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Barker)] TJ ET 0.271 0.267 0.267 rg BT 412.311 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 417.732 663.247 Td /F1 9.8 Tf [(Maria Rakowicz)] TJ ET 0.271 0.267 0.267 rg BT 486.528 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 491.949 663.247 Td /F1 9.8 Tf [(G. Bernhard )] TJ ET BT 26.250 651.342 Td /F1 9.8 Tf [(Landwehrmeyer)] TJ ET 0.271 0.267 0.267 rg BT 96.148 651.342 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 101.569 651.342 Td /F1 9.8 Tf [(Oliver Quarrell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 639.438 Td /F1 9.8 Tf [(Robertson L, Santini H, O'Donovan KL, Squitieri F, Barker RA, Rakowicz M, Landwehrmeyer GB, Quarrell O. Current )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(Pharmacological Management in Juvenile Huntingtons Disease. PLOS Currents Huntington Disease. 2012 Feb 6 . Edition 1. )] TJ ET BT 26.250 615.628 Td /F1 9.8 Tf [(doi: 10.1371/currents.RRN1304.)] TJ ET q 15.000 26.434 577.500 586.813 re W n 0.271 0.267 0.267 rg BT 26.250 586.526 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(Background: The clinical presentation of Juvenile Huntingtons Disease \(JHD\) can be very different from adult-onset HD with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(little evidence to guide symptomatic management.)] TJ ET BT 26.250 535.262 Td /F1 9.8 Tf [(Aim: To survey the current use of pharmacological treatments for JHD.)] TJ ET BT 26.250 515.857 Td /F1 9.8 Tf [(Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntingtons Disease )] TJ ET BT 26.250 503.952 Td /F1 9.8 Tf [(Network REGISTRY study.)] TJ ET BT 26.250 484.548 Td /F1 9.8 Tf [(Results: The most commonly prescribed agents were anti-psychotics \(24/45\), anti-depressants \(17/45\) and anti-parkinsonian )] TJ ET BT 26.250 472.643 Td /F1 9.8 Tf [(medications \(15/45\). 5 patients were taking more than 8 medications.)] TJ ET BT 26.250 453.238 Td /F1 9.8 Tf [(Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple )] TJ ET BT 26.250 441.333 Td /F1 9.8 Tf [(therapies, highlighting the need to rationalise medications.)] TJ ET BT 26.250 404.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 384.777 Td /F1 9.8 Tf [(We would like to acknowledge the funding for this project which we received from the Sheffield Childrens Hospital Charity )] TJ ET BT 26.250 372.872 Td /F1 9.8 Tf [(\(SCHC\).)] TJ ET BT 26.250 343.769 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 323.815 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is a dominantly inherited, neurodegenerative disorder, due to a \(CAG\)n repeat expansion in the HTT )] TJ ET BT 26.250 311.910 Td /F1 9.8 Tf [(gene [1] . In the majority of HD cases, onset is in adult life.)] TJ ET BT 26.250 292.506 Td /F1 9.8 Tf [(Juvenile HD \(JHD\)is defined as onset under 20 years of age )] TJ ET 0.267 0.267 0.267 rg BT 288.525 292.506 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 299.367 292.506 Td /F1 9.8 Tf [( and represents approximately 1-10% of cases )] TJ ET 0.267 0.267 0.267 rg BT 503.122 292.506 Td /F1 9.8 Tf [([3] [4] [5] [6] [7])] TJ ET 0.271 0.267 0.267 rg BT 568.174 292.506 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 280.601 Td /F1 9.8 Tf [(There is an inverse correlation between the age at onset of disease and the number of \(CAG\)n repeats)] TJ ET 0.267 0.267 0.267 rg BT 469.553 280.601 Td /F1 9.8 Tf [( [8] [9] [10])] TJ ET 0.271 0.267 0.267 rg BT 515.632 280.601 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 261.196 Td /F1 9.8 Tf [(Adult HD is characterised by a triad of clinical features including: chorea, cognitive decline and psychiatric disturbance or )] TJ ET BT 26.250 249.291 Td /F1 9.8 Tf [(behavioural disturbance)] TJ ET 0.267 0.267 0.267 rg BT 129.756 249.291 Td /F1 9.8 Tf [( [11] )] TJ ET 0.271 0.267 0.267 rg BT 151.440 249.291 Td /F1 9.8 Tf [(. However, in JHD, particularly in those with onset in the first decade, chorea is less likely to be )] TJ ET BT 26.250 237.387 Td /F1 9.8 Tf [(present and instead, patients are more likely to present with rigidity, bradykinesia, dystonia and gait disorder, ie. parkinsonian )] TJ ET BT 26.250 225.482 Td /F1 9.8 Tf [(features )] TJ ET 0.267 0.267 0.267 rg BT 64.187 225.482 Td /F1 9.8 Tf [([7] [11] [12] [13] [14] [15] [16] [17])] TJ ET 0.271 0.267 0.267 rg BT 207.844 225.482 Td /F1 9.8 Tf [( . In addition, JHD patients are more likely to develop epilepsy than adult-onset cases )] TJ ET 0.267 0.267 0.267 rg BT 26.250 213.577 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 42.513 213.577 Td /F1 9.8 Tf [( . The spectrum of features at presentation can also include ataxia, dysarthria, dysphagia, deterioration in school )] TJ ET BT 26.250 201.672 Td /F1 9.8 Tf [(performance or severe behavioural problems)] TJ ET 0.267 0.267 0.267 rg BT 220.236 201.672 Td /F1 9.8 Tf [( [11] [14] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 296.130 201.672 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 182.268 Td /F1 9.8 Tf [(There is currently no effective disease-modifying treatment for either adult onset HD or JHD; therefore, clinical care is )] TJ ET BT 26.250 170.363 Td /F1 9.8 Tf [(symptomatic and supportive. The very different presentation means that different treatments are likely to be used in the )] TJ ET BT 26.250 158.458 Td /F1 9.8 Tf [(management of JHD versus adult onset HD. Given the rarity of the condition, each treating clinician is unlikely to have seen )] TJ ET BT 26.250 146.553 Td /F1 9.8 Tf [(more than a few cases and there are no treatment guidelines. Therefore, gathering together the limited information available is )] TJ ET BT 26.250 134.649 Td /F1 9.8 Tf [(of significant benefit to both families and physicians and helps form the basis of future trials.)] TJ ET BT 26.250 115.244 Td /F1 9.8 Tf [(For UK families affected by JHD, we composed a questionnaire, to be completed by the family, listing their childs symptoms )] TJ ET BT 26.250 103.339 Td /F1 9.8 Tf [(and treatments. The study received M-REC and local R&D approval. Patients were identified through the Patients Support )] TJ ET BT 26.250 91.434 Td /F1 9.8 Tf [(Group and Hospital Clinicians \(Neurologists and Clinical Geneticists\).)] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Current Pharmacological Management in Juvenile )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntingtons Disease)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(February 6, 2012)] TJ ET BT 88.388 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 93.263 675.088 Td /F3 9.8 Tf [(Epidemiology)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Lisa Robertson)] TJ ET 0.271 0.267 0.267 rg BT 91.819 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 97.240 663.247 Td /F1 9.8 Tf [(Helen Santini)] TJ ET 0.271 0.267 0.267 rg BT 155.223 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 160.644 663.247 Td /F1 9.8 Tf [(Kirsty L O'Donovan)] TJ ET 0.271 0.267 0.267 rg BT 244.328 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 249.749 663.247 Td /F1 9.8 Tf [(Ferdinando Squitieri)] TJ ET 0.271 0.267 0.267 rg BT 336.992 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 342.413 663.247 Td /F1 9.8 Tf [(Roger A. Barker)] TJ ET 0.271 0.267 0.267 rg BT 412.311 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 417.732 663.247 Td /F1 9.8 Tf [(Maria Rakowicz)] TJ ET 0.271 0.267 0.267 rg BT 486.528 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 491.949 663.247 Td /F1 9.8 Tf [(G. Bernhard )] TJ ET BT 26.250 651.342 Td /F1 9.8 Tf [(Landwehrmeyer)] TJ ET 0.271 0.267 0.267 rg BT 96.148 651.342 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 101.569 651.342 Td /F1 9.8 Tf [(Oliver Quarrell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 639.438 Td /F1 9.8 Tf [(Robertson L, Santini H, O'Donovan KL, Squitieri F, Barker RA, Rakowicz M, Landwehrmeyer GB, Quarrell O. Current )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(Pharmacological Management in Juvenile Huntingtons Disease. PLOS Currents Huntington Disease. 