RARE DISEASE
Ataxia with vitamin E deficiency
Ataxia with vitamin E deficiency
Ataxia with vitamin E deficiency
Synonyms: AVED, Ataxia with isolated vitamin E deficiency, Familial isolated vitamin E deficiency, Friedreich-like ataxia, Isolated vitamin E deficiency
Synonyms: AVED, Ataxia with isolated vitamin E deficiency, Familial isolated vitamin E deficiency, Friedreich-like ataxia, Isolated vitamin E deficiency
Synonyms: AVED, Ataxia with isolated vitamin E deficiency, Familial isolated vitamin E deficiency, Friedreich-like ataxia, Isolated vitamin E deficiency
Drug discovery
1
drug
With orphan designation
Overview
Ataxia with Vitamin E Deficiency (AVED) is an autosomal recessive neurodegenerative disorder caused by mutations in the TTPA gene, impairing α-tocopherol transfer protein function. This results in severe vitamin E deficiency despite normal dietary intake, leading to progressive cerebellar ataxia, dysarthria, peripheral neuropathy, and retinitis pigmentosa. Symptoms typically manifest between ages 5–15, with untreated cases progressing to wheelchair dependence. Diagnosis requires serum vitamin E testing (lipid-adjusted levels) and genetic confirmation. High-dose vitamin E supplementation (800–1,500 mg/day) stabilizes or improves symptoms if initiated early [1][2][9][13].
Burden
Untreated patients develop severe disability (e.g., loss of ambulation within 8–20 years) [13][19].
Residual deficits (proprioceptive loss, dysarthria) persist even with treatment [9][15].
Economic/social burdens include chronic care needs and frequent misdiagnosis (e.g., Friedreich ataxia) [9][13].
Therapies
Lifelong high-dose vitamin E (α-tocopherol): 800–1,500 mg/day orally; doses up to 40 mg/kg/day in children [3][7][9].
Early treatment prevents progression; delayed intervention may only halt decline [9][15].
Monitoring: Annual neurologic exams and serum vitamin E levels to ensure adequacy (>12 µmol/L) [7][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
103 drug discovery papers about Ataxia with vitamin E deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
103 drug discovery papers about Ataxia with vitamin E deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-09 | Analysis of clinical pedigree characteristics in Chinese patients with ataxia with vitamin E deficiency.
The clinical and genetic features of ataxia with isolated vitamin E deficiency (AVED) patients in Chinese are remain not well understood. We enrolled 120 unrelated probands with clinically suspected autosomal recessive cerebellar ataxia (ARCA) at the Department of Neurology, China-Japan Friendship Hospital between 2014 and 2024. all probands underwent Whole-exome sequencing (WES), with candidate variants validated by Sanger sequencing and family cosegregation analysis. In silico pathogenicity analysis, including protein structure homology modeling and multispecies conservation analysis, was performed for novel variants. Plasma vitamin E levels were measured using high-performance liquid chromatography with diode array detection(HPLC-DAD). We identified 4 probands with biallelic TTPA variants, accounting for 3.33% of the ARCA cohort. Three probands were from consanguineous families, and 1 was from non- consanguineous family. The median age at onset was 15years (range 14-23years), with gait instability/ataxia as the universal initial symptom. Core clinical features included cerebellar ataxia (4/4), dysarthria (4/4), areflexia (2/4), scoliosis (4/4), foot deformity (3/4), and head titubation (3/4). Brain MRI revealed cerebellar atrophy in 3 patients, and all had markedly reduced serum vitamin E levels. We identified 2 novel missense variants (c.265C>A(p.P89T) and c.790A>G(p.M264V)). All patients received high-dose vitamin E supplementation, with 3/4 improved ataxia symptoms at 2-years follow-up. Our findings expand the clinical and genetic spectrum of AVED in China and support early evaluation of plasma vitamin E status and TTPA variants in patients with unexplained sporadic or recessive ataxia, as well as proactive screening of siblings and other at-risk relatives, even before symptom onset.
