Age-at-onset in Huntington disease

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Abstract

Background: In Huntington disease, the accurate determination of age-at-onset is critical to identify modifiers and therapies that aim to delay it.

Methods: Retrospective data from the European Huntington’s Disease Network’s REGISTRY. Data (age, gender, CAG repeat length, parent affected, and Unified Huntington’s Disease Rating Scale motor score, total functional capacity) from at least three visits in 423 REGISTRY participants were included. Data based extrapolations of individual age-at-onset using generalized linear mixed models based on individual slopes of motor score or total functional capacity, and predictions using the Langbehn, or Ranen formula, were compared with clinicians’ estimates.

Results: Concordance was best for the calculated onset using the REGISTRY UHDRS longitudinal motor scores. For total functional capacity, the investigator’s estimate was 4 years before the data derived age-at-onset. The concordance of predictions of probability of age-at-onset was ±20 years (difference in 25%tile).

Conclusions: Estimating or predicting age-at-onset in Huntington disease may be inaccurate. It can be useful to 1) add in the manifest population motor score regression derived age-at-onset as additional motor onset and 2) add total functional capacity regression derived age-at-onset for the onset of functional impact of Huntington disease when patients are in mid- to late-stage.

Formal Correction

This article has been formally corrected to address the following. All reference to and analysis of thePREDICT-HD dataset has been removed from the original version of this article at the request of the PREDICT-HD Statistics Team.

INTRODUCTION

Age-at-onset (AAO) in Huntington disease (HD) describes the point in time when a carrier of the mutated gene develops unequivocal HD signs. The accurate determination of AAO is critical to find factors that modify AAO and to develop and evaluate therapies that aim to delay it. In manifest HD, an autosomal dominant disease with a highly penetrant CAG repeat expansion mutation in the HTT gene, [1] a clinician estimates AAO retrospectively based on information from manifest patients, relatives, and carers. For AAO predictions in the prodromal phase the formula of Langbehn and colleagues uses CAG repeat length and age because of their well known influences on AAO and calculates the time to a predefined degree of probability of manifesting signs of HD. [2] However, CAG repeat length accounts for only about 50-60% of the variability, so other factors not modelled in this formula likely influence AAO. [3] Another formula published by Ranen and colleagues uses CAG repeat length and parental onset age to estimate AAO. [4] , [5] This may accommodate for some other inherited factors as an advantage over the Langbehn formula. However, it was derived from a small sample of affected parent-child pairs and needs to be validated in larger numbers of patients. [5]

The aim of this study is to compare clinicians’ estimates with data-based extrapolations of AAO, and predictions using the Langbehn, or Ranen formula. To this end we used data from the European Huntington’s Disease Network’s (EHDN) REGISTRY, a longitudinal observational study of HD for preparing statistical models. [6] , [7] REGISTRY enrols participants at any stage of HD including the prodromal phase. [6] , [7] We hypothesized that in the REGISTRY data agreement rates between the clinicians’ estimates of AAO and data based AAO would be low since we expected that the retrospective estimate of AAO in REGISTRY was imprecise. We further expected that data-based calculations of a motor onset is possible and less variable than clinicians’ estimates of AAO, and, similarly, that it is possible to calculate an onset of functional impairment.

METHODS

Participants

Retrospective data from an ongoing multicentre, longitudinal observational research study, EHDN’s REGISTRY, was used. REGISTRY is collecting data in Europe from symptomatic and pre-HD HTTmutation expansion carriers (with known CAG repeat length≥36).[6] , [7]Participants had at least three visits where age, gender, CAG repeat length, parent affected, and clinical data (Unified Huntington’s Disease Rating Scale motor score, total functional capacity) were available. [8]All REGISTRY data were from participants with manifest HD. This was defined as carrying the HD gene mutation and having a motor phenotype that with ≥ 99% certainty was unequivocal for HD (diagnostic confidence of 4 on motor UHDRS). [8]

Participants gave informed written consent according to the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines (http://www.ich.org/LOB/media/MEDIA482.pdf). Ethical approval was obtained from the local ethics committee for each study site contributing to REGISTRY.

Data analysis and statistics

AAO was calculated using generalized linear mixed models based on individual slopes of motor or TFC scores. This means for each participant a linear regression was calculated including intercept and slope of the independent factor across visit dates (Figure 1). Visit was included as random factor. Dependent variables were the date of examination of the motorscore, or TFC, independent variables were “motorscore” or “TFC.” The estimates of the regression were then used to extrapolate the AAO by calculating the age for a motorscore of 5, or a TFC of 12, our definitions of manifest disease (Figure 1).

For AAO predictions, the formula of Langbehn with the predicted probability of signs exceeding 0.6, 0.4 and 0.2 (i.e., “Langb 0.6,” “Langb 0.4,” and “Langb 0.2″), or the formula of Ranen and colleagues (“Ranen”), was used. [5] We emulated the prodromal stage in our manifest participants by going back in time to when each participant was pre-manifest. We arbitrarily chose an age of 10 years. Secondly, we calculated the disease burden from a participant’s age and CAG repeat length ((CAG n -35.5) X age = disease burden) and using the Langbehn formula predicted AAO at an age that corresponded to a disease burden of 200 (“LB DB 0.6″). [9]

One additional model was based on the CAG repeats, age of affected parent, the motorscore (population-slope) and gender as independent variables and the rater estimate as dependent variable (“Ranen extended”). A second model was estimated analogous to the Ranen formula (“Ranen analog”) based on CAG repeats and age of affected parent. Linear regression was used to assess the importance of these factors for the rater estimate. The regression estimates were used to populate the formula.

The pairwise Pearson correlation coefficients were estimated to investigate the linear correlation of each pair of formulae on “AAO.” We compared the different models for predicting AAO by calculating agreement rates with Clopper-Pearson 95% confidence intervals between pairs of estimates. If both methods arrived at the same result within a ±5 year bracket the agreement was defined as ‘1’. If the results were more than 5 years different the agreement was defined as ‘0’. For all participants, the agreement rate was expressed as % agreement within accepted range.

