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Intermediate CAG Repeats in Huntington's Disease: Analysis of COHORT

Intermediate CAG Repeats in Huntington's Disease: Analysis of COHORT Background: There is emerging evidence that clinical and neuro-pathological manifestations of Huntington’s disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27–35 CAG repeats) in the Huntingtin (HTT) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. Methods: Data from the Cooperative Huntington’s Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (#26), intermediate (27–35) and HD (>36) groups. The motor, cognitive and behavioral scores on the Unified Huntington’s Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. Results: Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. Discussion: Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediate CAG repeats. These results have important implications for the pathogenesis of the disease and genetic counseling. Keywords: Huntington disease, trinucleotide repeats, chorea, intermediate repeats, genetic counseling, huntingtin gene Citation: Ha AD, Beck CA, Jankovic J. Intermediate CAG Repeats in Huntington’s Disease: Analysis of COHORT. Tremor Other Hyperkinet Mov 2012;2: http://tremorjournal.org/article/view/64 * To whom correspondence should be addressed. E-mail: josephj@bcm.edu Editor: Elan D. Louis, Columbia UniversityUnited States of America Received: September 12, 2011 Accepted: October 20, 2011 Published: February 2, 2012 Copyright: ’ 2012 Ha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author(s) and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed. Funding: None. Competing Interests: The authors report no conflict of interest. further define the clinical characteristics of patients who possess CAG Introduction repeat lengths in the intermediate range as this has implications for Huntington’s disease (HD) is a progressive neurodegenerative understanding of the pathogenesis of the disease and for genetic disease with a variable worldwide occurrence but the prevalence in counseling. We hypothesize that a subset of individuals with the United States is estimated at 7–10 in 100,000. Inherited in an intermediate alleles demonstrates subtle clinical manifestations that autosomal dominant manner, HD is caused by an expanded cytosine- resemble a mild HD phenotype. The expression of these features may adenine-guanine (CAG) repeat length in the Huntingtin (HTT) gene on be related to other, currently unidentified, genetic and non-genetic chromosome 4p16.3, resulting in accumulation of mutant huntingtin modifying factors. protein in the brain. While genetically defined HD requires > 36 CAG Methods repeats, some individuals with a mutable normal allele, or intermediate CAG range (between 27 and 35 repeats), have been reported to exhibit Demographic, clinical and genetic data were analyzed, collected 2–6 features of HD. Although most subjects with CAG repeats in this from 45 centers in the United States, Canada and Australia that range are normal, intermediate repeats have the potential to expand participated in the Cooperative Huntington’s Observational Research into the disease range within one generation. In this study, we aim to Trial (COHORT), a prospective observational study examining Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG phenotypic characteristics and genetic factors in individuals from HD ‘normal’. Participant characteristics were compared across the three families. The COHORT study involved a baseline visit comprising an primary groups using descriptive statistics. Initial analysis compared assessment with the Mini-Mental State Examination (MMSE), a differences in demographic and clinical metrics for the intermediate neurological and physical examination, including body mass index versus normal and HD groups. Means were compared using analysis (BMI), and the Unified Huntington’s Disease Rating Scale 99 of covariance models adjusted for age and gender, while proportions (UHDRS 99), conducted by trained study personnel. The UHDRS were compared using Fisher’s exact tests. 99 evaluated four domains, consisting of motor function, cognition, Further analysis compared individual items from the motor and behavior, and functional capacity. The motor assessment comprised behavioral sections of the UHDRS. These items are scored on a 0–4 31 items, which included standardized ratings of chorea, dystonia, point ordinal scale, with 0 representing no impairment and 1–4 oculomotor function, as well as a measure of diagnostic confidence, representing increasing levels of impairment. For each item, the defined as the degree to which the examiner was confident that the distribution of scores was compared using a Wilcoxon rank sum test. subject met the definition of the unequivocal presence of an Comparisons were made between the intermediate and normal extrapyramidal movement disorder in a subject at risk for HD. groups. All hypothesis testing was conducted at the two-sided Follow-up visits were conducted yearly, and included the UHDRS 99, significance level of 5%. No corrections were made for multiple MMSE, a brief medical examination including height, weight and vital testing in this exploratory analysis. signs, and any additional information with regard to medical or mental Results health events. At each visit, subjects were also given the option of participating in a family history questionnaire, and providing speci- As of December 31, 2009, 2318 participants had enrolled in the mens for storage in a repository. In order to maintain consistency, the COHORT study. Information on CAG repeat length was not same individual for a particular subject performed the UHDRS from available for 333 individuals and they were therefore excluded from year to year. Approval for COHORT was obtained from the the analysis. Of the remaining 1985 subjects, 645 subjects were in the institutional review boards for human research. normal range and 50 were in the intermediate range. Baseline Inclusion criteria for enrollment in the COHORT study included a characteristics were assessed in the 1985 research participants number of categories of subjects. Individuals were eligible to (Table 1). There were significantly more females in the intermediate participate if they had been clinically affected by HD or were positive group than either the normal or the HD group. The level of education for the HD gene. Other subjects included in the COHORT were did not differ between intermediate and HD subjects, but the those who had not undergone genetic testing but were first degree proportion employed and married were both significantly lower in relatives of an