement of vitamin E, when the sequence proposed by the sources is the reverse (section 5.4) [1, 13]. The third is the heterogeneous biochemical response to an equal dose: in the brother, the level at 3 months was at the lower limit of the reference range, below the normal-high target recommended by GeneReviews; the article does not describe a dose adjustment or the chemical form used [1, 48].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends on when treatment starts and on the genotype. Without treatment, most patients lose independent walking between the ages of 11 and 50 [1]. With presymptomatic treatment, the manifestations do not appear [1, 34]. With early treatment, progression stops and some signs may regress, such as the intellectual deterioration and, in part, the ataxia; in the Tunisian series of Gabsi, improvement was greater with a disease duration of up to 15 years [1, 14, 68]. With late treatment, the disease stabilises, but the proprioceptive deficits, areflexia and gait instability persist [1, 10, 14]. Stability was documented over 36 years in one patient [38]. Some patients develop spasticity or retinitis pigmentosa during treatment [67]. Homozygous truncating genotypes (c.744del, c.513_514insTT, c.487del, c.400C>T in homozygosity) are associated with more severe forms and missense variants at poorly conserved amino acids with mild forms [8, 46, 47, 67]. The sources consulted provide no survival data for AVED; the figure of survival up to 25 years after onset, reported for hereditary ataxias in general, does not apply to treated AVED [6].

11.2. Initial assessment after diagnosis

The initial assessment recommended for the hereditary ataxias includes neurological examination with a baseline SARA, the search for upper and lower motor neuron signs and polyneuropathy, electromyography and nerve conduction studies when indicated, brain MRI, a rehabilitation consultation, speech and language therapy, nutritional and aspiration risk assessment, pulmonary function tests and sleep studies when there are symptoms, cognitive and psychiatric assessment (including the cerebellar cognitive affective syndrome scale, CCAS), the search for scoliosis and pes cavus, genetic counselling and family support [1, 6]. In AVED, baseline plasma alpha-tocopherol with lipid profile, ophthalmological assessment (pigmentary retinopathy and macular degeneration) and the search for cardiomyopathy, present in 19% of the Cavalier series, are added [1, 12].

11.3. Surveillance

The 6-month interval for measurement matches that recommended in section 7.3, and monthly monitoring in the first months applies to tocofersolan within the approved indication and not to AVED [1, 110]. There are no published surveillance guidelines for the hereditary ataxias in general, and the intervals in the table are expert review proposals [6].

12. Summary and Final Considerations

AVED is an autosomal recessive ataxia caused by biallelic variants in TTPA, which prevent the liver from re-exporting alpha-tocopherol into VLDL. The result is a severe deficiency of plasma vitamin E with normal intestinal absorption and lipids and a spinocerebellar and sensory degeneration with a Friedreich-type clinical picture: ataxia, areflexia, proprioceptive loss, Babinski sign and dysarthria, with head titubation, dystonia, retinopathy and, less often than in FRDA, cardiomyopathy. It usually begins between the ages of 5 and 15, but mild missense variants delay onset to adulthood.

The diagnosis rests on measurement of plasma alpha-tocopherol with a lipid profile, collected with protection from oxidation, in a patient with Friedreich-type ataxia, and on molecular confirmation of TTPA. Testing for the FXN GAA expansion is done in parallel, because NGS does not detect it; deletion analysis, the phase of the variants and multinucleotide variants complete the interpretation. The founder variants c.744del in North Africa and the Mediterranean and p.His101Gln in Japan allow targeted testing in those populations, and the European regional estimates place the prevalence between about 0.6 and 3.5 per million.

Treatment is lifelong oral supplementation with high-dose alpha-tocopherol, without a specific authorisation in any jurisdiction, with doses of 800–1500 mg/day in adults or about 40 mg/kg/day in children, adjusted to keep plasma alpha-tocopherol normal-high and monitored every 6 months. These doses exceed the tolerable upper intake level of the general population, which does not apply to supplementation under medical supervision, and require attention to the haemorrhagic risk with anticoagulants or vitamin K deficiency. The choice between RRR- and all-rac-alpha-tocopherol continues to divide the sources. The benefit, documented in series and not in trials, depends on when treatment starts: prevention in presymptomatic individuals, stabilisation and some improvement in those treated early, stabilisation with residual deficits in those treated late. For this reason, testing of siblings, including minors, is a priority of counselling. The differential diagnosis with abetalipoproteinaemia, FHBL1, chylomicron retention disease and the acquired deficiencies is made by the lipid profile and the digestive picture, and in these diseases vitamin E accompanies the other fat-soluble vitamins, in their own regimens.