2012 Feb 6 . Edition 1. )] TJ ET BT 26.250 615.628 Td /F1 9.8 Tf [(doi: 10.1371/currents.RRN1304.)] TJ ET q 15.000 26.434 577.500 586.813 re W n 0.271 0.267 0.267 rg BT 26.250 586.526 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(Background: The clinical presentation of Juvenile Huntingtons Disease \(JHD\) can be very different from adult-onset HD with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(little evidence to guide symptomatic management.)] TJ ET BT 26.250 535.262 Td /F1 9.8 Tf [(Aim: To survey the current use of pharmacological treatments for JHD.)] TJ ET BT 26.250 515.857 Td /F1 9.8 Tf [(Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntingtons Disease )] TJ ET BT 26.250 503.952 Td /F1 9.8 Tf [(Network REGISTRY study.)] TJ ET BT 26.250 484.548 Td /F1 9.8 Tf [(Results: The most commonly prescribed agents were anti-psychotics \(24/45\), anti-depressants \(17/45\) and anti-parkinsonian )] TJ ET BT 26.250 472.643 Td /F1 9.8 Tf [(medications \(15/45\). 5 patients were taking more than 8 medications.)] TJ ET BT 26.250 453.238 Td /F1 9.8 Tf [(Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple )] TJ ET BT 26.250 441.333 Td /F1 9.8 Tf [(therapies, highlighting the need to rationalise medications.)] TJ ET BT 26.250 404.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 384.777 Td /F1 9.8 Tf [(We would like to acknowledge the funding for this project which we received from the Sheffield Childrens Hospital Charity )] TJ ET BT 26.250 372.872 Td /F1 9.8 Tf [(\(SCHC\).)] TJ ET BT 26.250 343.769 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 323.815 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is a dominantly inherited, neurodegenerative disorder, due to a \(CAG\)n repeat expansion in the HTT )] TJ ET BT 26.250 311.910 Td /F1 9.8 Tf [(gene [1] . In the majority of HD cases, onset is in adult life.)] TJ ET BT 26.250 292.506 Td /F1 9.8 Tf [(Juvenile HD \(JHD\)is defined as onset under 20 years of age )] TJ ET 0.267 0.267 0.267 rg BT 288.525 292.506 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 299.367 292.506 Td /F1 9.8 Tf [( and represents approximately 1-10% of cases )] TJ ET 0.267 0.267 0.267 rg BT 503.122 292.506 Td /F1 9.8 Tf [([3] [4] [5] [6] [7])] TJ ET 0.271 0.267 0.267 rg BT 568.174 292.506 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 280.601 Td /F1 9.8 Tf [(There is an inverse correlation between the age at onset of disease and the number of \(CAG\)n repeats)] TJ ET 0.267 0.267 0.267 rg BT 469.553 280.601 Td /F1 9.8 Tf [( [8] [9] [10])] TJ ET 0.271 0.267 0.267 rg BT 515.632 280.601 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 261.196 Td /F1 9.8 Tf [(Adult HD is characterised by a triad of clinical features including: chorea, cognitive decline and psychiatric disturbance or )] TJ ET BT 26.250 249.291 Td /F1 9.8 Tf [(behavioural disturbance)] TJ ET 0.267 0.267 0.267 rg BT 129.756 249.291 Td /F1 9.8 Tf [( [11] )] TJ ET 0.271 0.267 0.267 rg BT 151.440 249.291 Td /F1 9.8 Tf [(. However, in JHD, particularly in those with onset in the first decade, chorea is less likely to be )] TJ ET BT 26.250 237.387 Td /F1 9.8 Tf [(present and instead, patients are more likely to present with rigidity, bradykinesia, dystonia and gait disorder, ie. parkinsonian )] TJ ET BT 26.250 225.482 Td /F1 9.8 Tf [(features )] TJ ET 0.267 0.267 0.267 rg BT 64.187 225.482 Td /F1 9.8 Tf [([7] [11] [12] [13] [14] [15] [16] [17])] TJ ET 0.271 0.267 0.267 rg BT 207.844 225.482 Td /F1 9.8 Tf [( . In addition, JHD patients are more likely to develop epilepsy than adult-onset cases )] TJ ET 0.267 0.267 0.267 rg BT 26.250 213.577 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 42.513 213.577 Td /F1 9.8 Tf [( . The spectrum of features at presentation can also include ataxia, dysarthria, dysphagia, deterioration in school )] TJ ET BT 26.250 201.672 Td /F1 9.8 Tf [(performance or severe behavioural problems)] TJ ET 0.267 0.267 0.267 rg BT 220.236 201.672 Td /F1 9.8 Tf [( [11] [14] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 296.130 201.672 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 182.268 Td /F1 9.8 Tf [(There is currently no effective disease-modifying treatment for either adult onset HD or JHD; therefore, clinical care is )] TJ ET BT 26.250 170.363 Td /F1 9.8 Tf [(symptomatic and supportive. The very different presentation means that different treatments are likely to be used in the )] TJ ET BT 26.250 158.458 Td /F1 9.8 Tf [(management of JHD versus adult onset HD. Given the rarity of the condition, each treating clinician is unlikely to have seen )] TJ ET BT 26.250 146.553 Td /F1 9.8 Tf [(more than a few cases and there are no treatment guidelines. Therefore, gathering together the limited information available is )] TJ ET BT 26.250 134.649 Td /F1 9.8 Tf [(of significant benefit to both families and physicians and helps form the basis of future trials.)] TJ ET BT 26.250 115.244 Td /F1 9.8 Tf [(For UK families affected by JHD, we composed a questionnaire, to be completed by the family, listing their childs symptoms )] TJ ET BT 26.250 103.339 Td /F1 9.8 Tf [(and treatments. The study received M-REC and local R&D approval. Patients were identified through the Patients Support )] TJ ET BT 26.250 91.434 Td /F1 9.8 Tf [(Group and Hospital Clinicians \(Neurologists and Clinical Geneticists\).)] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Current Pharmacological Management in Juvenile )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(Huntingtons Disease)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(February 6, 2012)] TJ ET BT 88.388 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 93.263 675.088 Td /F3 9.8 Tf [(Epidemiology)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(Lisa Robertson)] TJ ET 0.271 0.267 0.267 rg BT 91.819 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 97.240 663.247 Td /F1 9.8 Tf [(Helen Santini)] TJ ET 0.271 0.267 0.267 rg BT 155.223 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 160.644 663.247 Td /F1 9.8 Tf [(Kirsty L O'Donovan)] TJ ET 0.271 0.267 0.267 rg BT 244.328 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 249.749 663.247 Td /F1 9.8 Tf [(Ferdinando Squitieri)] TJ ET 0.271 0.267 0.267 rg BT 336.992 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 342.413 663.247 Td /F1 9.8 Tf [(Roger A. Barker)] TJ ET 0.271 0.267 0.267 rg BT 412.311 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 417.732 663.247 Td /F1 9.8 Tf [(Maria Rakowicz)] TJ ET 0.271 0.267 0.267 rg BT 486.528 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 491.949 663.247 Td /F1 9.8 Tf [(G. Bernhard )] TJ ET BT 26.250 651.342 Td /F1 9.8 Tf [(Landwehrmeyer)] TJ ET 0.271 0.267 0.267 rg BT 96.148 651.342 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 101.569 651.342 Td /F1 9.8 Tf [(Oliver Quarrell)] TJ ET 0.271 0.267 0.267 rg BT 26.250 639.438 Td /F1 9.8 Tf [(Robertson L, Santini H, O'Donovan KL, Squitieri F, Barker RA, Rakowicz M, Landwehrmeyer GB, Quarrell O. Current )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(Pharmacological Management in Juvenile Huntingtons Disease. PLOS Currents Huntington Disease. 2012 Feb 6 . Edition 1. )] TJ ET BT 26.250 615.628 Td /F1 9.8 Tf [(doi: 10.1371/currents.RRN1304.)] TJ ET q 15.000 26.434 577.500 586.813 re W n 0.271 0.267 0.267 rg BT 26.250 586.526 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(Background: The clinical presentation of Juvenile Huntingtons Disease \(JHD\) can be very different from adult-onset HD with )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(little evidence to guide symptomatic management.)] TJ ET BT 26.250 535.262 Td /F1 9.8 Tf [(Aim: To survey the current use of pharmacological treatments for JHD.)] TJ ET BT 26.250 515.857 Td /F1 9.8 Tf [(Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntingtons Disease )] TJ ET BT 26.250 503.952 Td /F1 9.8 Tf [(Network REGISTRY study.)] TJ ET BT 26.250 484.548 Td /F1 9.8 Tf [(Results: The most commonly prescribed agents were anti-psychotics \(24/45\), anti-depressants \(17/45\) and anti-parkinsonian )] TJ ET BT 26.250 472.643 Td /F1 9.8 Tf [(medications \(15/45\). 