Ataxia With Vitamin E Deficiency Research Articles

IUBMB‐Life 2019: Vitamin E—Regulatory Roles

Vitamin E has been first recognized as an essential molecule by Evans and Bishop almost 100 years ago, and it therefore is appropriate and timely to dedicate a full thematic issue of IUBMB-Life to its still debated and not yet completely elucidated essential and regulatory functions. In search for a specific transporter and receptor of vitamin E many regulatory effects have been identified and it appears that rather than by acting via one specific target, it affects many. Hence, there is good evidence that vitamin E has regulatory roles in the body—but its molecular mechanisms of action are still subject of investigations. Regulatory effects of vitamin E can be antioxidant/prooxidant by means of its redox-active chemical moieties, or non-antioxidant via interaction of its structural body with receptors, transporters, enzymes and transcription factors, and by modulating membranes and membrane domains such as lipid rafts. To exert regulatory effects vitamin E needs to be efficiently taken up from the diet and distributed in the body and the route taken was for long assumed to be mostly governed by its properties as a hydrophobic molecule. Seminal works done over the last decades revealed that only α-tocopherol (one of the eight natural vitamin E analogues [α-, β-, γ-, δ-tocopherols/tocotrienols] is preferentially enriched in the body by the hepatic α-tocopherol transfer protein [αTTP]), whereas the other seven analogues and excess α-tocopherol are not retained and rapidly metabolized. In addition to αTTP, several more proteins have been discovered that interact with vitamin E and distribute it in the body and in cells. Impaired uptake and transport of α-tocopherol due to genetic mutations in specific genes involved in its transport has been recognized as the reason for primary and secondary vitamin E deficiency syndromes, and in particular of ataxia with vitamin E deficiency (AVED), the main vitamin E deficiency syndrome resulting from αTTP mutations signifying the essential function of α-tocopherol for humans. Interestingly, the vitamin E analogues with lower bioavailability and higher metabolism in vivo have often higher activity at lower concentration in vitro despite their equal value as chemical antioxidants, suggesting that their elimination from the body possibly serves to minimize interference with some cellular functions. To unravel at a molecular level the regulatory roles and biological effects of the eight vitamin E analogues and their metabolites, their interactions with enzymes, receptors, membranes and transport proteins and the function of other natural analogues such as alpha-tocopheryl phosphate and alpha-tocopheryl nicotinate as well of a myriad of synthetic derivatives remains a challenging topic for future investigations. As discussed in this issue (issue 71:4 1-11), many cellular regulatory effects of vitamin E and its metabolites have been recognized modulating apoptosis/cell survival, ferroptosis, cell proliferation, angiogenesis, lipid metabolism, membrane properties and repair, long term potentiation, signal transduction and gene expression. These cellular effects often go beyond a simple antioxidant action and most likely contribute to the beneficial regulatory effects of vitamin E observed in a number of diseases and conditions, ranging from atherosclerosis, inflammation, diabetes, obesity, infection, immune regulation, wound healing, ischemia/reperfusion injury, reproduction, age-related macular degeneration (AMD), neurodegeneration, non-alcoholic steatohepatitis (NASH), cancer/metastasis, senescence and aging.

Chapter 5 - Recessive ataxias

Recessive ataxias (spinocerebellar ataxias, recessive or SCARs) are a heterogeneous group of rare, mostly neurodegenerative genetic disorders which usually start in childhood or early adult life. They can be subdivided into two major groups: predominant sensory or afferent ataxias, which are disorders mainly of the peripheral input to the cerebellum, and predominant cerebellar ataxias, in which the cerebellum is primarily affected. Next-generation sequencing technology has enabled the identification of >100 novel SCAR genes in the last 5 years, although most of them are ultrarare. To guide clinical workup and management in SCARs, we provide an up-to-date overview of the most frequent SCARs and their phenotypic features. These include Friedreich ataxia, spastic paraplegia type 7-related ataxia, autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and spectrin repeat-containing nuclear envelope protein (SYNE)-related ataxia. In some restricted populations ARSACS or ataxia with vitamin E deficiency (AVED) is most common. All require a high index of suspicion in patients who present with an early-onset disorder of balance, especially children, in whom normal development and the lack of typical clinical characteristics seen in later stages of the respective SCARs can confuse the clinical picture. We summarize the diagnostic features which can help guide diagnosis, the natural history for common SCARs, and the approach to therapy, both in current use and in ongoing clinical trials. We also provide a summary table for other clinically relevant SCARs. Based on the frequency data, phenotypes, and the cost-effectiveness of recent next-generation sequencing approaches, we conclude with a diagnostic algorithm for the workup of patients with unexplained SCAR.