13. References

1. Schuelke M. Ataxia with Vitamin E Deficiency. 2005 May 20 [Updated 2023 Mar 16]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1241/
2. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number #277460: Ataxia with vitamin E deficiency; AVED. Created 1986 Jun 4; last edited 2022 Feb 4. Available from: https://omim.org/entry/277460 (accessed 17 Oct 2026).
3. GeneGuidance. TTPA — Ataxia with isolated vitamin E deficiency (OMIM 277460; ORPHA:96), including Orphadata version 1.3.42 data (23 Jun 2026). Database consulted in the version of 26 Sep 2026.
4. Arita M, Sato Y, Miyata A, Tanabe T, Takahashi E, Kayden HJ, et al. Human alpha-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem J. 1995;306 ( Pt 2):437-443. doi:10.1042/bj3060437. PMID: 7887897. PMC1136538.
5. Orphanet. Ataxia with vitamin E deficiency (ORPHA:96). Available from: https://www.orpha.net/en/disease/detail/96
6. Perlman S. Hereditary Ataxia Overview. 1998 Oct 28 [Updated 2022 Jun 16; revised 2026 Jul 9]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1138/
7. Zortea M, Armani M, Pastorello E, Nunez GF, Lombardi S, Tonello S, et al. Prevalence of inherited ataxias in the province of Padua, Italy. Neuroepidemiology. 2004;23:275–80. PMID: 15297793.
8. Elkamil A, Johansen KK, Aasly J. Ataxia with vitamin e deficiency in norway. J Mov Disord. 2015;8(1):33-36. doi:10.14802/jmd.14030. PMID: 25614784. PMC4298717.
9. Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, et al. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics. 2010;11:1–12. PMID: 19440741.
10. El Euch-Fayache G, Bouhlal Y, Amouri R, Feki M, Hentati F. Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency. Brain. 2014;137(Pt 2):402-410. doi:10.1093/brain/awt339. PMID: 24369383.
11. Gotoda T, Arita M, Arai H, Inoue K, Yokota T, Fukuo Y, et al. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. N Engl J Med. 1995;333(20):1313-1318. doi:10.1056/nejm199511163332003. PMID: 7566022.
12. Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, et al. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet. 1998;62(2):301-310. doi:10.1086/301699. PMID: 9463307. PMC1376876.
13. de Silva R, Greenfield J, Cook A, Bonney H, Vallortigara J, Hunt B, et al. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis. 2019;14(1):51. doi:10.1186/s13023-019-1013-9. PMID: 30786918. PMC6381619.
14. Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, et al. Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol. 2001;8(5):477-481. doi:10.1046/j.1468-1331.2001.00273.x. PMID: 11554913.
15. European Reference Network for Rare Neurological Diseases (ERN-RND). Diagnostic flowchart — Ataxias (adult). Published 11 February 2019; last revision 16 September 2024. Available from: https://www.ern-rnd.eu/wp-content/uploads/2024/09/Final-Flowchart-adult-ataxias_en-New.pdf
16. National Ataxia Foundation. Minneapolis (MN): NAF; founded 1957. About NAF; All About Ataxia with Vitamin E Deficiency (AVED) [webinar]. Available from: https://www.ataxia.org/ (accessed 17 Oct 2026).
17. Associação Portuguesa de Ataxias Hereditárias (APAHE). Available from: https://www.apahe.pt/
18. Associação Brasileira de Ataxias Hereditárias e Adquiridas (ABAHE). Available from: https://abahe.org.br/
19. Burnett JR, Hooper AJ, Hegele RA. Abetalipoproteinemia. 2018 Oct 25 [revised 2022 May 19]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532447/
20. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 36, Inborn Errors of Lipoprotein Metabolism Presenting in Childhood (36.1 Disorders of Low Density Lipoprotein Metabolism; Tables 36.1, 36.2).
21. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-339. doi:10.1007/s10545-013-9665-4. PMID: 24288038.
22. Orphanet. Abetalipoproteinemia (ORPHA:14). Available from: https://www.orpha.net/en/disease/detail/14
23. Burnett JR, Hooper AJ, Hegele RA. APOB-Related Familial Hypobetalipoproteinemia. 2021 May 13 [revised 2021 Sep 9]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570370/
24. Wakabayashi T, Takahashi M, Okazaki H, Okazaki S, Yokote K, Tada H, et al. Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1. J Atheroscler Thromb. 2024;31(7):1005-1023. doi:10.5551/jat.rv22018. PMID: 38710625. PMC11224688.