individual with manifest or pre-manifest HD, older HD subjects. Baseline body mass index (BMI) was not significantly adolescents who had a parent with manifest HD or pre-manifest HD different between the normal and intermediate group. Of note, a enrolled in COHORT, or individuals who had not undergone DNA significantly greater proportion of subjects in the intermediate group testing but were grandparents or grandchildren of an individual reported at least one suicide attempt compared to the normal group. enrolled in COHORT who has manifest HD or pre-manifest HD. In the motor component of the UHDRS, the intermediate group Control subjects included spouses or caregivers of an individual had a significantly higher Total Maximal Dystonia Score (mean 0.01 enrolled in COHORT with manifest HD or pre-manifest HD. vs 0.10, p50.001) compared with the control group. In addition, Individuals with a family history of HD who had undergone DNA compared with the normal group, there was a significantly lower testing and did not carry the genetic mutation responsible for HD were proportion of subjects in the intermediate group with normal scores in also included. the following categories: Vertical Saccade Velocity (89.8% vs 96.0%, All CAG genotyping was performed on coded DNA samples at the p50.05), Maximal Dystonia RUE (95.9% vs 99.5%, p50.004), and DNA Laboratory in the Molecular Neurogenetics Unit, Massachusetts Maximal Chorea LLE (95.9% vs 99.2%, p50.03). The items that were General Hospital. The CAG repeat lengths were determined based on significantly different are presented in Figure 1. Scores on the Stroop whole blood and lymphocyte analysis, and if both methods did not Word Reading were lower in the intermediate group compared with yield the same result for a particular individual, testing was repeated the normal group (mean 90.0 vs 95.7, p50.02). In the behavioral until the discrepancy was resolved and a common value was obtained. domain, a lower proportion of subjects in the intermediate group The investigators and subjects did not have access to the results of received normal scores in Depressed Mood – Severity (48.0% vs genotyping. The subjects were assessed yearly, for as many follow-up 61.8%, p50.02) and Suicidal Thoughts – Severity (96.0% vs 99.4%, visits as possible. Raters were blinded to the results of DNA genotyping p50.01). There was a trend toward fewer intermediate subjects of the HTT gene. We report here baseline data collected through scoring normally on Suicidal Thoughts – Frequency (96.0% vs 99.1%, December 31, 2009. p50.05). Study participants were assigned into three primary groups. Subjects The UHDRS diagnostic confidence levels for each group are shown with an expanded CAG repeat length of 36 or more were classified in Figure 2. No differences in diagnostic confidence were detected positive for HD, those with a CAG repeat of 27–35 were classified as between the normal group and the intermediate (p50.86) group, ‘intermediate’, and those with less than 27 repeats were considered although there was a slightly higher proportion of subjects with Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J Table 1. Demographic and UHDRS Data 1 1 Normal (N) Intermediate (I) p-value Huntington’s p-value Disease (HD) (n5645) (n550) (N vs. I) (n51290) (HD vs. I) Age [years] 50.31 (13.29) 49.08 (13.13) 0.5828 48.80 (13.11) 0.8021 Female [%] 373 (57.8) 37 (74.0) 0.0256 708 (54.9) 0.0085 White [%] 602 (93.2) 48 (96.0) 0.7652 1206 (93.5) 0.7667 Employment status [% currently in labor 444 (68.8) 36 (72.0) 0.7513 429 (31.6) ,0.0001 force] Marital status [% currently married] 505 (78.3) 40 (80.0) 0.8600 777 (60.2) 0.0047 History of at least one suicide attempt [%] – Overall 9 (1.4) 3 (6.0) 0.0486 82 (6.4) 1.0000 – Females 7 (1.9) 3 (8.1) 0.0522 48 (6.8) 0.7346 – Males 2 (0.7) 0 (0) 1.0000 34 (5.8) 1.0000 Body mass index [kg/m ] – Overall 28.63 (6.47) 28.67 (7.00) 0.8787 25.69 (5.42) 0.0003 – Females 28.28 (6.76) 28.91 (7.76) 0.5416 25.55 (6.07) 0.0008 – Males 29.09 (6.03) 28.01 (4.45) 0.5391 25.87 (4.50) 0.1823 Motor assessment Total UHDRS motor assessment [0–124] 1.72 (2.91) 2.16 (3.14) 0.2581 30.11 (21.96) ,0.0001 Total maximal chorea score [0–28] 0.08 (0.41) 0.16 (0.59) 0.2245 7.72 (5.99) ,0.0001 Total maximal dystonia score [0–20] – Overall 0.01 (0.14) 0.10 (0.42) 0.0014 2.64 (3.60) ,0.0001 – Females 0.02 (0.18) 0.14 (0.49) 0.0001 2.56 (3.64) ,0.0001 – Males 0.004 (0.06) 0 (0) 0.9178 2.74 (3.56) 0.0103 Behavioral assessment UHDRS Behavioral frequency [0–44] 4.39 (4.33) 5.06 (4.48) 6.94 (6.25) UHDRS Behavioral frequency x severity 6.27 (9.12) 8.28 (10.87) 0.1945 13.51 (15.87) 0.0186 [0–176] Cognitive assessment Mini Mental State Examination [0–30] 29.12 (1.51) 28.96 (1.56) 0.3783 26.01 (4.30) ,0.0001 UHDRS Verbal fluency 40.25 (11.84) 38.44 (11.51) 0.1612 26.43 (14.88) ,0.0001 UHDRS Symbol digit modalities test 47.35 (10.91) 45.65 (9.79) 0.0734 30.11 (15.28) ,0.0001 UHDRS Stroop color naming 74.60 (15.32) 72.27 (12.58) 0.1264 52.05 (20.86) ,0.0001 Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG Table 1. Continued 1 1 Normal (N) Intermediate (I) p-value Huntington’s p-value Disease (HD) (n5645) (n550) (N vs. I) (n51290) (HD vs. I) UHDRS Stroop word reading – Overall 95.70 (18.36) 89.96 (16.67) 0.0187 67.39 (26.10) ,0.0001 – Females 96.90 (18.87) 88.19 (17.42) 0.0068 69.67 (26.00) ,0.0001 – Males 94.05 (17.53) 95.25 (13.46) 0.9647 64.66 (25.97) 0.0001 UHDRS Stroop interference 43.40 (13.35) 41.79 (11.59) 0.2201 30.43 (14.74) ,0.0001 UHDRS Independence assessment 99.83 (1.38) 99.49 (1.84) 0.0942 84.31 (16.47) ,0.0001 UHDRS Functional assessment 24.89 (1.05) 24.94 (0.32) 0.7427 20.31 (5.80) ,0.0001 UHDRS Total functional capacity 12.85 (0.76) 12.84 (0.59) 0.9021 9.31 (3.55) ,0.0001 2 3 Eye Movement Score [median (range)] p-value p-value (N vs I) (N vs I) Ocular Pursuit – Horizontal 0 (0–3) 0 (0–1) 0.9820 1 (0–4) ,0.0001 Ocular Pursuit – Vertical 0 (0–3) 0 (0–1) 0.9327 1 (0–4) ,0.0001 Saccade Initiation – Horizontal 0 (0–2) 0 (0–2) 0.1143 1 (0–4) ,0.0001 Saccade Initiation – Vertical 0 (0–2) 0 (0–1) 0.1788 1 (0–4) ,0.0001 Saccade Velocity – Horizontal 0 (0–1) 0 (0–1) 0.1096 1 (0–4) ,0.0001 Saccade Velocity – Vertical 0 (0–4) 0 (0–1) 0.0454 1 (0–4) ,0.0001 Abbreviations: N, Normal; I, Intermediate; HD, Huntington disease; n, sample size; UHDRS, Unified Huntington’s Disease Rating Scale. UHDRS scores are listed as mean (standard deviation) unless otherwise noted. Two-sided p-values for comparing means based on Analysis of covariance (ANCOVA) model adjusted for age and gender; proportions compared using two-sided Fisher’s exact test. Based on two-sided Wilcoxon test for comparing median score for