149 - Molecular Mechanisms of Vitamin E Transport in Hepatocytes

Alpha-tocopherol (vitamin E) is an essential plant lipid that scavenges free radicals in biological membranes, thereby preventing oxidative stress. In the liver, the alpha-tocopherol transfer protein (TTP) facilitates the secretion of ingested α-tocopherol to the circulation for uptake by extra hepatic tissues. We aim to understand the molecular mechanisms that regulate TTP activity in hepatocytes, and report here on our findings regarding intracellular trafficking of the protein and its ligands. In the absence of α-tocopherol, TTP localizes to lysosomal vesicles. After treatment with α-tocopherol, the protein redistributes to a diffuse cytosolic pattern, and this re-distribution is altered in TTP mutants that cause ataxia with vitamin E deficiency (AVED) in humans. Kinetic microscopy experiments show that upon binding α-tocopherol, TTP is transported to cell periphery by vesicles derived from recycling endosomes. The directionality of this vectorial transport of TTP to the plasma membrane id directed by inverse concentration gradients of α-tocopherol and PI(4,5)P2. These data allow us to develop a mechanistic model for TTP action, its modulation by physiological triggers, and the impact of disease-causing mutations in the protein.

Ataxia with Vitamin E Deficiency May Present with Cervical Dystonia.

BackgroundAtaxia with vitamin E deficiency (AVED) is an autosomal recessive disorder that usually presents with ataxia, areflexia, and proprioceptive and vibratory sensory loss. Dystonia has been reported rarely.Case ReportAn 11-year-old female presented with dystonic head tremor and cervical and bilateral arm dystonia. Her 14-year-old older brother had dystonic head tremor and generalized dystonia. One year later, the brother developed dysarthria, limb dysmetria, and gait ataxia. Compound heterozygous mutations in TTPA were detected, confirming the diagnosis of AVED.DiscussionAVED may present with dystonia rather than ataxia, and should be considered in the differential diagnosis of progressive dystonia.

Mechanisms of recognition and binding of α-TTP to the plasma membrane by multi-scale molecular dynamics simulations.

We used multiple sets of simulations both at the atomistic and coarse-grained level of resolution to investigate interaction and binding of α-tochoperol transfer protein (α-TTP) to phosphatidylinositol phosphate lipids (PIPs). Our calculations indicate that enrichment of membranes with such lipids facilitate membrane anchoring. Atomistic models suggest that PIP can be incorporated into the binding cavity of α-TTP and therefore confirm that such protein can work as lipid exchanger between the endosome and the plasma membrane. Comparison of the atomistic models of the α-TTP-PIPs complex with membrane-bound α-TTP revealed different roles for the various basic residues composing the basic patch that is key for the protein/ligand interaction. Such residues are of critical importance as several point mutations at their position lead to severe forms of ataxia with vitamin E deficiency (AVED) phenotypes. Specifically, R221 is main residue responsible for the stabilization of the complex. R68 and R192 exchange strong interactions in the protein or in the membrane complex only, suggesting that the two residues alternate contact formation, thus facilitating lipid flipping from the membrane into the protein cavity during the lipid exchange process. Finally, R59 shows weaker interactions with PIPs anyway with a clear preference for specific phosphorylation positions, hinting a role in early membrane selectivity for the protein. Altogether, our simulations reveal significant aspects at the atomistic scale of interactions of α-TTP with the plasma membrane and with PIP, providing clarifications on the mechanism of intracellular vitamin E trafficking and helping establishing the role of key residue for the functionality of α-TTP.

Ataxia with vitamin e deficiency in norway.

ObjectiveAtaxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurological disorder which usually starts in childhood. The clinical presentation is very similar to Friedreich ataxia, most patients have progressive truncal and extremity ataxia, areflexia, positive Babinski sign, dysarthria and sensory neuropathy.MethodsWe made an inquiry to our colleagues in Norway, we included information from a prevalence study published southern Norway and added data from our own known case.ResultsA newly published prevalence study of hereditary ataxias (total of 171 subjects) found only one subject with AVED in Southeast Norway. We describe two more patients, one from the Central part and one from the Northern part of Norway. All 3 cases had age of onset in early childhood (age of 4–5 years) and all experienced gait ataxia and dysarthria. The genetic testing confirmed that they had pathogenic mutations in the α-tocopherol transfer protein gene (TTPA). All were carriers of the non-sense c.400C > T mutation, one was homozygous for that mutation and the others were compound heterozygous, either with c.358G > A or c.513_514insTT. The homozygous carrier was by far the most severely affected case.ConclusionsWe estimate the occurrence of AVED in Norway to be at least 0.6 per million inhabitants. We emphasize that all patients who develop ataxia in childhood should be routinely tested for AVED to make an early diagnosis for initiating treatment with high dose vitamin E to avoid severe neurological deficits.