5 patients were taking more than 8 medications.)] TJ ET BT 26.250 453.238 Td /F1 9.8 Tf [(Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple )] TJ ET BT 26.250 441.333 Td /F1 9.8 Tf [(therapies, highlighting the need to rationalise medications.)] TJ ET BT 26.250 404.731 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 384.777 Td /F1 9.8 Tf [(We would like to acknowledge the funding for this project which we received from the Sheffield Childrens Hospital Charity )] TJ ET BT 26.250 372.872 Td /F1 9.8 Tf [(\(SCHC\).)] TJ ET BT 26.250 343.769 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 323.815 Td /F1 9.8 Tf [(Huntingtons disease \(HD\) is a dominantly inherited, neurodegenerative disorder, due to a \(CAG\)n repeat expansion in the HTT )] TJ ET BT 26.250 311.910 Td /F1 9.8 Tf [(gene [1] . In the majority of HD cases, onset is in adult life.)] TJ ET BT 26.250 292.506 Td /F1 9.8 Tf [(Juvenile HD \(JHD\)is defined as onset under 20 years of age )] TJ ET 0.267 0.267 0.267 rg BT 288.525 292.506 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 299.367 292.506 Td /F1 9.8 Tf [( and represents approximately 1-10% of cases )] TJ ET 0.267 0.267 0.267 rg BT 503.122 292.506 Td /F1 9.8 Tf [([3] [4] [5] [6] [7])] TJ ET 0.271 0.267 0.267 rg BT 568.174 292.506 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 280.601 Td /F1 9.8 Tf [(There is an inverse correlation between the age at onset of disease and the number of \(CAG\)n repeats)] TJ ET 0.267 0.267 0.267 rg BT 469.553 280.601 Td /F1 9.8 Tf [( [8] [9] [10])] TJ ET 0.271 0.267 0.267 rg BT 515.632 280.601 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 261.196 Td /F1 9.8 Tf [(Adult HD is characterised by a triad of clinical features including: chorea, cognitive decline and psychiatric disturbance or )] TJ ET BT 26.250 249.291 Td /F1 9.8 Tf [(behavioural disturbance)] TJ ET 0.267 0.267 0.267 rg BT 129.756 249.291 Td /F1 9.8 Tf [( [11] )] TJ ET 0.271 0.267 0.267 rg BT 151.440 249.291 Td /F1 9.8 Tf [(. However, in JHD, particularly in those with onset in the first decade, chorea is less likely to be )] TJ ET BT 26.250 237.387 Td /F1 9.8 Tf [(present and instead, patients are more likely to present with rigidity, bradykinesia, dystonia and gait disorder, ie. parkinsonian )] TJ ET BT 26.250 225.482 Td /F1 9.8 Tf [(features )] TJ ET 0.267 0.267 0.267 rg BT 64.187 225.482 Td /F1 9.8 Tf [([7] [11] [12] [13] [14] [15] [16] [17])] TJ ET 0.271 0.267 0.267 rg BT 207.844 225.482 Td /F1 9.8 Tf [( . In addition, JHD patients are more likely to develop epilepsy than adult-onset cases )] TJ ET 0.267 0.267 0.267 rg BT 26.250 213.577 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 42.513 213.577 Td /F1 9.8 Tf [( . The spectrum of features at presentation can also include ataxia, dysarthria, dysphagia, deterioration in school )] TJ ET BT 26.250 201.672 Td /F1 9.8 Tf [(performance or severe behavioural problems)] TJ ET 0.267 0.267 0.267 rg BT 220.236 201.672 Td /F1 9.8 Tf [( [11] [14] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 296.130 201.672 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 182.268 Td /F1 9.8 Tf [(There is currently no effective disease-modifying treatment for either adult onset HD or JHD; therefore, clinical care is )] TJ ET BT 26.250 170.363 Td /F1 9.8 Tf [(symptomatic and supportive. The very different presentation means that different treatments are likely to be used in the )] TJ ET BT 26.250 158.458 Td /F1 9.8 Tf [(management of JHD versus adult onset HD. Given the rarity of the condition, each treating clinician is unlikely to have seen )] TJ ET BT 26.250 146.553 Td /F1 9.8 Tf [(more than a few cases and there are no treatment guidelines. Therefore, gathering together the limited information available is )] TJ ET BT 26.250 134.649 Td /F1 9.8 Tf [(of significant benefit to both families and physicians and helps form the basis of future trials.)] TJ ET BT 26.250 115.244 Td /F1 9.8 Tf [(For UK families affected by JHD, we composed a questionnaire, to be completed by the family, listing their childs symptoms )] TJ ET BT 26.250 103.339 Td /F1 9.8 Tf [(and treatments. The study received M-REC and local R&D approval. 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We used monitored case report forms from the European Huntingtons Disease )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Research Network \(EHDN\) REGISTRY project. This is a multinational observational study see www.euro-hd.net/html/registry )] TJ ET 0.267 0.267 0.267 rg BT 26.250 731.762 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 42.513 731.762 Td /F1 9.8 Tf [( . All medications were grouped according to the WHO ATC classification.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(In the UK, 40 questionnaires were sent out and seven families responded. 38 REGISTRY patients with JHD were identified.)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(In the UK cohort, the most common symptoms reported by the families were speech difficulties\(7\), dysphagia\(6\), )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(stiffness/spasticity\(6\), sleeping difficulty\(5\), pain\(4\) and behavioural problems\(4\) . Equivalent data from REGISTRY was not )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(available.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(When the data was combined the median number of medications prescribed was four, with an arithmetic mean of five \(range 1-)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16\) \(Fig 1\).)] TJ ET 0.965 0.965 0.965 rg 26.250 430.048 555.000 197.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 627.952 m 581.250 627.952 l 581.250 627.202 l 26.250 627.202 l f 26.250 430.048 m 581.250 430.048 l 581.250 430.798 l 26.250 430.798 l f q 225.000 0 0 153.000 35.250 465.202 cm /I4 Do Q q 35.250 441.298 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 449.679 Td /F4 9.8 Tf [(Fig. 1: No of agents prescribed to each patient \(combined data\))] TJ ET Q BT 26.250 413.024 Td /F1 9.8 Tf [(In REGISTRY, the most commonly prescribed agents were anti-psychotics, anti-depressants, anti-parkinsonianmedications and )] TJ ET BT 26.250 401.119 Td /F1 9.8 Tf [(anti-epileptics \(Fig 2\). 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We used monitored case report forms from the European Huntingtons Disease )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Research Network \(EHDN\) REGISTRY project. This is a multinational observational study see www.euro-hd.net/html/registry )] TJ ET 0.267 0.267 0.267 rg BT 26.250 731.762 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 42.513 731.762 Td /F1 9.8 Tf [( . All medications were grouped according to the WHO ATC classification.)] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(In the UK, 40 questionnaires were sent out and seven families responded. 38 REGISTRY patients with JHD were identified.)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(In the UK cohort, the most common symptoms reported by the families were speech difficulties\(7\), dysphagia\(6\), )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(stiffness/spasticity\(6\), sleeping difficulty\(5\), pain\(4\) and behavioural problems\(4\) . Equivalent data from REGISTRY was not )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(available.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(When the data was combined the median number of medications prescribed was four, with an arithmetic mean of five \(range 1-)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16\) \(Fig 1\).)] TJ ET 0.965 0.965 0.965 rg 26.250 430.048 555.000 197.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 627.952 m 581.250 627.952 l 581.250 627.202 l 26.250 627.202 l f 26.250 430.048 m 581.250 430.048 l 581.250 430.798 l 26.250 430.798 l f q 225.000 0 0 153.000 35.250 465.202 cm /I10 Do Q q 35.250 441.298 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 449.679 Td /F4 9.8 Tf [(Fig. 1: No of agents prescribed to each patient \(combined data\))] TJ ET Q BT 26.250 413.024 Td /F1 9.8 Tf [(In REGISTRY, the most commonly prescribed agents were anti-psychotics, anti-depressants, anti-parkinsonianmedications and )] TJ ET BT 26.250 401.119 Td /F1 9.8 Tf [(anti-epileptics \(Fig 2\). 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Equivalent data from REGISTRY was not )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(available.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(When the data was combined the median number of medications prescribed was four, with an arithmetic mean of five \(range 1-)] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(16\) \(Fig 1\).)] TJ ET 0.965 0.965 0.965 rg 26.250 430.048 555.000 197.