SCA2 predictive testing in Cuba: challenging concepts and protocol evolution

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/10 5 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.

Prodromal spinocerebellar ataxia type 2: Prospects for early interventions and ethical challenges

“…Early diagnosis and treatment for genetic late‐onset neurodegenerative diseases could improve the quality of life for the mutation carriers and their families. The principal advantages lie mainly in knowing the actual risk of the disease over time and the physical and psychological preparation to cope with the disease . Additional benefits could result from the active interventions received sooner than is usually the case for manifest disease .…”

“…For SCA2, the main ethical dilemmas relating to the predictive genetic testing are the request of a diagnosis test by an at‐risk adolescent and the de facto predictive testing of minors resulting from the no‐interruption of the pregnancy by couples with a test‐positive fetus. Last, there is the question of the elevated frequency of the ATXN2 gene large normal and intermediate alleles, which are able to expand into full penetrance range under certain conditions or could be associated with other neurodegenerative disorders, such as amyotrophic lateral sclerosis …”

“…The last barrier is supported by the scarce genotypical and phenotypical characterizations of descendant asymptomatic at‐risk individuals worldwide. Nevertheless, in Cuba this barrier is surpassed because of the existence of a presymptomatic diagnostic program that started in 2003 and that has carried out molecular diagnosis on more than 1200 asymptomatic at‐risk individuals . Thus, for a long time the Cuban population of SCA2 preclinical individuals has undergone comprehensive characterization using multiple approaches, including clinical, imaging, and functional assessments .…”

Ethical issues in neurogenetics

“…For many patients, the decision is not to test, which is why pre-test counseling and informed decision-making are critical. Initially it was thought that the demand for testing would be high, but studies on the uptake of predictive genetic testing for Huntington disease (Bernhardt et al, 2009; Creighton et al, 2003; Morrison et al, 2011; Panas et al, 2011; Tassicker et al, 2009) and other hereditary neurogenetic conditions (Cruz-Marino et al, 2013; Cruz-Marino et al, 2015; Riedijk et al, 2009) found that the majority of at-risk individuals decide not to learn their carrier status.…”

Quality of Life and the Degree of Disease Acceptance In Patients with Spinocerebellar Ataxia

“…Globally, the highest number of people with SCA live in Cuba (6.57 cases/10(5) inhabitants) and in the Azores Island [5,6]. Globally, SCA1, SCA2, SCA3, SCA6 and SCA7 represent the highest numbers of cases [1].…”