2026-05-21 | Ataxia With Vitamin E Deficiency Syndrome and a Novel TTPA Variant: A Paired Case Report.
Ataxia with vitamin E deficiency (AVED) is a chronic progressive syndrome with low vitamin E levels, caused by biallelic pathogenic variants in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13.1. According to family segregation studies, we describe a novel putative variant in compound heterozygosity with a known pathogenic variant. Clinical and instrumental evaluations were performed at our Neuromuscular Unit. Two siblings had been experiencing clumsiness, which later evolved into progressive gait unsteadiness, with falls and dysarthria. Brain MRI, EMG, and nerve conduction studies were inconclusive, but focused clinical exome sequencing revealed biallelic variants in the TTPA gene in both, the pathogenetic maternally inherited variant c.513_514insTT (p.Thr172Leufs*5) on exon 3 and the previously undescribed paternally inherited variant c.158T > C (p.Leu53Pro) on exon 1. Their plasma vitamin E levels were low (<1.7 mg/L). Their relatives carried 1 single variant each, with normal vitamin E levels. After 6 months of oral vitamin supplementation with a laboratory response, disease progression has stopped, although their neurologic examination has not clearly ameliorated. Exome sequencing identified a new potentially pathogenic variant in AVED, an ultra-rare but treatable cause of inherited ataxia. We recommend prompt vitamin E supplementation in patients with AVED.
2025-11-14 | Systemic Mechanistic Framework of the Keyora Multi-Vitamin & Mineral Matrix: Metabolic, Antioxidant, and Neuro-Endocrine Axes in Human Nutritional Homeostasis
Abstract Micronutrient deficiency remains a pervasive but underappreciated driver of chronic disease, even in populations with adequate calorie intake. Epidemiological data show that low or marginal intakes of vitamin D, folate, iron, zinc, magnesium, and other key micronutrients are common worldwide and are associated with metabolic syndrome, type 2 diabetes mellitus, cardiovascular dysfunction, neurocognitive decline, mood and anxiety disorders, sleep disturbances, immune dysregulation, and impaired reproductive health. Beyond classical deficiency syndromes, subtle but persistent insufficiency disrupts mitochondrial bioenergetics, antioxidant defenses, and neuro–endocrine–immune communication, creating a biochemical milieu that accelerates inflammatory and oxidative aging. In this context, the present work develops a systems-level framework for understanding how a defined set of 13 vitamins (A, D₃, E, K₁, C, thiamine, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, biotin, pantothenic acid) and 7 minerals (calcium, magnesium, iron, zinc, copper, manganese, selenium) can be organized into an integrated “Keyora Multi-Vitamin & Mineral Matrix.” This matrix is mapped onto three interconnected mechanistic axes: a Metabolic–Mitochondrial Axis that sustains ATP generation, substrate utilization, insulin sensitivity, and physical and cognitive performance; an Antioxidant–Redox Axis that coordinates enzymatic and non-enzymatic defenses against reactive oxygen and nitrogen species, preserving vascular, neural, dermal, and genomic integrity; and a Neuro–Endocrine–Immune Axis that couples neurotransmitter balance, HPA/HPG-axis regulation, and immune competence. Across these axes, the paper synthesizes physiological and clinical evidence linking micronutrient patterns to disease-specific pathways in metabolic syndrome and type 2 diabetes mellitus, cardiovascular disease, neurocognitive decline and fatigue, depression, anxiety, and sleep disorders, Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD), menopausal symptoms and infertility, osteoporosis, sarcopenia and musculoskeletal degeneration, immune vulnerability, and skin and hair aging. Rather than treating vitamins and minerals as isolated agents, the Keyora Matrix is positioned as a coherent biochemical architecture in which nutrient clusters (e.g., B-complex plus magnesium and iron/copper; vitamin C–vitamin E–selenium–zinc; folate/B₁₂/B₆ plus vitamin D₃ and magnesium) act on shared pathways. By articulating this tri-axis model, the paper addresses a key gap between reductionist micronutrient research and the complex clinical reality of multimorbidity. It proposes a translational scaffold for designing and evaluating multi-nutrient formulations as foundational adjuncts in metabolic medicine, cardiovascular prevention, nutritional psychiatry, reproductive endocrinology, dermatology, and healthy aging. The framework is intended to guide both future mechanism-based clinical trials and precision nutrition strategies that move from simple deficiency correction toward systemic nutritional optimization and restoration of biochemical coherence.