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 627.952 m 581.250 627.952 l 581.250 627.202 l 26.250 627.202 l f 26.250 430.048 m 581.250 430.048 l 581.250 430.798 l 26.250 430.798 l f q 225.000 0 0 153.000 35.250 465.202 cm /I16 Do Q q 35.250 441.298 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 449.679 Td /F4 9.8 Tf [(Fig. 1: No of agents prescribed to each patient \(combined data\))] TJ ET Q BT 26.250 413.024 Td /F1 9.8 Tf [(In REGISTRY, the most commonly prescribed agents were anti-psychotics, anti-depressants, anti-parkinsonianmedications and )] TJ ET BT 26.250 401.119 Td /F1 9.8 Tf [(anti-epileptics \(Fig 2\). In the UK, the anti-psychotic was the most commonly prescribed agent \(Fig 3\).)] TJ ET 0.965 0.965 0.965 rg 26.250 211.333 555.000 179.905 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 391.238 m 581.250 391.238 l 581.250 390.488 l 26.250 390.488 l f 26.250 211.333 m 581.250 211.333 l 581.250 212.083 l 26.250 212.083 l f q 225.000 0 0 135.000 35.250 246.488 cm /I18 Do Q q 35.250 222.583 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 230.964 Td /F4 9.8 Tf [(Fig. 2: Classes of medicines prescribed \(European Data\))] TJ ET Q 0.965 0.965 0.965 rg 26.250 53.083 555.000 150.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 203.833 m 581.250 203.833 l 581.250 203.083 l 26.250 203.083 l f q 225.000 0 0 135.000 35.250 59.083 cm /I20 Do Q q 35.250 53.083 537.000 0.000 re W n Q Q q 225.000 0 0 153.000 35.250 465.202 cm /I22 Do Q q 225.000 0 0 135.000 35.250 246.488 cm /I24 Do Q q 225.000 0 0 135.000 35.250 59.083 cm /I26 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 130 0 obj << /Type /Annot /Subtype /Link /A 131 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 730.8601 42.5130 740.7807 ] >> endobj 131 0 obj << /Type /Action >> endobj 132 0 obj << /Type /Annot /Subtype /Link /A 133 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 465.2025 260.2500 618.2025 ] >> endobj 133 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2012/02/fig-1_2028129_001.png) >> endobj 134 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 204 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 437>> stream xA 0 =fy9뀟\U? 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X,8cH!DUB'7*BrAȸXw y˜1Bfʕ +++E;F4ܴi:":e˖P?|ʝ6IjE.q$▅)&2A\kGU"BĒn3 ?oY#hBVm1hgloKBXKTsp 1F6 6ʇ\<4 $Cnn& ,*8ܚ:P<%ПPvm11qA,"$؀+pO`ofRB#fő*)cPTxi5k<=8QQ\D(D$lm6 yRDYB Ɋ=+Ȋ^ GhP<1vl;Q5#(Upzg=^&s!#\e8y&JW`{r e m1$`9 8ڬ(idɦ*fN $'{źHƠbV̯XYQ^bnϝ=s]48 &hy7@y{MװD 8%hڷ /<񌳟Y Pzя–OsyO~}/sE;^o4W|tc2n $ycM>aٳ/Ow5fc%~Mj񘹩Cr6IF"g(OL ϟ?{,Z1kbNǮQnrk Q=z`{/۠b"*~_Ͽ?,qYϴ.Ky Lki#n_x)kMzaeY  H&N`VE&"=`=ӑf%"Q; hneq 8*M#lN~"=pL|]v=5{@SC}v':N"X_bXɊT>}x;[dxmflZzݪhFVhFGN#ֻw뚩QqChd\v40C”8W=pZfn`oaI-/sd]>X_Οad2cIS~6k Gj9—~tb$ʵZ2;L{\ _!M$`K914{(TO{[CTN[貳)E3)̶ PwW2ڇF`WdRF>6J$ˋݡ/=^{oںO?R$Ӳúj!{' . 8ȼm CL]wm3Pш (zI!+OlnSG׍Xfǩ?GC-_g|훯wW'5Č&ng}z%4og+)~[ ۭۛi晿+w>szM@cź"F (cX'1Mfx8k)FqWkpi~=Q};DbZjcz;w‚K s8+E$(֚mР^Y9eJ3@>.{J"͡G ;gq9-P(DK۳cA67 jY\GЩSi$N/4QlR[nM|[lX)q&aKF<H9۵M:"ZĖ⒛?5yG |NqR5Ďgag[代$1y^0-f"J'ql&h"F3Q sps2`C:ڑ~XRt08żk<+U(rs&@k\)L#EaxrlQ@zľ|lArհlxD A(s\AÁuDA^ yDT%XpeDrawcYȶǹhy[`V!ې9J#Wf>(t> endobj 179 0 obj << /Length 22521 >> stream q 15.000 48.122 577.500 728.878 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 3: Classes of medicines prescribed \(UK data\))] TJ ET Q BT 26.250 730.821 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(anti-epileptic\), followed jointly by: Tiapride \(anti-)] TJ ET BT 26.250 718.917 Td /F1 9.8 Tf [(psychotic\), Dopa and Dopa derivatives \(anti-parkinsonian\) and Tocopherol \(vitamin preparation\) \(Fig 4\).)] TJ ET 0.965 0.965 0.965 rg 26.250 530.631 555.000 178.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.036 m 581.250 709.036 l 581.250 708.286 l 26.250 708.286 l f 26.250 530.631 m 581.250 530.631 l 581.250 531.381 l 26.250 531.381 l f q 225.000 0 0 133.500 35.250 565.786 cm /I28 Do Q q 35.250 541.881 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 550.262 Td /F4 9.8 Tf [(Fig. 4: The most commonly prescribed medicines, arranged by group)] TJ ET Q BT 26.250 496.409 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 476.455 Td /F1 9.8 Tf [(The most commonly prescribed medication in our cohort was the anti-psychotic agent \(24/45 individuals\). In the UK group, the )] TJ ET BT 26.250 464.550 Td /F1 9.8 Tf [(family member completing the questionnaire was asked to give the indication for each medication, and for anti-psychotics this )] TJ ET BT 26.250 452.646 Td /F1 9.8 Tf [(included: agitation, behavioural problems and psychiatric disturbances, none of which are listed as diagnostic features of JHD. )] TJ ET BT 26.250 440.741 Td /F1 9.8 Tf [(This is important as it is recognised that children presenting with behavioural or psychiatric problems often experience a )] TJ ET BT 26.250 428.836 Td /F1 9.8 Tf [(significant delay in receiving a diagnosis of JHD)] TJ ET 0.267 0.267 0.267 rg BT 232.160 428.836 Td /F1 9.8 Tf [( [14])] TJ ET 0.271 0.267 0.267 rg BT 251.134 428.836 Td /F1 9.8 Tf [( , and our data would infer that such problems are common in this age )] TJ ET BT 26.250 416.931 Td /F1 9.8 Tf [(group affected by HD.)] TJ ET BT 26.250 397.527 Td /F1 9.8 Tf [(Anti-depressants and anti-parkinsonian agents were also frequently prescribed \(n=17 and n=15 respectively\) and some \(n=7\) )] TJ ET BT 26.250 385.622 Td /F1 9.8 Tf [(were taking a combination of anti-parkinsonian medications and anti-psychotics. This odd regime often reflects the combination )] TJ ET BT 26.250 373.717 Td /F1 9.8 Tf [(of dystonia and parkinsonism seen in JHD, although whether it is a useful combination is unclear especially given the )] TJ ET BT 26.250 361.812 Td /F1 9.8 Tf [(recognised parkinsonian side-effects of anti-psychotics)] TJ ET 0.267 0.267 0.267 rg BT 262.512 361.812 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 281.486 361.812 Td /F1 9.8 Tf [( . This side-effect is less frequent with the atypical anti-psychotics )] TJ ET BT 26.250 349.908 Td /F1 9.8 Tf [(than in first generation anti-psychotics, but does still occur and it may be difficult to distinguish from disease progression.)] TJ ET BT 26.250 330.503 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(8\), reflecting consistency in anti-epileptic prescribing. )] TJ ET BT 26.250 318.598 Td /F1 9.8 Tf [(This is in-line with prescribing practice in the management of childhood epilepsy of all causes)] TJ ET 0.267 0.267 0.267 rg BT 427.238 318.598 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 446.212 318.598 Td /F1 9.8 Tf [( ; Valproic acid is widely used )] TJ ET BT 26.250 306.693 Td /F1 9.8 Tf [(as first-line therapy for generalised seizures with a strong evidence base to support its efficacy )] TJ ET 0.267 0.267 0.267 rg BT 435.380 306.693 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 451.642 306.693 Td /F1 9.8 Tf [( . At present, as there is no )] TJ ET BT 26.250 294.789 Td /F1 9.8 Tf [(disease-modifiying therapy available, the optimum management of JHD encompasses the optimum management of the )] TJ ET BT 26.250 282.884 Td /F1 9.8 Tf [(associated symptoms.)] TJ ET BT 26.250 263.479 Td /F1 9.8 Tf [(Five patients were prescribed in excess of eight types of medications. The highest number of medications for any one patient )] TJ ET BT 26.250 251.574 Td /F1 9.8 Tf [(was sixteen, raising issues of polypharmacy. This is a particularly important issue in a group of patients with swallowing )] TJ ET BT 26.250 239.670 Td /F1 9.8 Tf [(difficulties. Three patients were on three or more anti-pyschotic agents or anti-parkinsonism agents simultaneously: which )] TJ ET BT 26.250 227.765 Td /F1 9.8 Tf [(highlights the fact that many cases of JHD appear to be refractory to pharmacotherapies.)] TJ ET BT 26.250 208.360 Td /F1 9.8 Tf [(An apparent difference in prescribing habits was noted between the two populations of patients studied: within the UK, opioids )] TJ ET BT 26.250 196.455 Td /F1 9.8 Tf [(were prescribed whereas in the REGISTRY group they were not, this may be due to variations in national restrictions)] TJ ET 0.267 0.267 0.267 rg BT 529.662 196.455 Td /F1 9.8 Tf [( [25])] TJ ET 0.271 0.267 0.267 rg BT 548.635 196.455 Td /F1 9.8 Tf [( . For )] TJ ET BT 26.250 184.551 Td /F1 9.8 Tf [(certain individuals with JHD, pain can be a feature and from our own experience this can be difficult to manage and the input of )] TJ ET BT 26.250 172.646 Td /F1 9.8 Tf [(a specialist pain team or palliative care specialists can be invaluable)] TJ ET 0.267 0.267 0.267 rg BT 319.949 172.646 Td /F1 9.8 Tf [( [26])] TJ ET 0.271 0.267 0.267 rg BT 338.923 172.646 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 153.241 Td /F1 9.8 Tf [(The diagnostic features of HD presenting in the first decade are a family history of HD, often in the father \(though onset in the )] TJ ET BT 26.250 141.336 Td /F1 9.8 Tf [(child may precede onset in the parent\), and two or more of the following: declining school performance, seizures, oral