Abstract
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/105 inhabitants) of SCA2 in the world. The existence of 753 affected individuals and 7173 relatives at risk prompted the development in 2001 of the first predictive testing program in the country. The medical records of over 1193 individuals, who requested the test within a 13-year period, were analyzed retrospectively. The presymptomatic and the prenatal tests had uptake rates of 43.4 and 23.9 %, respectively. Several ethical challenges resulted from this program. These include the following: (1) withdrawal due to the initial protocol’s length; (2) the request to participate by 16 at-risk adolescents; (3) the decision made by ten out of 33 couples with a test-positive fetus to carry the pregnancy to term, leading to de facto predictive testing of minors; (4) the elevated frequency of the ATXN2 gene large normal alleles (≥23 to 31 repeats) in the reference population. These issues have led to major changes in the guidelines of the predictive testing protocol: (1) the protocol length was shortened; (2) the inclusion criteria were expanded to reach at-risk adolescents with an interest in prenatal diagnosis; (3) interdisciplinary follow-up was offered to families in which test-positive fetuses were not aborted; (4) prenatal testing was made available to carriers of large normal alleles with ≥27 CAG repeats. The profiles of the participants were similar to those reported for other predictive testing programs for conditions like Huntington disease and familial adenomatous polyposis. The genetic counseling practices at the community level, the ample health education provided to the at-risk population, together with multidisciplinary and specialized attention to the affected families, are lessons from the Cuban experience that can be relevant for other international teams conducting predictive testing for other late-onset neurodegenerative disorders.
Similar content being viewed by others
References
Alonso ME, Ochoa A, Sosa AL et al (2009) Presymptomatic diagnosis in Huntington’s disease: the Mexican experience. Genet Test Mol Biomark 13(6):717–720
Anuario Estadístico de Cuba (2013) http://www.one.cu/aec2013/datos/03%20Poblacion.pdf. Accessed 29 Dec 2014
Auburger G, Orozco G, Ferreira R et al (1990) Autosomal dominant ataxia: genetic evidence for locus heterogeneity from a Cuban founder effect population. Am J Hum Genet 46(6):1163–1177
Barcia MC, García G, Torres-Cuevas E (1994) Historia de Cuba. La Colonia. Evolución socioeconómica y formación nacional. Tomo 1. Editora Política. La Habana, p 518. ISBN 9590100368,9789590100369
Codori AM, Zawacki KL, Petersen GM et al (2003) Genetic testing for hereditary colorectal cancer in children: long-term psychological effects. Am J Med Genet A 116A(2):117–128
Coelho T, Maia LF, da Silva AM et al (2013) Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 260(11):2802–2814
Creighton S, Almqvist EW, MacGregor D et al (2003) Predictive, prenatal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987 to 2000. Clin Genet 63(6):462–475
Cruz-Mariño T, Velázquez-Pérez L, González-Zaldívar Y et al (2013a) The Cuban program for predictive testing of SCA2: 11 years and 768 individuals to learn from. Clin Genet 83(6):518–524
Cruz-Mariño T, Velázquez-Pérez L, González-Zaldívar Y et al (2013b) Couples at risk for spinocerebellar ataxia type 2: the Cuban prenatal diagnosis experience. J Community Genet 4(4):451–460
Cruz-Mariño T, Velázquez-Pérez L, González-Zaldívar Y et al (2013c) Cuban Adolescents Requesting Presymptomatic Testing for Spinocerebellar Ataxia Type 2. ISRN Genetics, vol. 2013, p 5. doi:10.5402/2013/837202
Cruz-Mariño T, Laffita-Mesa JM, González-Zaldívar Y et al (2014) Large normal and intermediate alleles in the context of SCA2 prenatal diagnosis. J Genet Couns 23(1):89–96
