Ataxia With Isolated Vitamin E Deficiency Research Articles

Vitamin E - The Next 100 Years.

α-Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low-grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved. © 2018 IUBMB Life, 71(4):411-415, 2019.

A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia.

Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich's ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich's ataxia but was later found to have AVED.

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

Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation—c.717 del C (p.D239EfsX25)—in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration.

Ataxia with vitamin E deficiency with a mutation in a phospholipid transfer protein gene

Sirs, Ataxia with isolated vitamin E deficiency (AVED) is an autosomal-recessive spinocerebellar degeneration caused by a mutation of the a-tocopherol transfer protein gene (aTTP) [3, 8]. This report presents a case of juvenile spinocerebellar ataxia caused by mutations in the phospholipid transfer protein (PLTP) gene as well as the aTTP gene. This is the first report to indentify a mutation in the PLTP gene associated with vitamin E-mediated spinocerebellar ataxia. The proband was a 54-year-old female who had developed resting tremors in her right hand and ataxia at 14 years of age. At around 30 years of age, her bilateral visual acuity was decreased by retinitis pigmentosa. Her parents were second-degree cousins. On neurological examination she exhibited ataxia, dysarthria, hyporeflexia, decreased proprioceptive and vibratory sensations, and resting tremors of the extremities. The serum vitamin E concentration was observed to be about half normal level, 4.2 mg/l (normal: 10.8 ± 3.3 mg/l). The results of the following laboratory tests were normal: other fat-soluble vitamins, liverand pancreas-function tests, serum lipids, lipoproteins and apoproteins. The gene analysis revealed a homozygous H101Q mutation in the aTTP gene (Fig. 1a). In AVED, the genotype–phenotype correlation is confirmed, thus indicating that the H101Q mutation is associated with retinitis pigmentosa, late onset during the 3rd decade of life and very low serum vitamin E levels (Table 1) [3, 10, 11]. The clinical findings of the current patient characteristic of juvenile onset and a mild decrease in the serum vitamin E level suggested that other genes associated with vitamin E metabolism might affect the phenotype. Genomic analyses in the PLTP gene revealed the patient and her mother were heterozygous for a H154R mutation (Fig. 1b, c). This mutation was not found in 96 healthy subjects and was different from any previously reported polymorphisms. Following intestinal absorption of vitamin E, aTTP incorporates vitamin E into VLDL resulting in secretion from the liver to the circulation. The plasma PLTP transfers vitamin E from VLDL to HDL. HDL is the predominant source of vitamin E for the brain capillary endothelial cells which facilitates uptake of vitamin E to deliver it to the central nervous system [2, 9]. The PLTP is expressed in the brain, and PLTP knock-out studies showed that PLTP deficiency caused a decrease of vitamin E content in the brain and elevated plasma concentration of vitamin E [1, 6]. The proband and mother heterozygous for the H154R mutation showed a normal plasma PLTP concentration measured by ELISA [7]; however, the plasma PLTP activity was decreased to half the normal level measured by a PLTP assay kit (BioVision, Mountain View, CA) (Table 2). His154 is located in the N-terminal domain with conserved lipid-binding pockets associated with biochemical activity [4], and therefore this H154R mutation may induce the biological dysfunction of the PLTP without causing any impairment of intracellular trafficking. PLTP is an important factor regulating the size and composition of HDL and controlling plasma HDL levels [5]. The identification of the PLTP mutation may thus make it S. Kono (&) A. Otsuji K. Shirakawa H. Suzuki H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

First case of ataxia with isolated vitamin E deficiency in the Netherlands

We present a 36-year-old Dutch woman who suffered from a progressive form of cerebellar ataxia since school age. In her childhood she was diagnosed with Friedreich's ataxia. Genetic analysis of the frataxin gene at 34 years of age, however, had revealed no abnormal GAA triplet expansion. We identified two point mutations in the α-tocopherol transport protein ( α-TTP) gene on chromosome 8q13, and the diagnosis ataxia with isolated vitamin E deficiency (AVED) was made. This report illustrates the diagnosis AVED and its relation to vitamin E metabolism. It is important to evaluate previously made diagnoses when newly developed tests can be performed for confirmation.