Normals vs. Intermediates. Based on two-sided Wilcoxon test for comparing median score for Intermediates vs. HD. confidence category of 2 and 4 in the intermediate group compared to to the possibility of subtle motor, cognitive and behavioral abnorm- normal controls. alities in some subjects with intermediate CAG repeats, but the differences that were identified in the motor scores would not likely be Discussion clinically meaningful. Of potentially greater clinical significance was HD presents with motor dysfunction as well as disturbances in that of the behavioral findings, including the history of suicide cognitive and behavioral domains. Historically, this disease has been attempts, which was comparable between the intermediate, and HD associated with stigma affecting not only patients with HD, but also groups. Whether this finding reflects an inherent abnormality in those who are at risk for developing HD. In recent years, several subjects with intermediate CAG repeats, or a tendency that is cases have been reported in the literature, suggestive of clinical potentiated by the familial context, is unclear. Regardless, this finding manifestations of HD in individuals with intermediate CAG repeats, in 11,12 raises an area of interest for further studies, with possible relevance for whom likely phenocopy syndromes have been excluded. This clinical management and intervention. The abnormal findings raise observation, if confirmed, would have important implications for the possibility of whether an intermediate length allele is indeed genetic counseling. sufficient to cause pathology, in a particular genetic and environmental In our analysis of the COHORT data, we found statistically milieu. Thus, although relatively subtle, these abnormalities appear to significant differences in some UHDRS scores between the normal and be important and relevant, particularly when they occur in the setting intermediate group. These abnormalities tended to occur in some, but not all, subjects with intermediate repeats. The findings draw attention of a family history of HD. Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J In this study population, the frequency of intermediate alleles was 2.5%, which is in the frequency range (up to 6%) reported in control populations. Our figures do not include individuals whose larger allele may have been in the HD range, as these were excluded from the analysis. Hendricks et al. have estimated that the probability that a male who is a ‘high normal’ carrier will have a risk of an offspring with an expanded, penetrant, allele ranges from 1/6241 to 1/951. These low estimates, however, have been derived from prevalence studies of high normal alleles in the general population using a sample of primarily Parkinson’s disease cases. Our results should be interpreted with caution, particularly when comparing to the general population. Data from this study were collected from subjects with signs or symptoms suggestive of HD, or from family members, and should not be applied to an otherwise healthy individual with similarly sized alleles. An intermediate allele in a family with sporadic HD appears to be less stable than those present in the general population. We acknowledge that there are a number of limitations to this study. The differences that we identified between the normal and intermediate groups may have occurred by chance as a result of inter-rater variability, particularly if the distinction between normal and mild impairment was based on the presence of subtle signs. Although the UHDRS has a high rate of internal consistency within each of the domains, and is considered the ‘gold standard’ in HD 16,17 clinical trials, the scale was originally designed for manifest individuals, and therefore may not be as sensitive in early or mild disease. The application of the UHDRS in the assessment of the normal population is not well defined. Indeed, although we found that a lower proportion of intermediate subjects scored normally on vertical saccade velocity, we also note that the normal group included outliers with very high scores, up to 4, which were not present in the intermediate group (Table 1). Given that the analysis was conducted in an exploratory nature, adjustments for multiple comparisons were not applied. We do acknowledge however that the presence of numerous data sets may raise the possibility of a Type I error. A Bonferroni correction on all 84 hypothesis tests, consisting of 31 motor items, 25 behavioral items, and 28 demographic items, would establish a p-value of less than 0.0006 for statistical significance. The significant findings in our study, however, were all suggestive of abnormality in the intermediate group rather than the normal group, and as such, the possibility of all of these findings occurring by chance due to inter-rater variability in a blinded setting would seem less likely. We note that several relevant items such as mean diagnostic confidence did not demonstrate significant differences, and we postulate that this is related to the averaging effect in assessing mean scores, in a population where only a minority of subjects appear to be affected. Low BMI, which is described in prodromal individuals, was also not found in our intermediate population. Whether the spectrum of the intermediate phenotype has a tendency to overlap with gene- Figure 1. Difference in Various UHDRS Items between Subjects with Normal expanded individuals in only certain areas is unclear. Weight loss in HD (,27) and Intermediate (27–35) CAG Repeats (0 5 Normal; 1–4 Represents has been shown to correlate directly with the CAG repeat length. The Increasing Levels of Impairment). *p,0.05, **p,0.01, RUE 5 right upper extremity, LLE 5 left lower extremity eye movement abnormality identified in the intermediate group Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG Figure 2. Diagnostic Confidence at Baseline between the Normal, Intermediate, ‘High-Intermediate’ and HD Groups consisted only of vertical saccade velocity, and no differences were seen the normal, intermediate, and HD groups. In addition, our in ocular pursuit or saccadic initiation. Disturbances in eye motor comparison of means using analysis of covariance models was adjusted control appear to be associated with the degree of clinical severity, for age. and this would be in keeping with the mild phenotype of the The possibility of HD phenocopies must also be considered in an intermediate group. Although further analysis stratified to gender individual with signs or symptoms suggestive of HD. Although suggested that the total maximum dystonia score and UHDRS Stroop screening for HD phenocopies would have been