Direct mutation analysis for Huntington disease (HD) became possible in 1993 with the identification of an expanded CAG trinucleotide repeat as the mutation underlying the disease. Expansion of CAG length beyond 35 repeats may be associated with the clinical presentation of HD. HD has never been seen in a person with a CAG size of <36 repeats. Intermediate alleles are defined as being below the affected CAG range but have the potential to expand to >35 CAG repeats within one generation. Thus, children of intermediate allele carriers have a low risk of developing HD. Currently, the intermediate allele range for HD is between 27 and 35 CAG repeats. In this study, we review the current knowledge on intermediate alleles for HD including the CAG repeat range, the intermediate allele frequency, and the clinical implications of an intermediate allele predictive test result. The factors influencing CAG repeat expansion, including the CAG size of the intermediate allele, the sex and age of the transmitting parent, the family history, and the HD gene sequence and haplotype, will also be reviewed.

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.

Objectives: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using 1 H 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 Ͼ220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's 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 (ϳ15%) vs controls (p Ͻ 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (ϳ8%) and early HD (ϳ17%) vs controls (p Ͻ 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p Ͻ 0.01). In early HD, mI correlated with UHDRS motor score (R 2 ϭ 0.23, p Ͻ 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R 2 ϭ 0.30, p Ͻ 0.0001) and with disease burden score (R 2 ϭ 0.17, p Ͻ 0.005). Conclusions:We demonstrate lower putaminal tNAA in early HD compared to controls in a crosssection 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. Neurology ® 2010;75:1702-1710 GLOSSARY AD ϭ Alzheimer disease; Cr ϭ creatine; DBS ϭ disease burden score; Glu ϭ glutamate; GPC ϭ glycerophosphocholine; HD ϭ Huntington disease; mI ϭ myo-inositol; MR ϭ magnetic resonance; MRS ϭ 1 H magnetic resonance spectroscopy; NAA ϭ N-acetylaspartate; NAAG ϭ N-acetylaspartylglutamate; PC ϭ phosphocholine; PCr ϭ phosphocreatine; pre-HD ϭ premanifest Huntington disease; SNR ϭ signal-to-noise ratio; tCho ϭ total choline; tCr ϭ total creatine; TE ϭ echo time; tNAA ϭ total N-acetylaspartate; TR ϭ repetition time; UBC ϭ University of British Columbia; UHDRS ϭ Unified Huntington's Disease Rating Scale; VBM ϭ voxel-based morphometry.The eventual development of Huntington disease (HD) symptoms can be predicted through detection of CAG trinucleotide repeat expansion in the HTT gene 1 in premanifest gene carriers. However, definitive HD biomarkers, able to objectively identify disease onset and progression, are lacking. Evaluation of potential biomarkers are the focus of longitudinal studies such as TRACK-HD 2 and PREDICT-HD. H magnetic resonance spectroscopy (MRS) has previously been evaluated as a biomarker modality in premanifest and early HD. [4][5][6][7][8][9][10][11] However, the literature is conflicted with regard to the utility of metabolites such as total N-ac...

Autism Spectrum Disorders (ASDs) are complex neurodevelopmental disorders with many biological causes, including genetic, syndromic and environmental. Such etiologic heterogeneity impacts considerably upon parents' needs for understanding their child's diagnosis. A descriptive survey was designed to investigate parental views on the cause(s) of ASD in their child. Among the 41 parents who replied to the questionnaire, genetic influences (90.2%), perinatal factors (68.3%), diet (51.2%), prenatal factors (43.9%) and vaccines (40.0%) were considered to be the most significant contributory factors. Parents reported inaccurately high recurrence risks, misperceptions of the contribution of various putative factors, feelings of guilt and blame regarding their child's diagnosis, as well as a lack of advocacy for genetic counseling by non-geneticist professionals. This study offers clinicians and researchers further insight into what parents believe contributed to their child's diagnosis of ASD and will help facilitate genetic counseling for these families.

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.

Putaminal metabolites examined using cross-sectional magnetic resonance spectroscopy (MRS) can distinguish pre-manifest and early Huntington's 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.

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.

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.