Daoud H, Belzil V, Martins S et al (2011) Association of long ATXN2 CAG repeat sizes with increased risk ofamyotrophic lateral sclerosis. Arch Neurol 68(6):739–742
Douma KFL, Aaronson NK, Vasen HFA, Bleiker EMA (2008) Psychosocial issues in genetic testing for familial adenomatous polyposis: a review of the literature. Psychooncology 17(8):737–745
Dufrasne S, Roy M, Galvez M, Rosenblatt DS (2011) Experience over fifteen years with a protocol for predictive testing for Huntington disease. Mol Genet Metab 102(4):494–504
Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466(7310):1069–1075
Estrada R, Galarraga J, Orozco G et al (1999) Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol 97(3):306–310
European Community Huntington’s Disease Collaborative Study Group (1993) Ethical and social issues in presymptomatic testing for Huntington’s disease: a European Community collaborative study. J Med Genet 30(12):1028–1035
Guimarães L, Sequeiros J, Skirton H, Paneque M (2013) What counts as effective genetic counselling for presymptomatic testing in late-onset disorders? A study of the consultand’s perspective. J Genet Couns 22(4):437–447
Hawkins AK, Hayden MR (2011) A grand challenge: providing benefits of clinical genetics to those in need. Genet Med 13(3):197–200
Hawkins AK, Ho A, Hayden MR (2011) Lessons from predictive testing for Huntington disease: 25 years on. J Med Genet 48(10):649–650
HDSA (2012) Genetic testing for Huntington’s disease: its relevance and implications. US Huntington’s Disease Genetic Testing Group Revised 2003. Retrieved November 26, 2012, from https://www.hdsa.org/living-with-huntingtons/publications/index.html
Laffita-Mesa JM, Velázquez-Pérez L, Santos-Falcón N et al (2012) Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles. Eur J Hum Genet 20(1):41–49
Laffita-Mesa JM, Rodríguez-Pupo JM, Moreno-Sera R et al (2013) De novo mutations in ataxin-2 gene and ALS risk. PLoS One 8(8), e70560. doi:10.1371/journal.pone.0070560
Laffita-Mesa JM, Almaguer-Mederos LE, Kourí V et al (2014) Large normal alleles and SCA2 prevalence: lessons from a nationwide study and analysis of the literature. Clin Genet 86(1):96–98
Lantigua AC (2013) An overview of genetic counseling in Cuba. J Genet Couns 22(6):849–853
Ledo S, Paneque M, Rocha JC et al (2013) Predictive testing for two neurodegenerative disorders (FAP and HD): a psychological point of view. Open J Genetics 3:270–279
MacLeod R, Tibben A, Frontali M et al (2013) Recommendations for the predictive genetic test in Huntington’s disease. Clin Genet 83(3):221–231
Paneque M, Santos-Falcón N, Tamayo CV et al (2001) Type 2 spinocerebellar ataxia: acceptance of prenatal diagnosis in descendents at risk. Rev Neurol 33(10):904–908
Paneque HM, Prieto AL, Reynaldo RR et al (2007) Psychological aspects of presymptomatic diagnosis of spinocerebellar ataxia type 2 in Cuba. Community Genet 10(3):132–139
Paneque HM, Lemos C, Sousa A et al (2009) Role of the disease in the psychological impact of pre-symptomatic testing for SCA2 and FAP ATTRV30M: experience with the disease, kinship and gender of the transmitting parent. J Genet Couns 18(5):483–493
Paneque M, Mendes A, Guimarães et al (2014) Genetics Health Professionals’ Views on Quality of Genetic Counseling Service Provision for Presymptomatic Testing in Late-Onset Neurological Diseases in Portugal: Core Components, Specific Challenges and the Need for Assessment Tools. J Genet Couns. doi:10.1007/s10897-014-9784-6
Ramsoekh D, van Leerdam ME, Tops CMJ et al (2007) The use of genetic testing in hereditary colorectal cancer syndromes: genetic testing in HNPCC, (A)FAP and MAP. Clin Genet 72(6):562–567
Rodrigues CSM, Oliveira VZ, Camargo G et al (2012) Presymptomatic testing for neurogenetic diseases in Brazil: assessing who seeks and who follows through with testing. J Genet Couns 21(1):101–112