valuable, in a study Word Reading were due to the female intermediate subjects (Table 1), population consisting of HD individuals and their family members, it is the small numbers limit meaningful conclusions, and larger studies are unclear to what extent the possibility of HD phenocopies would have required. accounted for the results. The possibility of laboratory error should Another limitation of our analysis is the lack of robust follow-up also be considered, particularly when interpreting alleles bordering on data. Without the benefit of longitudinal assessment, disease onset may different penetrance classes. In this study, all CAG genotyping was potentially be missed, thus under-estimating the prevalence of performed in a single laboratory with considerable experience, on both abnormal phenotypes. The relatively small number of subjects with whole blood and lymphocytes. Despite these limitations, we believe intermediate CAG repeats who attended follow-up visits does not that the abnormal findings in the intermediate group are potential allow for meaningful interpretation of this component of data at this areas of interest that warrant further evaluation. Additional studies time. Variations in age may have influenced the onset of disease. In with larger sample sizes, follow-up assessments, and family data would this study, however, we found no significant differences in age between be valuable in further defining this population of subjects. In Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J conclusion, our exploratory analysis of the COHORT database 9. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord 1996;11:136–142, http://dx.doi.org/10. revealed statistically significant differences in many UHDRS scores 1002/mds.870110204. between normal and intermediate length CAG. Although not proven, 10. Rawlins M. Huntington’s disease out of the closet? Lancet 2010; these findings support the concept that clinically manifest disease may 376(9750):1372–1373, http://dx.doi.org/10.1016/S0140-6736(10)60974-9. occur in individuals with intermediate CAG repeats. 11. Ha AD, Jankovic J. Exploring the correlates of intermediate CAG Acknowledgements repeats in Huntington disease. Postgrad Med 2011;123:116–121, http://dx.doi. org/10.3810/pgm.2011.09.2466. We are grateful to the Huntington Study Group for providing the 12. Squitieri F, Esmaeilzadeh M, Ciarmiello A, et al. Caudate glucose COHORT database. hypometabolism in a subject carrying an unstable allele of intermediate We would like to thank Dr Ray Dorsey, Johns Hopkins University, CAG(33) repeat length in the Huntington’s disease gene. Mov Disord 2011;26: Baltimore, for his helpful comments and Dr Ira Shoulson, Georgetown 925–927, http://dx.doi.org/10.1002/mds.23623. University, Washington, DC, for his support. We also thank Anthony 13. Sequeiros J, Ramos EM, Cerqueira J, et al. Large normal and reduced Davidson, Baylor College of Medicine, Houston, for his assistance with penetrance alleles in Huntington disease: instability in families and frequency at data analysis. the laboratory, at the clinic and in the population. Clin Genet 2010;78:381–387, References http://dx.doi.org/10.1111/j.1399-0004.2010.01388.x. 14. Hendricks AE, Latourelle JC, Lunetta KL, et al. Estimating the 1. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis probability of de novo HD cases from transmissions of expanded penetrant to clinical treatment. Lancet Neurol 2011;10:83–98, http://dx.doi.org/10.1016/ CAG alleles in the Huntington disease gene from male carriers of high normal S1474-4422(10)70245-3. alleles (27–35 CAG). Am J Med Genet A 2009;149A:1375–1381, http://dx.doi. 2. Herishanu YO, Parvari R, Pollack Y, et al. Huntington disease in subjects org/10.1002/ajmg.a.32901. from an Israeli Karaite community carrying alleles of intermediate and 15. Goldberg YP, McMurray CT, Zeisler J, et al. Increased instability of expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? intermediate alleles in families with sporadic Huntington disease compared J Neurol Sci 2009;277:143–146, http://dx.doi.org/10.1016/j.jns.2008.11.005. to similar sized intermediate alleles in the general population. Hum Mol Genet 3. Groen JL, de Bie RM, Foncke EM, et al. Late-onset Huntington disease 1995;4:1911–1918, http://dx.doi.org/10.1093/hmg/4.10.1911. with intermediate CAG repeats: true or false? J Neurol Neurosurg Psychiatry 2010; 16. Curtis A, Mitchell I, Patel S, et al. A pilot study using nabilone for 81:228–230, http://dx.doi.org/10.1136/jnnp.2008.170902. symptomatic treatment in Huntington’s disease. Mov Disord 2009;24:2254–2259, 4. Andrich J, Arning L, Wieczorek S, et al. Huntington’s disease as caused by http://dx.doi.org/10.1002/mds.22809. 34 CAG repeats. Mov Disord 2008;23:879–881, http://dx.doi.org/10.1002/ 17. Kieburtz K, McDermott MP, Voss TS, et al. A randomized, placebo- mds.21958. controlled trial of latrepirdine in Huntington disease. Arch Neurol 2010;67:154– 5. Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington’s disease 160, http://dx.doi.org/10.1001/archneurol.2009.334. with 29 trinucleotide repeats. Mov Disord 2007;22:127–130, http://dx.doi.org/ 18. Vaccarino AL, Anderson K, Borowsky B, et al. An item response analysis 10.1002/mds.21195. of the motor and behavioral subscales of the unified Huntington’s disease rating 6. Biglan K, Jankovic J, Eberly S, et al. Longitudinal analysis of intermediate scale in huntington disease gene expansion carriers. Mov Disord 2011;26:877– CAGn repeat length expansion in the Prospective Huntington Disease At-Risk 884, http://dx.doi.org/10.1002/mds.23574. Observational Study (PHAROS). Mov Disord 2010(Suppl 2):S270. 19. Aziz NA, van der Burg JM, Landwehrmeyer GB, et al. Weight loss in 7. Semaka A, Creighton S, Warby S, et al. Predictive testing for Huntington Huntington disease increases with higher CAG repeat number. Neurology 2008; disease: interpretation and significance of intermediate alleles. Clin Genet 2006; 71:1506–1513, http://dx.doi.org/10.1212/01.wnl.0000334276.09729.0e. 70:283–294, http://dx.doi.org/10.1111/j.1399-0004.2006.00668.x. 20. Patel S, Jankovic J, Hood A, et al. Reflexive and volitional saccades: 8. Cooperative Huntington’s Observational Research Trial. www. Biomarkers of Huntington disease severity and progression. J Neurol Sci 2012 clinicaltrials.gov (accessed September 18, 2010). Feb 15;313(1-2):35-41. Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Tremor and Other Hyperkinetic Movements Pubmed Central

Intermediate CAG Repeats in Huntington's Disease: Analysis of COHORT

Tremor and Other Hyperkinetic Movements , Volume 2 – Feb 2, 2012

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Abstract

