⚙

Pathophysiology

3

Alpha-Tocopherol Transfer Protein Deficiency

Biallelic loss-of-function variants in TTPA abolish hepatic alpha-tocopherol transfer protein (alpha-TTP) activity. Alpha-TTP normally selects and transfers RRR-alpha-tocopherol within hepatocytes for incorporation into nascent very-low-density lipoprotein (VLDL); without functional alpha-TTP, alpha-tocopherol is not retained or re-secreted into plasma lipoproteins and is instead excreted, so dietary vitamin E cannot reach peripheral tissues.

vitamin transport GO:0051180 ↓ DECREASED VLDL alpha-tocopherol incorporation GO:0034379 ⚠ ABNORMAL

Downstream

Systemic Vitamin E Deficiency Failure to incorporate alpha-tocopherol into hepatic VLDL causes plasma and tissue vitamin E to fall to deficient levels.

Show evidence (2 references)

PMID:7719340 SUPPORT Human Clinical

"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)."

Identifies the core molecular lesion: impaired hepatic incorporation of alpha-tocopherol into secreted lipoproteins due to alpha-TTP.

PMID:7719340 SUPPORT Human Clinical

"Here we report the identification of three frame-shift mutations in the alpha TTP gene."

Loss-of-function (frameshift) TTPA mutations underlie the alpha-TTP deficiency.

Systemic Vitamin E Deficiency

Because alpha-tocopherol cannot be incorporated into plasma lipoproteins, serum vitamin E concentrations fall to very low levels despite normal dietary intake and normal intestinal absorption. Vitamin E is the major lipid-soluble chain-breaking antioxidant; its systemic depletion is the proximate biochemical hallmark of AVED and distinguishes it from malabsorption causes of vitamin E deficiency.

vitamin E metabolic process GO:0042360 ↓ DECREASED

Downstream

Oxidative Neuronal Damage Loss of the major lipid-soluble antioxidant exposes neural membranes to unchecked lipid peroxidation and oxidative injury.

Low levels of vitamin E The systemic biochemical state is directly measurable as low circulating vitamin E.

Show evidence (2 references)

PMID:25066259 SUPPORT Human Clinical

"AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function."

Confirms low plasma vitamin E and the resulting loss of antioxidant capacity as the central biochemical consequence.

PMID:15300460 SUPPORT Human Clinical

"AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E."

An Italian patient series confirms markedly reduced plasma vitamin E as the biochemical hallmark accompanying progressive spinocerebellar disease.

Oxidative Neuronal Damage

Loss of the lipid-soluble antioxidant vitamin E leaves neuronal and axonal membranes unprotected against lipid peroxidation and reactive oxygen species. Large-caliber myelinated sensory neurons of the dorsal root ganglia, the posterior columns (dorsal columns), and cerebellar pathways are preferentially vulnerable, producing the spinocerebellar degeneration that clinically resembles Friedreich ataxia.

dorsal root ganglion sensory neuron CL:1001451 cerebellar Purkinje cell CL:0000121

response to oxidative stress GO:0006979 ↑ INCREASED lipid peroxidation GO:0034440 ↑ INCREASED

Downstream

Progressive ataxia Oxidative injury in sensory and cerebellar pathways produces progressive ataxia.

Peripheral neuropathy Large-fiber sensory neuron injury produces peripheral neuropathy.

Loss of proprioception Posterior-column and sensory neuron vulnerability produces impaired proprioception.

Areflexia Large-fiber sensory neuropathy causes loss of deep tendon reflexes.

Retinitis pigmentosa Chronic antioxidant deficiency can injure the retina and produce pigmentary degeneration.

Show evidence (2 references)

PMID:25066259 SUPPORT Human Clinical

"Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED."

Attributes AVED neurodegeneration to dysregulation of the lipid-soluble antioxidant vitamin E (oxidative mechanism).

PMID:9463307 SUPPORT Human Clinical

"is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia."

Establishes the Friedreich-ataxia-like spinocerebellar neurodegenerative phenotype.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

18

Cardiovascular 1

Cardiomyopathy OCCASIONAL Cardiomyopathy HP:0001638

Show evidence (1 reference)

PMID:9463307 SUPPORT Human Clinical

"cardiomyopathy was found in only 19% of cases"

The large case series reports cardiomyopathy in 19% of AVED patients, less common than in Friedreich ataxia.

Eye 4

Decreased visual acuity Reduced visual acuity HP:0007663

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists decreased visual acuity among commonly observed features.

Retinitis pigmentosa Rod-cone dystrophy HP:0000510

Show evidence (1 reference)

PMID:25066259 SUPPORT Human Clinical

"Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment."

Establishes retinitis pigmentosa as the main cause of visual impairment in affected AVED patients.

Nystagmus FREQUENT Nystagmus HP:0000639

Show evidence (1 reference)

ORPHA:96 SUPPORT Other

"HP:0000639 | Nystagmus | Frequent (79-30%)"

Orphanet records nystagmus as a frequent AVED phenotype.

Nyctalopia FREQUENT Nyctalopia HP:0000662

Show evidence (1 reference)

ORPHA:96 SUPPORT Other

"HP:0000662 | Nyctalopia | Frequent (79-30%)"

Orphanet records nyctalopia as a frequent AVED phenotype.

Limbs 1

Pes cavus FREQUENT Pes cavus HP:0001761

Show evidence (1 reference)

ORPHA:96 SUPPORT Other

"HP:0001761 | Pes cavus | Frequent (79-30%)"

Orphanet records pes cavus as a frequent AVED phenotype.

Nervous System 6

Progressive ataxia Progressive cerebellar ataxia HP:0002073

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia."

GeneReviews lists progressive ataxia among the first manifestations of untreated AVED.

Areflexia Areflexia HP:0001284

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia."

GeneReviews lists areflexia among the first manifestations.

Dysarthria Dysarthria HP:0001260

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists dysarthria among commonly observed features.

Head titubation Head titubation HP:0002599

Show evidence (2 references)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists head titubation among commonly observed features.

PMID:9463307 SUPPORT Human Clinical

"head titubation was found in 28% of cases and dystonia in an additional 13%."

A large case series quantifies head titubation (28%) as a feature distinguishing AVED from Friedreich ataxia.

Dystonia OCCASIONAL Dystonia HP:0001332

Show evidence (1 reference)

PMID:9463307 SUPPORT Human Clinical

"head titubation was found in 28% of cases and dystonia in an additional 13%."

The large case series reports dystonia in 13% of patients (OCCASIONAL frequency band).

Peripheral neuropathy VERY_FREQUENT Peripheral neuropathy HP:0009830

Show evidence (1 reference)

ORPHA:96 SUPPORT Other

"HP:0009830 | Peripheral neuropathy | Very frequent (99-80%)"

Orphanet records peripheral neuropathy as a very frequent AVED phenotype.

Other 6

Loss of proprioception Impaired proprioception HP:0010831

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia."

GeneReviews lists loss of proprioception as an early manifestation.

Impaired vibratory sensation Impaired vibratory sensation HP:0002495

Show evidence (1 reference)

PMID:15300460 PARTIAL Human Clinical

"AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E."

The cited series documents progressive spinocerebellar (posterior column/sensory) involvement; impaired vibratory sensation is a component of this sensory ataxia but is not named verbatim in the abstract, so the support is partial.

Dysdiadochokinesis Dysdiadochokinesis HP:0002075

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists dysdiadochokinesia among commonly observed features.

Positive Romberg sign Positive Romberg sign HP:0002403

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists positive Romberg sign among commonly observed features.

Babinski sign Babinski sign HP:0003487

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign."

GeneReviews lists a positive Babinski sign among commonly observed features.