Figure 1. Illustration of age-at-onset extrapolation from longitudinal UHDRS motor, or total functional capacity (TFC), scores. Linear regression analysis calculates the age for a motorscore of 5 (motor score threshold), or a TFC of 12 (TFC threshold). The vertical lines illustrate the age of the participant at threshold (motor estimate, TFC estimate) and how these calculated onsets compare to the rater estimate.



RESULTS

REGISTRY participants

Data from 423 REGISTRY participants were included (205 male). The mean CAG repeat expansion was 44 (SD 4), this was similar in men and women. In 193 participants (46%) the gene was inherited from the mother and in 177 (42%) from the father, in 30 (7%) no signs of HD were reported in either parent, and in 23 (5%) the inheritance was unknown for both parents or for at least one parent, where the other parent was not affected. Eight participants (2%) had a juvenile onset (before the age of 20), and 24 (6%) had a late onset of HD above age 60. A motor onset was present in 303, other onset types in 120. The average motor score at enrolment was 35 (out of a possible 124), 158 (37%) participants were in stage 1, 120 (28%) in stage 2, 111 (26%) in stage 3, 30 (7%) in stage 4 and 4 (1%) in stage 5. Patients were first seen by investigators a median of 6 years after the estimated onset. The medium number of visits was 3 (range 3-18).

AAO extrapolation from longitudinal data

Sixty-six participants with a negative slope of the motor score were excluded because no individual AAO could be calculated. In the remaining 357 participants, on average the motor score increased linearly by 2.57 points per year. The mean AAO of data based extrapolated motor signs was 47 (range 13-81, SD 11.67).

Forty-four participants were excluded because the slope of the TFC was positive. This meant no individual TFC onset could be extrapolated based on longitudinal data. In the remaining 379 participants, on average the TFC score decreased linearly by 0.52 points per year. The TFC of the 251 patients in disease stages 1 or 2 decreased by 0.75 points per year compared to 128 patients in disease stages 3, 4, or 5 who on average lost 0.26 points per year. The mean extrapolated AAO was 48 (range 14-81, SD 12, Figure 2).

The investigator estimated AAO was 3 years before the motorscore calculated AAO (Table 1, Figure 2) with an agreement rate of 0.57 (Table 2). The calculated TFC onset was 4 years later than the investigator’s estimate (Table 1, Figure 2) with an agreement rate of 0.52 (Table 2).

Figure 2. REGISTRY data: difference to rater estimate. The boxes of the boxplots contain 50% of the data and the median (vertical solid line), the bars indicate the 25%tile and the empty dots outliers. Abbreviations: TFC ind: regression derived TFC age-at-onset. TFC ind – 4 ys: regression derived TFC age-at-onset minus 4 years. Motorscore ind: regression derived motor age-at-onset. R. analog: Ranen analogous. R. extended: Ranen extended.


Table 1.

Model N mean SD min Q25 median Q75 max
investigator (rater estimate) 423 44.08 11.32 10 35.5 44 51.5 77
Motor score 357 47.06 11.7 13 38 47 56 81
TFC score 379 48 12 14 40 49 56.5 81
Langbehn age 10 423 46.82 10.5 23 40 46 54 89
Langbehn db 200 417 46.65 10.1 23 40 46 55 74
Ranen 280 41.94 7.9 8 38 43 47 61
Ranen analogous 280 42.44 8.4 -6 38 44 48 59
Ranen extended 280 42.58 8.7 0 38 44 49 60

Table 1. REGISTRY data. AAO estimates and data based calculations. Abbreviations: TFC total functional capacity. Langbehn db: Langbehn disease burden.


Predicting AAO

The Langbehn formula (LB 06) predicted an AAO of 46.82 (SD 10.5, range 23-89) when 10 years of age; with age at a disease burden of 200, the predicted average AAO was 46.65 (SD 10.14, range 23-74). The agreement rate with the investigator’s estimate was 0.46 (Table 2). In 280 participants (140 women) with the necessary data the Ranen formula predicted an AAO of 41.9 years (SD 7.9, range 8-61). In that group of participants this is similar to the investigator’s estimates of 42 years. The agreement rate was 0.46 (Table 2).

Comparing formulae derived AAO

In a total of 206 REGISTRY patients (109 women) with complete data the best agreement rate was between the extrapolated AAOs on the longitudinal TFC and motor score data (0.76, Table 2). Using parent AAO and CAG repeats resulted in the following formula that best predicted the investigator’s AAO estimate (Ranen analog):

AAO=90.3918+0.3293*parent AAO-1.3996*CAG repeats

In a next step we entered all available data into a regression model for the prediction of the investigator’s estimate of AAO (Ranen extended). Motor score, parent AAO, CAG repeats, and gender significantly contributed to the regression model resulting in the following formula:

AAO=88.7546+0.0430*motorscore+0.3546*parent AAO-1.4311*CAG repeats+1.0124*gender (male=1, female=0). We then entered the dataset of each participant into this formula to arrive at the calculated AAO.

The data driven formula resembles the Ranen and Ranen analogous formula with high agreement rates (0.97, Table 2) while the agreement rates with other AAO calculations was much lower (Table 2).

We then assessed 145 participants with a motor onset. The findings were similar to the analyses including all participants regardless of major symptom at onset (Table 2); the rater estimated an earlier onset than the AAO from the regression analyses.

Table 2.

