Risk For Huntington's Disease Research Articles

Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS).

Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.

Huntington disease

In this issue of Neurology ® , Dr. Killoran and colleagues1 report new findings in people at risk for Huntington disease (HD). HD is an inherited illness that causes problems with movement, mood, behavior, and thinking. HD is a genetic disease (see About HD page). In order to understand the article by Dr. Killoran et al., it is helpful to have a little background on the genetics of HD. Every human being has 23 pairs of chromosomes. Human genes are located on the chromosomes. The HD gene sits on chromosome 4. Part of the gene is made up of repeating units of DNA abbreviated C-A-G. Different people have different numbers of CAG repeats. Having up to 26 CAG copies is considered normal. In people with HD, the number of CAG copies is higher than it should be. The gene test for HD counts the number of CAG repeats. This allows adult children of a person with HD to find out whether they have inherited from their parent the genetic abnormality (called a mutation) that causes the disease. As shown in the figure, a test result showing 40 or more CAG repeats means that the person will develop signs of HD at some point in his or her lifetime. A result showing 26 or fewer repeats means …

Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS

We aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study. The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington's Disease Rating Scale (UHDRS) by investigators unaware of participants' gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27-35, and nonexpanded controls <26. Fifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group's scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups. In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

Brain Growth in Children at Risk for Huntington Disease

Researchers at the University of Iowa and Washington University, St Louis, MO, studied the effect of the mutant Huntington gene (mHTT) on measures of growth in children at risk for Huntington disease (HD).

Measures of growth in children at risk for Huntington disease

The effect of mHTT on human development was examined by evaluating measures of growth in children at risk for Huntington disease (HD). Children at risk for HD with no manifest symptoms (no juvenile HD included) were enrolled and tested for gene expansion for research purposes only. Measurements of growth (height, weight, body mass index [BMI], and head circumference) in children tested as gene-expanded (n = 20, 7-18 years of age, CAG repeats ≥39) were compared to those of a large database of healthy children (n = 152, 7-18 years of age). Gene-expanded children had significantly lower measures of head circumference, weight, and BMI. Head circumference was abnormally low even after correcting for height, suggesting a specific deficit in brain growth, rather than a global growth abnormality. These results indicate that, compared to a control population, children who were estimated to be decades from HD diagnosis have significant differences in growth. Further, they suggest that mHTT may play a role in atypical somatic, and in particular, brain development.

Optimal Expectations and Limited Medical Testing: Evidence from Huntington Disease

We use novel data to study genetic testing among individuals at risk for Huntington disease (HD), a hereditary disease with limited life expectancy. Although genetic testing is perfectly predictive and carries little economic cost, presymptomatic testing is rare. Testing rates increase with increases in ex ante risk of having HD. Untested individuals express optimistic beliefs about their health and make decisions (e.g., retirement) as if they do not have HD, even though individuals with confirmed HD behave differently. We suggest that these facts can be reconciled by an optimal expectations model (Brunnermeier and Parker 2005). (JEL D84, I12)

Neurogenetics: Five new things.

Clinical neurology has benefitted greatly from recent remarkable advances in molecular genetics. In 1991, we could approximate a patient's risk for Huntington disease (HD) based only on linkage analysis. Now, 20 years later, not only can we identify the HD mutation with certainty, we can do the same with several hundred diseases. Whole genome or exome sequencing will soon allow for one-step interrogation of multiple genes for an even larger range of diseases. The recognition of these genes and their associated proteins in combination with new technology has led to creative new approaches to treatment. The challenge for the practicing neurologist is to provide clinically relevant and accurate interpretation of the genetic test results, with successfully treating once "incurable" neurogenetic diseases our ultimate goal.

Indexing disease progression at study entry with individuals at-risk for Huntington disease.

The identification of clinical and biological markers of disease in persons at risk for Huntington disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAP(S) . CAP(S) is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAP(S) had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAP(S) computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAP(S) distribution can be used to create a classification for mutation-positive individuals (Low-Med-High), which is, useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values. © 2011 Wiley-Liss, Inc.

Mutant Huntingtin Causes Metabolic Imbalance by Disruption of Hypothalamic Neurocircuits

In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.

Adoption and the communication of genetic risk: experiences in Huntington disease

Adoption agencies can use genetic information to determine the eligibility of prospective adoptive parents and to establish a child's suitability for adoption. We describe experiences and implications of communicating genetic risk for Huntington disease (HD) in the context of adoption. A secondary analysis was employed using data collected from a cross-sectional survey (n = 233) and two qualitative studies on the psychosocial effects of predictive testing for HD. We demonstrate several ethical and practical challenges in the search for and communication of genetic information for adoptees and their birth relatives. We also found that concern for adoption discrimination was reported by 13.7% of survey respondents (n = 32). Concerns were higher among tested respondents than those who had not been tested (n = 29 vs n = 3, p = 0.010). However, more respondents were concerned about being discriminated based on their family history (FHx) vs their genetic test results (GTR) (concern based on FHx: n = 18 vs based on GTR: n = 1 vs based on both: n =10). These findings contribute to the limited empirical literature by offering evidence on the experiences and implications of communicating genetic risk information in the context of adoption with reference to HD.