25. Orphanet. APOB-related familial hypobetalipoproteinemia (ORPHA:727915). Available from: https://www.orpha.net/en/disease/detail/727915
26. Burnett JR, Hooper AJ, Hegele RA. Chylomicron Retention Disease. 2022 Mar 24. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK578949/
27. Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis. 2010;5:24. doi:10.1186/1750-1172-5-24. PMID: 20920215. PMC2956717.
28. Orphanet. Chylomicron retention disease (ORPHA:71). Available from: https://www.orpha.net/en/disease/detail/71
29. Suárez Llanos JP, González Melo E, Mora Mendoza A, Iacampo Leiva LD, Moro Miguel MA. Celiac disease and malabsorption: a case report of ataxia secondary to vitamin E deficiency. Endocrinol Nutr. 2014;61(7):389-390. doi:10.1016/j.endonu.2014.03.013. PMID: 24840130.
30. Traber MG, Sokol RJ, Burton GW, Ingold KU, Papas AM, Huffaker JE, et al. Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver. J Clin Invest. 1990;85(2):397-407. doi:10.1172/jci114452. PMID: 2298915. PMC296438.
31. Sokol RJ, Kayden HJ, Bettis DB, Traber MG, Neville H, Ringel S, et al. Isolated vitamin E deficiency in the absence of fat malabsorption--familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med. 1988;111(5):548-559. PMID: 3361234.
32. Koht J, Bjørnarå KA, Jørum E, Tallaksen CM. Ataxia with vitamin E deficiency in southeast Norway, case report. Acta Neurol Scand Suppl. 2009(189):42-45. doi:10.1111/j.1600-0404.2009.01214.x. PMID: 19566498.
33. Ponten SC, Kwee ML, Wolters ECh, Zijlmans JC. First case of ataxia with isolated vitamin E deficiency in the Netherlands. Parkinsonism Relat Disord. 2007;13(5):315-316. doi:10.1016/j.parkreldis.2006.06.011. PMID: 17049453.
34. Amiel J, Maziere JC, Beucler I, Koenig M, Reutenauer L, Loux N, et al. Familial isolated vitamin E deficiency. Extensive study of a large family with a 5-year therapeutic follow-up. J Inherit Metab Dis. 1995;18(3):333-340. doi:10.1007/bf00710425. PMID: 7474901.
35. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 74–77 (Ataxic child).
36. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 70–73 (Ataxic adult).
37. Burck U, Goebel HH, Kuhlendahl HD, Meier C, Goebel KM. Neuromyopathy and vitamin E deficiency in man. Neuropediatrics. 1981;12(3):267-278. doi:10.1055/s-2008-1059657. PMID: 6945489.
38. Kohlschütter A, Finckh B, Nickel M, Bley A, Hübner C. First Recognized Patient with Genetic Vitamin E Deficiency Stable after 36 Years of Controlled Supplement Therapy. Neurodegener Dis. 2020;20(1):35-38. doi:10.1159/000508080. PMID: 32623435.
39. Traber MG. Human Vitamin E deficiency, and what is and is not Vitamin E?. Free Radic Biol Med. 2024;213:285-292. doi:10.1016/j.freeradbiomed.2024.01.024. PMID: 38242248. PMC10923111.
40. Harding AE, Matthews S, Jones S, Ellis CJ, Booth IW, Muller DP. Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med. 1985;313(1):32-35. doi:10.1056/nejm198507043130107. PMID: 4000224.
41. Kohlschütter A, Hübner C, Jansen W, Lindner SG. A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inherit Metab Dis. 1988;11 Suppl 2:149-152. doi:10.1007/bf01804221. PMID: 3141695.
42. Traber MG, Sokol RJ, Kohlschütter A, Yokota T, Muller DP, Dufour R, et al. Impaired discrimination between stereoisomers of alpha-tocopherol in patients with familial isolated vitamin E deficiency. J Lipid Res. 1993;34(2):201-210. doi:10.1016/s0022-2275(20)40747-3. PMID: 8429255.
43. Ben Hamida M, Belal S, Sirugo G, Ben Hamida C, Panayides K, Ionannou P, et al. Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology. 1993;43(11):2179-2183. doi:10.1212/wnl.43.11.2179. PMID: 8232925.
44. Ben Hamida C, Doerflinger N, Belal S, Linder C, Reutenauer L, Dib C, et al. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet. 1993;5(2):195-200. doi:10.1038/ng1093-195. PMID: 8252047.