All participants Participants with motor onset
Formula 1 Formula 2 N agreement rate 95% CI N Agreement rate 95% CI
Ranen Langb 06 206 0.50 0.43 0.58 145 0.49 0.41 0.57
Ranen Langb db 06 206 0.50 0.43 0.58 145 0.49 0.41 0.57
Ranen R. extended 206 0.97 0.94 0.99 145 0.96 0.91 0.98
Ranen R. analog 206 0.97 0.94 0.99 145 0.97 0.92 0.99
Ranen Motor 206 0.35 0.29 0.42 145 0.35 0.27 0.44
Ranen Rater 206 0.45 0.38 0.52 145 0.44 0.36 0.53
Ranen TFC 206 0.37 0.31 0.44 145 0.32 0.25 0.41
Langb 06 R. extended 206 0.63 0.56 0.69 145 0.59 0.50 0.67
Langb 06 R. Analog 206 0.65 0.58 0.72 145 0.60 0.52 0.68
Langb 06 Motor 206 0.50 0.43 0.57 145 0.57 0.48 0.65
Langb 06 TFC 206 0.51 0.44 0.58 145 0.55 0.47 0.63
Langb db 06 Langb 06 206 1.00 0.98 1.00 145 1.00 0.97 1.00
Langb db 06 R. extended 206 0.60 0.53 0.67 145 0.55 0.47 0.63
Langb db 06 R. Analog 206 0.64 0.57 0.70 145 0.59 0.50 0.67
Langb db 06 Motor 206 0.51 0.44 0.58 145 0.59 0.50 0.67
Langb db 06 TFC 206 0.51 0.44 0.58 145 0.55 0.47 0.63
R. extended R. analog 206 1.00 0.98 1.00 145 1.00 0.97 1.00
R. extended Motor 206 0.41 0.34 0.48 145 0.43 0.35 0.52
R. extended TFC 206 0.43 0.36 0.50 145 0.40 0.32 0.48
R. analog Motor 206 0.41 0.34 0.48 145 0.43 0.35 0.51
R. analog TFC 206 0.44 0.37 0.51 145 0.41 0.33 0.49
Motor TFC 206 0.76 0.69 0.81 145 0.73 0.65 0.80
Rater Langb 06 206 0.51 0.44 0.58 145 0.53 0.45 0.61
Rater Langb db 06 206 0.50 0.43 0.57 145 0.52 0.43 0.60
Rater R. extended 206 0.49 0.42 0.56 145 0.52 0.44 0.61
Rater R. analog 206 0.52 0.45 0.59 145 0.54 0.45 0.62
Rater Motor 206 0.58 0.51 0.65 145 0.61 0.52 0.69
Rater TFC 206 0.52 0.45 0.59 145 0.52 0.44 0.61

Table 2. Agreement rates (± 5years) between different formulae. Agreement rates between pairs of estimates were calculated with Clopper-Pearson 95% confidence intervals. If both methods arrived at the same result within a ±5 year bracket the agreement was defined as ‘1’. If the results were more than 5 years different the agreement was defined as ‘0’. For all participants, the agreement rate was expressed as % agreement within accepted range. Abbreviations: Langb db 06: calculated at an age corresponding to disease burden of 200, age when the predicted probability of signs exceeds 0.6. R. analog: Ranen analogous. R. extended: Ranen extended.


DISCUSSION

The present study assessed how a data derived age-at-onset compares to the rater’s estimate, the commonly used definition of AAO. Using longitudinal data from the REGISTRY large observational study, our results suggest that it can be useful to 1) add in the manifest population motor score regression derived AAO as additional motor onset; 2) when patients are in mid- to late-stage HD add TFC regression derived AAO for the onset of functional impact of HD; 3) predictions of AAO suggest a later onset than the actual emergence of unequivocal motor signs of HD.

Calculate age-at-onset in manifest HD

The current gold standard of AAO is a clinician’s estimate integrating data from the patient’s history, collateral history of family or carers and the examination of the patient. We compared a data derived AAO with the estimated AAO. We first used a simple regression analysis of longitudinal UHDRS motor score data and calculated the patient’s age when the motor score was 5 or greater, a cut-off used in TRACK-HD, a large longitudinal multi-centre study. [10], [11] The AAO from regressing motor scores was 3 years later than the median AAO estimated by REGISTRY investigators. The agreement rates between onset in REGISTRY data and the calculated motor onset revealed a difference of about 20 years in the 25%tile. REGISTRY participants were enrolled when they already had manifest HD. This means that at the REGISTRY enrolment visit the investigator may have had to judge AAO after many years of manifest disease. This AAO estimate would be less accurate than AAO observation. However, in REGISTRY an earlier estimated onset than that calculated from longitudinal motor scores may also suggest that investigators are not guided by motor signs alone.

Many studies of genetic modifiers relate their effect to a general onset of HD. It is possible that there are domain specific onset modifiers. Such domain specific modifying effects may be overlooked unless domain specific onsets are defined. Our data suggest that it is possible to use longitudinal motor score data to extrapolate a motor domain onset even in patients with a non-motor onset. This approach has the added advantage that it is based on data collected by certified UHDRS motor scale raters directly examining the patient. This removes some of the variability introduced by judging an onset retrospectively.

The UHDRS TFC reflects a general impact on the ability to work, handle finances, and the activities of daily living. [12] The calculated TFC onset was about 4 years later than the rater estimate indicating that it may take a number of years before HD manifestations have a substantial impact on daily life. The good agreement rate between the rater estimate and the calculated ‘TFC onset minus 4 years’ suggests this interval of 4 years is fairly robust and does not depend on the major sign at onset. A ‘TCF onset’ may add an important endpoint based on function. While in the prodromal phase new scales may have to be devised, in midstage HD patients the calculation of an onset of functional impairment using the TFC may help identify the factors that are most relevant to maintain function. [13]

Predicting age-at-onset in prodromal HD

Assuming our manifest participants were prodromal we compared AAO estimations in the REGISTRY data using the Langbehn, or Ranen, formula with the rater estimates of AAO. While the medians agree well, in a substantial proportion of cases the difference was as large as ±20 years. Overall, however, the Langbehn formula estimates the AAO later than the raters’ observed AAO. This suggests that unequivocal motor signs of HD manifest earlier, sometimes many years, than predicted using the Langbehn formula.

We next used the data to model predictions of the rater estimate of AAO. Integrating the parent AAO and the individual CAG repeat length resulted in a formula in very good agreement with the Ranen formula. The agreement rates of the Ranen, or Ranen analogous, formula with the rater estimate or the extrapolated AAO revealed a large window of ±20 years. Overall, the difference of the population based analyses, i.e. median, is unbiased, but on individual levels high deviances from the rater estimate were found. This suggests that other factors may also influence the AAO on an individual level that average out on a group level.

