Susan Creighton

Perceptions of genetic discrimination among people at risk for Huntington’s disease: a cross sectional survey

Objective To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington’s disease who had undergone genetic testing or remained untested. Design Cross sectional, self reported survey. Setting Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. Participants 233 genetically tested and untested asymptomatic people at risk for Huntington’s disease (response rate 80%): 167 underwent testing (83 had the Huntington’s disease mutation, 84 did not) and 66 chose not to be tested. Main outcome measures Self reported experiences of genetic discrimination and related psychological distress based on family history or genetic test results. Results Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings. There were few reports of discrimination in employment (6.9%), health care (8.6%), or public sector settings (3.9%). Although respondents who were aware that they carried the Huntington’s disease mutation reported the highest levels of discrimination, participation in genetic testing was not associated with increased levels of genetic discrimination. Family history of Huntington’s disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination. Psychological distress was associated with genetic discrimination (P<0.001). Conclusions Genetic discrimination was commonly reported by people at risk for Huntington’s disease and was a source of psychological distress. Family history, and not genetic testing, was the major reason for genetic discrimination.

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease

Objectives: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using 1H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance. Methods: Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was >220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntingtons Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. Results: Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (∼15%) vs controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (∼8%) and early HD (∼17%) vs controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R2 = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R2 = 0.30, p < 0.0001) and with disease burden score (R2 = 0.17, p < 0.005). Conclusions: We demonstrate lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.

Managing genetic discrimination : Strategies used by individuals found to have the Huntington disease mutation

The introduction of predictive testing for Huntington disease (HD) over 20 years ago has led to the advent of a new group of individuals found to have the HD mutation that are currently asymptomatic, yet destined in all likelihood to become affected at some point in the future. Genetic discrimination, a social risk associated with predictive testing, is the differential treatment of individuals based on genotypic difference rather than physical characteristics. While evidence for genetic discrimination exists, little is known about how individuals found to have the HD mutation cope with the potential for or experiences of genetic discrimination. The purpose of this study was to explore how individuals found to have the HD mutation manage the risk and experience of genetic discrimination. Semi‐structured individual interviews were conducted with 37 individuals who were found to have the HD mutation and analysed using grounded theory methods. The findings suggest four main strategies: “keeping low”, minimizing, pre‐empting and confronting genetic discrimination. Strategies varied depending on individuals’ level of engagement with genetic discrimination and the nature of the experience (actual experience of genetic discrimination or concern for its potential). This exploratory framework may explain the variation in approaches and reactions to genetic discrimination among individuals living with an increased risk for HD and may offer insight for persons at risk for other late‐onset genetic diseases to cope with genetic discrimination.

Genetic testing and Huntington's disease: issues of employment

Genetic information, employment, and Huntington’s disease (HD) Peter S Harper, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK The widespread publicity surrounding the recently reported case of a woman in Germany refused employment as a teacher because of a family history of HD provides a timely opportunity to examine whether and how genetic information is currently used in relation to employment, and how it might be used in the future. This issue appears to have arisen first for HD not because of any unique features of this disorder, but because it illustrates general issues in a more clear-cut form than is usually the case. Before considering the wider issues, some basic medical and genetic facts about HD need to be considered. HD is a progressive brain disease with both neurological and psychiatric features. Its onset is usually in middle life, though very variable; progression is slow, but most patients will be significantly affected after 5 years from onset, and few would be able to continue working in a stressful job after this time. In genetic terms, HD follows simple autosomal dominant inheritance; those with an affected parent have a 50% chance of inheriting the mutant gene and of developing the disorder at some point. This risk will depend on the individual’s age and on the length of time under consideration. Thus, a 25 year old with an affected parent would have a 7·5% risk of developing HD over the next 10 years and a 21% risk over the next 20 years. For a more distant relative, the risks would be much lower. Genetic testing for the unique mutation for HD is feasible at any age, regardless of whether a person is symptomatic or not. Current international guidelines on good practice for predictive testing recognise the importance of avoiding both pressure to be tested and disclosure to third parties of factors relevant to employment without specific consent. In the UK, fewer than 20% of those at risk decide to be tested, and insurance and employment issues rank low among the underlying reasons. There is currently a general UK moratorium on the need to disclose genetic test results for insurance purposes (including HD, except for the largest sums insured). The insurance situation could be a useful example for employment, although it should be noted that use of family history information is permitted in relation to insurance. Why should an employer wish to have information on the family history of an employee? There may be some benefits for the employee and others for the employer, and there is possibly substantial overlap. Information might be of use in

A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers

Putaminal metabolites examined using cross‐sectional magnetic resonance spectroscopy (MRS) can distinguish pre‐manifest and early Huntingtons Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty‐four participants (30 controls, 25 pre‐manifest HD, 29 early HD) recruited as part of TRACK‐HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK‐HD motor assessment. Statistical analyses included linear regression and one‐way analysis of variance (ANOVA). At all time‐points N‐acetyl aspartate and total N‐acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre‐manifest HD than in controls, whereas the gliosis marker myo‐inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross‐sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD‐affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi‐site assessments in large, pathologically diverse cohorts.

