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.
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.
We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.
Few population studies are available on epidemiological indexes of hereditary ataxias. An investigation on the prevalence rate of these movement disorders is in progress for the Veneto region, the main area of northeast Italy with a population of 4,490,586 inhabitants. The first results of this epidemiological survey concern the province of Padua, which numbers 845,203 residents (January 1, 2002). The prevalence rate of inherited ataxias has been estimated at 93.3 cases per million inhabitants. The most common types appeared to be the autosomal dominant forms, namely spinocerebellar ataxia type 1 and 2, with a prevalence of 24 per 1,000,000. In the same population, with a prevalence rate of 6 per 1,000,000, Friedreich’s ataxia was defined as the prominent recessive autosomal form. There were very rare cases of ataxia telangiectasia, ataxia with vitamin E deficiency and cerebellar ataxia with congenital muscular dystrophy, a recently identified autosomal recessive disease.
SCA6 is caused by CAG expansion in the alpha 1A voltage-dependent calcium channel subunit gene. The authors studied an Italian family in which one patient carried a fully expanded SCA6 allele with 26-CAG repeats, whereas the other affected family member was homozygous for an intermediate-size allele of 19-CAG repeats. Three family members, heterozygous for the intermediate allele, were clinically unaffected. The findings demonstrate a dose-dependent pathogenic effect of an intermediate CAG expansion in the SCA6 gene.
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