Clinical characteristics: Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens between ages five and 15 years. The first symptoms 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. The phenotype and disease severity vary widely among families with different pathogenic variants; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.
Diagnosis/testing: Presently, no consensus diagnostic criteria for AVED exist; the principal criterion for diagnosis is a Friedreich ataxia-like neurologic phenotype combined with markedly reduced plasma vitamin E (α-tocopherol) concentration and a normal lipoprotein profile in the absence of known causes of malabsorption. Identification of biallelic TTPA pathogenic variants on molecular genetic testing confirms the diagnosis.
Management: Treatment of manifestations: Lifelong high-dose oral vitamin E supplementation to bring plasma vitamin E concentrations into the high-normal range; treatment early in the disease process may to some extent reverse ataxia and mental deterioration.
Prevention of primary manifestations: Vitamin E therapy in presymptomatic children with biallelic TTPA pathogenic variants prevents development of symptoms.
Surveillance: Monitor plasma vitamin E concentration every six months, particularly in children.
Agents/circumstances to avoid: Smoking; occupations requiring quick responses or good balance.
Evaluation of relatives at risk: Evaluation for vitamin E deficiency, especially in younger sibs of a proband.
Other: Before attempting to drive a car, assessment to determine if the affected individual can drive safely.
Genetic counseling: AVED is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and carry one pathogenic variant; heterozygotes are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family have been identified.
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