2025-05-09 | Dietary and lifestyle interventions for the management of hereditary ataxias.
Hereditary ataxia (HA) is a diverse group of rare inherited neurological disorders characterised by cerebellar impairment and the progressive degeneration of spinocerebellar tracts and the spinal cord. These conditions manifest predominantly as unsteady gait, speech difficulties, dysphagia and motor skill impairment. The complex genetic causes and varied disease mechanisms underlying HA contribute to the multi-systemic symptoms which pose challenges in developing targeted effective treatments. Currently, available options for HA primarily focus on symptomatic management, highlighting a critical need for complementary therapeutic strategies, such as dietary and lifestyle interventions. This review explains recent findings on dietary and nutraceutical interventions, as well as lifestyle modifications such as exercise and rehabilitation programs for HA. It outlines common types of HA, including Friedreich ataxia, spinocerebellar ataxias, ataxia with vitamin E deficiency, ataxia-telangiectasia, and studies on a mixed cohort of patients with HA. The current management options, therapeutic implications of findings from pre-clinical and clinical data and future directions to advance the treatment of HA will also be discussed. The integration of nutraceuticals and rehabilitation programs with current methods of symptomatic management is encouraged for the holistic treatment of HA. These interventions will complement the use of various technological aids with the support of a multidisciplinary health and medical team to improve monitoring of the health status and disease progression of affected individuals; thus facilitating early treatment and an optimised clinical outcome.
2025-02-18 | Unique Effect of the High-Fat Meal on the Pharmacokinetics of Omaveloxolone Explained by Physiologically Based Biopharmaceutics Modeling
Objectives: Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the US and EU for the treatment of Friedreich ataxia in patients aged ≥16 years. It is approved at a dosage of 150 mg administered orally once daily on an empty stomach. Food-drug interactions can potentially alter the pharmacokinetic (PK) parameters of an oral drug, which may affect its efficacy and/or safety profile. Physiologically based biopharmaceutics modeling (PBBM) enables prediction of the PK profiles of oral drugs by integrating drug physicochemical properties and formulation factors with system physiological parameters. A PBBM was developed to predict and explain the effect of the US Food and Drug Administration high-fat meal on the PK of omaveloxolone. Methods: The PBBM was developed using physicochemical, dissolution, bile salt solubilization, precipitation, permeability, and in vitro and in vivo metabolism data. It was then validated across 9 distinct clinical scenarios that evaluated the impact of food, dose proportionality, and drug-drug interactions. Sensitivity analyses were performed to identify the parameters that could impact the absorption and metabolism of omaveloxolone in the fasted state. Results: The model’s predictive ability was evaluated based on the model’s performance indicators of maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC), which met predefined acceptance criteria across all analyzed clinical scenarios. Key parameters influencing the PK of omaveloxolone included bile salt solubilization, maximum rate of reaction of CYP3A4, particle size distribution, and permeability. The PBBM predicted a 350% increase in Cmax, with only a 15% increase in the AUC; this is consistent with clinical study findings. The effect of a high-fat meal on the PK of omaveloxolone is unique, as it differs from the linear correlation between Cmax and AUC ratios reported for other compounds from 323 food effect studies.[1-6] The PBBM showed that in vivo omaveloxolone absorption is solubility and dissolution rate limited. In the fed state, bile salt solubilization resulted in more rapid dissolution, leading to enhanced drug absorption in the upper gastrointestinal tract compared with the fasted state. Consequently, there was an increase in first-pass gut extraction, which explains a large transient elevation in Cmax without a corresponding increase in AUC. Conclusions: By mechanically integrating solubility and dissolution into PBBM, the unique impact of a high-fat meal on the PK profile of omaveloxolone was accurately anticipated. These findings reinforce the drug label recommendations on administration of omaveloxolone on an empty stomach. PBBM has the potential to predict the impact of food on drug PK and possibly eliminates the need for a clinical study.Citations: [1] Singh BN, Malhotra BK. Clin Pharmacokinet. 2004;43(15):1127-1156.[2] Qin H, et al. Basic Clin Pharmacol Toxicol. 2022;130(2):268-276.[3] Riedmaier AE, et al. AAPS J. 2020;22(6):123.[4] Omachi F, et al. J Pharm Health Care Sci. 2019;5:26.[5] Kesisoglou F, et al. AAPS J. 2023;25(4):60.[6] Li M, et al. CPT Pharmacometrics Syst Pharmacol. 2018;7(2):82-89.