Low levels of vitamin E VERY_FREQUENT Decreased circulating vitamin E concentration HP:0100513

Show evidence (1 reference)

ORPHA:96 SUPPORT Other

"HP:0100513 | Low levels of vitamin E | Very frequent (99-80%)"

Orphanet records low vitamin E levels as a very frequent AVED phenotype.

🧬

Genetic Associations

1

TTPA pathogenic variants (Causative biallelic pathogenic variants)

Gene: TTPA hgnc:12404 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:7719340 SUPPORT Human Clinical

"The finding of alpha TTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E"

Establishes TTPA (alpha-TTP) gene mutations as the cause of AVED.

💊

Medical Actions

2

High-dose oral vitamin E supplementation

Action: nutritional supplementation MAXO:0000106

Agent: alpha-tocopherol CHEBI:22470

Lifelong high-dose oral vitamin E (alpha-tocopherol) supplementation is the disease-modifying targeted therapy for AVED, dosed to bring plasma vitamin E into the high-normal range. Initiated in presymptomatic individuals it prevents disease manifestations; started early in symptomatic patients it can partially reverse ataxia and mental deterioration, though neurologic recovery is often slow and incomplete.

Mechanism Target:

MODULATES Systemic Vitamin E Deficiency — Oral alpha-tocopherol bypasses the alpha-TTP defect by mass action, restoring plasma vitamin E and tissue antioxidant protection.

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Lifelong targeted therapy with high-dose oral vitamin E supplementation (that brings plasma vitamin E concentrations into the high-normal range) initiated in presymptomatic individuals (e.g., younger sibs of an index case) prevents the manifestations of AVED."

GeneReviews defines high-dose oral vitamin E as the targeted, disease-modifying therapy that prevents manifestations.

Show evidence (3 references)

PMID:20301419 SUPPORT Human Clinical

"Vitamin E supplementation early in the disease course of a symptomatic individual may to some extent reverse ataxia and mental deterioration."

GeneReviews states that early supplementation can partially reverse symptoms in symptomatic individuals.

PMID:9931538 SUPPORT Human Clinical

"After initiation of high-dosage alpha-tocopherol therapy, the organic mental syndrome disappeared and cognitive function improved rapidly. Neurologic recovery, however, was slow and incomplete."

A treated patient case shows rapid cognitive improvement but slow, incomplete neurologic recovery with high-dose alpha-tocopherol.

PMID:15300460 SUPPORT Human Clinical

"Vitamin E supplementation therapy allowed a stabilization of the neurological conditions in most of the patients."

Long-term follow-up of an Italian cohort shows vitamin E supplementation stabilizes neurological status in most patients.

Multidisciplinary supportive care for ataxia

Action: supportive care MAXO:0000950

Supportive care for AVED is the same multidisciplinary management used for ataxia of other causes (physical, occupational, and speech therapy and assistive devices), alongside surveillance of plasma vitamin E in treated individuals.

Show evidence (1 reference)

PMID:20301419 SUPPORT Human Clinical

"Supportive care for those with ataxia and related findings is the same multidisciplinary care for individuals with ataxia of other causes."

GeneReviews specifies multidisciplinary supportive care as standard for ataxia-related findings in AVED.

{ }

Source YAML

click to show

name: Familial Isolated Vitamin E Deficiency
creation_date: "2026-06-03T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Ataxia with vitamin E deficiency
  term:
    id: MONDO:0010188
    label: familial isolated deficiency of vitamin E
description: >
  Ataxia with vitamin E deficiency (AVED), also called familial isolated
  vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease
  caused by biallelic loss-of-function variants in TTPA, encoding the hepatic
  alpha-tocopherol transfer protein (alpha-TTP). Loss of alpha-TTP activity
  prevents incorporation of alpha-tocopherol (vitamin E) into nascent very-low-
  density lipoproteins secreted by the liver, producing severe systemic vitamin
  E deficiency despite normal dietary intake and intestinal absorption. The
  resulting failure of lipid-soluble antioxidant protection causes oxidative
  damage to large myelinated sensory neurons, dorsal columns, and cerebellar
  pathways, producing a progressive spinocerebellar ataxia that closely
  resembles Friedreich ataxia. Lifelong high-dose oral vitamin E supplementation
  is disease-modifying and, when started presymptomatically, prevents clinical
  manifestations.
synonyms:
- AVED
- Ataxia with vitamin E deficiency
- Ataxia with isolated vitamin E deficiency
- Friedreich-like ataxia with selective vitamin E deficiency
parents:
- autosomal recessive metabolic cerebellar ataxia
- inborn vitamin metabolic disorder
references:
- reference: PMID:20301419
  title: "Ataxia with Vitamin E Deficiency."
  tags:
  - GeneReviews

pathophysiology:
- name: Alpha-Tocopherol Transfer Protein Deficiency
  description: >
    Biallelic loss-of-function variants in TTPA abolish hepatic
    alpha-tocopherol transfer protein (alpha-TTP) activity. Alpha-TTP normally
    selects and transfers RRR-alpha-tocopherol within hepatocytes for
    incorporation into nascent very-low-density lipoprotein (VLDL); without
    functional alpha-TTP, alpha-tocopherol is not retained or re-secreted into
    plasma lipoproteins and is instead excreted, so dietary vitamin E cannot
    reach peripheral tissues.
  biological_processes:
  - preferred_term: vitamin transport
    term:
      id: GO:0051180
      label: vitamin transport
    modifier: DECREASED
  - preferred_term: VLDL alpha-tocopherol incorporation
    term:
      id: GO:0034379
      label: very-low-density lipoprotein particle assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:7719340
    reference_title: "Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AVED patients have an \nimpaired ability to incorporate alpha-tocopherol into lipoproteins secreted by \nthe liver, a function putatively attributable to the alpha-tocopherol transfer \nprotein (alpha-TTP)."
    explanation: >
      Identifies the core molecular lesion: impaired hepatic incorporation
      of alpha-tocopherol into secreted lipoproteins due to alpha-TTP.
  - reference: PMID:7719340
    reference_title: "Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the identification of three frame-shift \nmutations in the alpha TTP gene."
    explanation: >
      Loss-of-function (frameshift) TTPA mutations underlie the alpha-TTP
      deficiency.
  downstream:
  - target: Systemic Vitamin E Deficiency
    description: >
      Failure to incorporate alpha-tocopherol into hepatic VLDL causes plasma
      and tissue vitamin E to fall to deficient levels.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7719340
      reference_title: "Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "AVED patients have an \nimpaired ability to incorporate alpha-tocopherol into lipoproteins secreted by \nthe liver"
      explanation: >
        Impaired hepatic incorporation of alpha-tocopherol into secreted
        lipoproteins directly produces systemic vitamin E deficiency.

- name: Systemic Vitamin E Deficiency
  description: >
    Because alpha-tocopherol cannot be incorporated into plasma lipoproteins,
    serum vitamin E concentrations fall to very low levels despite normal
    dietary intake and normal intestinal absorption. Vitamin E is the major
    lipid-soluble chain-breaking antioxidant; its systemic depletion is the
    proximate biochemical hallmark of AVED and distinguishes it from
    malabsorption causes of vitamin E deficiency.
  biological_processes:
  - preferred_term: vitamin E metabolic process
    term:
      id: GO:0042360
      label: vitamin E metabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:25066259
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AVED is \nassociated with low plasma vitamin E levels, which results in compromised \nantioxidant function."
    explanation: >
      Confirms low plasma vitamin E and the resulting loss of antioxidant
      capacity as the central biochemical consequence.
  - reference: PMID:15300460
    reference_title: "Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AVED patients have progressive \nspinocerebellar symptoms and markedly reduced plasma levels of vitamin E."
    explanation: >
      An Italian patient series confirms markedly reduced plasma vitamin E as
      the biochemical hallmark accompanying progressive spinocerebellar
      disease.
  downstream:
  - target: Oxidative Neuronal Damage
    description: >
      Loss of the major lipid-soluble antioxidant exposes neural membranes to
      unchecked lipid peroxidation and oxidative injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25066259
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dysregulation of this lipid-soluble antioxidant vitamin \nplays a major role in the neurodegeneration observed in AVED."
      explanation: >
        Vitamin E deficiency (loss of the lipid-soluble antioxidant) drives
        the oxidative neurodegeneration of AVED.
  - target: Low levels of vitamin E
    description: The systemic biochemical state is directly measurable as low circulating vitamin E.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:96
      reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100513 | Low levels of vitamin E | Very frequent (99-80%)"
      explanation: Orphanet records low vitamin E levels as a very frequent AVED phenotype.