Clinical and Genetic Study of Friedreich’s Ataxia and Ataxia with Vitamin E Deficiency in 44 Moroccan Families

Introduction: Friedreich ataxia (FRDA) is a multi-system autosomal-recessive disease, the most common one of the genetically inherited ataxias. FRDA occurs as a consequence of mutations in the frataxin gene, with an expansion of a GAA trinucleotide. Ataxia with vitamin E deficiency (AVED) is characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich’s ataxia (FA) but serum concentrations of vitamin E are low. Aim of study: To study clinical and genetic features of the Friedreich’s ataxia and AVED patients in 44 Moroccan families. Patients and Methods: Retrospective series of 72 Moroccan patients displaying Friedreich’s ataxia syndrome was recruited over a period of 22 years (1987-2009). All patients had a clinical and ophtalmological examinations, 30 patients underwent electromyography, and CT scan was performed in 29 patients. GAA repeats in the frataxin gene and the 744 del A mutation α-TTP gene were performed in all patients. Results: 17 patients (24% of cases) had the 744 del A mutation in the α-TTP gene responsible of ataxia with vitamin E deficiency (AVED) phenotype. 55 patients (76% of cases) had GAA expanded allele in the first intron of the frataxin gene. Phenotype-genotype correlation revealed a high frequency of head titubation, decreased visual acuity and slower disease progression in AVED than in Friedreich’s ataxia phenotype (p Our study represents a large series which highlight the clinical and genetic differences between AVED and Friedreich’s ataxia. AVED patients have a better prognosis after alpha-tocopherol treatment.

Ataxia with vitamin E deficiency: update of molecular diagnosis

Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disease, due to mutations in TTPA gene (Arita et al. in Biochem J 306(Pt. 2):437-443, 1995; Hentati et al. in Ann Neurol 39:295-300, 1996), which encodes for alpha-TTP, a cytosolic liver protein that is presumed to function in the intracellular transport of alpha-tocopherol. This disease is characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. The neurological symptoms include ataxia, dysarthria, hyporeflexia, and decreased vibration sense, sometimes associated with cardiomyopathy and retinitis pigmentosa (Mariotti et al. in Neurol Sci 25:130-137, 2004). Vitamin E supplementation improves symptoms and prevents disease progress (Doria-Lamba et al. in Eur J Pediatr 165(7):494-495, 2006). Over 20 mutations have been identified in patients with AVED. In the present paper we summarize the recent findings on molecular genetic of this disease including the list of the known mutations.

Ataxia with vitamin E deficiency in southeast Norway, case report

Ataxia with vitamin E deficiency (AVED) is a rare cause of hereditary ataxia in north European countries with unknown prevalence. Few cases are reported from these countries. Through a systematic population based study of hereditary ataxia in southeast Norway subjects were classified and investigated. To report a subject with ataxia due to vitamin E deficiency in Norway. One patient with AVED was identified. The subject was a 45 years old woman with progressive ataxia from preschool age. When she was 12 years old Friedreich's ataxia was diagnosed after neurological examination. At the age of 45 re-evaluation and re-examination was performed and genetic analysis of the Frataxin gene was negative. At that time she had truncal and extremities ataxia, titubation of the head, pes cavus, inverted plantar response, loss of proprioceptive and vibration sense and a severe sensory neuropathy. Vitamin E in serum was undetectable and genetic analysis detected a compound heterozygous mutation, p.A120T and p.R134X, in the alpha-tocopherol transport protein gene on chromosome 8q13. Vitamin E should always be assessed in progressive ataxia of genetic or unexplained causes and especially with a Friedreich's ataxia-like phenotype since treatment is available. AVED is rare in Norway, but exists, and we here report the first genetically confirmed subject with ataxia due to vitamin E deficiency in Norway.

