Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.
This is a preview of subscription content, log in to check access.
The authors would like to thank the individuals who agreed to participate in this study.
This work was supported by FIPE-HCPA – Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre – Project GPPG HCPA 16-320. EPM, GVF, MLSP and LBJ were supported by CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- Histogram showing the relationship between the children’s year of birth and year of onset of symptoms in the affected parent. Onset of symptoms is represented by “0” (zero), negative numbers represent the number of years before the onset of symptoms, while positive numbers represent the number of years after the onset of symptoms in the affected parent. (PNG 90 kb)
- Histogram describing the differences between ages at onset (delta-AO) of the affected individuals and their transmitting parents. Transmitting fathers were depicted as male transmissions; those of mothers were depicted as female transmissions. (PNG 72 kb)
Laffita-Mesa JM, Velázquez-Pérez LC, Santos Falcón N, et al. Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles. European Journal of Human Genetics. 2012;20(1):41–9. https://doi.org/10.1038/ejhg.2011.15.CrossRefPubMedGoogle Scholar
Montcel S.T, Durr A, Bauer P, et al. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Brain 2014. Pages 2444–2455.Google Scholar
Geschwind DH, Perlman S, Figueroa CP, Treiman LJ, Pulst SM. The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am J Hum Genet. 1997;60(4):842–50.PubMedPubMedCentralGoogle Scholar
Matilla-Dueñas A, Sánchez I, Corral-Juan M, Dávalos A, Alvarez R, Latorre P. Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias. Cerebellum. 2010 Jun;9(2):148–66.CrossRefGoogle Scholar
Magaña JJ, Velázquez-Pérez L, Cisneros B. Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives. Mol Neurobiol. 2013;47:90–104.CrossRefGoogle Scholar
Costanzi-Porrini S, Tessarolo D, Abbruzzese C, Liguori M, Ashizawa T, Giacanelli M. An interrupted 34-CAG repeat SCA-2 allele in patients with sporadic spinocerebellar ataxia. Neurology. 2000 Jan 25;54(2):491–3.CrossRefGoogle Scholar
Babovic-Vuksanovic D, Snow K, Patterson MC, Michels VV. Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet. 1998;79:383–7.CrossRefGoogle Scholar
Abdel-Aleem A, Zaki MS. Spinocerebellar ataxia type 2 (SCA2) in an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol. 2008;255:413–9.CrossRefGoogle Scholar
Di Fabio R, Santorelli F, Bertini E, et al. Infantile childhood onset of spinocerebellar ataxia type 2. Cerebellum. 2012;11:526–30.CrossRefGoogle Scholar
Figueroa KP, Coon H, Santos N, et al. Genetic analysis of age at onset variation in spinocerebellar ataxia type 2. Neurology: Genetics. 2017;3(3):e155.Google Scholar
Almaguer-Mederos LE, Mesa JML, González-Zaldívar Y, et al. Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in spinocerebellar ataxia type 2. Clin Genet. 2018:14.Google Scholar
Frontali M, Sabbadini G, Novelletto A, et al. Genetic fitness in Huntington’s Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions. 1996.CrossRefGoogle Scholar
Prestes PR, Saraiva-Pereira ML, Silveira I, Sequeiros J, Jardim LB. Machado Joseph disease enhances genetic fitness: a comparison between affected and unaffected women and between MJD and the general population. Ann Hum Genet. 2008;72:57–64.PubMedGoogle Scholar
Souza GN, Kersting N, Krum-Santos AC, Santos ASP, Furtado GV, Pacheco D, et al. Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions. Clin Genet. 2016 Aug;90(2):134–40.CrossRefGoogle Scholar
Platonov FA, Tyryshkin K, Tikhonov DG, Neustroyeva TS, Sivtseva TM, Yakovleva NV, et al. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1. Neurogenetics. 2016;17(3):179–85.CrossRefGoogle Scholar
Pereira FS, Monte TL, Locks-Coelho LD. Genes and mitochondrial polymorphism A10398G did not modify age at onset in spinocerebellar ataxia type 2 patients from South America. Cerebellum. 2015 Dec;14(6):728–30.CrossRefGoogle Scholar
Socal MP, Emmel VE, Rieder CR. Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions. Parkinsonism Relat Disord. 2009;15:374–8.CrossRefGoogle Scholar
de Castilhos RM, Furtado GV, Gheno TC, et al. Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related. Cerebellum. 2014;13:17–28.Google Scholar
Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science. 2017;356:eaal3321.CrossRefGoogle Scholar
Lorenzetti D, Bohlega S, Zoghbi HY. The expansion of the CAG repeat in ataxin-2 is a frequent cause of autosomal dominant spinocerebellar ataxia. Neurology. Oct 1997;49(4):1009–13.CrossRefGoogle Scholar
Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, et al. Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet. 2002;110:338–45.CrossRefGoogle Scholar