Ataxia with vitamin E deficiency (ORPHA:96)
A neurodegenerative disease belonging to the inherited cerebellar ataxias mainly characterized by progressive spino-cerebellar ataxia, loss of proprioception, areflexia, and is associated with a marked deficiency in vitamin E.
Epidemiology
Global prevalence is not known but population-based studies have been performed and prevalence can be extrapolated at approximately 1/300,000. AVED is the second most frequently inherited cerebellar ataxia in North Africa. As vitamin E deficiency might bring protection against malaria (see this term), it could explain a higher prevalence of AVED in Plasmodium infested areas.
Clinical description
AVED presents generally between ages 5 and 20 years with variable phenotype and severity. Progressive spino-cerebellar ataxia, areflexia and loss of proprioception, mainly in distal joint position and of vibration sense, induce a noticeable clumsiness and imbalance. Patients may have a characteristic head titubation. Tendon reflexes are dramatically reduced and extensor plantar reflexes are frequent. Cerebellar impairment frequently manifests as dysmetria, dysdiadochokinesia and dysarthria. Decreased visual acuity with retinitis pigmentosa may be seen. In some cases, disease onset is late (> 30 years) and the course is milder. On the contrary, in early-onset cases, the course is more severe, with an increased risk of cardiomyopathy. Overall, the clinical picture of AVED is close to that of Friedreich's ataxia (see this term).
Etiology
AVED is caused by mutations in the tocopherol (alpha) transfer protein gene (TTPA; 8q13). This protein binds alpha-tocopherol (a vitamin E isomer) and very-low-density lipoproteins (VLDLs) in the liver. When mutated, TTPA prevents vitamin E linking to VLDLs, preventing it to pass into general circulation. Many mutations have been identified, but p.His101Gln and c.744delA are respectively responsible for the late-onset/mild and early-onset/severe forms of the disease.
Diagnostic methods
Diagnosis is based on physical examination, on vitamin E plasma dosage and on exclusion of known causes of malabsorption. Laboratory findings reveal a very marked deficiency of vitamin E in plasma but normal levels of lipid and lipoprotein profiles. Neuroimaging does not show an obvious cerebellar atrophy in the first stages of the disease. Electromyography usually reveals a pure sensory neuronopathy (ganglionopathy). Molecular analysis confirms the diagnosis.
Differential diagnosis
Differential diagnosis mainly includes Friedreich ataxia, sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) and abetalipoproteinemia (see these terms). Other autosomal recessive cerebellar ataxias may be considered as well (Refsum disease, ataxia telangiectasia, Charcot-Marie-Tooth disease 1A and ataxia with oculomotor apraxia types 1 and 2 (see these terms)).
Antenatal diagnosis
Antenatal diagnosis is feasible via molecular genetic testing when the mutation has been identified in the family.
Genetic counseling
The disease has an autosomal recessive mode of inheritance, with a subsequent recurrence risk of 25%.
Management and treatment
Treatment is based on a lifelong high-dose vitamin E supplementation, which should be taken every day. When treated early, some symptoms could be reversible; in older patients disease progression can be slowed. It remains unknown whether in families of index cases vitamin E preventive treatment can be administered in presymptomatic individuals to prevent development of AVED.
Prognosis
Even if treated, patients frequently have a poor prognosis and become wheelchair bound within 8 and 20 years of age.

                            Last update: 
                            February 2013


                            - Expert reviewer(s): 
                            Pr Mathieu ANHEIM