- name: Oxidative Neuronal Damage
  description: >
    Loss of the lipid-soluble antioxidant vitamin E leaves neuronal and axonal
    membranes unprotected against lipid peroxidation and reactive oxygen
    species. Large-caliber myelinated sensory neurons of the dorsal root
    ganglia, the posterior columns (dorsal columns), and cerebellar pathways
    are preferentially vulnerable, producing the spinocerebellar
    degeneration that clinically resembles Friedreich ataxia.
  cell_types:
  - preferred_term: dorsal root ganglion sensory neuron
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: lipid peroxidation
    term:
      id: GO:0034440
      label: lipid oxidation
    modifier: INCREASED
  evidence:
  - reference: PMID:25066259
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysregulation of this lipid-soluble antioxidant vitamin \nplays a major role in the neurodegeneration observed in AVED."
    explanation: >
      Attributes AVED neurodegeneration to dysregulation of the lipid-soluble
      antioxidant vitamin E (oxidative mechanism).
  - reference: PMID:9463307
    reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is a rare autosomal recessive neurodegenerative disease \ncharacterized clinically by symptoms with often striking resemblance to those of \nFriedreich ataxia."
    explanation: >
      Establishes the Friedreich-ataxia-like spinocerebellar
      neurodegenerative phenotype.
  downstream:
  - target: Progressive ataxia
    description: Oxidative injury in sensory and cerebellar pathways produces progressive ataxia.
    causal_link_type: DIRECT
  - target: Peripheral neuropathy
    description: Large-fiber sensory neuron injury produces peripheral neuropathy.
    causal_link_type: DIRECT
  - target: Loss of proprioception
    description: Posterior-column and sensory neuron vulnerability produces impaired proprioception.
    causal_link_type: DIRECT
  - target: Areflexia
    description: Large-fiber sensory neuropathy causes loss of deep tendon reflexes.
    causal_link_type: DIRECT
  - target: Retinitis pigmentosa
    description: Chronic antioxidant deficiency can injure the retina and produce pigmentary degeneration.
    causal_link_type: DIRECT

phenotypes:
- name: Progressive ataxia
  description: >
    Progressive spinocerebellar ataxia is the cardinal manifestation,
    typically beginning between ages 5 and 15 years and resembling Friedreich
    ataxia.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first manifestations \ninclude progressive ataxia, clumsiness of the hands, loss of proprioception, and \nareflexia."
    explanation: >
      GeneReviews lists progressive ataxia among the first manifestations of
      untreated AVED.

- name: Loss of proprioception
  description: >
    Loss of proprioception (joint position sense) reflects degeneration of
    large sensory neurons and the dorsal columns.
  phenotype_term:
    preferred_term: Impaired proprioception
    term:
      id: HP:0010831
      label: Impaired proprioception
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first manifestations \ninclude progressive ataxia, clumsiness of the hands, loss of proprioception, and \nareflexia."
    explanation: >
      GeneReviews lists loss of proprioception as an early manifestation.

- name: Impaired vibratory sensation
  description: >
    Loss of vibration sense reflects degeneration of the large myelinated
    sensory fibers and posterior columns, part of the spinocerebellar/sensory
    ataxia phenotype.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:15300460
    reference_title: "Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "AVED patients have progressive \nspinocerebellar symptoms and markedly reduced plasma levels of vitamin E."
    explanation: >
      The cited series documents progressive spinocerebellar (posterior
      column/sensory) involvement; impaired vibratory sensation is a
      component of this sensory ataxia but is not named verbatim in the
      abstract, so the support is partial.

- name: Areflexia
  description: >
    Loss of deep tendon reflexes is an early and characteristic finding,
    reflecting large-fiber sensory neuropathy.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first manifestations \ninclude progressive ataxia, clumsiness of the hands, loss of proprioception, and \nareflexia."
    explanation: >
      GeneReviews lists areflexia among the first manifestations.

- name: Dysarthria
  description: Slurred or poorly articulated speech due to cerebellar involvement.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists dysarthria among commonly observed features.

- name: Dysdiadochokinesis
  description: Impaired ability to perform rapid alternating movements (cerebellar sign).
  phenotype_term:
    preferred_term: Dysdiadochokinesis
    term:
      id: HP:0002075
      label: Dysdiadochokinesis
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists dysdiadochokinesia among commonly observed features.

- name: Positive Romberg sign
  description: >
    A positive Romberg sign indicates proprioceptive (posterior column)
    sensory loss.
  phenotype_term:
    preferred_term: Positive Romberg sign
    term:
      id: HP:0002403
      label: Positive Romberg sign
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists positive Romberg sign among commonly observed features.

- name: Head titubation
  description: >
    Rhythmic head tremor (titubation) is a characteristic feature that helps
    distinguish AVED from Friedreich ataxia.
  phenotype_term:
    preferred_term: Head titubation
    term:
      id: HP:0002599
      label: Head titubation
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists head titubation among commonly observed features.
  - reference: PMID:9463307
    reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "head titubation was found in 28% of \ncases and dystonia in an additional 13%."
    explanation: >
      A large case series quantifies head titubation (28%) as a feature
      distinguishing AVED from Friedreich ataxia.

- name: Dystonia
  description: >
    Dystonia is observed in a minority of AVED patients and is one of the
    movement-disorder features reported alongside the cerebellar syndrome.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:9463307
    reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "head titubation was found in 28% of \ncases and dystonia in an additional 13%."
    explanation: >
      The large case series reports dystonia in 13% of patients (OCCASIONAL
      frequency band).

- name: Babinski sign
  description: >
    An extensor plantar response reflects involvement of the corticospinal
    (pyramidal) tracts.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists a positive Babinski sign among commonly observed
      features.

- name: Decreased visual acuity
  description: >
    Some individuals develop decreased visual acuity; in a subset this is
    associated with retinitis pigmentosa.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features often observed are dysdiadochokinesia, dysarthria, \npositive Romberg sign, head titubation, decreased visual acuity, and positive \nBabinski sign."
    explanation: >
      GeneReviews lists decreased visual acuity among commonly observed
      features.

- name: Retinitis pigmentosa
  description: >
    A subset of AVED patients develop retinitis pigmentosa, thought to be the
    main cause of visual impairment and attributable to chronic oxidative
    retinal damage from vitamin E deficiency.
  phenotype_term:
    preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:25066259
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some AVED patients \nexperience decreased visual acuity. Retinitis pigmentosa is thought to be the \nmain cause of this visual impairment."
    explanation: >
      Establishes retinitis pigmentosa as the main cause of visual impairment
      in affected AVED patients.