2026-06-09 | Analysis of clinical pedigree characteristics in Chinese patients with ataxia with vitamin E deficiency.
The clinical and genetic features of ataxia with isolated vitamin E deficiency (AVED) patients in Chinese are remain not well understood. We enrolled 120 unrelated probands with clinically suspected autosomal recessive cerebellar ataxia (ARCA) at the Department of Neurology, China-Japan Friendship Hospital between 2014 and 2024. all probands underwent Whole-exome sequencing (WES), with candidate variants validated by Sanger sequencing and family cosegregation analysis. In silico pathogenicity analysis, including protein structure homology modeling and multispecies conservation analysis, was performed for novel variants. Plasma vitamin E levels were measured using high-performance liquid chromatography with diode array detection(HPLC-DAD). We identified 4 probands with biallelic TTPA variants, accounting for 3.33% of the ARCA cohort. Three probands were from consanguineous families, and 1 was from non- consanguineous family. The median age at onset was 15years (range 14-23years), with gait instability/ataxia as the universal initial symptom. Core clinical features included cerebellar ataxia (4/4), dysarthria (4/4), areflexia (2/4), scoliosis (4/4), foot deformity (3/4), and head titubation (3/4). Brain MRI revealed cerebellar atrophy in 3 patients, and all had markedly reduced serum vitamin E levels. We identified 2 novel missense variants (c.265C>A(p.P89T) and c.790A>G(p.M264V)). All patients received high-dose vitamin E supplementation, with 3/4 improved ataxia symptoms at 2-years follow-up. Our findings expand the clinical and genetic spectrum of AVED in China and support early evaluation of plasma vitamin E status and TTPA variants in patients with unexplained sporadic or recessive ataxia, as well as proactive screening of siblings and other at-risk relatives, even before symptom onset.
2026-05-21 | Ataxia With Vitamin E Deficiency Syndrome and a Novel TTPA Variant: A Paired Case Report.
Ataxia with vitamin E deficiency (AVED) is a chronic progressive syndrome with low vitamin E levels, caused by biallelic pathogenic variants in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13.1. According to family segregation studies, we describe a novel putative variant in compound heterozygosity with a known pathogenic variant. Clinical and instrumental evaluations were performed at our Neuromuscular Unit. Two siblings had been experiencing clumsiness, which later evolved into progressive gait unsteadiness, with falls and dysarthria. Brain MRI, EMG, and nerve conduction studies were inconclusive, but focused clinical exome sequencing revealed biallelic variants in the TTPA gene in both, the pathogenetic maternally inherited variant c.513_514insTT (p.Thr172Leufs*5) on exon 3 and the previously undescribed paternally inherited variant c.158T > C (p.Leu53Pro) on exon 1. Their plasma vitamin E levels were low (<1.7 mg/L). Their relatives carried 1 single variant each, with normal vitamin E levels. After 6 months of oral vitamin supplementation with a laboratory response, disease progression has stopped, although their neurologic examination has not clearly ameliorated. Exome sequencing identified a new potentially pathogenic variant in AVED, an ultra-rare but treatable cause of inherited ataxia. We recommend prompt vitamin E supplementation in patients with AVED.