Background: There is emerging evidence that clinical and neuro-pathological manifestations of Huntington’s disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27–35 CAG repeats) in the Huntingtin (HTT) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. Methods: Data from the Cooperative Huntington’s Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (#26), intermediate (27–35) and HD (>36) groups. The motor, cognitive and behavioral scores on the Unified Huntington’s Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. Results: Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. Discussion: Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediate CAG repeats. These results have important implications for the pathogenesis of the disease and genetic counseling. Keywords: Huntington disease, trinucleotide repeats, chorea, intermediate repeats, genetic counseling, huntingtin gene Citation: Ha AD, Beck CA, Jankovic J. Intermediate CAG Repeats in Huntington’s Disease: Analysis of COHORT. Tremor Other Hyperkinet Mov 2012;2: http://tremorjournal.org/article/view/64 * To whom correspondence should be addressed. E-mail: josephj@bcm.edu Editor: Elan D. Louis, Columbia UniversityUnited States of America Received: September 12, 2011 Accepted: October 20, 2011 Published: February 2, 2012 Copyright: ’ 2012 Ha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author(s) and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed. Funding: None. Competing Interests: The authors report no conflict of interest. further define the clinical characteristics of patients who possess CAG Introduction repeat lengths in the intermediate range as this has implications for Huntington’s disease (HD) is a progressive neurodegenerative understanding of the pathogenesis of the disease and for genetic disease with a variable worldwide occurrence but the prevalence in counseling. We hypothesize that a subset of individuals with the United States is estimated at 7–10 in 100,000. Inherited in an intermediate alleles demonstrates subtle clinical manifestations that autosomal dominant manner, HD is caused by an expanded cytosine- resemble a mild HD phenotype. The expression of these features may adenine-guanine (CAG) repeat length in the Huntingtin (HTT) gene on be related to other, currently unidentified, genetic and non-genetic chromosome 4p16.3, resulting in accumulation of mutant huntingtin modifying factors. protein in the brain. While genetically defined HD requires > 36 CAG Methods repeats, some individuals with a mutable normal allele, or intermediate CAG range (between 27 and 35 repeats), have been reported to exhibit Demographic, clinical and genetic data were analyzed, collected 2–6 features of HD. Although most subjects with CAG repeats in this from 45 centers in the United States, Canada and Australia that range are normal, intermediate repeats have the potential to expand participated in the Cooperative Huntington’s Observational Research into the disease range within one generation. In this study, we aim to Trial (COHORT), a prospective observational study examining Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG phenotypic characteristics and genetic factors in individuals from HD ‘normal’. Participant characteristics were compared across the three families. The COHORT study involved a baseline visit comprising an primary groups using descriptive statistics. Initial analysis compared assessment with the Mini-Mental State Examination (MMSE), a differences in demographic and clinical metrics for the intermediate neurological and physical examination, including body mass index versus normal and HD groups. Means were compared using analysis (BMI), and the Unified Huntington’s Disease Rating Scale 99 of covariance models adjusted for age and gender, while proportions (UHDRS 99), conducted by trained study personnel. The UHDRS were compared using Fisher’s exact tests. 99 evaluated four domains, consisting of motor function, cognition, Further analysis compared individual items from the motor and behavior, and functional capacity. The motor assessment comprised behavioral sections of the UHDRS. These items are scored on a 0–4 31 items, which included standardized ratings of chorea, dystonia, point ordinal scale, with 0 representing no impairment and 1–4 oculomotor function, as well as a measure of diagnostic confidence, representing increasing levels of impairment. For each item, the defined as the degree to which the examiner was confident that the distribution of scores was compared using a Wilcoxon rank sum test. subject met the definition of the unequivocal presence of an Comparisons were made between the intermediate and normal extrapyramidal movement disorder in a subject at risk for HD. groups. All hypothesis testing was conducted at the two-sided Follow-up visits were conducted yearly, and included the UHDRS 99, significance level of 5%. No corrections were made for multiple MMSE, a brief medical examination including height, weight and vital testing in this exploratory analysis. signs, and any additional information with regard to medical or mental Results health events. At each visit, subjects were also given the option of participating in a family history questionnaire, and providing speci- As of December 31, 2009, 2318 participants had enrolled in the mens for storage in a repository. In order to maintain consistency, the COHORT study. Information on CAG repeat length was not same individual for a particular subject performed the UHDRS from available for 333 individuals and they were therefore excluded from year to year. Approval for COHORT was obtained from the the analysis. Of the remaining 1985 subjects, 645 subjects were in the institutional review boards for human research. normal range and 50 were in the intermediate range. Baseline Inclusion criteria for enrollment in the COHORT study included a characteristics were assessed in the 1985 research participants number of categories of subjects. Individuals were eligible to (Table 1). There were significantly more females in the intermediate participate if they had been clinically affected by HD or were positive group than either the normal or the HD group. The level of education for the HD gene. Other subjects included in the COHORT were did not differ between intermediate and HD subjects, but the those who had not undergone genetic testing but were first degree proportion employed and married were both significantly lower in relatives of an individual with manifest or pre-manifest HD, older HD subjects. Baseline body mass index (BMI) was not significantly adolescents who had a parent with manifest HD or pre-manifest HD different