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.

In their own words: Reports of stigma and genetic discrimination by people at risk for Huntington disease in the International RESPOND‐HD study

Genetic discrimination may be experienced in the day-to-day lives of people at risk for Huntington disease (HD), encompassing occurrences in the workplace, when seeking insurance, within social relationships, and during other daily encounters. At-risk individuals who have tested either positive or negative for the genetic expansion that causes HD, as well as at-risk persons with a 50% chance for developing the disorder but have not had DNA testing completed the International RESPOND-HD (I-RESPOND-HD) survey. One of the study's purposes was to examine perceptions of genetic stigmatization and discrimination. A total of 412 out of 433 participants provided narrative comments, and 191 provided related codable narrative data. The core theme, Information Control, refers to organizational policies and interpersonal actions. This theme was found in narrative comments describing genetic discrimination perceptions across employment, insurance, social, and other situations. These reports were elaborated with five themes: What They Encountered, What They Felt, What Others Did, What They Did, and What Happened. Although many perceptions were coded as hurtful, this was not true in all instances. Findings document that reports of genetic discrimination are highly individual, and both policy as well as interpersonal factors contribute to the outcome of potentially discriminating events.

Before chorea

Since the initial description of mild cognitive impairment (MCI), we have learned about the high prevalence of MCI compared to that of the common dementias.1 In this issue of Neurology ®, Duff et al.2 reveal that nearly 40% of those who are genetically at risk for Huntington disease (HD) meet criteria for MCI, using accepted cutoff scores, with higher rates in individuals closer to HD diagnosis. This prevalence rate is comparable to what is found for MCI in other neurodegenerative disorders such as Parkinson disease (PD).3 In contradistinction to pre-AD MCI and paralleling frequent findings in other basal ganglia disorders, Duff et al.2 found that MCI in their pre-HD cohort was predominantly nonamnestic in type, with single-domain …

Predictive Genetic Tests in Neurodegenerative Disorders: A Methodological Approach Integrating Psychological Counseling for At-Risk Individuals and Referring Clinicians

The identification of the molecular basis of numerous hereditary neurological disorders allowed the feasibility of predictive genetic tests for at-risk family members. In agreement with international guidelines, we tested a protocol for a predictive test to optimize cooperation among specialists, well-being of participants, and organization of clinical activities. The psychiatrist/psychologist did not meet the at-risk subjects, but cooperated with the team, integrating psychological support for participants and clinicians. We enrolled 60 subjects at risk for Huntington disease, and 32 at risk for spinocerebellar ataxias. Seventy-two subjects (78%) continued the visit program; 55 (60%) received the genetic result, and 38 subjects (41%) completed the program. Participation and outcome were similar in both groups. Mean psychological scores were all below significant levels; however, the need for psychological support was recognized for 5 mutation carriers and a non-carrier. Our data provide a methodological example of a simple and safe procedure for a predictive test, and indicate that the clinical conference represents a good setting to handle psychosocial impact associated with disclosure of genetic results in hereditary late-onset disorders.

Genetic adverse selection: Evidence from long-term care insurance and Huntington disease

Individual, personalized genetic information is increasingly available, leading to the possibility of greater adverse selection over time, particularly in individual-payer insurance markets. We use data on individuals at risk for Huntington disease (HD), a degenerative neurological disorder with significant effects on morbidity, to estimate adverse selection in long-term care insurance. We find strong evidence of adverse selection: individuals who carry the HD genetic mutation are up to 5 times as likely as the general population to own long-term care insurance. This finding is supported both by comparing individuals at risk for HD to those in the general population and by comparing across tested individuals in the HD-risk population with and without the HD mutation.

Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study.

Genetic discrimination-defined as the denial of rights, privileges, or opportunities or other adverse treatment based solely on genetic information (including family history)-is an important concern to patients, healthcare professionals, lawmakers, and family members at risk for carrying a deleterious gene. Data from the United States, Canada, and Australia were collected from 433 individuals at risk for Huntington disease (HD) who have tested either positive or negative for the gene that causes HD and family members of affected individuals who have a 50% risk for developing the disorder but remain untested. Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation. We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States, Canada, and Australia combined. The incidence of self-reported discrimination is less than the overall worry about the risk of discrimination, which is more prevalent in each domain. Despite a relatively low rate of perceived genetic discrimination in the areas of health insurance and employment, compared to the perception of discrimination and stigma in personal relationships, the cumulative burden of genetic discrimination across all domains of experience represents a challenge to those at risk for HD. The effect of this cumulative burden on daily life decisions remains unknown.