2025-11-14 | Systemic Mechanistic Framework of the Keyora Multi-Vitamin & Mineral Matrix: Metabolic, Antioxidant, and Neuro-Endocrine Axes in Human Nutritional Homeostasis
Abstract Micronutrient deficiency remains a pervasive but underappreciated driver of chronic disease, even in populations with adequate calorie intake. Epidemiological data show that low or marginal intakes of vitamin D, folate, iron, zinc, magnesium, and other key micronutrients are common worldwide and are associated with metabolic syndrome, type 2 diabetes mellitus, cardiovascular dysfunction, neurocognitive decline, mood and anxiety disorders, sleep disturbances, immune dysregulation, and impaired reproductive health. Beyond classical deficiency syndromes, subtle but persistent insufficiency disrupts mitochondrial bioenergetics, antioxidant defenses, and neuro–endocrine–immune communication, creating a biochemical milieu that accelerates inflammatory and oxidative aging. In this context, the present work develops a systems-level framework for understanding how a defined set of 13 vitamins (A, D₃, E, K₁, C, thiamine, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, biotin, pantothenic acid) and 7 minerals (calcium, magnesium, iron, zinc, copper, manganese, selenium) can be organized into an integrated “Keyora Multi-Vitamin & Mineral Matrix.” This matrix is mapped onto three interconnected mechanistic axes: a Metabolic–Mitochondrial Axis that sustains ATP generation, substrate utilization, insulin sensitivity, and physical and cognitive performance; an Antioxidant–Redox Axis that coordinates enzymatic and non-enzymatic defenses against reactive oxygen and nitrogen species, preserving vascular, neural, dermal, and genomic integrity; and a Neuro–Endocrine–Immune Axis that couples neurotransmitter balance, HPA/HPG-axis regulation, and immune competence. Across these axes, the paper synthesizes physiological and clinical evidence linking micronutrient patterns to disease-specific pathways in metabolic syndrome and type 2 diabetes mellitus, cardiovascular disease, neurocognitive decline and fatigue, depression, anxiety, and sleep disorders, Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD), menopausal symptoms and infertility, osteoporosis, sarcopenia and musculoskeletal degeneration, immune vulnerability, and skin and hair aging. Rather than treating vitamins and minerals as isolated agents, the Keyora Matrix is positioned as a coherent biochemical architecture in which nutrient clusters (e.g., B-complex plus magnesium and iron/copper; vitamin C–vitamin E–selenium–zinc; folate/B₁₂/B₆ plus vitamin D₃ and magnesium) act on shared pathways. By articulating this tri-axis model, the paper addresses a key gap between reductionist micronutrient research and the complex clinical reality of multimorbidity. It proposes a translational scaffold for designing and evaluating multi-nutrient formulations as foundational adjuncts in metabolic medicine, cardiovascular prevention, nutritional psychiatry, reproductive endocrinology, dermatology, and healthy aging. The framework is intended to guide both future mechanism-based clinical trials and precision nutrition strategies that move from simple deficiency correction toward systemic nutritional optimization and restoration of biochemical coherence.
2025-05-09 | Dietary and lifestyle interventions for the management of hereditary ataxias.
Hereditary ataxia (HA) is a diverse group of rare inherited neurological disorders characterised by cerebellar impairment and the progressive degeneration of spinocerebellar tracts and the spinal cord. These conditions manifest predominantly as unsteady gait, speech difficulties, dysphagia and motor skill impairment. The complex genetic causes and varied disease mechanisms underlying HA contribute to the multi-systemic symptoms which pose challenges in developing targeted effective treatments. Currently, available options for HA primarily focus on symptomatic management, highlighting a critical need for complementary therapeutic strategies, such as dietary and lifestyle interventions. This review explains recent findings on dietary and nutraceutical interventions, as well as lifestyle modifications such as exercise and rehabilitation programs for HA. It outlines common types of HA, including Friedreich ataxia, spinocerebellar ataxias, ataxia with vitamin E deficiency, ataxia-telangiectasia, and studies on a mixed cohort of patients with HA. The current management options, therapeutic implications of findings from pre-clinical and clinical data and future directions to advance the treatment of HA will also be discussed. The integration of nutraceuticals and rehabilitation programs with current methods of symptomatic management is encouraged for the holistic treatment of HA. These interventions will complement the use of various technological aids with the support of a multidisciplinary health and medical team to improve monitoring of the health status and disease progression of affected individuals; thus facilitating early treatment and an optimised clinical outcome.
