Can ataxin-2 be down-regulated by allele-specific de novo DNA methylation in SCA2 patients?

Spinocerebellar ataxia type 2 (SCA2) is caused by a CAG trinucleotide repeat expansion within the coding region of the ataxin-2 gene. Affected individuals typically have between 34 and 57 CAG repeats. Signs of the disorder generally begin in adulthood and include progressive ataxia, dysarthria, tremor, hyporeflexia, and slow saccades. As with other trinucleotide repeat disorders, SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at onset of clinically detectable disease, with neonatal cases of SCA2 being reported in individuals harboring over 200 CAG repeats. However, a wide range of age at onset is typically observed, especially in individuals with < 40 CAG repeats. CAG repeat number alone explains approximately 25-80% of the variability. In this paper, we hypothesize that the level of mutant ataxin-2 protein in affected cells contributes to these differences. One of the mechanisms that might influence this protein levels is de novo DNA methylation, which would specifically target the allele with the expanded CAG repeat leading to transcriptional silencing. Consequently, the symptoms of SCA2 would occur later in the patient's life history. Our postulations, as well as those previously reported to account for the phenotype of SCA2, are discussed.

Application of a Scale for the Assessment and Rating of Ataxia (SARA) in Friedreich's ataxia patients according to posturography is limited.

BACKGROUND: A scale for the Assessment and Rating of Ataxia (SARA) was developed for evaluation of autosomal dominant cerebellar ataxias (ADCA) and was also recommended for clinical trials of Friedreich's ataxia patients (FRDA). FRDA, unlike ADCA, is characterized as being a sensory type of ataxia for which the disease-specific Friedreich ataxia rating scale (FARS) was developed. The objective of this study was to determine whether SARA and FARS scores are associated with posturographic parameters in FRDA patients. METHOD: Adult patients with genetically confirmed FRDA (n=11) and ADCA (n=13) were evaluated by SARA, FARS and posturography. RESULTS: FRDA patients' postural stability parameters, in stance with visual control, correlated with balance impairment in FARS (r=0.622; p<0.05) and SARA (r=0.735; p<0.05). Without visual control, only FARS correlated with balance impairment (r=0.732; p<0.05). CONCLUSION: The SARA, in FRDA patients, correlates with stance with visual control but not without visual control which emphasizes sensory ataxia. This suggests that application of the SARA in Friedreich's ataxia patients according to posturography is possible but presumably limited and FARS, although being a more time consuming scale, may have advantages over SARA in FRDA patients.

Uses of the postural stability test for differential diagnosis of hereditary ataxias.

Friedreich's ataxia (FRDA) and spinocerebellar ataxia type 2 (SCA 2) are among the most commonly diagnosed hereditary ataxias in Czech Republic. Although criteria differentiate the ataxias, disorder onset symptoms may be similar. Our goal was to determine whether and to what degree of validity posturographic examination may be utilized, with the aim of differential diagnosis; which specific posturographic parametres are suitable for differential diagnosis; and which differences in FRDA and SCA 2 patient posturographic findings may be established. 17 SCA 2 and 12 FRDA patients were examined with ten healthy controls. A multi-sensor tenzometric platform was used for posturographic examination. Toe standing position was added to basic tests, including standing position with and without visual control. There was no difference between patients in standing position with visual control but there were distinct differences between FRDA and SCA 2 patients, based on upright stance without visual control and medio-lateral deviation. There were no differences between patients in toe standing position, suggesting not only the cerebellum, but also deep sensation, helps to create the so-called adaptive controller. Posturography is attested to as a useful method for differential diagnosis of hereditary ataxias and provides neurophysiological findings in cerebellar and sensoric ataxias.

Absence of spinocerebellar ataxia type 3/Machado-Joseph disease within ataxic patients in the Czech population.

Although spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease is the most common type of SCA worldwide, we did not identify any cases of the disease amongst SCA patients in the Czech population. It has been proposed that the prevalence of large normal alleles correlates with the frequency of various types of SCA. We have therefore attempted to resolve the absence of SCA3 in our population by investigating, within 204 normal chromosomes, the frequency and nature of CAG repeats as well as two intragenic polymorphisms. We found that large normal alleles with more than 33 CAG repeats were observed at a frequency of only 0.49%. Whereas most of the expanded alleles worldwide have the CA haplotype, this was the least common (5.4%) variant observed in our study, although it was associated with a larger mean CAG repeat length (26.9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus.