The advent of recombinant DNA technology made it possible for the first time to predict the future onset of a genetic condition, prior to the appearance of any signs or symptoms. These developments enabled persons at risk for a genetic disease to see into their health future in a way that few others have been able to do. Use of the technology also enabled diagnoses to be made with a greater degree of accuracy and gave parents the option of testing a fetus at risk to determine whether it had inherited the familial condition. However, these new opportunities were accompanied by new ethical challenges in health care. Was it acceptable to offer testing when there was no means of preventing or curing the disease? Could prior knowledge of a person’s fate have a detrimental effect on their lives? How could the best interests of the patient be served?

Predictive testing for adult-onset neurological conditions has been the focus of much discussion and research. This chapter focuses on the counseling and testing for Huntington disease, but the principles discussed are equally pertinent to testing for
a range of adult-onset genetic conditions, including other long-term neurological conditions and familial cancer.

Huntington disease (HD) is an autosomal dominant genetic condition that has a profound impact on the life and health of affected individuals and their families. The gene mutation that is associated with HD has an effect on the functioning of the brain as it causes atrophy of the basal ganglia and cerebral cortex (NCBI 2007). The difficulties that arise for the affected individual fall into three main categories: movement disorder, depression, and dementia (Melone, Jori, and Peluso 2005).

The onset of symptoms of the disease can occur at any age, including childhood or adolescence, but most commonly occurs during middle age. In adults, the first signs may be forgetfulness, clumsiness, and difficulty in performing certain intellectual functions. However, as the disease progresses over the ensuing 15-20 years, involuntary choreic movements (uncoordinated, spastic jerking) and dementia usually become increasingly debilitating (Skirton and Glendinning 1997). Major causes of death are pneumonia (due to immobility and aspiration) or cardiovascular disease. However, because of changes in both physical and cognitive functioning, death may be accidental or due to suicide (Sorenson and Fenger 1992).

The huntingtin (scientific name) gene is located on chromosome 4. Each person has two copies of the gene, one inherited from each parent. An expansion of one copy of this gene will result in the person developing the disease, and the size of the expansion loosely correlates with the age of onset. That is to say that if one copy of the gene, if it is the abnormal version, will have a greater number of repeats of the three nucleotide base sequence, “CAG,” and thus result in the appearance of the disease. The normal number of repeats in the huntingtin gene is 11-29, while the number of repeats in the abnormal version will range from 40 to 80 (from the website of the National Institutes of Health, National Human Genome Research Institute, http://www.genome.gov/10001215). In population terms, the larger the expansion, the earlier the onset. However, it is not possible to accurately predict the age of onset of the disease in individual cases.

The offspring of a person with one expanded gene will have a 50% chance of inheriting the gene mutation, and therefore of developing HD (NCBI 2007). As the age of onset is commonly in middle age, many affected persons have children before they develop signs and symptoms. Those children are often involved in the care of the affected parent and are very familiar with the physical, psychological, and social impact of the disease on the family.

Since George Huntington published the first paper on HD (Huntington, 1872), the heritability of HD has been understood and risk assessments for family members have been based on the autosomal dominant inheritance pattern (one copy of the gene from one parent is sufficient to cause manifestation of the associated health condition). Prior to discovery of the gene locus associated with HD, counseling a person who had a parent with the condition was a matter of conveying the information that the individual was born with a 50% chance of inheriting the disease. As the at-risk person grew older, the chances could be modified according to age-related tables. Thus, based on empirical evidence, a person born at 50% risk was said to have a chance of about 30% of having inherited the condition if they reached the age of 50 without developing any signs or symptoms (Harper, Walker, Tyler, Newcombe, and Davies 1979). Couples who were considering pregnancy had the option of not having a biological child or taking the risk that the child would be affected in the future. Some were advised by healthcare professionals not to have children in order to stamp out the disease.

However, with the advent of recombinant DNA technology, opportunities for genetic testing became a reality. The site of the gene on chromosome 4 was located in 1983 (Gusella, Wexler, Conneally, Naylor, Anderson, Tanzi, et al. 1983), enabling genetic testing to be performed by linkage analysis, tracking the faulty gene through the family using markers that were closely associated with (near) the gene. This necessitated using DNA samples from a number of family members, both affected and unaffected. In these circumstances, it was virtually impossible to maintain confidentiality of the person being tested, since he or she was compelled to ask relatives to donate a blood sample for DNA extraction and testing. In addition to the ethical aspects, in practical terms it was not possible to test those who had no living affected relatives or whose family genetic structure was uninformative (for example, there might be missing information about the condition of family members, or there might not be family members who manifested signs or symptoms of HD).

However, in 1993 the expansion in the huntingtin gene associated with HD was identified, and testing was simplified (Huntington’s Disease Collaborative Research Group 1993). Once HD had been confirmed as the correct diagnosis in the family, each individual’s sample could be tested without the need to involve other family members.

Initially, predictive genetic testing was performed under the auspices of clinical research projects. Naturally, there were concerns about possible adverse effects of testing for a serious condition for which there was no effective treatment. Candidates for testing underwent a number of psychometric tests (e.g., measuring levels of depression and anxiety), as well as a mandatory three sessions of pre-test counseling and post-test follow-up. However, as the research indicated that few adverse events were reported following testing (such as serious mental health problems), clinical services began to offer predictive testing on a widespread basis, using the research protocol as a model for preparation and follow-up care (Craufurd and Tyler 1992).

For some years these stringent protocols were observed, but gradually the need for patient autonomy, variation in the support needs of different families, and the lack of evidence of substantial harm (e.g., suicide attempts or serious mental health problems) from testing were acknowledged. Currently, many centers adhere to the guidelines published by the International Huntington Association (2005) but are willing to adopt a flexible approach to take the needs and preferences of individuals and families into account.

Prior to the introduction of predictive testing for HD, the majority of persons at risk reported an interest in testing and the intention to utilise the test personally (Evers-Kiebooms, Cassiman, and van den Berghe 1987; Kessler, Field, Worth, and Mosbarger 1987). However, following availability of the test, the uptake (actually having the test) was considerably less than predicted, with a maximum of 16% of at-risk individuals proceeding with the test (Maat-Kievit, Vegter-van der Vlis, Zoeteweij, Losekoot, van Haeringen, and Roos 2000).

Earlier, the number of patients being tested was affected by the need to also obtain samples from family members. However, this cannot entirely explain the discrepancy between intention and behaviour, because it was observed that the uptake did not change dramatically after the direct mutation tests became available. Following an initial surge in the number of tests after the direct test was introduced (possibly due to those people who were previously unwilling or unable to involve their families presenting for testing), the numbers of persons undergoing testing decreased. Currently, approximately 18%-24% of those eligible seek predictive testing (Maat-Kievit et al. 2000; Harper, Lim, and Craufurd 2000). It may be that respondents to the
early studies agreed with predictive testing in principle, rather than as a personal option. It is also possible that for patients who were faced with the reality of the certainty of the results of mutational analysis rather than a risk estimate, living with the risk was preferable.