Spinocerebellar Ataxias in Brazil—Frequencies and Modulating Effects of Related Genes

Abstract

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

“…IPD and AD retrieved from 11 studies comprised four cohorts from Europe,6 7 17 18 three from Asia,8 19 20 one from North America,6 one from Central America21 and three from Brazil 5 22 23. Brazilian cohorts comprised the Rio Grande do Sul (Brazil-RS) cohort23 and cohorts from other Brazilian regions (Brazil-non-RS cohorts): namely, subjects from São Paulo State22 and those described by Neurogenetics Network, a consortium of Brazilian researchers 5. Using both IPDs and ADs, the global linear correlation coefficient between CAGexp and log 10 (AO) was r=−0.743 (95% CI -0.768 to -0.713, p<0.001), meaning that, on average, the causative mutation determines about 55.2% (50.8%–59.0%) of the AO variability in SCA3/MJD worldwide.…”

“…Lack of confirmation in other cohorts is most likely attributed to small sample sizes6 7 or inclusion of ATXN2 in regression analysis as a continuous variable 5. Whether the modulatory effect of ATXN2 would be due to the CAG tract directly, or another genetically linked variant, is still unknown.…”

Nonmotor Symptoms in Patients with Spinocerebellar Ataxia Type 10

“…The occurrence of these features, particularly seizures, is not uniform as a large SCA10 series from Brazil with 60 patients from 10 families described ataxia as the sole manifestation, with seizures detected in a frequency similar to that expected for the general population [4]. In contrast, in a series of 23 SCA10 patients from different Brazilian states, epilepsy was found in 65% of the cases, presenting with tonic-clonic seizures or combinations of myoclonic, complex partial, and generalized tonic-clonic seizures [5]. …”

Voxel‐based meta‐analysis of gray and white matter volume abnormalities in spinocerebellar ataxia type 2

“…Therefore, the atrophy of these regions may result in basic cerebellar signs like ataxia in SCA2 patients. The lobule VI/VII and Crus I of cerebellum are associated with language, verbal working memory, spatial processing, executive functions, and emotional control (D'Agata, Caroppo, Baudino et al., 2011; de Castilhos et al., 2014; Stoodley & Schmahmann, 2009). The atrophy in cerebellar lobule Crus II of cerebellum also plays a role in cognitive impairments, which has been reported (Stoodley & Schmahmann, 2010).…”