Molecular mechanisms of a‐tocopherol transfer protein (a‐TTP)‐dependent a‐tocopherol transfer in hepatocytes

α Tocopherol transfer protein (α TTP) is a cytosolic 30 kDa protein that is highly expressed in the liver. α TTP is also known as the causative gene for AVED (ataxia with isolated vitamin E deficiency). Secretion of α tocopherol from hepatocytes by α TTP is essential for the maintenance of plasma α tocopherol concentrations. Although the physiological function of α TTP is well understood, precise mechanisms of α tocopherol transfer by α TTP in hepatocytes remain largely unknown. There are six α TTP point mutations known to cause AVED. Among these mutations, R59W is of particular interest. Although the α tocopherol binding capacities of wild-type and R59W α TTP were almost the same, patients with this mutation show undetectable plasma vitamin E levels and a severe phenotype. We have found that wild-type α TTP binds to PIPs, but R59W α TTP cannot bind to them. Moreover, the in vitro α tocopherol transfer activity of the wild-type α TTP increased with the increasing content of PIPs in the acceptor liposomes, while the transfer activity by R59W α TTP did not. From these results, we strongly suggest that α tocopherol transferred to the PIPs enriched inner leaflet of the plasma membrane by α TTP is readily secreted extracellularly by a certain ABC transporter.

Efficacious vitamin E treatment in a child with ataxia with isolated vitamin E deficiency

Vitamin E deficiency can cause a progressive spinocerebellar ataxia similar to Friedreich ataxia phenotype [2, 3]. Differential diagnosis between the two forms is based on serum level of vitamin E and is very important for prognosis because in patients with ataxia with isolated vitamin E deficiency (AVED) vitamin E supplementation allows a stabilization of the neurological conditions [3, 6] and may lead to clinical improvement [4]. We report the case of a young patient with AVED with a complete regression of ataxia after early and long-term vitamin E oral supplementation. Our case strongly suggests early recognition and treatment of vitamin E deficiency to improve disease outcome. AVED (OMIM #277460) is a rare autosomal recessive neurodegenerative disease caused by mutations in the αtocopherol transfer protein (TTPA) gene, which maps to locus 8q13.1-q13.3 on chromosome 8 [3]. The deficit reduces the capacity to incorporate α-tocopherol (the most biologically active form of vitamin E) into very low density lipoproteins secreted by the liver and therefore into plasma and tissues [1]; it affects particularly the nervous system, where neurons are more vulnerable to free-radical damage [5]. The disease was characterized clinically and the defective gene localized to proximal chromosome 8q by Ben Hamida et al. in 1993 [2]. Neurological findings include spinocerebellar degeneration and mild to moderate axonal sensory neuropathy (less severe than in Freidreich ataxia), with clinical picture of ataxia, areflexia, dysarthria, and impaired proprioception. AVED should be differentiated from other syndromes with vitamin E deficiency, which can be caused by intestinal and liver diseases, malabsorption or malnutrition [1]. An 8-year-old girl came to our attention for progressive ataxia since the age of 3 years. She was the only child of healthy consanguineous parents (3rd degree) with a family history of a not defined ataxia in the father’s line. Neurological examination disclosed spinocerebellar degeneration with clinical features of important trunkal ataxia, head tremor, dysmetria, areflexia, bilateral Babinski sign, pes cavus with retraction of Achilles tendon on left the side. Tests for cholestatic liver disease, fat malabsorption and abetalipoproteinemia showed no pathologic alterations. Brain and spine magnetic resonance imaging, fundus examination, electroencephalogram, electrocardiogram, as well as motor conduction velocity (MCV) on peroneal and median nerves resulted unrevealing. Alphafetoprotein (to rule out Ataxia-Telangiectasia) and molecular DNA analysis for Friedereich ataxia were both negative. Sensory conduction velocity (SCV) on sural and median nerves were suggestive of axonal sensory neuropathy and somatosensory evoked potentials (SEP) showed the alteration of bilateral somatosensory conduction. Alpha-tocopherol level was below the sensitivity of the test (normal values 0.5–2.0 mg/dl) and thus high-dose vitamin E supplementation was given at the dosage of 1200– 1500 mg/day until the serum concentration raised to 1.23 mg/dL. DNA analysis for the detection of the two most common mutations of the α-TTP gene in patients from Mediterranean population [6] showed homozygous 744delA mutation. After only six months we witnessed complete resolution of trunkal and limb ataxia as well as SCVand SEP normalization. Deep tendon reflexes remained abolished and the foot deformity persisted requiring surgical correction. We want to highlight the importance of the assay of vitamin E serum levels in Friedreich-like ataxia. In our case the truncating homozygous 744delA mutation caused the complete abolishment of α-TTP synthesis with a severe and early phenotype of the disease [1, 4]. However, early and high-dose oral supplementation could lead to complete L. Doria-Lamba (*) . E. De Grandis . E. Cristiani . I. Fiocchi . L. Montaldi . P. Grosso Operative Unit of Child Neuropsychiatry, Department of Neurosciences, Ophthalmology and Genetics, G Gaslini Institute, University of Genoa, L.go Gaslini 5, 16148 Genoa, Italy e-mail: lauradoria@ospedale-gaslini.ge.it Tel.: +39-010-5636702 Fax: +39-010-381303

The Molecular Basis of Vitamin E Retention: Structure of Human α-Tocopherol Transfer Protein

α-Tocopherol transfer protein (α-TTP) is a liver protein responsible for the selective retention of α-tocopherol from dietary vitamin E, which is a mixture of α, β, γ, and δ-tocopherols and the corresponding tocotrienols. The α-TTP-mediated transfer of α-tocopherol into nascent VLDL is the major determinant of plasma α-tocopherol levels in humans. Mutations in the α-TTP gene have been detected in patients suffering from low plasma α-tocopherol and ataxia with isolated vitamin E deficiency (AVED). The crystal structure of α-TTP reveals two conformations. In its closed tocopherol-charged form, a mobile helical surface segment seals the hydrophobic binding pocket. In the presence of detergents, an open conformation is observed, which probably represents the membrane-bound form. The selectivity of α-TTP for RRR-α-tocopherol is explained from the van der Waals contacts occurring in the lipid-binding pocket. Mapping the known mutations leading to AVED onto the crystal structure shows that no mutations occur directly in the binding pocket.

Ataxia with vitamin E deficiency and severe dystonia: report of a case

Mutation of the gene for α-tocopherol transfer protein causes ataxia with isolated vitamin E deficiency, a disorder usually stabilized or improved after vitamin E supplementation. Dystonia has rarely been described in ataxia with isolated vitamin E deficiency (AVED) patients. We present the case of a young boy with AVED, whose neurological and extra-neurological cardinal symptoms of the disease improved after vitamin E supplementation but who progressively developed generalized dystonia.

Hereditary Ataxias

Hereditary Ataxias

Ataxia with isolated vitamin E deficiency: a Japanese family carrying a novel mutation in the alpha-tocopherol transfer protein gene.

We report a Japanese family with ataxia with isolated vitamin E deficiency (AVED). Gene analysis revealed a single nucleotide substitution of T to C at nucleotide position 2 in the alpha-tocopherol transfer protein gene (TTPA). This substitution abolishes the start codon. The proband and his affected sister were homozygous for this mutation, and their serum alpha-tocopherol concentrations were remarkably reduced. Relations between the mutations and clinical features are discussed.

Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein.

Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease which maps to chromosome 8q13. AVED patients have an impaired ability to incorporate alpha-tocopherol into lipoproteins secreted by the liver, a function putatively attributable to the alpha-tocopherol transfer protein (alpha-TTP). Here we report the identification of three frame-shift mutations in the alpha TTP gene. A 744delA mutation accounts for 68% of the mutant alleles in the 17 families analysed and appears to have spread in North Africa and Italy. This mutation correlates with a severe phenotype but alters only the C-terminal tenth of the protein. Two other mutations were found in single families. The finding of alpha TTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.