- name: Cardiomyopathy
  description: >
    Cardiomyopathy occurs in a minority of AVED patients, at a lower frequency
    than in Friedreich ataxia, with which AVED is otherwise easily confused.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:9463307
    reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiomyopathy \nwas found in only 19% of cases"
    explanation: >
      The large case series reports cardiomyopathy in 19% of AVED patients,
      less common than in Friedreich ataxia.

- name: Low levels of vitamin E
  description: >
    Markedly reduced circulating vitamin E is the biochemical hallmark of AVED
    and follows directly from impaired alpha-tocopherol transfer.
  phenotype_term:
    preferred_term: Low levels of vitamin E
    term:
      id: HP:0100513
      label: Decreased circulating vitamin E concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:96
    reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100513 | Low levels of vitamin E | Very frequent (99-80%)"
    explanation: Orphanet records low vitamin E levels as a very frequent AVED phenotype.

- name: Peripheral neuropathy
  description: >
    Peripheral nerve involvement contributes to sensory ataxia, areflexia, and
    impaired proprioception.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: ORPHA:96
    reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009830 | Peripheral neuropathy | Very frequent (99-80%)"
    explanation: Orphanet records peripheral neuropathy as a very frequent AVED phenotype.

- name: Nystagmus
  description: Involuntary eye movements from cerebellar/ocular motor involvement.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:96
    reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
    explanation: Orphanet records nystagmus as a frequent AVED phenotype.

- name: Nyctalopia
  description: Night blindness associated with retinal involvement in AVED.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:96
    reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000662 | Nyctalopia | Frequent (79-30%)"
    explanation: Orphanet records nyctalopia as a frequent AVED phenotype.

- name: Pes cavus
  description: High-arched feet occurring as part of the Friedreich-like neuro-orthopedic phenotype.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:96
    reference_title: "Ataxia with vitamin E deficiency (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001761 | Pes cavus | Frequent (79-30%)"
    explanation: Orphanet records pes cavus as a frequent AVED phenotype.

genetic:
- name: TTPA pathogenic variants
  gene_term:
    preferred_term: TTPA
    term:
      id: hgnc:12404
      label: TTPA
  association: Causative biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:7719340
    reference_title: "Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding of alpha TTP gene mutations in AVED patients \nsubstantiates the therapeutic role of vitamin E"
    explanation: >
      Establishes TTPA (alpha-TTP) gene mutations as the cause of AVED.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:9463307
      reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "is a rare autosomal recessive neurodegenerative disease"
      explanation: AVED is inherited in an autosomal recessive manner.
  variants:
  - name: Biallelic TTPA pathogenic variants
    description: >
      Reported disease-causing TTPA variants include frameshift, insertion,
      point, and nonsense variants. The 744delA frameshift is the major
      mutation in North Africa and Italy and correlates with a severe
      phenotype.
    gene:
      preferred_term: TTPA
      term:
        id: hgnc:12404
        label: TTPA
    clinical_significance: PATHOGENIC
    type: loss_of_function_variant
    evidence:
    - reference: PMID:7719340
      reference_title: "Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A 744delA mutation accounts for 68% of the \nmutant alleles in the 17 families analysed and appears to have spread in North \nAfrica and Italy. This mutation correlates with a severe phenotype"
      explanation: >
        Identifies 744delA as the most common TTPA allele, associated with
        a severe phenotype.
    - reference: PMID:9463307
      reference_title: "Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We now \nhave identified a total of 13 mutations in 27 families."
      explanation: >
        Demonstrates allelic heterogeneity of pathogenic TTPA variants
        across many families.

treatments:
- name: High-dose oral vitamin E supplementation
  description: >
    Lifelong high-dose oral vitamin E (alpha-tocopherol) supplementation is
    the disease-modifying targeted therapy for AVED, dosed to bring plasma
    vitamin E into the high-normal range. Initiated in presymptomatic
    individuals it prevents disease manifestations; started early in
    symptomatic patients it can partially reverse ataxia and mental
    deterioration, though neurologic recovery is often slow and incomplete.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
    therapeutic_agent:
    - preferred_term: alpha-tocopherol
      term:
        id: CHEBI:22470
        label: alpha-tocopherol
  target_mechanisms:
  - target: Systemic Vitamin E Deficiency
    treatment_effect: MODULATES
    description: >
      Oral alpha-tocopherol bypasses the alpha-TTP defect by mass action,
      restoring plasma vitamin E and tissue antioxidant protection.
    evidence:
    - reference: PMID:20301419
      reference_title: "Ataxia with Vitamin E Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lifelong targeted therapy with high-dose oral \nvitamin E supplementation (that brings plasma vitamin E concentrations into the \nhigh-normal range) initiated in presymptomatic individuals (e.g., younger sibs \nof an index case) prevents the manifestations of AVED."
      explanation: >
        GeneReviews defines high-dose oral vitamin E as the targeted,
        disease-modifying therapy that prevents manifestations.
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E supplementation \nearly in the disease course of a symptomatic individual may to some extent \nreverse ataxia and mental deterioration."
    explanation: >
      GeneReviews states that early supplementation can partially reverse
      symptoms in symptomatic individuals.
  - reference: PMID:9931538
    reference_title: "Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After initiation of high-dosage alpha-tocopherol therapy, the \norganic mental syndrome disappeared and cognitive function improved rapidly. \nNeurologic recovery, however, was slow and incomplete."
    explanation: >
      A treated patient case shows rapid cognitive improvement but slow,
      incomplete neurologic recovery with high-dose alpha-tocopherol.
  - reference: PMID:15300460
    reference_title: "Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E supplementation therapy allowed a stabilization of the \nneurological conditions in most of the patients."
    explanation: >
      Long-term follow-up of an Italian cohort shows vitamin E
      supplementation stabilizes neurological status in most patients.

- name: Multidisciplinary supportive care for ataxia
  description: >
    Supportive care for AVED is the same multidisciplinary management used for
    ataxia of other causes (physical, occupational, and speech therapy and
    assistive devices), alongside surveillance of plasma vitamin E in treated
    individuals.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301419
    reference_title: "Ataxia with Vitamin E Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive care for \nthose with ataxia and related findings is the same multidisciplinary care for \nindividuals with ataxia of other causes."
    explanation: >-
      GeneReviews specifies multidisciplinary supportive care as standard for
      ataxia-related findings in AVED.

📚

References & Deep Research

References

1

PMID:20301419

Ataxia with Vitamin E Deficiency.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Familial Isolated Vitamin E Deficiency (AVED) — Comprehensive Disease Characteristics Report

Edison Scientific Literature 21 citations 2026-06-03T23:11:11.758834

Familial Isolated Vitamin E Deficiency (AVED) — Comprehensive Disease Characteristics Report

1. Disease Information

Overview / definition

Familial isolated vitamin E deficiency—also referred to as ataxia with isolated vitamin E deficiency (AVED)—is a rare, potentially treatable autosomal recessive neurodegenerative disorder caused by impaired hepatic handling/transport of α‑tocopherol (vitamin E), leading to very low circulating vitamin E and progressive neurologic disease resembling Friedreich ataxia (FA). (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)

Key identifiers and nomenclature

OMIM/MIM disease number: 277460 (explicitly stated) (hoshino1999ataxiawithisolated pages 22-23)
Gene OMIM noted in one source: TTPA OMIM*600415 (referenced in a case report) (zhang2021clinicalandgenetic pages 1-4)
Orphanet / ICD‑10 / ICD‑11 / MeSH / MONDO: Not retrievable from the currently available full-text evidence in this run; therefore not reported here.