45. Doerflinger N, Linder C, Ouahchi K, Gyapay G, Weissenbach J, Le Paslier D, et al. Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families. Am J Hum Genet. 1995;56(5):1116-1124. PMID: 7726167. PMC1801469.
46. Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet. 1995;9(2):141-145. doi:10.1038/ng0295-141. PMID: 7719340.
47. Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MS, He X, et al. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol. 1996;39(3):295-300. doi:10.1002/ana.410390305. PMID: 8602747.
48. Baso G, Magri F, Sciacco M, Corti SP, Comi GP, Ronchi D, et al. Ataxia With Vitamin E Deficiency Syndrome and a Novel TTPA Variant: A Paired Case Report. Neurol Genet. 2026;12(3):e200399. doi:10.1212/nxg.0000000000200399. PMID: 42164107. PMC13186537.
49. Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington (DC): National Academies Press; 2000. Chapter 6, Vitamin E. Available from: https://www.ncbi.nlm.nih.gov/books/NBK225461/ (accessed 17 Oct 2026).
50. Azzi A, Atkinson J, Ozer NK, Manor D, Wallert M, Galli F. Vitamin E discussion forum position paper on the revision of the nomenclature of vitamin E. Free Radic Biol Med. 2023;207:178-180. doi:10.1016/j.freeradbiomed.2023.06.029. PMID: 37463635. PMC10681751.
51. Eggersdorfer M, Schmidt K, Péter S, Richards J, Winklhofer-Roob B, Hahn A, et al. Vitamin E: Not only a single stereoisomer. Free Radic Biol Med. 2024;215:106-111. doi:10.1016/j.freeradbiomed.2024.02.013. PMID: 38401827.
52. Witt-Wallert M, Atkinson J, Azzi A, Bartolini D, Birringer M, Bonrath W, et al. Beyond 100 years of vitamin E and related molecules - Milestones and open challenges. Mol Aspects Med. 2026;109:101477. doi:10.1016/j.mam.2026.101477. PMID: 42096852.
53. Müller-Schmehl K, Beninde J, Finckh B, Florian S, Dudenhausen JW, Brigelius-Flohé R, et al. Localization of alpha-tocopherol transfer protein in trophoblast, fetal capillaries' endothelium and amnion epithelium of human term placenta. Free Radic Res. 2004;38:413–20. PMID: 15190938.
54. Schuelke M, Elsner A, Finckh B, Kohlschütter A, Hübner C, Brigelius-Flohé R. Urinary alpha-tocopherol metabolites in alpha-tocopherol transfer protein-deficient patients. J Lipid Res. 2000;41:1543–51. doi:10.1016/S0022-2275(20)31986-6. PMID: 11013295.
55. Schuelke M, Finckh B, Sistermans EA, Ausems MG, Hübner C, von Moers A. Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy. Neurology. 2000;55(10):1584-1586. doi:10.1212/wnl.55.10.1584. PMID: 11094124.
56. Qian J, Atkinson J, Manor D. Biochemical consequences of heritable mutations in the alpha-tocopherol transfer protein. Biochemistry. 2006;45(27):8236-8242. doi:10.1021/bi060522c. PMID: 16819822.
57. Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M, et al. Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry. 2000;68(4):521-525. doi:10.1136/jnnp.68.4.521. PMID: 10727494. PMC1736898.
58. Zouari M, Feki M, Ben Hamida C, Larnaout A, Turki I, Belal S, et al. Electrophysiology and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency. Neuromuscul Disord. 1998;8(6):416-425. doi:10.1016/s0960-8966(98)00051-0. PMID: 9713861.
59. Yokota T, Igarashi K, Uchihara T, Jishage K, Tomita H, Inaba A, et al. Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc Natl Acad Sci U S A. 2001;98(26):15185-15190. doi:10.1073/pnas.261456098. PMID: 11752462. PMC65004.
60. Ulatowski L, Parker R, Warrier G, Sultana R, Butterfield DA, Manor D. Vitamin E is essential for Purkinje neuron integrity. Neuroscience. 2014;260:120-129. doi:10.1016/j.neuroscience.2013.12.001. PMID: 24342566. PMC3943241.
61. Shorer Z, Parvari R, Bril G, Sela BA, Moses S. Ataxia with isolated vitamin E deficiency in four siblings. Pediatr Neurol. 1996;15:340–3. PMID: 8972536.