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

While Friedreich's ataxia (FRDA) and ataxia telangiectasia (AT) are known to be the two most frequent forms of autosomal recessive cerebellar ataxia (ARCA), knowledge on the other forms of ARCA has been obtained only recently, and they appear to be rarer. Little is known about the epidemiological features and the relative frequency of the ARCAs and only few data are available about the comparative features of ARCAs. We prospectively studied 102 suspected ARCA cases from Eastern France (including 95 from the Alsace region) between 2002 and 2008. The diagnostic procedure was based on a sequential strategic scheme. We examined the clinical, paraclinical and molecular features of the large cohort of patients and compared features and epidemiology according to molecular diagnosis. A molecular diagnosis could be established for 57 patients; 36 were affected with FRDA, seven with ataxia plus oculomotor apraxia type 2 (AOA2), four with AT, three with ataxia plus oculomotor apraxia type 1 (AOA1), three with Marinesco-Sjögren syndrome, two with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), one with ataxia with vitamin E deficiency (AVED) and one with autosomal recessive cerebellar ataxia type 2 (ARCA2). The group of patients with no identified mutation had a significantly lower spinocerebellar degeneration functional score corrected for disease duration (SDFS/DD ratio; p = 0.002) and comprised a significantly higher proportion of cases with onset after 20 years (p < 0.01). Extensor plantar reflexes were rarer and cerebellar atrophy was more frequent in the group of patients with a known non-Friedreich ARCA compared to all other patients (p < 0.0001 and p = 0.0003, respectively). Lower limb areflexia and electroneuromyographic evidences of peripheral neuropathy were more frequent in the Friedreich ataxia group than in the group with a known non-Friedreich ataxia and were more frequent in the later group than in the group with no identified mutation (p = 0.0001 and p = 0.01, respectively). The overall prevalence of ARCA in Alsace is 1/19,000. We can infer the prevalence of FRDA in Alsace to be 1/50,000 and infer that AT is approximately eight times less frequent than FRDA. MSS, AOA2 and ARSACS appear only slightly less frequent than AT. Despite the broad variability of severity, Friedreich ataxia patients are clinically distinct from the other forms of ARCA. Patients with no identified mutation have more often a pure cerebellar degenerative disease or a spastic ataxia phenotype. It appears that ARCA cases can be divided into two major groups of different prognosis, an early-onset group with a highly probable genetic cause and an adult-onset group with better prognosis for which a genetic cause is more difficult to prove but not excluded. ARCAs are rare, early-disabling and genetically heterogeneous diseases dominated by FRDA. Several of the recently identified ARCAs, such as AVED, ARSACS, AOA1, AOA2 and MSS, have a prevalence close to AT and should be searched for extensively irrespective of ethnic origins. The strategic scheme is a useful tool for the diagnosis of ARCAs in clinical practice.

Ataxia with vitamin E deficiency (AVED); an example of the contribution of research in molecular genetic to counselling in Morocco

Ataxia with vitamin E deficiency (AVED); an example of the contribution of research in molecular genetic to counselling in Morocco

Autosomal recessive cerebellar ataxias

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

Biochemical Consequences of Heritable Mutations in the α-Tocopherol Transfer Protein

Tocopherol transfer protein (TTP) regulates vitamin E status by facilitating the secretion of tocopherol from liver to circulating lipoproteins. Heritable mutations in the ttpA gene, encoding for TTP, result in ataxia with vitamin E deficiency (AVED) syndrome, typified by low vitamin E levels and a plethora of neurological disorders. The molecular mechanisms by which TTP facilitates tocopherol secretion are presently unknown. We recently showed that vitamin E is taken up by hepatocytes through an endocytic process and that, shortly following uptake, the vitamin is found primarily in lysosomes. We showed further that TTP is localized to late endocytic vesicles and that it facilitates the intracellular trafficking of tocopherol from lysosomes to the plasma membrane. To gain insight into the molecular mechanisms that underlie TTP actions, we studied the physiological impact of three naturally occurring heritable mutations in the ttpA gene (the R59W, R221W, and A120T substitutions). We found that these mutations impair the ability of TTP to facilitate the secretion of vitamin E from cells. Furthermore, the degree of impairment corresponded to the severity of the AVED pathology associated with each mutation. In cells that express mutated TTP proteins, vitamin E did not traffic to the plasma membrane and remained "trapped" in lysosomes. In addition, we observed that substitution mutations that cause the AVED syndrome impart a marked instability on the TTP protein. These observations suggest that the physiological role of TTP is anchored in its ability to direct vitamin E trafficking from the endocytic compartment to transport vesicles that deliver the vitamin to the site of secretion at the plasma membrane.