2025-02-18 | Unique Effect of the High-Fat Meal on the Pharmacokinetics of Omaveloxolone Explained by Physiologically Based Biopharmaceutics Modeling
Objectives: Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the US and EU for the treatment of Friedreich ataxia in patients aged ≥16 years. It is approved at a dosage of 150 mg administered orally once daily on an empty stomach. Food-drug interactions can potentially alter the pharmacokinetic (PK) parameters of an oral drug, which may affect its efficacy and/or safety profile. Physiologically based biopharmaceutics modeling (PBBM) enables prediction of the PK profiles of oral drugs by integrating drug physicochemical properties and formulation factors with system physiological parameters. A PBBM was developed to predict and explain the effect of the US Food and Drug Administration high-fat meal on the PK of omaveloxolone. Methods: The PBBM was developed using physicochemical, dissolution, bile salt solubilization, precipitation, permeability, and in vitro and in vivo metabolism data. It was then validated across 9 distinct clinical scenarios that evaluated the impact of food, dose proportionality, and drug-drug interactions. Sensitivity analyses were performed to identify the parameters that could impact the absorption and metabolism of omaveloxolone in the fasted state. Results: The model’s predictive ability was evaluated based on the model’s performance indicators of maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC), which met predefined acceptance criteria across all analyzed clinical scenarios. Key parameters influencing the PK of omaveloxolone included bile salt solubilization, maximum rate of reaction of CYP3A4, particle size distribution, and permeability. The PBBM predicted a 350% increase in Cmax, with only a 15% increase in the AUC; this is consistent with clinical study findings. The effect of a high-fat meal on the PK of omaveloxolone is unique, as it differs from the linear correlation between Cmax and AUC ratios reported for other compounds from 323 food effect studies.[1-6] The PBBM showed that in vivo omaveloxolone absorption is solubility and dissolution rate limited. In the fed state, bile salt solubilization resulted in more rapid dissolution, leading to enhanced drug absorption in the upper gastrointestinal tract compared with the fasted state. Consequently, there was an increase in first-pass gut extraction, which explains a large transient elevation in Cmax without a corresponding increase in AUC. Conclusions: By mechanically integrating solubility and dissolution into PBBM, the unique impact of a high-fat meal on the PK profile of omaveloxolone was accurately anticipated. These findings reinforce the drug label recommendations on administration of omaveloxolone on an empty stomach. PBBM has the potential to predict the impact of food on drug PK and possibly eliminates the need for a clinical study.Citations: [1] Singh BN, Malhotra BK. Clin Pharmacokinet. 2004;43(15):1127-1156.[2] Qin H, et al. Basic Clin Pharmacol Toxicol. 2022;130(2):268-276.[3] Riedmaier AE, et al. AAPS J. 2020;22(6):123.[4] Omachi F, et al. J Pharm Health Care Sci. 2019;5:26.[5] Kesisoglou F, et al. AAPS J. 2023;25(4):60.[6] Li M, et al. CPT Pharmacometrics Syst Pharmacol. 2018;7(2):82-89.
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Drug Discovery Landscape
1 orphan drug designation for Ataxia with vitamin E deficiency.
1 orphan drug designation for Ataxia with vitamin E deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Tocophersolan oral solution (vitamin E-tpgs) | — | FDA | 1988-04-15 | — | Sterling Winthrop |
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