Ataxia with Vitamin E Deficiency

Clinical characteristics: Untreated ataxia with vitamin E deficiency (AVED) generally manifests between ages five and 15 years. The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. Although age of onset and disease course are more uniform within a given family, disease manifestations and their severity can vary even among sibs.

When lifelong high-dose vitamin E supplementation is initiated in presymptomatic individuals, manifestations of AVED do not develop.

Diagnosis/testing: The diagnosis of AVED is established in a proband with suggestive findings and biallelic pathogenic variants in TTPA identified by molecular genetic testing.

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

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

Surveillance: Monitor plasma vitamin E concentration in treated individuals – particularly children – every six months. For symptomatic individuals, regular evaluations to monitor the individual's response to supportive care and to identify emergence of new manifestations.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease.

Genetic counseling: AVED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TTPA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the TTPA pathogenic variants have been identified in an affected family member, carrier detection for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.