Utility of a Fluorescent Vitamin E Analogue as a Probe for Tocopherol Transfer Protein Activity

The tocopherol transfer protein (TTP) is a member of the CRAL-TRIO family of lipid binding proteins that facilitates vitamin E transfer between membrane vesicles in vitro. In cultured hepatocytes, TTP enhances the secretion of tocopherol to the media; presumably, tocopherol transfer is at the basis of this biological activity. The mechanism underlying ligand transfer by TTP is presently unknown, and available tools for monitoring this activity suffer from complicated assay procedure and poor sensitivity. We report the characterization of a fluorescent vitamin E analogue, (R)-2,5,7,8-tetramethylchroman-2-[9-(7-nitrobenz[1,2,5]oxadiazol-4-ylamino)nonyl]chroman-6-ol (NBD-TOH), as a sensitive and convenient probe for the ligand binding and transfer activities of TTP. Upon binding to TTP, NBD-TOH fluorescence is blue shifted, and its intensity is greatly enhanced. We used these properties to accurately determine the affinity of NBD-TOH to TTP. The analogue binds to TTP reversibly and with high affinity (K(d) = 8.5 +/- 6 nM). We determined the affinity of NBD-TOH to a TTP protein in which lysine 59 is replaced with a tryptophan. When occurring in humans, this heritable mutation causes the ataxia with vitamin E deficiency (AVED) disorder. We find that the affinity of NBD-TOH to this mutant TTP is greatly diminished (K(d) = 71 +/- 19 nM). NBD-TOH functioned as a sensitive fluorophore in fluorescent resonance energy transfer (FRET) experiments. Using the fluorescent lipids TRITC-DHPE or Marina Blue-DHPE as a donor or an acceptor for NBD-TOH fluorescence, we obtained high-resolution kinetic data for tocopherol movement out of lipid bilayers, a key step in the TTP-facilitated ligand transfer reaction.

Vitamin E deficiency ataxia with (744 del A) mutation on α-TTP gene: genetic and clinical peculiarities in Moroccan patients

Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich’s ataxia (FA). Molecular analysis is needed for an early differential diagnosis, in order to initiate therapeutic vitamin E supplementation before damage develops. We studied 16 patients from seven Moroccan families presenting an autosomal recessive Friedreich-like ataxia with vitamin E deficiency. Our patients were homozygous for 744 del A mutation of α-TTP gene. Compilation of clinical records revealed a great phenotypic variability and some features indicating a new possible role of vitamin E in hypothalamo-hypophysial system regulation and cardiomyopathy prevention. Early vitamin E supplementation may provide considerable improvement of neurological signs and other associated abnormalities. Clinical heterogeneity is for involvement of other non-genetic defect and indicated another role of vitamin E, which should be better studied.

Ataxias cerebelosas autosómicas recesivas. Clasificación, aspectos genéticos y fisiopatología

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs. They use to have early onset before the age of 20. Based on pathogenic mechanisms five main types may be distinguished: congenital (developmental disorder), mitochondrial ataxias, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, and degenerative ataxia with unknown pathogenesis. The most frequent in Caucasian population are Friedreich ataxia and ataxia-telangiectasia. Other forms are much less common, and include abetaliproteinemia, ataxia with vitamin E deficiency (AVED), ataxia with oculomotor apraxia types 1 (AOA1) and 2 (AOA2), early onset cerebellar ataxia with retained reflexes, Charlevoix-Saguenay spastic ataxia, and Joubert syndrome. The prevalence of ARCA has been estimated to 7 in 100,000 inhabitants. These diseases are due to mutations in specific genes, some of which and its encoded proteins have been identified, such as FRDA (frataxin) in Friedreich ataxia, APTX (aprataxin) in AOA1, alphaTTP (alpha-tocopherol transfer protein) in AVED, and STX (senataxin) in AOA2. Due to autosomal recessive inheritance, previous familial history of affected individuals unlikely.Most of these cerebellar ataxias have no specific treatment with exception of the ataxia associated with deficiency coenzyme Q10 and abetalipoproteinemia. Clinical diagnosis must be confirmed by ancillary tests such as neuroimaging (magnetic resonance, scanning), electrophysiological examination, and mutation analysis when the causative gene has been identified. Correct clinical and genetic diagnosis is important for appropriate prognosis and genetic counseling and, in some instances, pharmacological treatment.

Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families.

Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disorder due to mutations in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13. AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E. We studied neurological phenotype at diagnosis, and long-term effect of vitamin E supplementation in 16 patients from 12 Italian families. The most common mutations were the 744delA and 513insTT. Two novel TTPA mutations were identified: a severe truncating mutation (219insAT) in a homozygous patient, and a Gly246Arg missense mutation (G246R) in a compound heterozygous patient. The missense mutation was associated with a mild and slowly progressive form of the disease. Vitamin E supplementation therapy allowed a stabilization of the neurological conditions in most of the patients. However, development of spasticity and retinitis pigmentosa was noted in a few patients during therapy. Prompt genetic characterization of AVED patients may allow an effective early treatment and an adequate genetic counseling.

Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency.

Human alpha-tocopherol (alpha-T) transfer protein (ATTP) plays a central role in vitamin E homeostasis, preventing degradation of alpha-T by routing this lipophilic molecule for secretion by hepatocytes. Mutations in the gene encoding ATTP have been shown to cause a severe deficiency in alpha-T, which results in a progressive neurodegenerative spinocerebellar ataxia, known as ataxia with vitamin E deficiency (AVED). We have determined the high-resolution crystal structure of human ATTP with (2R,4'R,8'R)-alpha-T in the binding pocket. Surprisingly, the ligand is sequestered deep in the hydrophobic core of the protein, implicating a large structural rearrangement for the entry and release of alpha-T. A comparison to the structure of a related protein, Sec14p, crystallized without a bona fide ligand, shows a possibly relevant open conformation for this family of proteins. Furthermore, of the known mutations that cause AVED, one mutation, L183P, is located directly in the binding pocket. Finally, three mutations associated with AVED involve arginine residues that are grouped together on the surface of ATTP. We propose that this positively charged surface may serve to orient an interacting protein, which might function to regulate the release of alpha-T through an induced change in conformation of ATTP.

Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families

Fifteen Moroccan families with a phenotype resembling Friedreich Ataxia (FA) were studied. Seven families (13 patients) had the 744 del A mutation in the alpha-tocopherol transfer protein (α-TTP) gene, characteristic of ataxia with vitamin E deficiency (AVED). The other eight families (16 patients) had GAA expansions in the first intron of the frataxin gene. The clinical differences between the two groups differed. AVED caused by the 744 del A could be distinguished by head titubation, lower frequency of the neuropathy and slower disease progression, decreased visual activity and retinitis pigmentosa, which has also been associated with a His 101 Gln missense mutation in the α-TTP gene. The neurological disorder associated with vitamin E deficiency can be improved by the alpha-tocopherol treatment.

Serum Vitamin E and Lipid-adjusted Vitamin E Assessment in Friedreich Ataxia Phenotype Patients and Unaffected Family Members

Friedreich ataxia (FA) is an autosomal recessive spinocerebellar syndrome with onset before age 25, characterized by progressive cerebellar ataxia, dysarthria, areflexia, sensory loss in lower limbs, pyramidal weakness, and Babinski signs (1). It is caused by an intronic expanded unstable GAA repeat in the frataxin gene (2) located on chromosome 9q13-q21 (3). Investigating five Tunisian families with typical FA phenotype, Ben Hamida et al. (4) had excluded linkage to the locus of FA in two families and provided evidence for genetic heterogeneity of the disease. Patients belonging to families not linked to the locus of FA showed very low serum vitamin E (VE) with no evidence of lipid malabsorption. The role of VE in maintaining human nervous system function is established, and the role of VE deficiency in neurologic disorders of a-β-lipoproteinemia and biliary atresia is well accepted (5)(6). Several reports (4)(7)(8)(9)(10) have described patients with a progressive spinocerebellar syndrome associated with very low serum VE in the absence of fat malabsorption or a-β-lipoproteinemia. This disease, termed ataxia with VE deficiency (AVED), is inherited with an autosomal recessive pattern (3)(4). The abnormal gene was mapped to chromosome 8q (11) and identified as the gene encoding for α-tocopherol transfer protein (α-TTP) (12). Because it is difficult to distinguish on the basis of clinical features between AVED patients in whom VE supplementation may be beneficial (7)(13)(14) and those with classic FA, we assessed serum VE, total cholesterol (TC), and triglycerides (TGs) in our patients with FA clinical phenotype …