Rodríguez-Labrada R, Velázquez-Pérez L, Canales-Ochoa N et al (2011) Subtle rapid eye movement sleep abnormalities in presymptomatic spinocerebellar ataxia type 2 gene carriers. Mov Disord 26(2):347–350
Rolim L, Leite A, Ledo S et al (2006) Psychological aspects of pre-symptomatic testing for Machado-Joseph disease and familial amyloid polyneuropathy type I. Clin Genet 69(4):297–305
Sequeiros J (1996) Protocolo geral do Programa Nacional de Teste Preditivo e Aconselha-mento Genético na Doença de Machado-Jo-seph. In: Sequeiros J (ed) O Teste Preditivo da Doença de Machado-Joseph. Porto, UnIGENe, pp 123–149
Sequeiros J, Martindale J, Seneca S (2010a) Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias. Eur J Hum Genet 18(11):1188–1195
Sequeiros J, Martindale J, Seneca S (2010b) EMQN best practice guidelines for molecular genetic testing of SCAs. Eur J Hum Genet 18(11):1173–1176
Simpson SA, Harper PS, On behalf of the UK Huntington’s Disease Prediction Consortium (2001) Prenatal testing for Huntington’s disease: experience within the UK 1994-1998. J Med Genet 38(5):333–335
Simpson SA, Zoeteweij MW, Nys K et al (2002) Prenatal testing for Huntington’s disease: a European collaborative study. Eur J Hum Genet 10(11):689–693
Skirton H, Goldsmith L, Jackson L, Tibben A (2013) Quality in genetic counselling for presymptomatic testing–clinical guidelines for practice across the range of genetic conditions. Eur J Hum Genet 21(3):256–260
Velázquez-Pérez L, Cruz-Sánchez G, Santos-Falcón N et al (2009a) Molecular epidemiology of spinocerebellar ataxias in Cuba: insights into SCA2 founder effect in Holguin. Neurosci Lett 454(2):157–160
Velázquez-Pérez L, Díaz R, Pérez-González R et al (2009b) Motor decline in presymptomatic spinocerebellar ataxia type 2 gene carriers. PLoS One 4(4):e5398
Velázquez-Pérez L, Seifried C, Abele M et al (2009c) Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2. Clin Neurophysiol 120(3):632–635
Velázquez-Pérez L, Rodríguez-Labrada R, Canales-Ochoa N et al (2014a) Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study. Lancet Neurol 13(5):482–489
Velázquez-Pérez L, Rodríguez-Labrada R, Cruz-Rivas EM et al (2014b) Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease. Cerebellum 13(5):568–579
Acknowledgments
The authors are deeply indebted to the SCA2 Cuban families and to the Cuban Ministry of Health. We would like to praise the work of BSc Nieves Santos Falcón, MD Karell Escalona Batallán, MD Humberto Jorge Cedeño, MD Ruben Reynaldo Armiñan, MD Mercedes Velázquez, BSc Nalia Canales Ochoa, BSc Arnoy Peña Acosta, BSc Roberto Rodríguez Labrada, and BSc Rafael Bestard. We are thankful to José Luis Guisao Martínez for the language corrections and to MD Patrick MacLeod for his contribution to the program along these years.
Compliance with ethical guidelines
The presymptomatic testing and the prenatal diagnosis procedures are in compliance with the laws existing in Cuba. They are in accordance with the ethical standards of CIRAH and with the Helsinki declaration of 1975 as revised in 2000. All participants were informed about PST and PND procedures and protocol, as well as the possibility of using information from their clinical records in clinical research and they gave their separate written consent for both.
Conflict of interest
Authors declare no conflicts of interest
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is part of the special issue on “Genetics and Ethics in Latin America.”
Tania Cruz-Mariño and Yaimeé Vázquez-Mojena contributed equally to this work.
Rights and permissions
About this article
Cite this article
Cruz-Mariño, T., Vázquez-Mojena, Y., Velázquez-Pérez, L. et al. SCA2 predictive testing in Cuba: challenging concepts and protocol evolution. J Community Genet 6, 265–273 (2015). https://doi.org/10.1007/s12687-015-0226-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12687-015-0226-4