motor )] TJ ET BT 26.250 129.432 Td /F1 9.8 Tf [(dysfunction, rigidity and gait disorder )] TJ ET 0.267 0.267 0.267 rg BT 187.193 129.432 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 203.456 129.432 Td /F1 9.8 Tf [( . We analysed the data based on age of diagnosis \(Fig 4\); we hypothesized that those )] TJ ET BT 26.250 117.527 Td /F1 9.8 Tf [(who were older at diagnosis may have a profile more akin to adult JHD with a lower incidence of rigidity, dystonia and epilepsy. )] TJ ET BT 26.250 105.622 Td /F1 9.8 Tf [(We therefore divided patients into three groups, those diagnosed at 10 years of age or under \(n=6\), those diagnosed between )] TJ ET BT 26.250 93.717 Td /F1 9.8 Tf [(11 to 15 years of age \(n=12\) and those diagnosed between 16 to 20 years \(n=26\). The age at diagnosis was unknown in one )] TJ ET BT 26.250 81.813 Td /F1 9.8 Tf [(case \(n=1\). We observed that those who were diagnosed at 10 years or under were significantly more likely to be prescribed a )] TJ ET BT 26.250 69.908 Td /F1 9.8 Tf [(muscle relaxant than those diagnosed between ages 11-20 years \(Fishers exact test, p=0.01\). There was no apparent trend )] TJ ET BT 26.250 58.003 Td /F1 9.8 Tf [(between younger age at diagnosis and the frequency of prescription of anti-epileptics or anti-parkinsonian agents.)] TJ ET Q q 15.000 48.122 577.500 728.878 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 3: Classes of medicines prescribed \(UK data\))] TJ ET Q BT 26.250 730.821 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(anti-epileptic\), followed jointly by: Tiapride \(anti-)] TJ ET BT 26.250 718.917 Td /F1 9.8 Tf [(psychotic\), Dopa and Dopa derivatives \(anti-parkinsonian\) and Tocopherol \(vitamin preparation\) \(Fig 4\).)] TJ ET 0.965 0.965 0.965 rg 26.250 530.631 555.000 178.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.036 m 581.250 709.036 l 581.250 708.286 l 26.250 708.286 l f 26.250 530.631 m 581.250 530.631 l 581.250 531.381 l 26.250 531.381 l f q 225.000 0 0 133.500 35.250 565.786 cm /I30 Do Q q 35.250 541.881 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 550.262 Td /F4 9.8 Tf [(Fig. 4: The most commonly prescribed medicines, arranged by group)] TJ ET Q BT 26.250 496.409 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 476.455 Td /F1 9.8 Tf [(The most commonly prescribed medication in our cohort was the anti-psychotic agent \(24/45 individuals\). In the UK group, the )] TJ ET BT 26.250 464.550 Td /F1 9.8 Tf [(family member completing the questionnaire was asked to give the indication for each medication, and for anti-psychotics this )] TJ ET BT 26.250 452.646 Td /F1 9.8 Tf [(included: agitation, behavioural problems and psychiatric disturbances, none of which are listed as diagnostic features of JHD. )] TJ ET BT 26.250 440.741 Td /F1 9.8 Tf [(This is important as it is recognised that children presenting with behavioural or psychiatric problems often experience a )] TJ ET BT 26.250 428.836 Td /F1 9.8 Tf [(significant delay in receiving a diagnosis of JHD)] TJ ET 0.267 0.267 0.267 rg BT 232.160 428.836 Td /F1 9.8 Tf [( [14])] TJ ET 0.271 0.267 0.267 rg BT 251.134 428.836 Td /F1 9.8 Tf [( , and our data would infer that such problems are common in this age )] TJ ET BT 26.250 416.931 Td /F1 9.8 Tf [(group affected by HD.)] TJ ET BT 26.250 397.527 Td /F1 9.8 Tf [(Anti-depressants and anti-parkinsonian agents were also frequently prescribed \(n=17 and n=15 respectively\) and some \(n=7\) )] TJ ET BT 26.250 385.622 Td /F1 9.8 Tf [(were taking a combination of anti-parkinsonian medications and anti-psychotics. This odd regime often reflects the combination )] TJ ET BT 26.250 373.717 Td /F1 9.8 Tf [(of dystonia and parkinsonism seen in JHD, although whether it is a useful combination is unclear especially given the )] TJ ET BT 26.250 361.812 Td /F1 9.8 Tf [(recognised parkinsonian side-effects of anti-psychotics)] TJ ET 0.267 0.267 0.267 rg BT 262.512 361.812 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 281.486 361.812 Td /F1 9.8 Tf [( . This side-effect is less frequent with the atypical anti-psychotics )] TJ ET BT 26.250 349.908 Td /F1 9.8 Tf [(than in first generation anti-psychotics, but does still occur and it may be difficult to distinguish from disease progression.)] TJ ET BT 26.250 330.503 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(8\), reflecting consistency in anti-epileptic prescribing. )] TJ ET BT 26.250 318.598 Td /F1 9.8 Tf [(This is in-line with prescribing practice in the management of childhood epilepsy of all causes)] TJ ET 0.267 0.267 0.267 rg BT 427.238 318.598 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 446.212 318.598 Td /F1 9.8 Tf [( ; Valproic acid is widely used )] TJ ET BT 26.250 306.693 Td /F1 9.8 Tf [(as first-line therapy for generalised seizures with a strong evidence base to support its efficacy )] TJ ET 0.267 0.267 0.267 rg BT 435.380 306.693 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 451.642 306.693 Td /F1 9.8 Tf [( . At present, as there is no )] TJ ET BT 26.250 294.789 Td /F1 9.8 Tf [(disease-modifiying therapy available, the optimum management of JHD encompasses the optimum management of the )] TJ ET BT 26.250 282.884 Td /F1 9.8 Tf [(associated symptoms.)] TJ ET BT 26.250 263.479 Td /F1 9.8 Tf [(Five patients were prescribed in excess of eight types of medications. The highest number of medications for any one patient )] TJ ET BT 26.250 251.574 Td /F1 9.8 Tf [(was sixteen, raising issues of polypharmacy. This is a particularly important issue in a group of patients with swallowing )] TJ ET BT 26.250 239.670 Td /F1 9.8 Tf [(difficulties. Three patients were on three or more anti-pyschotic agents or anti-parkinsonism agents simultaneously: which )] TJ ET BT 26.250 227.765 Td /F1 9.8 Tf [(highlights the fact that many cases of JHD appear to be refractory to pharmacotherapies.)] TJ ET BT 26.250 208.360 Td /F1 9.8 Tf [(An apparent difference in prescribing habits was noted between the two populations of patients studied: within the UK, opioids )] TJ ET BT 26.250 196.455 Td /F1 9.8 Tf [(were prescribed whereas in the REGISTRY group they were not, this may be due to variations in national restrictions)] TJ ET 0.267 0.267 0.267 rg BT 529.662 196.455 Td /F1 9.8 Tf [( [25])] TJ ET 0.271 0.267 0.267 rg BT 548.635 196.455 Td /F1 9.8 Tf [( . For )] TJ ET BT 26.250 184.551 Td /F1 9.8 Tf [(certain individuals with JHD, pain can be a feature and from our own experience this can be difficult to manage and the input of )] TJ ET BT 26.250 172.646 Td /F1 9.8 Tf [(a specialist pain team or palliative care specialists can be invaluable)] TJ ET 0.267 0.267 0.267 rg BT 319.949 172.646 Td /F1 9.8 Tf [( [26])] TJ ET 0.271 0.267 0.267 rg BT 338.923 172.646 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 153.241 Td /F1 9.8 Tf [(The diagnostic features of HD presenting in the first decade are a family history of HD, often in the father \(though onset in the )] TJ ET BT 26.250 141.336 Td /F1 9.8 Tf [(child may precede onset in the parent\), and two or more of the following: declining school performance, seizures, oral motor )] TJ ET BT 26.250 129.432 Td /F1 9.8 Tf [(dysfunction, rigidity and gait disorder )] TJ ET 0.267 0.267 0.267 rg BT 187.193 129.432 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 203.456 129.432 Td /F1 9.8 Tf [( . We analysed the data based on age of diagnosis \(Fig 4\); we hypothesized that those )] TJ ET BT 26.250 117.527 Td /F1 9.8 Tf [(who were older at diagnosis may have a profile more akin to adult JHD with a lower incidence of rigidity, dystonia and epilepsy. )] TJ ET BT 26.250 105.622 Td /F1 9.8 Tf [(We therefore divided patients into three groups, those diagnosed at 10 years of age or under \(n=6\), those diagnosed between )] TJ ET BT 26.250 93.717 Td /F1 9.8 Tf [(11 to 15 years of age \(n=12\) and those diagnosed between 16 to 20 years \(n=26\). The age at diagnosis was unknown in one )] TJ ET BT 26.250 81.813 Td /F1 9.8 Tf [(case \(n=1\). We observed that those who were diagnosed at 10 years or under were significantly more likely to be prescribed a )] TJ ET BT 26.250 69.908 Td /F1 9.8 Tf [(muscle relaxant than those diagnosed between ages 11-20 years \(Fishers exact test, p=0.01\). There was no apparent trend )] TJ ET BT 26.250 58.003 Td /F1 9.8 Tf [(between younger age at diagnosis and the frequency of prescription of anti-epileptics or anti-parkinsonian agents.)] TJ ET Q q 15.000 48.122 577.500 728.878 re W n 0.965 0.965 0.965 rg 26.250 747.845 555.000 29.