62. Marzouki N, Benomar A, Yahyaoui M, Birouk N, Elouazzani M, Chkili T, et al. Vitamin E deficiency ataxia with (744 del A) mutation on alpha-TTP gene: genetic and clinical peculiarities in Moroccan patients. Eur J Med Genet. 2005;48(1):21-28. doi:10.1016/j.ejmg.2005.01.014. PMID: 15953402.
63. National Center for Biotechnology Information. ClinVar: TTPA[gene], pathogenic/likely pathogenic. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=TTPA%5Bgene%5D
64. Kara B, Uzümcü A, Uyguner O, Rosti RO, Koçbaş A, Ozmen M, et al. Ataxia with vitamin E deficiency associated with deafness. Turk J Pediatr. 2008;50(5):471-475. PMID: 19102053.
65. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166. PMC5765404. Tool: https://rest.variantvalidator.org/
66. Yokota T, Shiojiri T, Gotoda T, Arita M, Arai H, Ohga T, et al. Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alpha-tocopherol transfer protein gene. Ann Neurol. 1997;41(6):826-832. doi:10.1002/ana.410410621. PMID: 9189046.
67. Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, et al. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004;25(3):130-137. doi:10.1007/s10072-004-0246-z. PMID: 15300460.
68. Schuelke M, Mayatepek E, Inter M, Becker M, Pfeiffer E, Speer A, et al. Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency. J Pediatr. 1999;134(2):240-244. doi:10.1016/s0022-3476(99)70424-5. PMID: 9931538.
69. Biglari S, Nikuei P, Mir A, Vahidnezhad H, Youssefian L, Moghaddam AS, et al. Ataxia With Vitamin E Deficiency: Case Series, Vitamin E Therapy Response, Founder Effect, and In Silico Analysis. Clin Genet. 2025;107(3):366-368. doi:10.1111/cge.14658. PMID: 39702880.
70. Iwasa K, Shima K, Komai K, Nishida Y, Yokota T, Yamada M. Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene. J Neurol Sci. 2014;345(1-2):228-230. doi:10.1016/j.jns.2014.07.001. PMID: 25066259.
71. Fernández-Burriel M, Martínez-Rubio D, Lupo V, Pérez-Colosía V, Piñán-López E, Palau F, et al. A novel delins mutation in the alpha-TTP gene in a family segregating ataxia with isolated vitamin E deficiency. Pediatr Res. 2008;64(3):262-264. doi:10.1203/pdr.0b013e31817d9bf7. PMID: 18458655.
72. Lv P, Liu L, Hao Y, Zhou Z, Chen X, Zhang L. Analysis of clinical pedigree characteristics in Chinese patients with ataxia with vitamin E deficiency. Mol Genet Metab. 2026;148(4):110167. doi:10.1016/j.ymgme.2026.110167. PMID: 42259017.
73. Zaki-Dizaji M, Sarband MM. MNV-aware molecular characterization of a rare homozygous TTPA complex allele in ataxia with vitamin E deficiency. Mol Genet Genomics. 2026;301(1):184. doi:10.1007/s00438-026-02512-1. PMID: 42711446.
74. Holla VV, Gurram S, Kamath SD, Arunachal G, Kamble N, Yadav R, et al. Genetically Proven Ataxia With Vitamin E Deficiency With Predominant Cervicobrachial Dystonic Presentation: A Case Report From India. J Mov Disord. 2024;17(2):220-222. doi:10.14802/jmd.23227. PMID: 38105474. PMC11082611.
75. Shiojiri T, Yokota T, Fujimori N, Mizusawa H. Familial ataxia with isolated vitamin E deficiency not due to mutation of alpha-TTP. J Neurol. 1999;246(10):982. doi:10.1007/s004150050499. PMID: 10552255.
76. Kono S, Otsuji A, Hattori H, Shirakawa K, Suzuki H, Miyajima H. Ataxia with vitamin E deficiency with a mutation in a phospholipid transfer protein gene. J Neurol. 2009;256(7):1180-1181. doi:10.1007/s00415-009-5075-9. PMID: 19252769.
77. Kruer MC, Jepperson TN, Weimer JM, Mroch A, Davis-Keppen L, Crotwell P, et al. Mutations in VLDLR associated with ataxia with secondary vitamin E deficiency. Mov Disord. 2013;28(13):1904-1905. doi:10.1002/mds.25573. PMID: 23813796.
78. Cellini E, Piacentini S, Nacmias B, Forleo P, Tedde A, Bagnoli S, et al. A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. Arch Neurol. 2002;59(12):1952-1953. PMID: 12470185.
