Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPAgene in Italian families

Abstract

Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disorder due to mutations in the alpha-tocopherol transfer protein (TTPA) gene on chromosome 8q13. AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E. We studied neurological phenotype at diagnosis, and long-term effect of vitamin E supplementation in 16 patients from 12 Italian families. The most common mutations were the 744delA and 513insTT. Two novel TTPA mutations were identified: a severe truncating mutation (219insAT) in a homozygous patient, and a Gly246Arg missense mutation (G246R) in a compound heterozygous patient. The missense mutation was associated with a mild and slowly progressive form of the disease. Vitamin E supplementation therapy allowed a stabilization of the neurological conditions in most of the patients. However, development of spasticity and retinitis pigmentosa was noted in a few patients during therapy. Prompt genetic characterization of AVED patients may allow an effective early treatment and an adequate genetic counseling.

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

“…Electro-retinographic measurements have shown attenuated activities in α-TTP-KO mice compared with WT mice indicating retinal degeneration which was accelerated by feeding α-T deficient diet to α-TTP-KO mice (Tanito et al, 2007). Since some AVED patients develop retinal degeneration (Mariotti et al, 2004;Yokota et al, 1996) the α-TTP-KO mice may be relevant to exploring the potential of dietary α-T in the prevention of age-related retinal degeneration. α-T deficiency caused by the deletion of α-TTP gene also accelerated Alzheimer Disease phenotype in transgenic mice that overexpress human APP 695 with a double mutation (Nishida et al, 2006).…”

Autosomal recessive ataxias: 20 types, and counting

“…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 .…”

“…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 .…”

“…AVED is caused by mutations in the a-tocopherol transfer protein gene (TTPA), which codes a protein responsible for transferring a-tocopherol from chilomicrons to VLDL 26,27 . TTPA disfunction causes very low level of circulating a-tocopherol and tissue deficiency of this vitamin 27 .…”