Synonyms / alternative names

Ataxia with isolated vitamin E deficiency (AVED) (hoshino1999ataxiawithisolated pages 22-23)
Ataxia with vitamin E deficiency (hoshino1999ataxiawithisolated pages 22-23)
Familial isolated vitamin E deficiency (used interchangeably with AVED in the literature) (cavalier1998ataxiawithisolated pages 7-8)

Evidence sources (individual vs aggregated)

The information summarized here is derived primarily from aggregated cohorts (e.g., multicenter family series) and individual case reports describing biochemically and genetically confirmed AVED. (cavalier1998ataxiawithisolated pages 7-8, holla2024geneticallyprovenataxia pages 1-2, iwasa2014retinitispigmentosaand pages 2-3, hoshino1999ataxiawithisolated pages 22-23)

2. Etiology

Disease causal factors

Primary cause: biallelic pathogenic variants in TTPA, encoding α‑tocopherol transfer protein (α‑TTP/αTTP). (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)

Mechanistically, α‑TTP binds α‑tocopherol and supports its incorporation into circulating lipoproteins (e.g., VLDL); dysfunction yields very low serum/plasma vitamin E despite preserved intestinal absorption. (holla2024geneticallyprovenataxia pages 1-2, iwasa2014retinitispigmentosaand pages 2-3)

Risk factors

Genetic: autosomal recessive inheritance; consanguinity appears in some families/case reports. (esmer2013clinicalandmolecular pages 2-4, hoshino1999ataxiawithisolated pages 22-23)
Environmental: not a primary driver in AVED; however, prolonged untreated deficiency is a major risk for irreversible neurologic sequelae (see prognosis/treatment). (esmer2013clinicalandmolecular pages 2-4, cavalier1998ataxiawithisolated pages 7-8)

Protective factors

Early, sustained vitamin E supplementation is repeatedly emphasized as protective against progression and irreversible damage. (esmer2013clinicalandmolecular pages 2-4, cavalier1998ataxiawithisolated pages 7-8)

Gene–environment interactions

Direct gene–environment interactions were not described in the available evidence. The most actionable interaction is genotype × timing of treatment, where delayed supplementation is associated with incomplete reversibility of neurologic deficits. (esmer2013clinicalandmolecular pages 2-4)

3. Phenotypes

Core clinical phenotype

AVED typically presents with a FA-like neurologic syndrome including: * Progressive gait/limb ataxia (stoiloudis2022vitaminedeficiency pages 42-44, hoshino1999ataxiawithisolated pages 22-23) * Hyporeflexia/areflexia (stoiloudis2022vitaminedeficiency pages 42-44, hoshino1999ataxiawithisolated pages 22-23) * Loss of proprioception and vibration sense (posterior column involvement) (stoiloudis2022vitaminedeficiency pages 42-44, hoshino1999ataxiawithisolated pages 22-23) * Dysarthria (stoiloudis2022vitaminedeficiency pages 42-44) * Peripheral neuropathy/sensory involvement (iwasa2014retinitispigmentosaand pages 2-3)

Additional/variable features: * Head titubation / tremor; dystonia (cavalier1998ataxiawithisolated pages 7-8, stoiloudis2022vitaminedeficiency pages 42-44) * Extensor plantar response / Babinski (stoiloudis2022vitaminedeficiency pages 42-44) * Retinopathy/retinitis pigmentosa; macular degeneration in some individuals, particularly with long-standing deficiency (iwasa2014retinitispigmentosaand pages 2-3, hoshino1999ataxiawithisolated pages 22-23) * Cardiomyopathy occurs but at lower frequency than FA in cohort data (cavalier1998ataxiawithisolated pages 7-8, stoiloudis2022vitaminedeficiency pages 42-44)

Phenotype statistics from a recent compiled frequency table

A review snippet reports phenotype frequencies (interpretable as proportion of affected individuals in the compiled dataset): * Absent tendon reflexes 94.7% * Gait disturbance 93.4% * Plantar extensor response 85.5% * Posterior column involvement 67.1% * Speech disturbance/dysarthria 61.8% * Head titubation 40.8% * Retinitis pigmentosa 2.3% * Cardiomyopathy 1.5% (stoiloudis2022vitaminedeficiency pages 42-44)

A large family series found cardiomyopathy 19%, head titubation 28%, and dystonia 13% (in addition to the FA-like presentation). (cavalier1998ataxiawithisolated pages 7-8)

Age of onset and progression

Typical onset is late childhood to early adolescence, but reports include onset ranging from early childhood/infancy to adulthood (including the 4th decade in some descriptions). (holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4)
Untreated disease is described as generally manifesting between ages 5 and 15 years in one definition-style source. (esmer2013clinicalandmolecular pages 2-4)

Suggested HPO terms (examples)

Cerebellar ataxia — HP:0001251
Areflexia — HP:0001284
Loss of proprioception — HP:0002355 (or related sensory ataxia terms)
Decreased vibratory sensation — HP:0002495
Dysarthria — HP:0001260
Peripheral neuropathy — HP:0009830
Head tremor / titubation — HP:0002326 (tremor)
Dystonia — HP:0001332
Retinitis pigmentosa — HP:0000510
Cardiomyopathy — HP:0001638

(These HPO codes are suggested to standardize phenotype capture; detailed mapping should be verified against the current HPO release.)

4. Genetic / Molecular Information

Causal gene

TTPA (α‑tocopherol transfer protein gene). (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)

Protein and molecular role

α‑TTP binds α‑tocopherol and enables its export from the liver into circulating lipoproteins (described as incorporation into VLDL), supporting systemic delivery of vitamin E; deficiency leads to neuronal oxidative injury. (holla2024geneticallyprovenataxia pages 1-2, iwasa2014retinitispigmentosaand pages 2-3)

Inheritance

Autosomal recessive; many reported individuals are homozygous in consanguineous families or biallelic (including compound heterozygous) in non-consanguineous settings. (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)

Pathogenic variants (examples explicitly described in retrieved evidence)

c.744delA — repeatedly highlighted as a major mutation in North Africa / Mediterranean and associated with earlier/severe course in some reports (esmer2013clinicalandmolecular pages 2-4, zhang2021clinicalandgenetic pages 1-4)
c.513_514insTT, c.486delT, c.400C>T (European-origin recurrent mutations noted in one report) (esmer2013clinicalandmolecular pages 2-4)
c.205-1G>C (splice-site; exon 2 skipping with premature stop described) (esmer2013clinicalandmolecular pages 2-4)
c.717delC (p.D239EfsX25) (frameshift; associated with retinal disease in a case report) (iwasa2014retinitispigmentosaand pages 2-3)
NM_000370.3:c.58dupC (p.His20ProfsTer56) (frameshift; 2024 case report) (holla2024geneticallyprovenataxia pages 1-2)
c.473C>T (p.Phe185Ser) (novel homozygous variant in a 2021 report) (zhang2021clinicalandgenetic pages 1-4)
Start-codon abolishing variant (Japanese family; “abolishes the start codon”) (hoshino1999ataxiawithisolated pages 23-24)

Genotype–phenotype correlation

One large series distinguished milder vs more severe functional classes and reported that some missense variants (e.g., H101Q) can be associated with milder, later-onset phenotypes, whereas truncating/nonconservative variants associate with earlier/severe disease. (cavalier1998ataxiawithisolated pages 7-8)

Population allele frequencies / gnomAD

Population allele frequencies were not available in the retrieved evidence and are not reported here.

5. Environmental Information

AVED is fundamentally genetic; non-genetic contributors are mainly secondary causes of vitamin E deficiency that are important for differential diagnosis (e.g., fat malabsorption syndromes) rather than etiologic contributors to familial isolated deficiency. Cohort/case evidence emphasizes that AVED patients can have intact intestinal absorption with low circulating vitamin E. (holla2024geneticallyprovenataxia pages 1-2, cavalier1998ataxiawithisolated pages 7-8)

6. Mechanism / Pathophysiology

Causal chain (current understanding from retrieved evidence)

Biallelic TTPA pathogenic variants → defective α‑TTP function (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)
Impaired hepatic handling/export of α‑tocopherol via circulating lipoproteins (VLDL described) → very low serum/plasma α‑tocopherol despite intact absorption (holla2024geneticallyprovenataxia pages 1-2, iwasa2014retinitispigmentosaand pages 2-3)
Reduced antioxidant capacity in nervous system → oxidative injury to neurons (explicitly invoked as mechanism in a 2024 case report) (holla2024geneticallyprovenataxia pages 1-2)
Progressive neurodegeneration of cerebellar and sensory pathways → ataxia, proprioceptive loss, neuropathy, pyramidal signs, and in some patients retinal degeneration and cardiomyopathy. (stoiloudis2022vitaminedeficiency pages 42-44, iwasa2014retinitispigmentosaand pages 2-3)

Molecular pathways / processes (ontology suggestions)

GO Biological Process (suggested):
response to oxidative stress — GO:0006979
lipid transport — GO:0006869
regulation of lipid localization — GO:1905952
GO Cellular Component (suggested):
very-low-density lipoprotein particle — GO:0034361
Cell types (CL suggestions):
hepatocyte — CL:0000182 (site of major α‑TTP expression/function implied by hepatic export role)
neuron — CL:0000540 (target of oxidative injury)

(These terms are proposed for KB standardization; the retrieved evidence provides qualitative support for oxidative injury and lipoprotein-mediated trafficking but does not provide a full pathway map.)

Molecular profiling (transcriptomics/proteomics/metabolomics)

Not reported in the retrieved evidence.

7. Anatomical Structures Affected

Primary systems/organs

Nervous system (cerebellar and sensory pathways; peripheral nerves) (stoiloudis2022vitaminedeficiency pages 42-44, iwasa2014retinitispigmentosaand pages 2-3)
Eye/retina in a subset (retinitis pigmentosa; macular degeneration) (iwasa2014retinitispigmentosaand pages 2-3, hoshino1999ataxiawithisolated pages 22-23)
Heart in a subset (cardiomyopathy) (cavalier1998ataxiawithisolated pages 7-8, stoiloudis2022vitaminedeficiency pages 42-44)

Suggested UBERON terms (examples)

cerebellum — UBERON:0002037
spinal cord (posterior columns implied) — UBERON:0002240
peripheral nerve — UBERON:0001021
retina — UBERON:0000966
heart — UBERON:0000948

8. Temporal Development

Onset

Typically late childhood/early adolescence, but can range to adult onset depending on genotype and other factors. (holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4)

Course

Progressive without treatment; vitamin E therapy can halt progression and stabilize or partially improve signs, especially when initiated early. (esmer2013clinicalandmolecular pages 2-4, cavalier1998ataxiawithisolated pages 7-8, mariotti2004ataxiawithisolated pages 7-10)

9. Inheritance and Population

Inheritance pattern

Autosomal recessive. (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)

Epidemiology / distribution

Robust prevalence/incidence estimates were not available in the retrieved evidence. However: * Recurrent mutation patterns suggest enrichment in North Africa / Mediterranean populations (e.g., c.744delA described as a major mutation in North Africa). (esmer2013clinicalandmolecular pages 2-4)

Founder effects

Founder/recurrent alleles are reported in specific regions: * c.744delA: emphasized as a major/frequent mutation in North Africa / Mediterranean (esmer2013clinicalandmolecular pages 2-4, zhang2021clinicalandgenetic pages 1-4) * Additional recurrent European-origin alleles noted: c.513_514insTT, c.486delT, c.400C>T (esmer2013clinicalandmolecular pages 2-4)

Carrier frequency and penetrance were not provided in the retrieved evidence.

10. Diagnostics

Core diagnostic pattern (real-world implementation)

AVED is suggested by: 1. Neurologic syndrome resembling FA (ataxia, areflexia, posterior column signs) (hoshino1999ataxiawithisolated pages 22-23) 2. Markedly low plasma/serum α‑tocopherol (vitamin E) with otherwise non-explanatory routine workup; multiple case reports emphasize low α‑tocopherol (e.g., 0.12 mg/dL reported in one case) (iwasa2014retinitispigmentosaand pages 2-3) 3. Evidence that intestinal absorption may be intact and lipid profile may be normal (noted explicitly in a 2024 case report and other descriptions) (holla2024geneticallyprovenataxia pages 1-2, vera2021pearls&oysters pages 1-5) 4. Confirmatory genetic testing demonstrating biallelic TTPA pathogenic variants (holla2024geneticallyprovenataxia pages 1-2)

One report states that diagnostic testing should include α‑tocopherol determination and that AVED levels should be <1.7 mg/L. (esmer2013clinicalandmolecular pages 2-4)

Genetic testing modalities

Evidence supports use of: * Single-gene sequencing of TTPA (with exon/intron junction evaluation in one report; mutation detection rate stated as ~90% in that source) (esmer2013clinicalandmolecular pages 2-4) * Whole exome sequencing (WES) as a practical route to diagnosis after excluding common ataxias (zhang2021clinicalandgenetic pages 1-4)

Differential diagnosis (examples from evidence context)

Friedreich ataxia (clinical resemblance is explicitly emphasized) (cavalier1998ataxiawithisolated pages 7-8, hoshino1999ataxiawithisolated pages 22-23)
Other causes of vitamin E deficiency (e.g., fat malabsorption syndromes) should be excluded when interpreting low vitamin E; AVED differs by preserved absorption and isolated deficiency. (holla2024geneticallyprovenataxia pages 1-2)

11. Outcome / Prognosis

Natural history

Without therapy, AVED is progressive and can lead to substantial disability. (esmer2013clinicalandmolecular pages 2-4)

Treatment-modified prognosis

Multiple sources stress that early initiation of vitamin E can halt progression and may improve established signs, whereas delayed therapy may leave residual irreversible deficits (e.g., persistent proprioceptive/gait impairment). (esmer2013clinicalandmolecular pages 2-4, cavalier1998ataxiawithisolated pages 7-8)

12. Treatment

Disease-specific therapy: vitamin E replacement

High-dose oral vitamin E (α‑tocopherol) is the central disease-modifying intervention.

Evidence-based statements on benefit: * “The administration of vitamin E supplements in divided doses daily has resulted in cessation of progression … and in amelioration of established neurological abnormalities.” (cavalier1998ataxiawithisolated pages 7-8) * Early supplementation is highlighted as necessary “before irreversible damage develops.” (cavalier1998ataxiawithisolated pages 7-8)

Dosing (examples explicitly reported)

Recommended range 800–1500 mg/day or ~40 mg/kg/day in children (esmer2013clinicalandmolecular pages 2-4)
Case regimens: 800 mg/day (iwasa2014retinitispigmentosaand pages 2-3); 400 mg three times daily (zhang2021clinicalandgenetic pages 1-4); 1,200 IU/day (holla2024geneticallyprovenataxia pages 1-2); 2,000 units/day (vera2021pearls&oysters pages 1-5)

Outcomes

Stabilization over 2 years with 400 mg TID in one case report (zhang2021clinicalandgenetic pages 1-4)
Stabilization (no improvement) reported after short follow-up in a 2024 case report treated with 1,200 IU/day (holla2024geneticallyprovenataxia pages 1-2)
Long-term therapy “led to stabilization of neurological status in most patients” in an Italian cohort report. (mariotti2004ataxiawithisolated pages 7-10)

Supportive/rehabilitative therapies

Symptomatic pharmacotherapy may be used for movement disorder components (e.g., dystonia treated with clonazepam and trihexyphenidyl in a 2024 case report). (holla2024geneticallyprovenataxia pages 1-2)

Suggested MAXO terms (examples)

Vitamin supplementation — MAXO:0000112 (vitamin E supplementation as subtype)
Dietary supplement therapy — MAXO:0000087
Genetic counseling — MAXO:0000077 (mentioned as part of management planning in reviews/clinical practice; monitoring and counseling are explicitly recommended in one review snippet) (stoiloudis2022vitaminedeficiency pages 42-44)

13. Prevention

Primary/secondary/tertiary prevention

In AVED, “prevention” is primarily secondary/tertiary through: * Early biochemical screening for vitamin E deficiency in patients with FA-like ataxia and prompt genetic confirmation (cavalier1998ataxiawithisolated pages 7-8) * Lifelong vitamin E therapy to prevent progression/complications (esmer2013clinicalandmolecular pages 2-4)

Prenatal/preimplantation options were not discussed in the retrieved evidence.