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 747.845 m 581.250 747.845 l 581.250 748.595 l 26.250 748.595 l f q 35.250 759.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 767.476 Td /F4 9.8 Tf [(Fig. 3: Classes of medicines prescribed \(UK data\))] TJ ET Q BT 26.250 730.821 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(anti-epileptic\), followed jointly by: Tiapride \(anti-)] TJ ET BT 26.250 718.917 Td /F1 9.8 Tf [(psychotic\), Dopa and Dopa derivatives \(anti-parkinsonian\) and Tocopherol \(vitamin preparation\) \(Fig 4\).)] TJ ET 0.965 0.965 0.965 rg 26.250 530.631 555.000 178.405 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 709.036 m 581.250 709.036 l 581.250 708.286 l 26.250 708.286 l f 26.250 530.631 m 581.250 530.631 l 581.250 531.381 l 26.250 531.381 l f q 225.000 0 0 133.500 35.250 565.786 cm /I32 Do Q q 35.250 541.881 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 550.262 Td /F4 9.8 Tf [(Fig. 4: The most commonly prescribed medicines, arranged by group)] TJ ET Q BT 26.250 496.409 Td /F4 12.0 Tf [(Discussion)] TJ ET BT 26.250 476.455 Td /F1 9.8 Tf [(The most commonly prescribed medication in our cohort was the anti-psychotic agent \(24/45 individuals\). In the UK group, the )] TJ ET BT 26.250 464.550 Td /F1 9.8 Tf [(family member completing the questionnaire was asked to give the indication for each medication, and for anti-psychotics this )] TJ ET BT 26.250 452.646 Td /F1 9.8 Tf [(included: agitation, behavioural problems and psychiatric disturbances, none of which are listed as diagnostic features of JHD. )] TJ ET BT 26.250 440.741 Td /F1 9.8 Tf [(This is important as it is recognised that children presenting with behavioural or psychiatric problems often experience a )] TJ ET BT 26.250 428.836 Td /F1 9.8 Tf [(significant delay in receiving a diagnosis of JHD)] TJ ET 0.267 0.267 0.267 rg BT 232.160 428.836 Td /F1 9.8 Tf [( [14])] TJ ET 0.271 0.267 0.267 rg BT 251.134 428.836 Td /F1 9.8 Tf [( , and our data would infer that such problems are common in this age )] TJ ET BT 26.250 416.931 Td /F1 9.8 Tf [(group affected by HD.)] TJ ET BT 26.250 397.527 Td /F1 9.8 Tf [(Anti-depressants and anti-parkinsonian agents were also frequently prescribed \(n=17 and n=15 respectively\) and some \(n=7\) )] TJ ET BT 26.250 385.622 Td /F1 9.8 Tf [(were taking a combination of anti-parkinsonian medications and anti-psychotics. This odd regime often reflects the combination )] TJ ET BT 26.250 373.717 Td /F1 9.8 Tf [(of dystonia and parkinsonism seen in JHD, although whether it is a useful combination is unclear especially given the )] TJ ET BT 26.250 361.812 Td /F1 9.8 Tf [(recognised parkinsonian side-effects of anti-psychotics)] TJ ET 0.267 0.267 0.267 rg BT 262.512 361.812 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 281.486 361.812 Td /F1 9.8 Tf [( . This side-effect is less frequent with the atypical anti-psychotics )] TJ ET BT 26.250 349.908 Td /F1 9.8 Tf [(than in first generation anti-psychotics, but does still occur and it may be difficult to distinguish from disease progression.)] TJ ET BT 26.250 330.503 Td /F1 9.8 Tf [(The most commonly prescribed individual medication was Valproic acid \(8\), reflecting consistency in anti-epileptic prescribing. )] TJ ET BT 26.250 318.598 Td /F1 9.8 Tf [(This is in-line with prescribing practice in the management of childhood epilepsy of all causes)] TJ ET 0.267 0.267 0.267 rg BT 427.238 318.598 Td /F1 9.8 Tf [( [23])] TJ ET 0.271 0.267 0.267 rg BT 446.212 318.598 Td /F1 9.8 Tf [( ; Valproic acid is widely used )] TJ ET BT 26.250 306.693 Td /F1 9.8 Tf [(as first-line therapy for generalised seizures with a strong evidence base to support its efficacy )] TJ ET 0.267 0.267 0.267 rg BT 435.380 306.693 Td /F1 9.8 Tf [([24])] TJ ET 0.271 0.267 0.267 rg BT 451.642 306.693 Td /F1 9.8 Tf [( . At present, as there is no )] TJ ET BT 26.250 294.789 Td /F1 9.8 Tf [(disease-modifiying therapy available, the optimum management of JHD encompasses the optimum management of the )] TJ ET BT 26.250 282.884 Td /F1 9.8 Tf [(associated symptoms.)] TJ ET BT 26.250 263.479 Td /F1 9.8 Tf [(Five patients were prescribed in excess of eight types of medications. The highest number of medications for any one patient )] TJ ET BT 26.250 251.574 Td /F1 9.8 Tf [(was sixteen, raising issues of polypharmacy. This is a particularly important issue in a group of patients with swallowing )] TJ ET BT 26.250 239.670 Td /F1 9.8 Tf [(difficulties. Three patients were on three or more anti-pyschotic agents or anti-parkinsonism agents simultaneously: which )] TJ ET BT 26.250 227.765 Td /F1 9.8 Tf [(highlights the fact that many cases of JHD appear to be refractory to pharmacotherapies.)] TJ ET BT 26.250 208.360 Td /F1 9.8 Tf [(An apparent difference in prescribing habits was noted between the two populations of patients studied: within the UK, opioids )] TJ ET BT 26.250 196.455 Td /F1 9.8 Tf [(were prescribed whereas in the REGISTRY group they were not, this may be due to variations in national restrictions)] TJ ET 0.267 0.267 0.267 rg BT 529.662 196.455 Td /F1 9.8 Tf [( [25])] TJ ET 0.271 0.267 0.267 rg BT 548.635 196.455 Td /F1 9.8 Tf [( . For )] TJ ET BT 26.250 184.551 Td /F1 9.8 Tf [(certain individuals with JHD, pain can be a feature and from our own experience this can be difficult to manage and the input of )] TJ ET BT 26.250 172.646 Td /F1 9.8 Tf [(a specialist pain team or palliative care specialists can be invaluable)] TJ ET 0.267 0.267 0.267 rg BT 319.949 172.646 Td /F1 9.8 Tf [( [26])] TJ ET 0.271 0.267 0.267 rg BT 338.923 172.646 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 153.241 Td /F1 9.8 Tf [(The diagnostic features of HD presenting in the first decade are a family history of HD, often in the father \(though onset in the )] TJ ET BT 26.250 141.336 Td /F1 9.8 Tf [(child may precede onset in the parent\), and two or more of the following: declining school performance, seizures, oral motor )] TJ ET BT 26.250 129.432 Td /F1 9.8 Tf [(dysfunction, rigidity and gait disorder )] TJ ET 0.267 0.267 0.267 rg BT 187.193 129.432 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 203.456 129.432 Td /F1 9.8 Tf [( . We analysed the data based on age of diagnosis \(Fig 4\); we hypothesized that those )] TJ ET BT 26.250 117.527 Td /F1 9.8 Tf [(who were older at diagnosis may have a profile more akin to adult JHD with a lower incidence of rigidity, dystonia and epilepsy. )] TJ ET BT 26.250 105.622 Td /F1 9.8 Tf [(We therefore divided patients into three groups, those diagnosed at 10 years of age or under \(n=6\), those diagnosed between )] TJ ET BT 26.250 93.717 Td /F1 9.8 Tf [(11 to 15 years of age \(n=12\) and those diagnosed between 16 to 20 years \(n=26\). The age at diagnosis was unknown in one )] TJ ET BT 26.250 81.813 Td /F1 9.8 Tf [(case \(n=1\). We observed that those who were diagnosed at 10 years or under were significantly more likely to be prescribed a )] TJ ET BT 26.250 69.908 Td /F1 9.8 Tf [(muscle relaxant than those diagnosed between ages 11-20 years \(Fishers exact test, p=0.01\). There was no apparent trend )] TJ ET BT 26.250 58.003 Td /F1 9.8 Tf [(between younger age at diagnosis and the frequency of prescription of anti-epileptics or anti-parkinsonian agents.)] TJ ET Q q 225.000 0 0 133.500 35.250 565.786 cm /I34 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 180 0 obj << /Type /Annot /Subtype /Link /A 181 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 565.7858 260.2500 699.2858 ] >> endobj 181 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2012/02/newfig42.png) >> endobj 182 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 178 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 385>> stream xA 0 =fy9뀟\ endstream endobj 183 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 178 /SMask 182 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 38445>> stream xwUյ8w镙a W [%FchOMbb-."(`^C}^k3?|sY{ϾEL:===c޽J!5%.Ԍ$+I5Cb%ǨyH$w xl^^d^&!D8ݮ@ O"YKhQˢEaYC'Ɩ6_/E[19!"I/`yk8\{"''Ռg8ol/>myƎG8k9i{$7%X݀Rr1 ڜ]7U9FN{9$ pY%i8؇ P( yg:1 W+/N*<ƒf#Nr$5/|z2A8NN< .!4gL(FV|D%##B_ Q wl,/>13K]Bd-Wvy/x,.N`VBmcf>dhc'31s>L(%"sj+cu 4"IBD:! 