Article

Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, Paris, France.
Neurology (Impact Factor: 8.29). 12/2007; 69(21):1970-5. DOI: 10.1212/01.wnl.0000269323.21969.db
Source: PubMed

ABSTRACT

Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.
We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.
Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.
These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

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Available from: Agnès Camuzat, Mar 18, 2015
    • "The repeat instability is also present within an individual, as different tissues may have cell populations with different repeat sizes (Lopes-Cendes et al., 1996; Martins et al., 2005; Matsuura et al., 2004; Silveira et al., 2000). These diseases are characterized by cognitive, movement, or neuromuscular impairment with childhood or adulthood onset, depending on the repeat motif, length, and gene location (Charles et al., 2007; Coutinho et al., 2013; La Spada and Taylor, 2010; Nelson et al., 2013; Seixas et al., 2005 Seixas et al., , 2011 Vale et al., 2010; Yu et al., 2011). Since the early 1990s, with the discovery of the fragile X syndrome (FXS) and spinobulbar muscular atrophy numerous neurological and neuromuscular diseases caused by repeat expansions have been identified (Kremer et al., 1991; La Spada et al., 1991; Liquori et al., 2001; Nelson et al., 2013; Verkerk et al., 1991). "
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    ABSTRACT: An astonishing number of neurological diseases result from expansion of unstable repetitive sequences causing alterations in key neuronal processes. Some are progressive late-onset conditions related to aging, such as the spinocerebellar ataxias. In several of these pathologies, the expanded repeat is transcribed, producing an expanded RNA repeat that causes neurodegeneration by a complex mechanism, comprising 3 main pathways. These include (1) accumulation in the nucleus of RNA foci, resulting from sequestration of RNA-binding proteins functioning in important neuronal cascades; (2) decrease in availability of RNA-binding proteins, such as splicing factors, causing alternative splicing misregulation with imbalance in the expression ratio of neuronal isoforms; and (3) generation of neurotoxic peptides, produced from repeat-associated non-ATG-initiated translation across the RNA repeat, in all reading frames. Recently, 2 pathologies characterized by impaired motor function, cognitive decline, or/and degeneration of motor neurons have been found that have broaden our understanding of these diseases. Moreover, the finding of compromised nucleocytoplasmic transport opens new avenues for research. This review will cover the amazing progress regarding these conditions.
    No preview · Article · Dec 2015
    • "Thirteen spinocerebellar ataxia type 2 (SCA2) patients for which the threshold number of CAG repeats in ATXN2 gene was 33 [11] [12] and 11 FRDA patients, all homozygotes for expanded GAA repeat in the FRDA gene, genetically confirmed by the Ataxia Center at Motol Hospital in Prague, were assessed by the SARA semi-quantitative clinical rating scale. Patients with FRDA in addition were assessed by FARS. "
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    ABSTRACT: 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.
    No preview · Article · Jun 2014
    • "Thirteen spinocerebellar ataxia type 2 (SCA2) patients for which the threshold number of CAG repeats in ATXN2 gene was 33 [11] [12] and 11 FRDA patients, all homozygotes for expanded GAA repeat in the FRDA gene, genetically confirmed by the Ataxia Center at Motol Hospital in Prague, were assessed by the SARA semi-quantitative clinical rating scale. Patients with FRDA in addition were assessed by FARS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. Adult patients with genetically confirmed FRDA (n=11) and ADCA (n=13) were evaluated by SARA, FARS and posturography. 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). 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.
    No preview · Article · Apr 2014 · Journal of the neurological sciences
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