Conclusions and limitations

A methodological limitation relates to the assumption of linear progression. Rates of decline of TFC in our study agree reasonably well with previous data in documenting the rate of decline is slower in the later stages of the disease than in the earlier stages probably reflecting a floor effect. [12] Progression of HD may not be linear in all stages. Since the population was too small further studies need to investigate rates of progression of HD in large data sets using for example non-linear statistical models. We had to exclude a substantial proportion of participants from the data based extrapolations because the slopes were in the wrong direction. Such individuals present a challenge for the proposed technique of estimating individual onset by extrapolating backwards.

Our results suggest inaccuracies of the concept of a rater estimated AAO. Observing the onset may result in a more accurate AAO than estimating the AAO from a distance of many years even if experienced HD clinicians use all available information from patients, relatives, and carers. We do not have an objective measure of AAO, or the truth, so we cannot reliably say which of the AAOs we have evaluated is the best. AAO implies it is possible to identify a point in time when HD signs manifest while clinically it would be more appropriate to refer to a transition period of sometimes several years from the prodromal to the manifest stage of HD. Based on our results we suggest to add in manifest HD cohorts a data derived AAO, especially for the motor domain. This may be particularly important when using REGISTRY data where the rater estimate of AAO seems less reliable. For predictions of AAO in the prodromal phase of HD, our data suggest that the Langbehn formula works better than the formula integrating parental AAO. The challenge for the future is to find objective means to define AAO, both predicted and retrospective. REGISTRY and PREDICT-HD, and also TRACK-HD, offer large collections of longitudinal data that can be used to meet this challenge. [10]