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The diversity of their problems means they are often prescribed medications which exceed )] TJ ET BT 26.250 467.550 Td /F1 9.8 Tf [(the area of expertise of a single hospital specialist. Their medications require regular review by a team of experts, in the face of )] TJ ET BT 26.250 455.646 Td /F1 9.8 Tf [(evolving symptoms. Polypharmacy is an issue in this group, highlighting a potential need for reviewing and stopping medicines, )] TJ ET BT 26.250 443.741 Td /F1 9.8 Tf [(especially when they appear to be ineffective.)] TJ ET BT 26.250 424.336 Td /F1 9.8 Tf [(Identifying current practice is only a first step towards establishing an evidence base for treatment guidelines. JHD is a rare )] TJ ET BT 26.250 412.431 Td /F1 9.8 Tf [(condition which means that international collaboration is essential to gather information on the effectiveness of symptomatic )] TJ ET BT 26.250 400.527 Td /F1 9.8 Tf [(management. Projects such as REGISTRY are vital in order to establish such information. Ultimately we would hope that it will )] TJ ET BT 26.250 388.622 Td /F1 9.8 Tf [(be possible to use such a database to identify affected patients and conduct a randomised trial on the effectiveness of different )] TJ ET BT 26.250 376.717 Td /F1 9.8 Tf [(symptomatic treatments in this form of HD.)] TJ ET BT 26.250 340.115 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 320.160 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 283.558 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 263.604 Td /F1 9.8 Tf [(We would like to acknowledge the time and effort of the patients and families who participated in this study.)] TJ ET BT 26.250 251.699 Td /F1 9.8 Tf [(We would also like to acknowledge Mrs. Wendy Swan, Clinical Research Co-ordinator, for her assistance with research )] TJ ET BT 26.250 239.794 Td /F1 9.8 Tf [(governance.)] TJ ET BT 26.250 227.889 Td /F1 9.8 Tf [(We would also like to acknowledge the following individuals from the REGISTRY study: )] TJ ET BT 26.250 215.985 Td /F1 9.8 Tf [(Registry Steering commmittee: A-C Bachoud-Lvi, AR Bentivoglio, I Biunno, RM Bonelli, J-M Burgunder, SB Dunnett, JJ )] TJ ET BT 26.250 204.080 Td /F1 9.8 Tf [(Ferreira, OJ Handley, A Heiberg, T Illmann, GB Landwehrmeyer, J Levey, JE Nielsen, M Pivrinta, RAC Roos, A Rojo )] TJ ET BT 26.250 192.175 Td /F1 9.8 Tf [(Sebastin, SJ Tabrizi, W Vandenberghe, C Verellen-Dumoulin, J Zaremba, T Uhrova, J Wahlstrm )] TJ ET BT 26.250 180.270 Td /F1 9.8 Tf [(Language coordinators: Katrin Barth, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuana Garde, Reineke Bos, )] TJ ET BT 26.250 168.366 Td /F1 9.8 Tf [(Christine Held, Kerstin Koppers; Matilde Laur, Asuncin Martnez Descals, Tiago Mestre, Sara Minster, Daniela Monza, Jenny )] TJ ET BT 26.250 156.461 Td /F1 9.8 Tf [(Townhill \(formerly Naji\), Michael Orth, Helene Padieu, Laurent Paterski; Nadia Peppa, Susana Pro Koivisto, Amandine Rialland, )] TJ ET BT 26.250 144.556 Td /F1 9.8 Tf [(Niini Rren \(formerly Heinonen\) Pavla ainkov, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-An, )] TJ ET BT 26.250 132.651 Td /F1 9.8 Tf [(Elizaveta Yudina \(formerly Tarasova\), Daniel Zielonka, Paola Zinzi )] TJ ET BT 26.250 120.747 Td /F1 9.8 Tf [(Contributors to the data collection between 2004 and April 2009)] TJ ET BT 26.250 101.342 Td /F1 9.8 Tf [(AUSTRIA )] TJ ET BT 26.250 89.437 Td /F1 9.8 Tf [(Innsbruck \(Universittsklinik Innsbruck, Neurologie\): Florian Brugger, Caroline Hepperger;Anna Hotter;Philipp Mahlknecht, )] TJ ET BT 26.250 77.532 Td /F1 9.8 Tf [(Michael Nocker, Klaus Seppi; Gregor Wenning, )] TJ ET BT 26.250 65.628 Td /F1 9.8 Tf [(BELGIUM )] TJ ET BT 26.250 53.723 Td /F1 9.8 Tf [(Leuven \(Universitair Ziekenhuis Gasthuisberg\): Wim Vandenberghe )] TJ ET BT 26.250 41.818 Td /F1 9.8 Tf [(GERMANY )] TJ ET Q q 15.000 27.532 577.500 749.468 re W n 0.965 0.965 0.965 rg 26.250 576.845 555.000 200.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 576.845 m 581.250 576.845 l 581.250 577.595 l 26.250 577.595 l f q 225.000 0 0 155.250 35.250 612.000 cm /I38 Do Q q 35.250 588.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 596.476 Td /F4 9.8 Tf [(Fig. 5: Comparison of medications prescribed in JHD at different ages)] TJ ET Q BT 26.250 542.624 Td /F4 12.0 Tf [(Conclusions)] TJ ET BT 26.250 522.669 Td /F1 9.8 Tf [(We set out to identify which medications were being prescribed for symptomatic relief in JHD; this has not been done before. )] TJ ET BT 26.250 510.765 Td /F1 9.8 Tf [(We identified that anti-psychotics were the most commonly prescribed agent and that anti-depressants and anti-parkinsonian )] TJ ET BT 26.250 498.860 Td /F1 9.8 Tf [(medications were also frequently prescribed in the JHD group.)] TJ ET BT 26.250 479.455 Td /F1 9.8 Tf [(JHD patients have complex needs. The diversity of their problems means they are often prescribed medications which exceed )] TJ ET BT 26.250 467.550 Td /F1 9.8 Tf [(the area of expertise of a single hospital specialist. Their medications require regular review by a team of experts, in the face of )] TJ ET BT 26.250 455.646 Td /F1 9.8 Tf [(evolving symptoms. Polypharmacy is an issue in this group, highlighting a potential need for reviewing and stopping medicines, )] TJ ET BT 26.250 443.741 Td /F1 9.8 Tf [(especially when they appear to be ineffective.)] TJ ET BT 26.250 424.336 Td /F1 9.8 Tf [(Identifying current practice is only a first step towards establishing an evidence base for treatment guidelines. JHD is a rare )] TJ ET BT 26.250 412.431 Td /F1 9.8 Tf [(condition which means that international collaboration is essential to gather information on the effectiveness of symptomatic )] TJ ET BT 26.250 400.527 Td /F1 9.8 Tf [(management. Projects such as REGISTRY are vital in order to establish such information. Ultimately we would hope that it will )] TJ ET BT 26.250 388.622 Td /F1 9.8 Tf [(be possible to use such a database to identify affected patients and conduct a randomised trial on the effectiveness of different )] TJ ET BT 26.250 376.717 Td /F1 9.8 Tf [(symptomatic treatments in this form of HD.)] TJ ET BT 26.250 340.115 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 320.160 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 283.558 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 263.604 Td /F1 9.8 Tf [(We would like to acknowledge the time and effort of the patients and families who participated in this study.)] TJ ET BT 26.250 251.699 Td /F1 9.8 Tf [(We would also like to acknowledge Mrs. Wendy Swan, Clinical Research Co-ordinator, for her assistance with research )] TJ ET BT 26.250 239.794 Td /F1 9.8 Tf [(governance.)] TJ ET BT 26.250 227.889 Td /F1 9.8 Tf [(We would also like to acknowledge the following individuals from the REGISTRY study: )] TJ ET BT 26.250 215.985 Td /F1 9.8 Tf [(Registry Steering commmittee: A-C Bachoud-Lvi, AR Bentivoglio, I Biunno, RM Bonelli, J-M Burgunder, SB Dunnett, JJ )] TJ ET BT 26.250 204.080 Td /F1 9.8 Tf [(Ferreira, OJ Handley, A Heiberg, T Illmann, GB Landwehrmeyer, J Levey, JE Nielsen, M Pivrinta, RAC Roos, A Rojo )] TJ ET BT 26.250 192.175 Td /F1 9.8 Tf [(Sebastin, SJ Tabrizi, W Vandenberghe, C Verellen-Dumoulin, J Zaremba, T Uhrova, J Wahlstrm )] TJ ET BT 26.250 180.270 Td /F1 9.8 Tf [(Language coordinators: Katrin Barth, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuana Garde, Reineke Bos, )] TJ ET BT 26.250 168.366 Td /F1 9.8 Tf [(Christine Held, Kerstin Koppers; Matilde Laur, Asuncin Martnez Descals, Tiago Mestre, Sara Minster, Daniela Monza, Jenny )] TJ ET BT 26.250 156.461 Td /F1 9.8 Tf [(Townhill \(formerly Naji\), Michael Orth, Helene Padieu, Laurent Paterski; Nadia Peppa, Susana Pro Koivisto, Amandine Rialland, )] TJ ET BT 26.250 144.556 Td /F1 9.8 Tf [(Niini Rren \(formerly Heinonen\) Pavla ainkov, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-An, )] TJ ET BT 26.250 132.651 Td /F1 9.8 Tf [(Elizaveta Yudina \(formerly Tarasova\), Daniel Zielonka, Paola Zinzi )] TJ ET BT 26.250 120.747 Td /F1 9.8 Tf [(Contributors to the data collection between 2004 and April 2009)] TJ ET BT 26.250 101.342 Td /F1 9.8 Tf [(AUSTRIA )] TJ ET BT 26.250 89.437 Td /F1 9.8 Tf [(Innsbruck \(Universittsklinik Innsbruck, Neurologie\): Florian Brugger, Caroline Hepperger;Anna Hotter;Philipp Mahlknecht, )] TJ ET BT 26.250 77.532 Td /F1 9.8 Tf [(Michael Nocker, Klaus Seppi; Gregor Wenning, )] TJ ET BT 26.250 65.628 Td /F1 9.8 Tf [(BELGIUM )] TJ ET BT 26.250 53.723 Td /F1 9.8 Tf [(Leuven \(Universitair Ziekenhuis Gasthuisberg\): Wim Vandenberghe )] TJ ET BT 26.250 41.818 Td /F1 9.8 Tf [(GERMANY )] TJ ET Q q 15.000 27.532 577.500 749.468 re W n 0.965 0.965 0.965 rg 26.250 576.845 555.000 