Poster 24: Worry and Experience of Genetic Discrimination in Persons at Risk for Huntington Disease

Background Genetic discrimination (defined as the denial of rights, privileges, or opportunities, or other adverse treatment based solely on genetic information) is of concern to individuals at risk for developing Huntington disease (HD). Some prior surveys of genetic discrimination have included an examination of the prevalence of worry about genetic discrimination as contrasted to the prevalence of discriminatory experiences. The International RESPOND-HD (I-RESPOND-HD) survey compares and contrasts these two distinct psychological and experiential traits. Methods A total of 433 persons completed the I-RESPOND-HD survey examining the perceptions and experience of genetic discrimination. Participants had previously undergone predictive testing for the genetic mutation that causes HD (PREDICT-HD; n = 310), or had a 50% risk for developing HD due to family history but had chosen not to be tested (PHAROS; n = 123). Respondents lived in the United States (n = 293), Australia (n = 93), or Canada (n = 46). Using qualitative and quantitative assessments, the survey instrument provides a comprehensive set of questions designed to elicit descriptions of the perception of genetic discrimination and how such discrimination might negatively influence respondents (worry). Results Participants self-report a much higher rate of worry about genetic discrimination than actual discriminatory events. Overall, 51.2% of respondents report worrying about the possibility of discrimination within relationships, but only 32.9% actually experienced such discrimination within their personal relationships. Participants similarly reported a higher rate of worry than actual discrimination in the context of insurance (70.0% worried, 25.9% experienced), employment (44.0% worried, 6.5% experienced), and in other transactions (33.3% worried, 4.6% experienced). Conclusion Individuals at risk for HD worry about potential discrimination at a rate higher than that at which they experience such incidents. This exaggerated worry may motivate them to place subtle and/or overt limits on themselves, such as keeping their family history a secret, abstaining from genetic testing, or passing by opportunities to change employers.

“Am I my genes?”: Questions of identity among individuals confronting genetic disease

PurposeTo explore many questions raised by genetics concerning personal identities that have not been fully investigated. MethodsWe interviewed in depth, for 2 hours each, 64 individuals who had or were at risk for Huntington disease, breast cancer, or alpha-1 antitrypsin deficiency. ResultsThese individuals struggled with several difficult issues of identity. They drew on a range of genotypes and phenotypes (e.g., family history alone; mutations, but no symptoms; or symptoms). They often felt that their predicament did not fit preexisting categories well (e.g., “sick,” “healthy,” “disabled,” “predisposed”), due in part to uncertainties involved (e.g., unclear prognoses, since mutations may not produce symptoms). Hence, individuals varied in how much genetics affected their identity, in what ways, and how negatively. Factors emerged related to disease, family history, and other sources of identity. These identities may, in turn, shape disclosure, coping, and other health decisions. ConclusionsIndividuals struggle to construct a genetic identity. They view genetic information in highly subjective ways, varying widely in what aspects of genetic information they focus on and how. These data have important implications for education of providers (to assist patients with these issues), patients, and family members; and for research, to understand these issues more fully.

Genetic Counselors’ Perceived Responsibilities Regarding Reproductive Issues for Patients at Risk for Huntington Disease

Research indicates that health care professionals' attitudes may affect patients' decisions regarding prenatal Huntington Disease testing, but few studies have sampled genetic counselors. In this qualitative study, genetic counselors described their experiences counseling individuals at risk for HD regarding reproductive decision-making. Five major research questions were investigated: 1) What are genetic counselor responsibilities? 2) What issues arise for patients and counselors? 3) How do counselors reconcile prenatal testing with presymptomatic testing? 4) To what extent are counselors' initial expectations of at-risk patients' beliefs and behaviors met? and 5) What advice would counselors offer to novice practitioners about working with this patient population? Fifteen genetic counselors experienced in counseling individuals at risk for HD participated in a semi-structured phone interview that yielded several themes. For example, participants identified their primary responsibility as information provision; less prevalent were psychosocial support and facilitating decision making. The most common ethical challenge was testing prenatally for HD which also results in presymptomatic testing of minors. Participants were divided about how directive to be in response to this ethical issue and about termination of a gene positive pregnancy.

Progression in prediagnostic Huntington disease

ObjectiveTo examine rates of decline in individuals at risk for Huntington disease (HD).Methods106 individuals at risk for HD completed a battery of neurocognitive, psychomotor and oculomotor tasks at two visits,...