Acknowledgements

Expansion of Collaborator List

European Huntington’s Disease Registry Contributors

A-C Bachoud-Lévi,Registry Steering committee AR Bentivoglio, Registry Steering committee I Biunno, R Bonelli, Registry Steering committee J-M Burgunder, Registry Steering committee SB Dunnett, Registry Steering committee JJ Ferreira, Registry Steering committee OJ Handley, Registry Steering committee A Heiberg, Registry Steering committee T Illmann, Registry Steering committee GB Landwehrmeyer, Registry Steering committee J Levey, Registry Steering committee JE Nielsen, Registry Steering committee M Päivärinta, Registry Steering committee RAC Roos, Registry Steering committee A Rojo Sebastián, Registry Steering committee SJ Tabrizi, Registry Steering committee W Vandenberghe, Registry Steering committee C Verellen-Dumoulin, Registry Steering committee J Zaremba, Registry Steering committee T Uhrova, Registry Steering committee J Wahlström, Registry Steering committee T Illmann,Information technology M Wallner, Information technology Katrin Barth,Central coordination and Language coordinator Leonor Correia-Guedes, Central coordination and Language coordinator Ana Maria Finisterra,Central coordination and Language coordinator Monica Bascuñana Garde, Central coordination and Language coordinator Reineke Bos, Central coordination and Language coordinator Sabrina Burg, Central coordination and Language coordinator Daniel Ecker, Central coordination and Language coordinator Olivia J Handley, Central coordination and Language coordinator Christine Held, Central coordination and Language coordinator Kerstin Koppers, Central coordination and Language coordinator Mathilde Laurà, Central coordination and Language coordinator Asunción Martínez Descals, Central coordination and Language coordinator Tim McLean, Central coordination and Language coordinator Tiago Mestre,Central coordination and Language coordinator Sara Minster,Central coordination and Language coordinator Daniela Monza, Central coordination and Language coordinator Jenny Townhill (formerly Naji), Central coordination and Language coordinator Michael Orth, Central coordination and Language coordinator Helene Padieu, Central coordination and Language coordinator Laurent Paterski, Central coordination and Language coordinator Nadia Peppa, Central coordination and Language coordinator Susana Pro Koivisto, Central coordination and Language coordinator Amandine Rialland, Central coordination and Language coordinator Niini Røren (formerly Heinonen), Central coordination and Language coordinator Pavla Šašinková, Central coordination and Language coordinator Patricia Trigo Cubillo, Central coordination and Language coordinator Christine Tritsch, Central coordination and Language coordinator Marlene R van Walsem, Central coordination and Language coordinator Marie-Noelle Witjes-Ané,Central coordination and Language coordinator Elizaveta Yudina (formerly Tarasova),Central coordination and Language coordinator Daniel Zielonka, Central coordination and Language coordinator Eugeniusz Zielonka, Central coordination and Language coordinator Paola Zinzi, Central coordination and Language coordinator Raphael M. Bonelli, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Brigitte Herranhof, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Anna Holl (formerly Hödl), Graz (LKH Graz, Abteilung für Psychiatrie), Austria Markus Magnet, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Daniela Otti, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Annamaria Painold, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Karin Reisinger, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Monika Scheibl, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Helmut Schöggl, Graz (LKH Graz, Abteilung für Psychiatrie), Austria Pascale Ribaï, Charleroi, Institut de Pathologie et de Génétique (IPG), Belgium Christine Verellen-Dumoulin, Charleroi, Institut de Pathologie et de Génétique (IPG), Belgium Andrea Boogaerts, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium Wim Vandenberghe, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium Dimphna van Reijen, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium Jiří Klempíř; Extrapyramidové centrum, Neurologická klinika, 1. LF UK a VFN, Prague, Czech Republic Jan Roth, Extrapyramidové centrum, Neurologická klinika, 1. LF UK a VFN, Prague, Czech Republic Jørgen E. Nielsen, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Lena E. Hjermind, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Oda Jakobsen, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Jette Stokholm, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Lis Hasholt, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Anne Nørremølle, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Sven Asger Sørensen, Hukommelsesklinikken, Rigshospitalet; Panum Instituttet, Copenhage, Denmark Heli Hiivola, Rehabilitation Centre Suvituuli, Turku-Suvituuli, Finland Kirsti Martikainen, Rehabilitation Centre Suvituuli, Turku-Suvituuli, Finland Katri Tuuha, Rehabilitation Centre Suvituuli, Turku-Suvituuli, Finland Maire Santala, Terveystalo Healthcare Service Centre, Tamper, Finland Christoph Michael Kosinski, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Eva Milkereit, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Daniela Probst, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Christian Sass, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany JohannesSchiefer, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Christiane Schlangen, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Cornelius J. Werner, Universitätsklinikum Aachen, Neurologische Klinik, Aachen, Germany Harald Gelderblom, Klinik und Poliklinik für Neurologie – Charité – Universitätsmedizin Berlin, Berlin, Germany Josef Priller, Klinik und Poliklinik für Neurologie – Charité – Universitätsmedizin Berlin, Berlin, Germany Harald Prüß, Klinik und Poliklinik für Neurologie – Charité – Universitätsmedizin Berlin, Berlin, Germany Eike Jakob Spruth, Klinik und Poliklinik für Neurologie – Charité – Universitätsmedizin Berlin, Berlin, Germany Jürgen Andrich, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Gisa Ellrichmann, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Rainer Hoffmann, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Christian Prehn, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Carsten Saft, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Stephan Salmen, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Christiane Stamm, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Tanja Steiner, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Katrin Straßburge, Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital, Bochum, Germany Herwig Lange, Reha Zentrum in Dinslaken im Gesundheitszentrums Lang, Dinslake, German Matthias Löhle, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie, Dresden, Germany Simone Schmidt, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie, Dresden, Germany Alexander Storch, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie, Dresden, Germany Annett Wolz, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie, Dresden, Germany Martin Wolz, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie, Dresden, Germany Johann Lambeck, Universitätsklinik Freiburg, Neurologie, Freiburg, Germany Birgit Zucker, Universitätsklinik Freiburg, Neurologie, Freiburg, Germany Ute Hidding, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Jan Lewerenz, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Alexander Münchau, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Michael Orth, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Jenny Schmalfeld, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Lars Stubbe, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Simone Zittel, Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Hamburg, Germany Walburgis Heinicke, Psychatrium Heiligenhafen, Heiligenhafe, Germany Bernhard Longinus, Klinik für Psychiatrie und Psychotherapie Marburg-Süd, Marburg KP, Germany Jens Carsten Möller, Universität Marburg, Neurologie, Marburg Uni, Germany Ida Rissling, Universität Marburg, Neurologie, Marburg Uni, Germany Alexander Peinemann, Huntington-Ambulanz im Neuro-Kopfzentrum – Klinikum rechts der Isar der Neurologischen Klinik und Poliklinik der Technischen Universität München, München, Germany Michael Städtler, Huntington-Ambulanz im Neuro-Kopfzentrum – Klinikum rechts der Isar der Neurologischen Klinik und Poliklinik der Technischen Universität München, München, Germany Adolf Weindl, Huntington-Ambulanz im Neuro-Kopfzentrum – Klinikum rechts der Isar der Neurologischen Klinik und Poliklinik der Technischen Universität München, München, Germany Stefan Bohlen, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Münste, Germany Eva Hölzner, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Münste, Germany Herwig Lange, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Münste, Germany Ralf Reilmann, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Münste, German Antonie Beister, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Matthias Dose, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Kathrin Hammer, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Janina Kieni, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Gabriele Leythaeuser, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Ralf Marquard, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Tina Raab, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Sven Richter, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Amina Selimbegovic-Turkovic, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Caroline Schrenk, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Michele Schuierer;, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Alexandra Wiedemann, Isar-Amper-Klinikum – Klinik Taufkirchen (Vils), Taufkirchen, Germany Katrin Barth, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Andrea Buck, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Julia Connemann, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Daniel Ecker, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Carolin Eschenbach, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Christine Held, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Bernhard Landwehrmeyer, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Franziska Lezius, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Anke Niess, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Michael Orth, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Sigurd Süßmuth, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Sonja Trautmann, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Patrick Weydt, Universitätsklinikum Ulm, Neurologie, Ulm, Germany Claudia Cormio, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ di Bari, Bari, Italy Olimpia Difruscolo, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ di Bari, Bari, Italy Vittorio Sciruicchio, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ di Bari, Bari, Italy Claudia Serpino, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ di Bari, Bari, Italy Marina de Tommaso, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ di Bari, Bari, Italy Elisabetta Bertini, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Elena Ghelli, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Andrea Ginestroni, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Francesca Massaro, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Claudia Mechi, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Marco Paganini, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Silvia Piacentini, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Silvia Pradella, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Anna Maria Romoli, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Sandro Sorbi, Dipartimento di Scienze Neurologiche e Psichiatriche Universita’ degli Studi di Firenze-Azienda Ospedaliera Universitaria Careggi, Florence, Italy Giovanni Abbruzzese, Dipartimento di Neuroscienze, Oftalmologia e Genetica (DiNOG), Università di Genova, Genoa, Italy Monica Bandettini di Poggio, Dipartimento di Neuroscienze, Oftalmologia e Genetica (DiNOG), Università di Genova, Genoa, Italy Giovanna Ferrandes, Dipartimento di Neuroscienze, Oftalmologia e Genetica (DiNOG), Università di Genova, Genoa, Italy Paola Mandich, Dipartimento di Neuroscienze, Oftalmologia e Genetica (DiNOG), Università di Genova, Genoa, Italy Roberta Marchese, Dipartimento di Neuroscienze, Oftalmologia e Genetica (DiNOG),Università di Genova, Genoa, Italy

Alberto Albanese, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Daniela Di Bella, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Stefano Di Donato, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Cinzia Gellera, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Silvia Genitrini, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Caterina Mariotti, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Daniela Monza, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Lorenzo Nanetti, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Dominga Paridi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Paola Soliveri, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Chiara Tomasello, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Giuseppe De Michele, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Luigi Di Maio, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Carlo Rinaldi, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Cinzia Valeria Russo, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Elena Salvatore, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Tecla Tucci, Dipartimento di Scienze NeurologicheAzienda Ospedaliera Universitaria Federico II, Naples, Italy Francesca Elifani, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Sara Orobello, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Silvia Alberti, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Annamaria Griguoli, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Enrico Amico, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Annunziata De Nicola, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Tiziana Martino, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy Ferdinando Squitier, Centro di Neurogenetica e Malattie Rare – IRCCS Neuromed, Pozzilli (IS), Italy