79. Maalej M, Kammoun F, Kharrat M, Bouchaala W, Ammar M, Mkaouar-Rebai E, et al. A first description of ataxia with vitamin E deficiency associated with MT-TG gene mutation. Acta Neurol Belg. 2021;121(6):1733-1740. doi:10.1007/s13760-020-01490-4. PMID: 32979145.
80. Bouhlal Y, Zouari M, Kefi M, Ben Hamida C, Hentati F, Amouri R. Autosomal recessive ataxia caused by three distinct gene defects in a single consanguineous family. J Neurogenet. 2008;22(2):139-148. PMID: 18569450.
81. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical Approach to Inborn Errors of Metabolism in Paediatrics (1.5, 1.5.2.3, 1.6.4, 1.6.5; Tables 1.19, 1.20, 1.28, 1.29, 1.30, 1.37).
82. Li J, Lin Z, Jin N, Zheng X, Luo W. Isolated Head Tremor as an Initial Presentation of Ataxia with Vitamin E Deficiency: A Case Report. Mov Disord Clin Pract. 2023;10(11):1680-1682. doi:10.1002/mdc3.13886. PMID: 37982115. PMC10654837.
83. Becker AE, Vargas W, Pearson TS. Ataxia with Vitamin E Deficiency May Present with Cervical Dystonia. Tremor Other Hyperkinet Mov (N Y). 2016;6:374. doi:10.7916/d8b85820. PMID: 27274910. PMC4884265.
84. Pradeep S, Ali T, Guduru Z. Ataxia with Vitamin E Deficiency with Predominant Cervical Dystonia. Mov Disord Clin Pract. 2020;7(1):100-103. doi:10.1002/mdc3.12871. PMID: 31970222. PMC6962681.
85. Angelini L, Erba A, Mariotti C, Gellera C, Ciano C, Nardocci N. Myoclonic dystonia as unique presentation of isolated vitamin E deficiency in a young patient. Mov Disord. 2002;17(3):612-614. doi:10.1002/mds.10026. PMID: 12112220.
86. Ashrafi MR, Pourbakhtyaran E, Rohani M, Shalbafan B, Tavasoli AR, Hosseinpour S, et al. Follow-up of 25 patients with treatable ataxia: A comprehensive case series study. Clin Case Rep. 2022;10(4):e05777. doi:10.1002/ccr3.5777. PMID: 35474986. PMC9020174.
87. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2, Inborn Errors of Metabolism in Adults – A Diagnostic Approach to Neurological and Psychiatric Presentations (2.3.3, 2.3.4, 2.3.9, 2.3.11; Tables 2.4, 2.11, 2.13).
88. Benomar A, Yahyaoui M, Meggouh F, Bouhouche A, Boutchich M, Bouslam N, et al. Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families. J Neurol Sci. 2002;198(1-2):25-29. doi:10.1016/s0022-510x(02)00057-6. PMID: 12039660.
89. Abramowicz S, Dentel A, Chouraqui M, Bodaghi B, Touhami S. Atypical retinopathy in ataxia with vitamin E deficiency: report of a sibship. Neurogenetics. 2024;25(1):33-38. doi:10.1007/s10048-023-00741-9. PMID: 38105315.
90. Lucas-Del-Pozo S, Moreno-Martínez D, Tejero-Ambrosio M, Hernández-Vara J. Vitamin E deficiency ataxia in a family with possible cardiac involvement. Neurologia (Engl Ed). 2021;36(1):92-94. doi:10.1016/j.nrl.2020.02.001. PMID: 32183996.
91. Müller KI, Bekkelund SI. Epilepsy in a patient with ataxia caused by vitamin E deficiency. BMJ Case Rep. 2011;2011:bcr0120113728. doi:10.1136/bcr.01.2011.3728. PMID: 22696689. PMC3089935.
92. Rossato M, Mariotti C. Normal spermatogenesis and sperm function in a subject affected by cerebellar ataxia due to congenital vitamin E deficiency. Andrologia. 2014;46(3):322-324. doi:10.1111/and.12076. PMID: 23445347.
93. Bonello M, Ray P. A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia. Case Rep Neurol Med. 2016;2016:8342653. doi:10.1155/2016/8342653. PMID: 26989534. PMC4771890.
