Clinical Guidance

To date, only two pathogenic variants have shown clear-cut genotype-phenotype correlations:

• The pathogenic variant is associated with late-onset disease (age 30 years) with a mild disease course, and increased risk for pigmentary retinopathy. This variant is primarily reported in individuals of Japanese descent .

• The pathogenic variant is associated with early onset and a more severe disease course, and slightly increased risk for cardiomyopathy. However, disease severity may vary considerably, and even in persons from the same family the onset of manifestations may vary between ages three and 12 years . This variant is mainly observed in individuals of Mediterranean or North African descent.

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Diagnostic Criteria

No consensus clinical diagnostic criteria for ataxia with vitamin E deficiency (AVED) have been published.

Suggestive Findings

AVED should be suspected a proband with the following clinical and laboratory findings and family history.

Clinical features

• Onset between ages five and 15 years

• Progressive cerebellar findings including the following:

• Gait ataxia

• Clumsiness of the hands

• Loss of proprioception (especially distal joint position and vibration sense)

• Dysdiadochokinesia

• Positive Romberg sign

• Head titubation

• Lower motor neuron involvement. Areflexia

• Upper motor neuron involvement. Positive Babinski sign

• Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy

Supportive laboratory findings

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Differential Diagnosis

Friedreich ataxia (FRDA). The age of onset is similar in ataxia with vitamin E deficiency (AVED) and FRDA; however, only in AVED are plasma vitamin E concentrations low . Certain clinical signs may also help distinguish the two disorders; however, the distinction cannot be made on clinical grounds alone. FRDA is caused by biallelic pathogenic variants in FXN and is inherited in an autosomal recessive manner. Other ataxias. Because AVED typically presents with ataxia or clumsiness in late childhood, AVED should be included in the differential diagnosis of all ataxias with the same age of onset (see Hereditary Ataxia Overview). Malnutrition/ reduced vitamin E uptake. To become vitamin E deficient, healthy individuals have to consume a diet depleted in vitamin E over months.

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Management Guidelines

No clinical practice guidelines for ataxia with vitamin E deficiency (AVED) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Hereditary Ataxia Overview, Table 6, are recommended.

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. With treatment, plasma vitamin E concentrations can become normal. Presymptomatic individuals. When vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), manifestations of AVED do not develop . No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) [, , , , , , , ]. One of the following vitamin E preparations is used:

• The chemically manufactured racemic form, all-rac--tocopherol acetate

• The naturally occurring form, RRR--tocopherol

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Clinical Guidance

Individuals with AVED should avoid:

• Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations ;

• Occupations requiring quick responses or good balance.

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"

Surveillance Guidelines

Targeted Therapy

For those on vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high-normal range. Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although -tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement . Discontinuation of vitamin E supplementation, even temporarily, leads to a drop in plasma vitamin E concentration within two to three days and to a prolonged drop in TRAP, even after reinitiating vitamin E supplementation .

Symptomatic Individuals

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hereditary Ataxia Overview, Table 8, are recommended.

Source: GeneReviews — "Ataxia with Vitamin E Deficiency"