Anna Rita Bentivoglio, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Claudio Catalli, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Raffaella Di Giacopo, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Alfonso Fasano, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Marina Frontali, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Arianna Guidubaldi, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Tamara Ialongo, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Gioia Jacopini, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Giovanna Loria, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Carla Piano, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Piccininni Chiara, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Davide Quaranta, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Silvia Romano, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Francesco Soleti, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Maria Spadaro, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Paola Zinzi, Istituto di Neurobiologia e Medicina Molecolare & Istituto di Scienze e Tecnologie della Cognizione /CNR;Istituto di Neurologia Università Cattolica del Sacro Cuore, Rome, Italy

Monique S.E. van Hout, Medisch Spectrum Twente, Ensched, Netherlands Jeroen P.P. van Vugt, Medisch Spectrum Twente, Ensched, Netherlands A. Marit de Weert, Medisch Spectrum Twente, Ensched, Netherlands J.J.W. Bolwijn, Polikliniek Neurologie, Groningen, Netherlands M. Dekker, Polikliniek Neurologie, Groningen, Netherlands K.L. Leenders, Polikliniek Neurologie, Groningen, Netherlands J.C.H. van Oostrom, Polikliniek Neurologie, Groningen, Netherlands Reineke Bos, Leiden University Medical Centre (LUMC), Leide, Netherlands Eve M. Dumas, Leiden University Medical Centre (LUMC), Leide, Netherlands Caroline K. Jurgens, Leiden University Medical Centre (LUMC), Leide, Netherlands Simon J. A. van den Bogaard, Leiden University Medical Centre (LUMC), Leide, Netherlands Raymund A.C. Roos, Leiden University Medical Centre (LUMC), Leide, Netherlands Ellen P. ‘t Hart, Leiden University Medical Centre (LUMC), Leide, Netherlands Marie-Noëlle Witjes-Ané, Leiden University Medical Centre (LUMC), Leide, Netherlands Berry Kremer, Universitair Medisch Centrum St. Radboud, Neurology, Nijmege, Netherlands C.C.P. Verstappen, Universitair Medisch Centrum St. Radboud, Neurology, Nijmege, Netherland Arvid Heiberg, Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology, Oslo University Hospital, Norway Marleen R van Walsem, Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology, Oslo University Hospital, Norway Jan Frich, Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology, Oslo University Hospital, Norway Olaf Aaserud, Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology, Oslo University Hospital, Norway Raghild Wehu, Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology, Oslo University Hospital, Norway Kathrine Bjørgo, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Madelein Fannemel, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Per Gørvell, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Eirin Lorentzen, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Susana Pro Koivisto, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Lars Retterstøl, Ulleval, Dept of Medical Genetics and Department, Oslo University Hospital, Norway Inga Bjørnevoll, St. Olavs Hospital, Trondheim, Norway Sigrid Botne Sando, St. Olavs Hospital, Trondheim, Norway Emilia Sitek, St. Adalbert Hospital, Gdansk; Medical University of Gdansk, Neurological and Psychiatric Nursing Dpt., Gdansk, Poland Jaroslaw Slawek, St. Adalbert Hospital, Gdansk; Medical University of Gdansk, Neurological and Psychiatric Nursing Dpt., Gdansk, Poland Witold Soltan, St. Adalbert Hospital, Gdansk; Medical University of Gdansk, Neurological and Psychiatric Nursing Dpt., Gdansk, Poland Magdalena Boczarska-Jedynak, Silesian Medical University Katowice, Katowice, Poland Barbara Jasinska-Myga, Silesian Medical University Katowice, Katowice, Poland Gregorz Opala, Silesian Medical University Katowice, Katowice, Poland Gabriela Kłodowska – Duda, Silesian Medical University Katowice, Katowice, Poland Krzysztof Banaszkiewicz, Krakowska Akademia Neurologii, Krako, Poland Andrzej Szczudlik, Krakowska Akademia Neurologii, Krako, Poland Monika Rudzińska, Krakowska Akademia Neurologii, Krako, Poland Magdalena Wójcik, Krakowska Akademia Neurologii, Krako, Poland Małgorzata Dec, Krakowska Akademia Neurologii, Krako, Poland Malgorzata Krawczyk, Krakowska Akademia Neurologii, Krako, Poland Anna Bryl, Medical University of Poznań, Poznan, Poland Anna Ciesielska, Medical University of Poznań, Poznan, Poland Aneta Klimberg, Medical University of Poznań, Poznan, Poland Jerzy Marcinkowski, Medical University of Poznań, Poznan, Poland Justyna Sempołowicz, Medical University of Poznań, Poznan, Poland Daniel Zielonka, Medical University of Poznań, Poznan, Poland Husam Samara, Medical University of Poznań, Poznan, Poland Piotr Janik, Medical University of Warsaw, Neurology, Warsaw-MU, Poland Anna Gogol, Medical University of Warsaw, Neurology, Warsaw-MU, Poland Hubert Kwiecinski, Medical University of Warsaw, Neurology, Warsaw-MU, Poland Zygmunt Jamrozik, Medical University of Warsaw, Neurology, Warsaw-MU, Poland Jakub Antczak, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Katarzyna Jachinska, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Maria Rakowicz, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Przemyslaw Richter, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Danuta Ryglewicz, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Grzegorz Witkowski, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Elzbieta Zdzienicka, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Jacek Zaremba, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Anna Sułek, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Wioletta Krysa, Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology, Warsaw-IPiN, Poland Tiago Mestre, Hospital de Santa Maria; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal Leonor Correia-Guedes, Hospital de Santa Maria; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal Miguel Coelho, Hospital de Santa Maria; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal Joaquim J Ferreira, Hospital de Santa Maria; Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal Ângela Timóteo, Hospital Fernando da Fonseca, Lisbon, Portugal Cristina Costa, Hospital Fernando da Fonseca, Lisbon, Portugal Miguel Gago, Hospital de São João, Porto, Portugal Carolina Garrett, Hospital de São João, Porto, Portugal Maria Rosália Guerra, Hospital de São João, Porto, Portugal Carmen Durán Herrera, Hospital Infanta Cristina, Badajoz, Spain Patrocinio Moreno Garcia, Hospital Infanta Cristina, Badajoz, Spain Francisco Barrero, Hospital Universitario San Cecilio, Neurología, Granada, Spain Blas Morale, Hospital Universitario San Cecilio, Neurología, Granada, Spain Esther Cubo, Servicio de Neurología Hospital General Yagüe, Burgos, Spain Natividad Mariscal, Servicio de Neurología Hospital General Yagüe, Burgos, Spain Jesús Sánchez, Servicio de Neurología Hospital General Yagüe, Burgos, Spain Fernando Alonso-Frech, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain Maria Rabasa Perez, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain María Fenollar, Hospital Clínico Universitario San Carlos, Madrid-Clinico, Spain Rocío García-Ramos García, Hospital Clínico Universitario San Carlos, Madrid-Clinico, Spain Purificacion Pin Quiroga, Hospital Clínico Universitario San Carlos, Madrid-Clinico, Spain Susana Vázquez Rivera, Hospital Clínico Universitario San Carlos, Madrid-Clinico, Spain Clara Villanuev, Hospital Clínico Universitario San Carlos, Madrid-Clinico, Spain Mónica Bascuñana, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain Marta Fatás Ventura, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain Guillermo García Ribas, Garcia Riva, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain Justo García de Yébenes, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain José Luis López – Sendón Moreno, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain Patricia Trigo Cubillo, Hospital Ramón y Cajal, Neurología, Madrid RYC, Spain Pedro J García Ruíz, Madrid-Fundación Jiménez Díaz, Madrid FJD, Spain Asunción Martínez-Descals, Madrid-Fundación Jiménez Díaz, Madrid FJD, Spain María José Saiz Artiga, Madrid-Fundación Jiménez Díaz, Madrid FJD, Spain Vicenta Sánchez, Madrid-Fundación Jiménez Díaz, Madrid FJD, Spain Miquel Aguilar Barbera, Barcelona-Hospital Mútua de Terrassa, Spain Dolors Badenes Guia, Barcelona-Hospital Mútua de Terrassa, Spain Laura Casas Hernanz, Barcelona-Hospital Mútua de Terrassa, Spain Judit López Catena, Barcelona-Hospital Mútua de Terrassa, Spain Ana Rojo Sebastián, Barcelona-Hospital Mútua de Terrassa, Spain Pilar Quiléz Ferrer, Barcelona-Hospital Mútua de Terrassa, Spain Gemma Tome Carruesco, Barcelona-Hospital Mútua de Terrassa, Spain Jordi Bas, Hospital Universitari de Bellvitge, Barcelona-Bellvitge, Spain Núria Busquets, Hospital Universitari de Bellvitge, Barcelona-Bellvitge, Spain Matilde Calopa, Hospital Universitari de Bellvitge, Barcelona-Bellvitge, Spain Maria Teresa Buongiorno, Barcelona- Hospital Clinico, Spain Esteban Muñoz, Barcelona- Hospital Clinico, Spain Marina Dalmau Elorza, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Cristóbal Díez-Aja López, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Santiago Durán-Sindreu Terol, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Misericordia Floriach Robert, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Belén Garzón Ruíz, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Ana González Casado, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Isabel Haro Martínez, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Celia Mareca Viladrich, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Regina Pons i Càrdenas, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Elvira Roca, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Joan Roig Llesoy, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Jesús Miguel Ruiz Idiago, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Mar Ruíz Vergara, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Socorro Soriano García, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Antonio Villa Riballo, Hospital Mare de Deu de La Merced, Barcelona-Merced, Spain Aranzazú Gorospe, Hospital Son Dureta, Palma, Spain Inés Legarda, Hospital Son Dureta, Palma, Spain Penelope Navas Arques, Hospital Son Dureta, Palma, Spain María José Torres Rodríguez, Hospital Son Dureta, Palma, Spain Barbara Vives, Hospital Son Dureta, Palma, Spain Itziar Gaston, Hospital Virgen del Camino, Medical Genetic, Pamplona, Spain Maria A. Ramos-Arroyo,Hospital Virgen del Camino, Medical Genetic, Pamplona, Spain Maria Dolores Martinez-Jaurrieta, Hospital Virgen del Camino, Medical Genetic, Pamplona, Spain Sven E Pålhagen, Karolinska University Hospital, Stockholm, Sweden Martin Paucar, Karolinska University Hospital, Stockholm, Sweden Per Svenningsson, Karolinska University Hospital, Stockholm, Sweden Tina Walldén Reza-Soltani, Karolinska University Hospital, Stockholm, Sweden Arja Höglund, Karolinska University Hospital, Stockholm, Sweden Britta Sandströ, Karolinska University Hospital, Stockholm, Sweden Joakim Tedroff, NeuroHealth Consulting Sweden HB, Karolinska Institute, Stockholm-Ersta, Sweden Mona Esmaeilzadeh, NeuroHealth Consulting Sweden HB, Karolinska Institute, Stockholm-Ersta, Sweden Elisabeth Winnberg, NeuroHealth Consulting Sweden HB, Karolinska Institute, Stockholm-Ersta, Sweden Anders Johansson, Uppsala University Hospital, Uppsal, Sweden Leif Wiklund, Uppsala University Hospital, Uppsal, Sweden Camilla Ekwall, Uppsala University Hospital, Uppsal, Sweden Marie-Louise Göller, Uppsala University Hospital, Uppsal, Sweden Yvonne Björn, Uppsala University Hospital, Uppsal, Sweden Jean-Marc Burgunder, Neurologische Klinik des Inselspitals, Bern, Switzerland Yvonne Burgunder, Neurologische Klinik des Inselspitals, Bern, Switzerland Yanik Stebler, Neurologische Klinik des Inselspitals, Bern, Switzerland Alain Kaelin, Zentrum für Bewegungsstörungen, Neurologische Klinik und Poliklinik, Bern, Switzerland Irene Romero, Zentrum für Bewegungsstörungen, Neurologische Klinik und Poliklinik, Bern, Switzerland Michael Schüpbach, Zentrum für Bewegungsstörungen, Neurologische Klinik und Poliklinik, Bern, Switzerland Sabine Weber Zaugg, Zentrum für Bewegungsstörungen, Neurologische Klinik und Poliklinik, Bern, Switzerland Roisin Jack, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Kirsty Matheson, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Zosia Miedzybrodzka, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Daniela Rae, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Sheila Simpson, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Fiona Summers, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Alexandra Ure, NHS Grampian, Clinical Genetics Centre, Aberdeen, UK Adrienne Curtis, The Barberry Centre, Dept of Psychiatry, Birmingham, UK Jenny de Souza (Keylock), The Barberry Centre, Dept of Psychiatry, Birmingham, UK Hugh Rickards, The Barberry Centre, Dept of Psychiatry, Birmingham, UK Jan Wright, The Barberry Centre, Dept of Psychiatry, Birmingham, UK Matthew Armstrong, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Roger A. Barker, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Deidre O’Keefe, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Anna Di Pietro, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Kate Fisher, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Anna Goodman, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Susan Hill, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Ann Kershaw, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Sarah Mason, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Nicole Paterson, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Rachel Swain, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Lucy Raymon, Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Monica Busse, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Stephen Dunnett, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Catherine Clenaghan, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Ruth Fullham, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Sarah Hunt, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Lesley