94. ClinicalTrials.gov API v2. Searches "ataxia with vitamin E deficiency", "TTPA", "familial isolated vitamin E deficiency", "abetalipoproteinemia", "tocofersolan"; records NCT05687474, NCT03655223, NCT01457690, NCT00004574, NCT03582384. Available from: https://clinicaltrials.gov/api/v2/studies
95. European Reference Network for Rare Neurological Diseases (ERN-RND). Diagnostic flowchart for early onset ataxias. Consented July 2020. Available from: https://www.ern-rnd.eu/wp-content/uploads/2020/11/ERN-RND-Diagnostic-flowchart-for-early-Ataxias_final.pdf
96. Feki M, Belal S, Feki H, Souissi M, Frih-Ayed M, Kaabachi N, et al. Serum vitamin E and lipid-adjusted vitamin E assessment in Friedreich ataxia phenotype patients and unaffected family members. Clin Chem. 2002;48(3):577-579. doi:10.1093/clinchem/48.3.577. PMID: 11861456.
97. Finckh B, Kontush A, Commentz J, Hübner C, Burdelski M, Kohlschütter A. Monitoring of ubiquinol-10, ubiquinone-10, carotenoids, and tocopherols in neonatal plasma microsamples using high-performance liquid chromatography with coulometric electrochemical detection. Anal Biochem. 1995;232:210–6. PMID: 8747477.
98. Cuerq C, Restier L, Drai J, Blond E, Roux A, Charriere S, et al. Establishment of reference values of α-tocopherol in plasma, red blood cells and adipose tissue in healthy children to improve the management of chylomicron retention disease, a rare genetic hypocholesterolemia. Orphanet J Rare Dis. 2016;11(1):114. doi:10.1186/s13023-016-0498-8. PMID: 27520363. PMC4982212.
99. Usuki F, Maruyama K. Ataxia caused by mutations in the alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry. 2000;69:254–6. PMID: 10896705.
100. Brandsma R, Verschuuren-Bemelmans CC, Amrom D, Barisic N, Baxter P, Bertini E, et al. A clinical diagnostic algorithm for early onset cerebellar ataxia. Eur J Paediatr Neurol. 2019;23(5):692-706. doi:10.1016/j.ejpn.2019.08.004. PMID: 31481303.
101. van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, et al. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol. 2014;21(4):552-562. doi:10.1111/ene.12341. PMID: 24418350.
102. Aschoff CAM, Silva TO, Hasan A, Migliorini E, Donis KC, Rare Genomes Project Consortium, et al. The Real Life of Ataxia Patients Without a Vertical Family History: a Twenty-year Experience in South Brazil. Cerebellum. 2026;25(5):128. doi:10.1007/s12311-026-02067-2. PMID: 42616279. PMC13490217.
103. Maver A, Lohmann K, Urbanczyk LM, Arnesen A, Barić I, Bauer P, et al. Consensus recommendations for next-generation sequencing-based genetic testing in Rare Neurological diseases. Eur J Hum Genet. 2026;34(10):1503-1512. doi:10.1038/s41431-026-02198-4. PMID: 42521809. PMC13634049.
104. Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, et al. Current Diagnosis and Management of Abetalipoproteinemia. J Atheroscler Thromb. 2021;28(10):1009-1019. doi:10.5551/jat.rv17056. PMID: 33994405. PMC8560840.
105. Willison HJ, Muller DP, Matthews S, Jones S, Kriss A, Stead RJ, et al. A study of the relationship between neurological function and serum vitamin E concentrations in patients with cystic fibrosis. J Neurol Neurosurg Psychiatry. 1985;48(11):1097-1102. doi:10.1136/jnnp.48.11.1097. PMID: 4078574. PMC1028567.
106. Synofzik M, Schüle R. Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways. Mov Disord. 2017;32:332–45. doi:10.1002/mds.26944. PMID: 28195350.
107. Burnett JR, Hooper AJ. Vitamin E and oxidative stress in abetalipoproteinemia and familial hypobetalipoproteinemia. Free Radic Biol Med. 2015;88:59–62. doi:10.1016/j.freeradbiomed.2015.05.044. PMID: 26086616.
108. Ataxia UK. Medical Guidelines. London: Ataxia UK. Available from: https://www.ataxia.org.uk/healthcare-professionals/resources-for-healthcare-professionals/medical-guidelines/
109. Office of Dietary Supplements, National Institutes of Health. Vitamin E: Fact Sheet for Health Professionals. Updated 2021 Mar 26. Available from: https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/
110. European Medicines Agency. Vedrop 50 mg/ml oral solution (tocofersolan): summary of product characteristics. Puteaux: Recordati Rare Diseases; first authorisation 24 July 2009; last product information update 16 December 2024. Available from: https://www.ema.europa.eu/en/documents/product-information/vedrop-epar-product-information_en.pdf
111. Fogel BL, Klopstock T, Lynch DR, Maltecca F, Verma M, Minassian BA, et al. Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies. Ann Neurol. 2025;98(3):448-470. doi:10.1002/ana.27271. PMID: 40464291. PMC12392066.
