Ataxia with Isolated Vitamin E Deficiency: Heterogeneity of Mutations and Phenotypic Variability in a Large Number of Families

Abstract

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

“…α-T is also required for the health of human CNS. This is vividly demonstrated in Ataxia with Vitamin E Deficiency (AVED) patients who present with neurological symptoms of varying severity (Cavalier et al, 1998;Gotoda et al, 1995;Schuelke et al, 1999;Tamaru et al, 1997). Neurological deficits similar to those of the AVED subjects are also observed in transgenic mice with a deletion of the α-TTP gene (Yokota et al, 2001;Yokota et al, 1987).…”

Two Faces of Vitamin E in the Lung

“…a-Tocopherol levels are also affected by genetic variants. Mutations in liver a-tocopherol transfer protein result in human a-tocopherol deficiency (14). It is also reported that human plasma levels of a-tocopherol but not g-tocopherol are increased in male adults and children by the apolipoprotein A5 1131T.C gene polymorphism (15,16).…”

Autosomal recessive ataxias: 20 types, and counting

“…Age of onset usually varied from 4 to 20 years, with outliers ranging from 2 to 52 years 24,25 . Clinical manifestations are characterized by progressive trunk and limbs ataxia, dysarthria, disturbance of positional and vibratory lower limbs senses, Babinski sign and abolished deep tendon reflexes.…”

“…Clinical manifestations are characterized by progressive trunk and limbs ataxia, dysarthria, disturbance of positional and vibratory lower limbs senses, Babinski sign and abolished deep tendon reflexes. Scoliosis and pes cavus are commonly seen [24][25][26] , yet retinopathy is less frequent 25,26 . Dystonia (13%) and head titubation (28%) are more commonly seen in AVED than in FA 24,26 .…”

“…Scoliosis and pes cavus are commonly seen [24][25][26] , yet retinopathy is less frequent 25,26 . Dystonia (13%) and head titubation (28%) are more commonly seen in AVED than in FA 24,26 . Cardiomyopathy and an acute cardiac event might be associated with premature death among AVED cases 25,26 .…”