Jones, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Una Jones, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Hanan Khalil, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Sara Minster, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Michael Owen, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Kathleen Price, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Jenny Townshill,The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Anne Rosser, The Institute of Medical Genetics, University Hospital of Wales, Cardif, UK Maureen Edwards, Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Teresa Hughes (Scottish Huntington´s Association), Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Marie McGill, Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Pauline Pearson, Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Mary Porteous, Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Paul Smith (Scottish Huntington´s Association), Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Adam Zeman, Molecular Medicine Centre, Western General Hospital, Department of Clinical Genetics, Edinburg, UK Peter Brockie, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Jillian Foster, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Nicola Johns, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Sue McKenzie, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Jean Rothery, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Gareth Thomas, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Shona Yates, Scottish Huntington’s Association Whyteman’s Brae Hospital, Fife, UK Joanne Miller, Abercromby Center, Glasgow, UK Stuart Ritchie, Abercromby Center, Glasgow, UK Liz Burrows, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Amy Fletcher, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Alison Harding, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Fiona Laver, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Mark Silva, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Aileen Thomson, Department of Neurology Gloucestershire Royal Hospital, Gloucester, UK Peter Burns, Castle Hill Hospital, Hull, UK Carol Chu, Castle Hill Hospital, Hull, UK Carole Evans, Castle Hill Hospital, Hull, UK Stephanie Hamer, Castle Hill Hospital, Hull, UK Ivana Markova, Castle Hill Hospital, Hull, UK Julie Miller, Castle Hill Hospital, Hull, UK Ashok Raman, Castle Hill Hospital, Hull, UK Kathy Barnes, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Carol Chu, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Emma Hobson, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Stuart Jamieson, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Ivana Markova, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Jenny Thomson, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Jean Toscano, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Sue Wild, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Pam Yardumian, Chapel Allerton Hospital, Department of Clinical Genetics, Leeds , UK Colin Bourne, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Carole Clayton, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Heather Dipple, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Jackie Clapton, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Janet Grant, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Diana Gross, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Caroline Hallam, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Julia Middleton, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Ann Murch,Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Dawn Patino, Leicestershire Partnership Trust, Mill Lodge, Leicester, UK Thomasin Andrews, Guy’s Hospital, London, UK Andrew Dougherty, Guy’s Hospital, London, UK Fred Kavalier, Guy’s Hospital, London, UK Charlotte Golding, Guy’s Hospital, London, UK Alison Lashwood, Guy’s Hospital, London, UK Dene Robertson, Guy’s Hospital, London, UK Deborah Ruddy,Guy’s Hospital, London, UK Anna Whait, Guy’s Hospital, London, UK Michael Patton, St. Georges-Hospital, London, UK Maria Peterson, St. Georges-Hospital, London, UK Sarah Rose, St. Georges-Hospital, London, UK Thomasin Andrews, The National Hospital for Neurology and Neurosurgery, London, UK Stefania Bruno, The National Hospital for Neurology and Neurosurgery, London, UK Charlotte Golding, The National Hospital for Neurology and Neurosurgery, London, UK Nayana Lahiri, The National Hospital for Neurology and Neurosurgery, London, UK Marianne Novak, The National Hospital for Neurology and Neurosurgery, London, UK Aakta Patel, The National Hospital for Neurology and Neurosurgery, London, UK Elisabeth Rosser, The National Hospital for Neurology and Neurosurgery, London, UK Sarah Tabrizi, The National Hospital for Neurology and Neurosurgery, London, UK Rachel Taylor, The National Hospital for Neurology and Neurosurgery, London, UK Thomas Warner, The National Hospital for Neurology and Neurosurgery, London, UK Edward Wild, The National Hospital for Neurology and Neurosurgery, London, UK Natalie Arran, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Jenny Callaghan, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK David Craufurd, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Ruth Fullam, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Liz Howard, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Susan Huson, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Lucy Partington-Jones, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Julie Snowden, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Andrea Sollom, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Jennifer Thompson, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Cheryl Stopford, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Nichola Verstraelen (formerly Ritchie), Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Leann Westmoreland, Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Andrea H Nemeth, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK Gill Siuda, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK David Harrison, Heathleigh Unit, Mount Gould Hospital, Plymouth, UK Max Hughes, Heathleigh Unit, Mount Gould Hospital, Plymouth, UK Andrew Parkinson, Heathleigh Unit, Mount Gould Hospital, Plymouth, UK Beverley Soltysiak, Heathleigh Unit, Mount Gould Hospital, Plymouth, UK Oliver Bandmann, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Alyson Bradbury, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Paul Gill, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Helen Fairtlough, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Kay Fillingham, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Isabella Foustanos, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Kirsty O’Donovan, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Nadia Peppa, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Katherine Tidswell, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK Oliver Quarrell, The Royal Hallamshire Hospital– Sheffield Children’s Hospital, Sheffield, UK

Acknowledgements

This research is supported by CHDI Foundation, Inc. We thank the REGISTRY sites and the study participants for their time and effort.

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