Huntington’s disease (HD) is a monogenic disorder that is caused by a CAG repeat expansion in the HTT gene. However, beyond the CAG repeat size other genes also contribute to variations in neurodegeneration of the cortex and striatum as well as the timing of disease onset1,2. The standard method to find genetic modifiers of HD has been the use of genome-wide association studies (GWAS) of large numbers of unrelated patients1,3-5. Previous efforts in this vein have identified single nucleotide variants (SNVs) significantly associated with pathways involved in DNA damage and handling that modify HD age of onset (AO)1,3-8. However, many of these associations have small effect sizes, and typically it is not known whether the SNVs identified with GWAS are the basis for the modifying effect. Here, to augment modifier GWAS, we set out to identify variants that may modify AO in HD by performing family-based studies. We performed whole genome sequencing in families with HD in which individuals with similar CAG expansions showed variation in AO (ranging from a 3- to 20-year difference). We examined the segregation of every variant in the genome and associated the occurrence of those variants with AO. Focusing on rare and uncommon variants, we used a priori knowledge to examine the proximity of our top variants to previously reported GWAS loci. Further, we developed an HD impact scoring system to rank each variant and highlight those most likely to be impactful in the context of influencing the pathology associated with the CAG repeat expansion mutation. Pathway enrichment analysis of these genes revealed numerous pathways previously implicated in HD, as well as novel pathways that may be important in disease onset. Finally, we showed that a putative AO modifier in the ovarian-tumor-domain-containing deubiquitinase 3 (OTUD3) gene correlated with an altered rate of degeneration in patient-derived neurons, and that knockdown of OTUD3 accelerated degeneration in a human cell model of HD, validating our approach. This family-based strategy creates a novel resource for the HD community and establishes a framework that could be applied to study genetic modifiers of many other rare familial diseases.
Purpose.: Abnormalities in saccades appear to be sensitive and specific biomarkers in the prediagnostic stages of Huntington disease (HD). The goal of this study was to evaluate test–retest reliability of saccadic measures in prediagnostic carriers of the HD gene expansion (PDHD) and normal controls (NC). Methods.: The study sample included 9 PDHD and 12 NC who completed two study visits within an approximate 1-month interval. At the first visit, all participants completed a uniform clinical evaluation. A high-resolution, video-based system was used to record eye movements during completion of a battery of visually guided, antisaccade, and memory-guided tasks. Latency, velocity, gain, and percentage of errors were quantified. Test–retest reliability was estimated by calculating the intraclass correlation (ICC) of the saccade measures collected at the first and second visits. In addition, an equality test based on Fisher's z-transformation was used to evaluate the effects of group (PDHD and NC) and the subject's sex on ICC. Results.: The percentage of errors showed moderate to high reliability in the antisaccade and memory-guided tasks (ICC = 0.64–0.93). The latency of the saccades also demonstrated moderate to high reliability (ICC = 0.55–0.87) across all tasks. The velocity and gain of the saccades showed moderate reliability. The ICC was similar in the PDHD and NC groups. There was no significant effect of sex on the ICC. Conclusions.: Good reliability of saccadic latency and percentage of errors in both antisaccade and memory-guided tasks suggests that these measures could serve as biomarkers to evaluate progression in HD.
The objective of this study was to evaluate visual scanning strategies in carriers of the Huntington disease (HD) gene expansion and to test whether there is an association between measures of visual scanning and cognitive performance. The study sample included control (NC, n = 23), prediagnostic (PDHD, n = 21), and subjects recently diagnosed with HD (HD, n = 19). All participants completed a uniform clinical evaluation that included examination by neurologist and molecular testing. Eye movements were recorded during completion of the Digit Symbol Subscale (DS) test. Quantitative measures of the subject's visual scanning were evaluated using joint analysis of eye movements and performance on the DS test. All participants employed a simple visual scanning strategy when completing the DS test. There was a significant group effect and a linear trend of decreasing frequency and regularity of visual scanning from NC to PDHD to HD. The performance of all groups improved slightly and in a parallel fashion across the duration of the DS test. There was a strong correlation between visual scanning measures and the DS cognitive scores. While all individuals employed a similar visual scanning strategy, the visual scanning measures grew progressively worse from NC to PDHD to HD. The deficits in visual scanning accounted, at least in part, for the decrease in the DS score.
