CAG repeat length and clinical features in three Italian families with spinocerebellar ataxia type 2 (SCA2): early impairment of Wisconsin Card Sorting Test and saccade velocity

Abstract

We report on the clinical, neuropsychological, neurophysiological, computerized eye movement, magnetic resonance imaging (MRI) and molecular findings from 17 individuals affected with spinocerebellar ataxia type 2 (SCA2) belonging to three families. The average age at onset of the symptoms was 35.6, 11.9 (mean, SD) years. The mean age at onset of the symptoms in the parents was 44.8, 8.2 years, and in the offspring it was 28.7, 7.2 years. In 12 parent-child pairs, the mean anticipation was -15.75, 9.1 years (range -8.1 to -23.3 years, t = -4.9, P = < 0.002). The mutated SCA2 alleles ranged from 38 to 42 CAG repeats, while the normal alleles ranged from 22 to 24 repeats, with 97% of the alleles having 22 repeats. Small differences in the number of CAG repeats influenced the age at onset and rate of progression of the disease considerably. Indeed, patients presenting with their first symptom at an age of 35 years or later with a slower course of the disease harboured between 38 and 39 repeats. In contrast, patients carrying > or = 40 CAG repeats manifested the disease prior to 30 years of age and had a faster disease progression toward incapacity. The presenting symptom was always gait ataxia. Slow saccades occured from the beginning of the disease despite normal delay, accuracy and smooth pursuit eye movements. The neuropsychological study showed early and selective impairment of conceptual reasoning ability, as detected by the Wisconsin Card Sorting Test (WCST). It is noteworthy that a significant mutual relationship was observed between performance on the WCST and saccade velocity. All of these findings favour the hypothesis that the disease process of SCA2 in regions other than the cerebellum and brain stem affects severely and early those cortical structures involved in the control of both visually guided saccades and WCST performance.

Executive deficit in spinocerebellar ataxia type 2 is related to expanded CAG repeats: Evidence from antisaccadic eye movements

“…A similar relationship with polyglutamine expansions has been previously demonstrated for the saccadic velocity in SCA2 patients (Velazquez-Perez et al, 2004), which supports the key application of electronystagmography in the search of putative endophenotypical parameters for this disorder. Previous studies in SCA2 detected no association between CAG repeats and executive deficits, probably due to an insufficient number of patients, compared to the present work (Gambardella et al, 1998;Le Pira et al, 2002;Storey et al, 1999). Nevertheless, it was recently demonstrated that executive control is related to the abnormal expansion of GAA repeats in adult patients with Friedreich Ataxia, using standardized neuropsychological tests (Nachbauer et al, 2014).…”

Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia

“…Poor performance on the WCST, suggesting disturbance of abstract reasoning and the ability to shift cognitive sets to changing contingencies, is associated with damage to the dorsolateral prefrontal cortex or its connection to (sub)cortical structures [29]. Poor performance on the WCST has been described in SCA 1 and particularly SCA 2 families [30][31][32][33]. Similar cognitive defects have also been described in SCA 3 [34].…”

Dissociation between motor and cognitive impairments in SCA2: Evidence from a follow-up study

“…Sirs: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease in which, besides motor disturbances, cognition could also be impaired [2][3][4][7][8][9]. Nevertheless, it is unclear whether the cognitive functions of SCA2 patients worsen over time as observed for motor disturbances.…”