between the normal and intermediate group. Of note, a enrolled in COHORT, or individuals who had not undergone DNA significantly greater proportion of subjects in the intermediate group testing but were grandparents or grandchildren of an individual reported at least one suicide attempt compared to the normal group. enrolled in COHORT who has manifest HD or pre-manifest HD. In the motor component of the UHDRS, the intermediate group Control subjects included spouses or caregivers of an individual had a significantly higher Total Maximal Dystonia Score (mean 0.01 enrolled in COHORT with manifest HD or pre-manifest HD. vs 0.10, p50.001) compared with the control group. In addition, Individuals with a family history of HD who had undergone DNA compared with the normal group, there was a significantly lower testing and did not carry the genetic mutation responsible for HD were proportion of subjects in the intermediate group with normal scores in also included. the following categories: Vertical Saccade Velocity (89.8% vs 96.0%, All CAG genotyping was performed on coded DNA samples at the p50.05), Maximal Dystonia RUE (95.9% vs 99.5%, p50.004), and DNA Laboratory in the Molecular Neurogenetics Unit, Massachusetts Maximal Chorea LLE (95.9% vs 99.2%, p50.03). The items that were General Hospital. The CAG repeat lengths were determined based on significantly different are presented in Figure 1. Scores on the Stroop whole blood and lymphocyte analysis, and if both methods did not Word Reading were lower in the intermediate group compared with yield the same result for a particular individual, testing was repeated the normal group (mean 90.0 vs 95.7, p50.02). In the behavioral until the discrepancy was resolved and a common value was obtained. domain, a lower proportion of subjects in the intermediate group The investigators and subjects did not have access to the results of received normal scores in Depressed Mood – Severity (48.0% vs genotyping. The subjects were assessed yearly, for as many follow-up 61.8%, p50.02) and Suicidal Thoughts – Severity (96.0% vs 99.4%, visits as possible. Raters were blinded to the results of DNA genotyping p50.01). There was a trend toward fewer intermediate subjects of the HTT gene. We report here baseline data collected through scoring normally on Suicidal Thoughts – Frequency (96.0% vs 99.1%, December 31, 2009. p50.05). Study participants were assigned into three primary groups. Subjects The UHDRS diagnostic confidence levels for each group are shown with an expanded CAG repeat length of 36 or more were classified in Figure 2. No differences in diagnostic confidence were detected positive for HD, those with a CAG repeat of 27–35 were classified as between the normal group and the intermediate (p50.86) group, ‘intermediate’, and those with less than 27 repeats were considered although there was a slightly higher proportion of subjects with Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J Table 1. Demographic and UHDRS Data 1 1 Normal (N) Intermediate (I) p-value Huntington’s p-value Disease (HD) (n5645) (n550) (N vs. I) (n51290) (HD vs. I) Age [years] 50.31 (13.29) 49.08 (13.13) 0.5828 48.80 (13.11) 0.8021 Female [%] 373 (57.8) 37 (74.0) 0.0256 708 (54.9) 0.0085 White [%] 602 (93.2) 48 (96.0) 0.7652 1206 (93.5) 0.7667 Employment status [% currently in labor 444 (68.8) 36 (72.0) 0.7513 429 (31.6) ,0.0001 force] Marital status [% currently married] 505 (78.3) 40 (80.0) 0.8600 777 (60.2) 0.0047 History of at least one suicide attempt [%] – Overall 9 (1.4) 3 (6.0) 0.0486 82 (6.4) 1.0000 – Females 7 (1.9) 3 (8.1) 0.0522 48 (6.8) 0.7346 – Males 2 (0.7) 0 (0) 1.0000 34 (5.8) 1.0000 Body mass index [kg/m ] – Overall 28.63 (6.47) 28.67 (7.00) 0.8787 25.69 (5.42) 0.0003 – Females 28.28 (6.76) 28.91 (7.76) 0.5416 25.55 (6.07) 0.0008 – Males 29.09 (6.03) 28.01 (4.45) 0.5391 25.87 (4.50) 0.1823 Motor assessment Total UHDRS motor assessment [0–124] 1.72 (2.91) 2.16 (3.14) 0.2581 30.11 (21.96) ,0.0001 Total maximal chorea score [0–28] 0.08 (0.41) 0.16 (0.59) 0.2245 7.72 (5.99) ,0.0001 Total maximal dystonia score [0–20] – Overall 0.01 (0.14) 0.10 (0.42) 0.0014 2.64 (3.60) ,0.0001 – Females 0.02 (0.18) 0.14 (0.49) 0.0001 2.56 (3.64) ,0.0001 – Males 0.004 (0.06) 0 (0) 0.9178 2.74 (3.56) 0.0103 Behavioral assessment UHDRS Behavioral frequency [0–44] 4.39 (4.33) 5.06 (4.48) 6.94 (6.25) UHDRS Behavioral frequency x severity 6.27 (9.12) 8.28 (10.87) 0.1945 13.51 (15.87) 0.0186 [0–176] Cognitive assessment Mini Mental State Examination [0–30] 29.12 (1.51) 28.96 (1.56) 0.3783 26.01 (4.30) ,0.0001 UHDRS Verbal fluency 40.25 (11.84) 38.44 (11.51) 0.1612 26.43 (14.88) ,0.0001 UHDRS Symbol digit modalities test 47.35 (10.91) 45.65 (9.79) 0.0734 30.11 (15.28) ,0.0001 UHDRS Stroop color naming 74.60 (15.32) 72.27 (12.58) 0.1264 52.05 (20.86) ,0.0001 Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG Table 1. Continued 1 1 Normal (N) Intermediate (I) p-value Huntington’s p-value Disease (HD) (n5645) (n550) (N vs. I) (n51290) (HD vs. I) UHDRS Stroop word reading – Overall 95.70 (18.36) 89.96 (16.67) 0.0187 67.39 (26.10) ,0.0001 – Females 96.90 (18.87) 88.19 (17.42) 0.0068 69.67 (26.00) ,0.0001 – Males 94.05 (17.53) 95.25 (13.46) 0.9647 64.66 (25.97) 0.0001 UHDRS Stroop interference 43.40 (13.35) 41.79 (11.59) 0.2201 30.43 (14.74) ,0.0001 UHDRS Independence assessment 99.83 (1.38) 99.49 (1.84) 0.0942 84.31 (16.47) ,0.0001 UHDRS Functional assessment 24.89 (1.05) 24.94 (0.32) 0.7427 20.31 (5.80) ,0.0001 UHDRS Total functional capacity 12.85 (0.76) 12.84 (0.59) 0.9021 9.31 (3.55) ,0.0001 2 3 Eye Movement Score [median (range)] p-value p-value (N vs I) (N vs I) Ocular Pursuit – Horizontal 0 (0–3) 0 (0–1) 0.9820 1 (0–4) ,0.0001 Ocular Pursuit – Vertical 0 (0–3) 0 (0–1) 0.9327 1 (0–4) ,0.0001 Saccade Initiation – Horizontal 0 (0–2) 0 (0–2) 0.1143 1 (0–4) ,0.0001 Saccade Initiation – Vertical 0 (0–2) 0 (0–1) 0.1788 1 (0–4) ,0.0001 Saccade Velocity – Horizontal 0 (0–1) 0 (0–1) 0.1096 1 (0–4) ,0.0001 Saccade Velocity – Vertical 0 (0–4) 0 (0–1) 0.0454 1 (0–4) ,0.0001 Abbreviations: N, Normal; I, Intermediate; HD, Huntington disease; n, sample size; UHDRS, Unified Huntington’s Disease Rating Scale. UHDRS scores are listed as mean (standard deviation) unless otherwise noted. Two-sided p-values for comparing means based on Analysis of covariance (ANCOVA) model adjusted for age and gender; proportions compared using two-sided Fisher’s exact test. Based on two-sided Wilcoxon test for comparing median score for Normals vs. Intermediates. Based on two-sided Wilcoxon test for comparing median score for Intermediates vs. HD. confidence category of 2 and 4 in the intermediate group compared to to the