14. Other Species / Natural Disease

Cross-species disease analogs for TTPA were not established in the retrieved evidence for AVED itself.

15. Model Organisms

The retrieved evidence set used for this report did not include detailed model organism phenotyping for AVED; therefore model organism details are not reported here.

Recent developments and latest research (prioritizing 2023–2024)

2024: Phenotypic expansion / diagnostic reminder

A 2024 case report emphasizes that AVED can present with prominent cervicobrachial dystonic tremor and may have normal MRI, reinforcing the need to consider AVED in atypical movement disorder presentations because it is “potentially treatable.” (Journal of Movement Disorders, Apr 2024; https://doi.org/10.14802/jmd.23227) (holla2024geneticallyprovenataxia pages 1-2)

Ongoing research gap

Within the retrieved evidence, there were no disease-specific interventional clinical trials captured for AVED, consistent with AVED management being dominated by replacement therapy rather than novel therapeutics (clinical trial retrieval returned no relevant AVED trials).

Practical applications / real-world implementation summary

Clinical workflow: FA-like ataxia → check serum/plasma α‑tocopherol → if markedly low and not explained by malabsorption/lipid abnormalities → sequence TTPA (or use WES panels for recessive ataxia) → begin high-dose vitamin E promptly and monitor serum vitamin E and neurologic progression. (cavalier1998ataxiawithisolated pages 7-8, holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4)

Structured summary table

Disease / synonym(s)	Key identifiers explicitly supported in evidence	Causal gene / protein	Inheritance	Hallmark laboratory finding	Typical onset	Core phenotypes (with frequency when available)	Recurrent / founder or notable variants mentioned	Treatment and outcomes	Key references
Familial isolated vitamin E deficiency; Ataxia with isolated vitamin E deficiency (AVED); Ataxia with vitamin E deficiency (cavalier1998ataxiawithisolated pages 7-8, hoshino1999ataxiawithisolated pages 22-23)	OMIM/MIM 277460 explicitly stated for AVED (hoshino1999ataxiawithisolated pages 22-23); TTPA transcript/protein entry noted as *OMIM600415** in one report (zhang2021clinicalandgenetic pages 1-4)	TTPA encoding α-tocopherol transfer protein (α-TTP / αTTP); α-TTP binds α-tocopherol and mediates incorporation into VLDL / circulating lipoproteins (zhang2021clinicalandgenetic pages 1-4, iwasa2014retinitispigmentosaand pages 2-3)	Autosomal recessive; biallelic / homozygous or compound heterozygous TTPA variants reported (holla2024geneticallyprovenataxia pages 1-2, hoshino1999ataxiawithisolated pages 22-23)	Markedly low plasma/serum vitamin E (α-tocopherol) despite intact intestinal absorption and otherwise normal lipids in reported cases; one snippet notes AVED levels should be <1.7 mg/L (esmer2013clinicalandmolecular pages 2-4, vera2021pearls&oysters pages 1-5, holla2024geneticallyprovenataxia pages 1-2)	Usually late childhood to early adolescence; broader reported range from early childhood/infancy to adulthood/fourth decade; untreated disease often manifests 5–15 years (holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4, hoshino1999ataxiawithisolated pages 22-23)	Friedreich-like phenotype with progressive ataxia, areflexia/hyporeflexia, loss of proprioception/vibration sense, dysarthria, sensory neuropathy; extra-neurologic/other features can include head titubation/dystonia, retinitis pigmentosa, scoliosis, cardiomyopathy. Frequency data from one review: absent tendon reflexes 94.7%, gait disturbance 93.4%, extensor plantar response 85.5%, posterior column involvement 67.1%, dysarthria 61.8%, head titubation 40.8%, retinitis pigmentosa 2.3%, cardiomyopathy 1.5% (stoiloudis2022vitaminedeficiency pages 42-44). Earlier cohort found cardiomyopathy 19%, head titubation 28%, dystonia 13% (cavalier1998ataxiawithisolated pages 7-8).	Recurrent/founder variants mentioned: c.744delA major in North Africa / Mediterranean and associated with earlier/severe disease; c.513_514insTT, c.486delT, c.400C>T (R134X) in European-origin families; H101Q associated with milder, late-onset phenotype; additional reported variants include c.205-1G>C, c.473C>T (p.F185S), c.717delC (p.D239EfsX25), c.58dupC (p.His20ProfsTer56), and a start-codon mutation in a Japanese family (esmer2013clinicalandmolecular pages 2-4, cavalier1998ataxiawithisolated pages 7-8, holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4, iwasa2014retinitispigmentosaand pages 2-3, hoshino1999ataxiawithisolated pages 22-23)	Lifelong high-dose oral vitamin E replacement. Reported recommendations/examples: 800–1500 mg/day or about 40 mg/kg/day in children; case regimens include 800 mg/day, 400 mg three times daily, 1,200 IU/day, and 2,000 units/day. Early treatment can halt progression, stabilize disease, and sometimes improve established neurologic abnormalities; delayed treatment may leave persistent proprioceptive/gait deficits (esmer2013clinicalandmolecular pages 2-4, vera2021pearls&oysters pages 1-5, holla2024geneticallyprovenataxia pages 1-2, zhang2021clinicalandgenetic pages 1-4, iwasa2014retinitispigmentosaand pages 2-3, cavalier1998ataxiawithisolated pages 7-8, mariotti2004ataxiawithisolated pages 7-10)	Cavalier 1998, Am J Hum Genet, DOI: https://doi.org/10.1086/301699 (cavalier1998ataxiawithisolated pages 7-8); Hoshino 1999, Ann Neurol, DOI: https://doi.org/10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9 (hoshino1999ataxiawithisolated pages 22-23); Iwasa 2014, J Neurol Sci, DOI: https://doi.org/10.1016/j.jns.2014.07.001 (iwasa2014retinitispigmentosaand pages 2-3); Holla 2024, J Mov Disord, DOI: https://doi.org/10.14802/jmd.23227 (holla2024geneticallyprovenataxia pages 1-2)

Table: This table condenses the evidence-backed core facts for familial isolated vitamin E deficiency / AVED, including identifiers, genetics, phenotype, variants, and treatment. It is useful as a quick reference for knowledge-base population while limiting claims to those explicitly present in the provided snippets.