The LRRK2 G2019S mutation is found at higher frequency among Parkinson disease (PD) patients of Ashkenazi Jewish (AJ) ancestry. This study was designed to test whether an internet-based approach could be an effective approach to screen and identify mutation carriers. Individuals with and without PD of AJ ancestry were recruited and consented through an internet-based study website. An algorithm was applied to a series of screening questions to identify individuals at increased risk to carry the LRRK2 G2019S mutation. About 1000 individuals completed the initial screening. Around 741 qualified for mutation testing and 650 were tested. Seventy-two individuals carried at least one LRRK2 G2019S mutation; 38 with PD (12.5%) and 34 without (10.1%). Among the AJ PD participants, each affected first-degree relative increased the likelihood the individual was LRRK2+ [OR = 4.7; 95% confidence interval = (2.4–9.0)]. The same was not observed among the unaffected AJ subjects (P = 0.11). An internet-based approach successfully screened large numbers of individuals to identify those with risk factors increasing the likelihood that they carried a LRRK2 G2019S mutation. A similar approach could be implemented in other disorders to identify individuals for clinical trials, biomarker analyses and other types of research studies.
Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington's disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance.Three groups of participants were recruited: (1) Imminent and early manifest HD (early HD, n = 8); (2) premanifest (presymptomatic) CAG+ (preHD, n = 10); and (3) CAG unexpanded (CAG-) controls (n = 12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional MRI during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis.Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG- group decreased progressively in a well-documented reward detection network that includes the presupplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG- group.These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD. (PsycINFO Database Record (c) 2011 APA, all rights reserved).
To examine rates of decline in individuals at risk for Huntington disease (HD).
Methods
106 individuals at risk for HD completed a battery of neurocognitive, psychomotor and oculomotor tasks at two visits, approximately 2.5 years apart. Participants were classified as: (1) without the CAG expansion (normal controls, NC; n=68) or (2) with the CAG expansion (CAG+; n=38). The CAG+ group was further subdivided into those near to (near; n=19) or far from (far; n=19) their estimated age of onset. Longitudinal performance in the CAG+ group was evaluated with a repeated measures model with two main effects (time to onset, visit) and their interaction. Analysis of covariance was employed to detect differences in longitudinal performance in the three groups (NC, near and far).
Results
In the CAG+, the interaction term was significant (p≤0.02) for four measures (movement time, alternate button tapping, variability of latency for a memory guided task and percentage of errors for a more complex memory guided task), suggesting the rate of decline was more rapid as subjects approached onset. Longitudinal progression in the three groups differed for several variables (p<0.05). In most, the near group had significantly faster progression than NC; however, comparisons of the NC and far groups were less consistent.
Conclusions
Different patterns of progression were observed during the prediagnostic period. For some measures, CAG+ subjects closer to estimated onset showed a more rapid decline while for other measures the CAG+ group had a constant rate of decline throughout the prediagnostic period that was more rapid than in NC.
Longitudinal studies of neurocognitive function in prediagnosis Huntington disease (pre-HD) have been few, and duration of follow-up has been brief. In this study, 155 individuals at-risk for HD completed a battery of cognitive and motor tasks at two study visits approximately 10 years apart. Participants were classified as: (1) at-risk, without the CAG expansion (healthy controls, NC; n = 112), or (2) CAG expanded (CAG+; n = 43). To examine the rate of decline at different stages of the pre-HD period, participants in the CAG+ group were further characterized as converters (i.e., individuals who developed manifest HD over the course of the study; n = 21) or nonconverters (n = 22), and their performances were compared. The CAG+ group exhibited faster rates of neurocognitive decline over the course of the study, relative to the NC group. In addition, more rapid decline was associated with closer proximity to estimated age of disease onset in the CAG+ group. Faster rates of motor and psychomotor decline were observed in the CAG+ converter group, relative to the nonconverters. These findings suggest that neurocognitive decline in pre-HD, particularly in motor and psychomotor domains, begins insidiously and accelerates as individuals approach disease onset.