possibility of subtle motor, cognitive and behavioral abnorm- normal controls. alities in some subjects with intermediate CAG repeats, but the differences that were identified in the motor scores would not likely be Discussion clinically meaningful. Of potentially greater clinical significance was HD presents with motor dysfunction as well as disturbances in that of the behavioral findings, including the history of suicide cognitive and behavioral domains. Historically, this disease has been attempts, which was comparable between the intermediate, and HD associated with stigma affecting not only patients with HD, but also groups. Whether this finding reflects an inherent abnormality in those who are at risk for developing HD. In recent years, several subjects with intermediate CAG repeats, or a tendency that is cases have been reported in the literature, suggestive of clinical potentiated by the familial context, is unclear. Regardless, this finding manifestations of HD in individuals with intermediate CAG repeats, in 11,12 raises an area of interest for further studies, with possible relevance for whom likely phenocopy syndromes have been excluded. This clinical management and intervention. The abnormal findings raise observation, if confirmed, would have important implications for the possibility of whether an intermediate length allele is indeed genetic counseling. sufficient to cause pathology, in a particular genetic and environmental In our analysis of the COHORT data, we found statistically milieu. Thus, although relatively subtle, these abnormalities appear to significant differences in some UHDRS scores between the normal and be important and relevant, particularly when they occur in the setting intermediate group. These abnormalities tended to occur in some, but not all, subjects with intermediate repeats. The findings draw attention of a family history of HD. Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J In this study population, the frequency of intermediate alleles was 2.5%, which is in the frequency range (up to 6%) reported in control populations. Our figures do not include individuals whose larger allele may have been in the HD range, as these were excluded from the analysis. Hendricks et al. have estimated that the probability that a male who is a ‘high normal’ carrier will have a risk of an offspring with an expanded, penetrant, allele ranges from 1/6241 to 1/951. These low estimates, however, have been derived from prevalence studies of high normal alleles in the general population using a sample of primarily Parkinson’s disease cases. Our results should be interpreted with caution, particularly when comparing to the general population. Data from this study were collected from subjects with signs or symptoms suggestive of HD, or from family members, and should not be applied to an otherwise healthy individual with similarly sized alleles. An intermediate allele in a family with sporadic HD appears to be less stable than those present in the general population. We acknowledge that there are a number of limitations to this study. The differences that we identified between the normal and intermediate groups may have occurred by chance as a result of inter-rater variability, particularly if the distinction between normal and mild impairment was based on the presence of subtle signs. Although the UHDRS has a high rate of internal consistency within each of the domains, and is considered the ‘gold standard’ in HD 16,17 clinical trials, the scale was originally designed for manifest individuals, and therefore may not be as sensitive in early or mild disease. The application of the UHDRS in the assessment of the normal population is not well defined. Indeed, although we found that a lower proportion of intermediate subjects scored normally on vertical saccade velocity, we also note that the normal group included outliers with very high scores, up to 4, which were not present in the intermediate group (Table 1). Given that the analysis was conducted in an exploratory nature, adjustments for multiple comparisons were not applied. We do acknowledge however that the presence of numerous data sets may raise the possibility of a Type I error. A Bonferroni correction on all 84 hypothesis tests, consisting of 31 motor items, 25 behavioral items, and 28 demographic items, would establish a p-value of less than 0.0006 for statistical significance. The significant findings in our study, however, were all suggestive of abnormality in the intermediate group rather than the normal group, and as such, the possibility of all of these findings occurring by chance due to inter-rater variability in a blinded setting would seem less likely. We note that several relevant items such as mean diagnostic confidence did not demonstrate significant differences, and we postulate that this is related to the averaging effect in assessing mean scores, in a population where only a minority of subjects appear to be affected. Low BMI, which is described in prodromal individuals, was also not found in our intermediate population. Whether the spectrum of the intermediate phenotype has a tendency to overlap with gene- Figure 1. Difference in Various UHDRS Items between Subjects with Normal expanded individuals in only certain areas is unclear. Weight loss in HD (,27) and Intermediate (27–35) CAG Repeats (0 5 Normal; 1–4 Represents has been shown to correlate directly with the CAG repeat length. The Increasing Levels of Impairment). *p,0.05, **p,0.01, RUE 5 right upper extremity, LLE 5 left lower extremity eye movement abnormality identified in the intermediate group Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Ha AD, Beck CA, Jankovic J Huntington’s Disease Intermediate CAG Figure 2. Diagnostic Confidence at Baseline between the Normal, Intermediate, ‘High-Intermediate’ and HD Groups consisted only of vertical saccade velocity, and no differences were seen the normal, intermediate, and HD groups. In addition, our in ocular pursuit or saccadic initiation. Disturbances in eye motor comparison of means using analysis of covariance models was adjusted control appear to be associated with the degree of clinical severity, for age. and this would be in keeping with the mild phenotype of the The possibility of HD phenocopies must also be considered in an intermediate group. Although further analysis stratified to gender individual with signs or symptoms suggestive of HD. Although suggested that the total maximum dystonia score and UHDRS Stroop screening for HD phenocopies would have been valuable, in a study Word Reading were due to the female intermediate subjects (Table 1), population consisting of HD