Beyond the patient: The broader impact of genetic discrimination among individuals at risk of Huntington disease†‡

We aimed to address gaps in current understanding of the scope and impact of discrimination, by examining a cohort of individuals at‐risk for Huntington disease (HD), to describe the prevalence of concern for oneself and ones family in multiple domains; strategies used to mitigate discrimination; and the extent to which concerns relate to experiences. We conducted a cross‐sectional survey of 293 individuals at‐risk for HD (80% response rate); 167 respondents were genetically tested and 66 were not. Fear of discrimination was widespread (86%), particularly in the insurance, family and social settings. Approximately half of concerned individuals experienced discrimination (40–62%, depending on genetic status). Concern was associated with “keeping quiet” about ones risk of HD or “taking action to avoid” discrimination. Importantly, concern was highly distressing for some respondents (21% for oneself; 32% for relatives). Overall, concerned respondents with high education levels, who discovered their family history at a younger age, and those who were mutation‐positive were more likely to report experiences of discrimination than others who were concerned. Concerns were rarely attributed to genetic test results alone. Concern about genetic discrimination is frequent among individuals at‐risk of HD and spans many settings. It influences behavioral patterns and can result in high levels of self‐rated distress, highlighting the need for practice and policy interventions.

When access is an issue: exploring barriers to predictive testing for Huntington disease in British Columbia, Canada

Predictive testing (PT) for Huntington disease (HD) requires several in-person appointments. This requirement may be a barrier to testing so that at risk individuals do not realize the potential benefits of PT. To understand the obstacles to PT in terms of the accessibility of services, as well as exploring mechanisms by which this issue may be addressed, we conducted an interview study of individuals at risk for HD throughout British Columbia, Canada. Results reveal that the accessibility of PT can be a barrier for two major reasons: distance and the inflexibility of the testing process. Distance is a structural barrier, and relates to the time and travel required to access PT, the financial and other opportunity costs associated with taking time away from work and family to attend appointments and the stress of navigating urban centers. The inflexibility of the testing process barrier relates to the emotional and psychological accessibility of PT. The results of the interview study reveal that there are access barriers to PT that deter individuals from receiving the support, information and counseling they require. What makes accessibility of PT services important is not just that it may result in differences in quality of life and care, but because these differences may be addressed with creative and adaptable solutions in the delivery of genetic services. The study findings underscore the need for us to rethink and personalize the way we deliver such services to improve access issues to prevent inequities in the health care system.

Factors associated with experiences of genetic discrimination among individuals at risk for huntington disease

The purpose of this study was to identify factors that are associated with experiencing genetic discrimination (GD) among individuals at risk for Huntington disease (HD). Multivariable logistic regression analysis was used to examine factors associated with experiencing GD in data from a cross‐sectional, self‐report survey of 293 individuals at risk for HD. The study sample comprised 167 genetically tested respondents, and 66 who were not tested (80% response rate). Overall, individuals who learn they are at risk for HD at a younger age (OR = 3.1; 95% CI: 1.5–6.2; P = 0.002), are mutation‐positive (OR = 2.8; 95% CI: 1.4–6.0; P = 0.006), or are highly educated (OR = 2.7; 95% CI: 1.4–5.1; P = 0.002) are more likely to experience GD, particularly in insurance, family, and social settings. Further, younger age was associated with discrimination in insurance (OR = 0.97; 95% CI: 0.94–1.00; P = 0.038). This study provides evidence that some people who are at risk for HD were more likely to experience GD than others. Individuals who learned they are at risk for HD at a younger age and those who are mutation‐positive were more likely to experience GD, particularly in insurance, family, and social settings. Younger individuals were more likely to experience discrimination in the insurance setting. Overall, highly educated individuals were also more likely to report discrimination. These results provide direction for clinical and family discussions, counseling practice, and policy aimed at mitigating experiences of GD.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae.

N02 Providing predictive testing via telehealth to improve access to predictive testing for HD: results of a pilot study

Background Predictive testing (PT) for HD requires several in-person appointments. A previous interview study of individuals at risk for HD in British Columbia (BC), Canada revealed that the accessibility of PT can be a barrier for two major reasons: distance and the inflexibility of the testing process. Based on the results of this study, coupled with expert consultation, an effective and practical portable telehealth testing protocol was developed, including an informational website and locally supported telehealth appointments. Aims The objective of this project was to conduct a pilot project to examine whether this telehealth protocol can improve access to HD PT while maintaining quality of care and support for those undergoing the process. Methods Consented individuals underwent PT via the telehealth protocol and were asked to complete surveys throughout the testing process to capture several important factors including: overall experience of the telehealth process, information and understanding, support and accessibility of care. Results A total of 29 individuals enrolled in the pilot study. Results reveal that patients undergoing PT via the telehealth service report a positive response to the service on a number of factors: (1) Flexibility/ease of set up of appointments; (2) Avoid expense and time related to travelling to appointments; (3) Allows support people to more easily attend the appointment; (4) Individuals can get home easily; (5) May spare unnecessary visits. Conclusions This pilot study reveals that providing PT via telehealth improves access to PT while maintaining quality of care and support.