112. Agarwal A, Garg D, Srivastava AK. Ataxia with Vitamin E Deficiency: A Never to be Missed Treatable Ataxia. Ann Indian Acad Neurol. 2023;26(6):1011-1012. doi:10.4103/aian.aian_666_23. PMID: 38229626. PMC10789410.
113. Cuerq C, Henin E, Restier L, Blond E, Drai J, Marçais C, et al. Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease. J Lipid Res. 2018;59(9):1640-1648. doi:10.1194/jlr.M085043. PMID: 30021760. PMC6121919.
114. U.S. Food and Drug Administration. Drugs@FDA: tocopherol/vitamin E/tocofersolan. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/
115. European Medicines Agency. Vedrop (tocofersolan): EPAR — medicine overview. Amsterdam: EMA; 2009 [updated 2024 Dec 16]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/vedrop
116. Martinello F, Fardin P, Ottina M, Ricchieri GL, Koenig M, Cavalier L, et al. Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci. 1998;156(2):177-179. doi:10.1016/s0022-510x(98)00038-0. PMID: 9588854.
117. Zesiewicz TA, Wilmot G, Kuo SH, Perlman S, Greenstein PE, Ying SH, et al. Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia [RETIRED]: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(10):464-471. doi:10.1212/wnl.0000000000005055. PMID: 29440566. PMC5863491.
118. Panicker JN, Fanciulli A, Skoric MK, Kaplan T, Aleksovska K, et al. European Academy of Neurology (EAN)/European Federation of Autonomic Societies (EFAS)/International Neuro-Urology Society (INUS) guidelines for practising neurologists on the assessment and treatment of neurogenic urinary and sexual symptoms (NEUROGED guidelines). Eur J Neurol. 2025;32(4):e70119. doi:10.1111/ene.70119. Version for ataxias and hereditary spastic paraplegias published by the European Reference Network for Rare Neurological Diseases (ERN-RND) on 28 July 2026. Available from: https://www.ern-rnd.eu/wp-content/uploads/2026/09/Final-Neuroged-Guidelines-ataxias-and-HSP.pdf
119. Sharpe PC, Duly EB, MacAuley D, McCrum EE, Mulholland C, Stott G, et al. Total radical trapping antioxidant potential (TRAP) and exercise. QJM. 1996;89:223–8. PMID: 8731567.
120. Traber MG, Manor D. Vitamin E. Adv Nutr. 2012;3:330–1. doi:10.3945/an.112.002139. PMID: 22585906.
121. Morris AAM, Jones S. Medications Used in the Treatment of Inborn Errors of Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 45.
122. Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3:19. doi:10.1186/1750-1172-3-19. PMID: 18611256.
123. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 302–305 (Retinal receptor dystrophies).
124. Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye. 2001;15:525–30. doi:10.1038/eye.2001.167. PMID: 11767031.
125. Lazdovska K, Baborikina A, Krutovs V, Rozevska M, Ķēniņa V. Hereditary and Non-hereditary Cerebellar Ataxias in Latvia: Six Years of Experience at the National Reference Centre (ERN-RND Affiliated Partner). Cerebellum. 2026;25(5):145. doi:10.1007/s12311-026-02084-1. PMID: 42802208. PMC13616843.
126. Dy Closas AMF, Yu JRT, Saranza G, Fugoso L Jr. Cerebellar ataxia in the Philippines: a scoping review of reported cases and practical approach. J Neural Transm (Vienna). 2026. doi:10.1007/s00702-026-03192-2. PMID: 42573616.
127. Genome Aggregation Database (gnomAD) v4 (dataset gnomad_r4), gene TTPA (GRCh38). Available from: https://gnomad.broadinstitute.org/gene/ENSG00000137561?dataset=gnomad_r4
128. Tabuena MD, Morigaki R, Miyamoto R, Mure H, Yamamoto N, Miyake K, et al. Ataxia with vitamin E deficiency in the Philippines : A case report of two siblings. J Med Invest. 2021;68(3.4):400-403. doi:10.2152/jmi.68.400. PMID: 34759169.
129. MedlinePlus Genetics. Ataxia with vitamin E deficiency. Bethesda (MD): National Library of Medicine. Available from: https://medlineplus.gov/genetics/condition/ataxia-with-vitamin-e-deficiency/