individuals and their family members, it is the small numbers limit meaningful conclusions, and larger studies are unclear to what extent the possibility of HD phenocopies would have required. accounted for the results. The possibility of laboratory error should Another limitation of our analysis is the lack of robust follow-up also be considered, particularly when interpreting alleles bordering on data. Without the benefit of longitudinal assessment, disease onset may different penetrance classes. In this study, all CAG genotyping was potentially be missed, thus under-estimating the prevalence of performed in a single laboratory with considerable experience, on both abnormal phenotypes. The relatively small number of subjects with whole blood and lymphocytes. Despite these limitations, we believe intermediate CAG repeats who attended follow-up visits does not that the abnormal findings in the intermediate group are potential allow for meaningful interpretation of this component of data at this areas of interest that warrant further evaluation. Additional studies time. Variations in age may have influenced the onset of disease. In with larger sample sizes, follow-up assessments, and family data would this study, however, we found no significant differences in age between be valuable in further defining this population of subjects. In Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services Huntington’s Disease Intermediate CAG Ha AD, Beck CA, Jankovic J conclusion, our exploratory analysis of the COHORT database 9. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord 1996;11:136–142, http://dx.doi.org/10. revealed statistically significant differences in many UHDRS scores 1002/mds.870110204. between normal and intermediate length CAG. Although not proven, 10. Rawlins M. Huntington’s disease out of the closet? Lancet 2010; these findings support the concept that clinically manifest disease may 376(9750):1372–1373, http://dx.doi.org/10.1016/S0140-6736(10)60974-9. occur in individuals with intermediate CAG repeats. 11. Ha AD, Jankovic J. Exploring the correlates of intermediate CAG Acknowledgements repeats in Huntington disease. Postgrad Med 2011;123:116–121, http://dx.doi. org/10.3810/pgm.2011.09.2466. We are grateful to the Huntington Study Group for providing the 12. Squitieri F, Esmaeilzadeh M, Ciarmiello A, et al. Caudate glucose COHORT database. hypometabolism in a subject carrying an unstable allele of intermediate We would like to thank Dr Ray Dorsey, Johns Hopkins University, CAG(33) repeat length in the Huntington’s disease gene. Mov Disord 2011;26: Baltimore, for his helpful comments and Dr Ira Shoulson, Georgetown 925–927, http://dx.doi.org/10.1002/mds.23623. University, Washington, DC, for his support. We also thank Anthony 13. Sequeiros J, Ramos EM, Cerqueira J, et al. Large normal and reduced Davidson, Baylor College of Medicine, Houston, for his assistance with penetrance alleles in Huntington disease: instability in families and frequency at data analysis. the laboratory, at the clinic and in the population. Clin Genet 2010;78:381–387, References http://dx.doi.org/10.1111/j.1399-0004.2010.01388.x. 14. Hendricks AE, Latourelle JC, Lunetta KL, et al. Estimating the 1. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis probability of de novo HD cases from transmissions of expanded penetrant to clinical treatment. Lancet Neurol 2011;10:83–98, http://dx.doi.org/10.1016/ CAG alleles in the Huntington disease gene from male carriers of high normal S1474-4422(10)70245-3. alleles (27–35 CAG). Am J Med Genet A 2009;149A:1375–1381, http://dx.doi. 2. Herishanu YO, Parvari R, Pollack Y, et al. Huntington disease in subjects org/10.1002/ajmg.a.32901. from an Israeli Karaite community carrying alleles of intermediate and 15. Goldberg YP, McMurray CT, Zeisler J, et al. Increased instability of expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? intermediate alleles in families with sporadic Huntington disease compared J Neurol Sci 2009;277:143–146, http://dx.doi.org/10.1016/j.jns.2008.11.005. to similar sized intermediate alleles in the general population. Hum Mol Genet 3. Groen JL, de Bie RM, Foncke EM, et al. Late-onset Huntington disease 1995;4:1911–1918, http://dx.doi.org/10.1093/hmg/4.10.1911. with intermediate CAG repeats: true or false? J Neurol Neurosurg Psychiatry 2010; 16. Curtis A, Mitchell I, Patel S, et al. A pilot study using nabilone for 81:228–230, http://dx.doi.org/10.1136/jnnp.2008.170902. symptomatic treatment in Huntington’s disease. Mov Disord 2009;24:2254–2259, 4. Andrich J, Arning L, Wieczorek S, et al. Huntington’s disease as caused by http://dx.doi.org/10.1002/mds.22809. 34 CAG repeats. Mov Disord 2008;23:879–881, http://dx.doi.org/10.1002/ 17. Kieburtz K, McDermott MP, Voss TS, et al. A randomized, placebo- mds.21958. controlled trial of latrepirdine in Huntington disease. Arch Neurol 2010;67:154– 5. Kenney C, Powell S, Jankovic J. Autopsy-proven Huntington’s disease 160, http://dx.doi.org/10.1001/archneurol.2009.334. with 29 trinucleotide repeats. Mov Disord 2007;22:127–130, http://dx.doi.org/ 18. Vaccarino AL, Anderson K, Borowsky B, et al. An item response analysis 10.1002/mds.21195. of the motor and behavioral subscales of the unified Huntington’s disease rating 6. Biglan K, Jankovic J, Eberly S, et al. Longitudinal analysis of intermediate scale in huntington disease gene expansion carriers. Mov Disord 2011;26:877– CAGn repeat length expansion in the Prospective Huntington Disease At-Risk 884, http://dx.doi.org/10.1002/mds.23574. Observational Study (PHAROS). Mov Disord 2010(Suppl 2):S270. 19. Aziz NA, van der Burg JM, Landwehrmeyer GB, et al. Weight loss in 7. Semaka A, Creighton S, Warby S, et al. Predictive testing for Huntington Huntington disease increases with higher CAG repeat number. Neurology 2008; disease: interpretation and significance of intermediate alleles. Clin Genet 2006; 71:1506–1513, http://dx.doi.org/10.1212/01.wnl.0000334276.09729.0e. 70:283–294, http://dx.doi.org/10.1111/j.1399-0004.2006.00668.x. 20. Patel S, Jankovic J, Hood A, et al. Reflexive and volitional saccades: 8. Cooperative Huntington’s Observational Research Trial. www. Biomarkers of Huntington disease severity and progression. J Neurol Sci 2012 clinicaltrials.gov (accessed September 18, 2010). Feb 15;313(1-2):35-41. Tremor and Other Hyperkinetic Movements The Center for Digital Research and Scholarship http://www.tremorjournal.org Columbia University Libraries/Information Services

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Tremor and Other Hyperkinetic MovementsPubmed Central

Published: Feb 2, 2012

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