URLs and publication dates (from retrieved evidence)

Cavalier et al., 1998-02, American Journal of Human Genetics: https://doi.org/10.1086/301699 (cavalier1998ataxiawithisolated pages 7-8)
Hoshino et al., 1999-06, Annals of Neurology: https://doi.org/10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9 (hoshino1999ataxiawithisolated pages 23-24)
Iwasa et al., 2014-10, Journal of the Neurological Sciences: https://doi.org/10.1016/j.jns.2014.07.001 (iwasa2014retinitispigmentosaand pages 1-2)
Zea Vera et al., 2021-01, Neurology: https://doi.org/10.1212/WNL.0000000000010853 (vera2021pearls&oysters pages 1-5)
Holla et al., 2024-04, Journal of Movement Disorders: https://doi.org/10.14802/jmd.23227 (holla2024geneticallyprovenataxia pages 1-2)

Notes on limitations of this tool-based report

Ontology identifiers beyond OMIM (e.g., Orphanet, MONDO, MeSH, ICD-10/11) could not be verified from the retrieved full-text evidence in this run and are therefore omitted rather than inferred.
Population prevalence/incidence and population allele frequencies (gnomAD) were not present in the retrieved evidence snippets.
Model organism evidence was not present in the retrieved evidence snippets used for citation; therefore it is not summarized here.

References

(holla2024geneticallyprovenataxia pages 1-2): Vikram V. Holla, Sandeep Gurram, Sneha D. Kamath, Gautham Arunachal, Nitish Kamble, Ravi Yadav, and Pramod Kumar Pal. Genetically proven ataxia with vitamin e deficiency with predominant cervicobrachial dystonic presentation: a case report from india. Journal of Movement Disorders, 17:220-222, Apr 2024. URL: https://doi.org/10.14802/jmd.23227, doi:10.14802/jmd.23227. This article has 0 citations and is from a peer-reviewed journal.
(hoshino1999ataxiawithisolated pages 22-23): Masataka Hoshino, Naoki Masuda, Yasuhiko Ito, Miho Murata, Jun Goto, Masaki Sakurai, and Ichiro Kanazawa. Ataxia with isolated vitamin e deficiency: a japanese family carrying a novel mutation in the α‐tocopherol transfer protein gene. Annals of Neurology, 45:809-812, Jun 1999. URL: https://doi.org/10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9, doi:10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9. This article has 38 citations and is from a highest quality peer-reviewed journal.
(zhang2021clinicalandgenetic pages 1-4): Linwei Zhang, Xiangfei Zhang, Pu Lv, and Dantao Peng. Clinical and genetic study of ataxia with vitamin e deficiency. ArXiv, Feb 2021. URL: https://doi.org/10.21203/rs.3.rs-175944/v1, doi:10.21203/rs.3.rs-175944/v1. This article has 0 citations.
(cavalier1998ataxiawithisolated pages 7-8): Laurent Cavalier, Karim Ouahchi, Herbert J. Kayden, Stephano Di Donato, Laurence Reutenauer, Jean-Louis Mandel, and Michel Koenig. Ataxia with isolated vitamin e deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. American journal of human genetics, 62 2:301-10, Feb 1998. URL: https://doi.org/10.1086/301699, doi:10.1086/301699. This article has 383 citations and is from a highest quality peer-reviewed journal.
(iwasa2014retinitispigmentosaand pages 2-3): Kazuo Iwasa, Keisuke Shima, Kiyonobu Komai, Yoichiro Nishida, Takanori Yokota, and Masahito Yamada. 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. Journal of the neurological sciences, 345 1-2:228-30, Oct 2014. URL: https://doi.org/10.1016/j.jns.2014.07.001, doi:10.1016/j.jns.2014.07.001. This article has 28 citations and is from a peer-reviewed journal.
(esmer2013clinicalandmolecular pages 2-4): C Esmer, AS Martínez, and ER Palomo. Clinical and molecular findings in a patient with ataxia with vitamin e deficiency, homozygous for the c. 205-1g› c mutation in the ttpa gene. Unknown journal, 2013.
(stoiloudis2022vitaminedeficiency pages 42-44): P Stoiloudis, AN Terzakis, and N Smyrni. Vitamin e deficiency: clinical characteristics, diagnosis and management. Unknown journal, 2022.
(hoshino1999ataxiawithisolated pages 23-24): Masataka Hoshino, Naoki Masuda, Yasuhiko Ito, Miho Murata, Jun Goto, Masaki Sakurai, and Ichiro Kanazawa. Ataxia with isolated vitamin e deficiency: a japanese family carrying a novel mutation in the α‐tocopherol transfer protein gene. Annals of Neurology, 45:809-812, Jun 1999. URL: https://doi.org/10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9, doi:10.1002/1531-8249(199906)45:6<809::aid-ana19>3.0.co;2-9. This article has 38 citations and is from a highest quality peer-reviewed journal.
(mariotti2004ataxiawithisolated pages 7-10): C. Mariotti, C. Gellera, M. Rimoldi, R. Mineri, G. Uziel, G. Zorzi, D. Pareyson, G. Piccolo, D. Gambi, S. Piacentini, F. Squitieri, R. Capra, B. Castellotti, and S. Di Donato. Ataxia with isolated vitamin e deficiency: neurological phenotype, clinical follow-up and novel mutations in ttpagene in italian families. Neurological Sciences, 25:130-137, Jul 2004. URL: https://doi.org/10.1007/s10072-004-0246-z, doi:10.1007/s10072-004-0246-z. This article has 181 citations and is from a peer-reviewed journal.
(vera2021pearls&oysters pages 1-5): Alonso Zea Vera, Wei Liu, Cameron Thomas, and Donald L. Gilbert. Pearls & oy-sters: a novel presentation of ataxia with vitamin e deficiency caused by ttpa gene mutation. Jan 2021. URL: https://doi.org/10.1212/wnl.0000000000010853, doi:10.1212/wnl.0000000000010853. This article has 5 citations and is from a highest quality peer-reviewed journal.
(iwasa2014retinitispigmentosaand pages 1-2): Kazuo Iwasa, Keisuke Shima, Kiyonobu Komai, Yoichiro Nishida, Takanori Yokota, and Masahito Yamada. 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. Journal of the neurological sciences, 345 1-2:228-30, Oct 2014. URL: https://doi.org/10.1016/j.jns.2014.07.001, doi:10.1016/j.jns.2014.07.001. This article has 28 citations and is from a peer-reviewed journal.

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Familial Isolated Vitamin E Deficiency (AVED) — Comprehensive Disease Characteristics Report

1. Disease Information

Overview / definition

Key identifiers and nomenclature

Synonyms / alternative names

Evidence sources (individual vs aggregated)

2. Etiology

Disease causal factors

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

Core clinical phenotype

Phenotype statistics from a recent compiled frequency table

Age of onset and progression

Suggested HPO terms (examples)

4. Genetic / Molecular Information

Causal gene

Protein and molecular role

Inheritance

Pathogenic variants (examples explicitly described in retrieved evidence)

Genotype–phenotype correlation

Population allele frequencies / gnomAD

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (current understanding from retrieved evidence)

Molecular pathways / processes (ontology suggestions)

Molecular profiling (transcriptomics/proteomics/metabolomics)

7. Anatomical Structures Affected

Primary systems/organs

Suggested UBERON terms (examples)

8. Temporal Development

Onset

Course

9. Inheritance and Population

Inheritance pattern

Epidemiology / distribution

Founder effects

10. Diagnostics

Core diagnostic pattern (real-world implementation)

Genetic testing modalities

Differential diagnosis (examples from evidence context)

11. Outcome / Prognosis

Natural history

Treatment-modified prognosis

12. Treatment

Disease-specific therapy: vitamin E replacement

Dosing (examples explicitly reported)

Outcomes

Supportive/rehabilitative therapies

Suggested MAXO terms (examples)

13. Prevention

Primary/secondary/tertiary prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent developments and latest research (prioritizing 2023–2024)

2024: Phenotypic expansion / diagnostic reminder

Ongoing research gap

Practical applications / real-world implementation summary

Structured summary table

URLs and publication dates (from retrieved evidence)

Notes on limitations of this tool-based report

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