200.155 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 576.845 m 581.250 576.845 l 581.250 577.595 l 26.250 577.595 l f q 225.000 0 0 155.250 35.250 612.000 cm /I40 Do Q q 35.250 588.095 537.000 17.905 re W n 0.271 0.267 0.267 rg BT 35.250 596.476 Td /F4 9.8 Tf [(Fig. 5: Comparison of medications prescribed in JHD at different ages)] TJ ET Q BT 26.250 542.624 Td /F4 12.0 Tf [(Conclusions)] TJ ET BT 26.250 522.669 Td /F1 9.8 Tf [(We set out to identify which medications were being prescribed for symptomatic relief in JHD; this has not been done before. )] TJ ET BT 26.250 510.765 Td /F1 9.8 Tf [(We identified that anti-psychotics were the most commonly prescribed agent and that anti-depressants and anti-parkinsonian )] TJ ET BT 26.250 498.860 Td /F1 9.8 Tf [(medications were also frequently prescribed in the JHD group.)] TJ ET BT 26.250 479.455 Td /F1 9.8 Tf [(JHD patients have complex needs. The diversity of their problems means they are often prescribed medications which exceed )] TJ ET BT 26.250 467.550 Td /F1 9.8 Tf [(the area of expertise of a single hospital specialist. Their medications require regular review by a team of experts, in the face of )] TJ ET BT 26.250 455.646 Td /F1 9.8 Tf [(evolving symptoms. Polypharmacy is an issue in this group, highlighting a potential need for reviewing and stopping medicines, )] TJ ET BT 26.250 443.741 Td /F1 9.8 Tf [(especially when they appear to be ineffective.)] TJ ET BT 26.250 424.336 Td /F1 9.8 Tf [(Identifying current practice is only a first step towards establishing an evidence base for treatment guidelines. JHD is a rare )] TJ ET BT 26.250 412.431 Td /F1 9.8 Tf [(condition which means that international collaboration is essential to gather information on the effectiveness of symptomatic )] TJ ET BT 26.250 400.527 Td /F1 9.8 Tf [(management. Projects such as REGISTRY are vital in order to establish such information. Ultimately we would hope that it will )] TJ ET BT 26.250 388.622 Td /F1 9.8 Tf [(be possible to use such a database to identify affected patients and conduct a randomised trial on the effectiveness of different )] TJ ET BT 26.250 376.717 Td /F1 9.8 Tf [(symptomatic treatments in this form of HD.)] TJ ET BT 26.250 340.115 Td /F4 12.0 Tf [(Competing Interests)] TJ ET BT 26.250 320.160 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 283.558 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 263.604 Td /F1 9.8 Tf [(We would like to acknowledge the time and effort of the patients and families who participated in this study.)] TJ ET BT 26.250 251.699 Td /F1 9.8 Tf [(We would also like to acknowledge Mrs. Wendy Swan, Clinical Research Co-ordinator, for her assistance with research )] TJ ET BT 26.250 239.794 Td /F1 9.8 Tf [(governance.)] TJ ET BT 26.250 227.889 Td /F1 9.8 Tf [(We would also like to acknowledge the following individuals from the REGISTRY study: )] TJ ET BT 26.250 215.985 Td /F1 9.8 Tf [(Registry Steering commmittee: A-C Bachoud-Lvi, AR Bentivoglio, I Biunno, RM Bonelli, J-M Burgunder, SB Dunnett, JJ )] TJ ET BT 26.250 204.080 Td /F1 9.8 Tf [(Ferreira, OJ Handley, A Heiberg, T Illmann, GB Landwehrmeyer, J Levey, JE Nielsen, M Pivrinta, RAC Roos, A Rojo )] TJ ET BT 26.250 192.175 Td /F1 9.8 Tf [(Sebastin, SJ Tabrizi, W Vandenberghe, C Verellen-Dumoulin, J Zaremba, T Uhrova, J Wahlstrm )] TJ ET BT 26.250 180.270 Td /F1 9.8 Tf [(Language coordinators: Katrin Barth, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuana Garde, Reineke Bos, )] TJ ET BT 26.250 168.366 Td /F1 9.8 Tf [(Christine Held, Kerstin Koppers; Matilde Laur, Asuncin Martnez Descals, Tiago Mestre, Sara Minster, Daniela Monza, Jenny )] TJ ET BT 26.250 156.461 Td /F1 9.8 Tf [(Townhill \(formerly Naji\), Michael Orth, Helene Padieu, Laurent Paterski; Nadia Peppa, Susana Pro Koivisto, Amandine Rialland, )] TJ ET BT 26.250 144.556 Td /F1 9.8 Tf [(Niini Rren \(formerly Heinonen\) Pavla ainkov, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-An, )] TJ ET BT 26.250 132.651 Td /F1 9.8 Tf [(Elizaveta Yudina \(formerly Tarasova\), Daniel Zielonka, Paola Zinzi )] TJ ET BT 26.250 120.747 Td /F1 9.8 Tf [(Contributors to the data collection between 2004 and April 2009)] TJ ET BT 26.250 101.342 Td /F1 9.8 Tf [(AUSTRIA )] TJ ET BT 26.250 89.437 Td /F1 9.8 Tf [(Innsbruck \(Universittsklinik Innsbruck, Neurologie\): Florian Brugger, Caroline Hepperger;Anna Hotter;Philipp Mahlknecht, )] TJ ET BT 26.250 77.532 Td /F1 9.8 Tf [(Michael Nocker, Klaus Seppi; Gregor Wenning, )] TJ ET BT 26.250 65.628 Td /F1 9.8 Tf [(BELGIUM )] TJ ET BT 26.250 53.723 Td /F1 9.8 Tf [(Leuven \(Universitair Ziekenhuis Gasthuisberg\): Wim Vandenberghe )] TJ ET BT 26.250 41.818 Td /F1 9.8 Tf [(GERMANY )] TJ ET Q q 225.000 0 0 155.250 35.250 612.000 cm /I42 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 238 0 obj << /Type /Annot /Subtype /Link /A 239 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 612.0000 260.2500 767.2500 ] >> endobj 239 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2012/02/newfig5pic.png) >> endobj 240 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 207 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 443>> stream xA 0 =fy9뀟\ٍ endstream endobj 241 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 207 /SMask 240 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 300 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 38650>> stream xw|T7̤d  Ch7Q{WEbޫ~x`EQtjh!3ٿ?NrZ{}s>k]}d&QfΜw=tRKZZڋ/ccP2᢬ n=yeueosr`͟?1fRoEQYP^1v h4h_*g:eH$"#4E1Z6O1PGFV2'/&Z2Y2J#̇=(aNIX*J=A(XyB2RBhUI,!:";(3P=ub8YPzR/=.xѰDNDBJ'࡚4FB] U2pٚp7#`(9=_*dk $.@⣓]`# & { Yɤq4 dJ?#؈(3ѵn' zx70e'2- >(Dg 4.v($ ԖF k?L?"bFZ#Ad4Ȇ`/>5!FL?22"6B( R|3 1+Na"bDIy>+`"K9Q/],pS4ӏEx.x-IIQB)צTmDLɴk7r(V8^54e!"@; 5zYD_Vg/^BP]m_XlQ"N!FuѠ*a'<>dqa|27vqp$yBlW1YmYKȖ*ڢ|V>bdc}@,<;ta`e[U;~PXʃ1͇S?u|' B{̾q߰E.? =;H:r O{ }e=ГZ_ɮSo?x=armXöa=Bf}eUͭ/ھiCB@0U6$44|Adv8ߘ7{GmңO묌p9ܟ_qܬfn^0oVlǘx9jsZ\||nw'L2GpҰ9 r.j1c'K|w/_9;p[Αo ~qޜKY0_Pr\a9!೙BSMrIЂ5 yWչ}/cG0R=P|u!!{v_Rzl ~.5-r9cvV9wc&t 3?hdc{y:4.y]ߘ0՚v㙊CD}\_=VKܛ_`lOoXm㿾{ڤVk]QRc7Zp ?[yzZcY{%'L3jμi#ְV`kZw Ֆork_7@:]̜Kzj ^(kӷYVkc3\˪_κlXA6ƾxnfҠ[ao/?m߼rj?O9h̀nVk̛ms26>C~iŽfvDhj>6moZaQ8qzExˇ_\ g}3=hg5V5cՂ֤!S^hPrԭ\hNo-nY}iS..!yƌ ,[,?Bw?4i3t䛡ܵOYG @l6.hxzۥz&챊fkDWퟍ2okmihhhnm'9ح_`M|G8ÉZG --.]uװ+ wjQ__Ȃͧ|7fd׾Նܐm\G[3~fjmiudYpEޒ-R鉵>˫}b VbζZ9k~lQ=ǷVXYw6'zƋ<Ʒxd"0W[sm?=w7_>ߓ}跌ڛij..gXG+@ksSӕ>:=lќ<\Vw'ax==yKxꖖ6;v V)ܾO^ztKm֚z嫝Vy퍕~ܞa͕X wa'w6܆VGkg&=\x}vYGf .,n,كۚ]8Tg֯_}-.t=|~ɩyϾׇllG]f\>oÿZ(d.X˗}{z:}d2=oɏ\7>s@aO$DDtGK?>4^tD'cxwϟ? ꖣ왆IFyٺM:X;;⎋eڢxړ*Ζ?WT%fhs:]SVW_:sCn;t2z 5Wρ]t 2bAB'fq_. 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_^U^I9"PTvҋŢ94RT9<tA#*Рt\Pe遲uME X* 88\UA-D)@G0 aV77(b2Ti8TRoT 1&6h-p/6,XZa-XD+'1\Qh"!ً -Bhf )V UD**q whae juw-JV dT'wR-C6fa`R5OAۇN&QTID>Ib!'S8Ñ;a$:vJEF:ɎFޱPP܉;*Aʇ;#1D8(RPF:!$mRK ~#EӢZ#*(XYDK&ue-N> endobj 253 0 obj << /Length 20536 >> stream 0.271 0.267 0.267 rg q 15.000 36.991 577.500 740.009 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Aachen \(Universittsklinikum Aachen, Neurologische Klinik\): Christoph Michael Kosinski; Daniela Probst; Christian Sass; )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Johannes Schiefer; Christiane Schlangen; Cornelius J. Werner )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Bochum \(Huntington-Zentrum \(NRW\) Bochum im St. Josef-Hospital\): Jrgen Andrich; Rainer Hoffmann; Christian Prehn, )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(Carsten Saft; Stephan Salmen; Katrin Straburger )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(Hamburg \(Universittsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fr Neurologie\): Alexander Mnchau; Michael Orth; )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(Lars Stubbe; Simone Zittel )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(Heiligenhafen \(Psychatrium Heiligenhafen\): Walburgis Heinicke )] TJ ET BT 26.250 684.143 Td /F1 9.8 Tf [(Marburg Uni \(Universitt Marburg, Neurologie\): Jens Carsten Mller; Ida Rissling )] TJ ET BT 26.250 672.238 Td /F1 9.8 Tf [(Mnster \(Universittsklinikum Mnster, Klinik und Poliklinik fr Neurologie\): Stefan Bohlen; Herwig Lange; Ralf Reilmann )] TJ ET BT 26.250 660.333 Td /F1 9.8 Tf [(Ulm \(Universittsklinikum Ulm, Neurologie\): Daniel Ecker; Carolin Eschenbach, Bernhard Landwehrmeyer; Franziska Lezius; )] TJ ET BT 26.250 648.429 Td /F1 9.8 Tf [(Michael Orth; Sonja Trautmann, Patrick Weydt)] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(ITALY)] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Bari \(Clinica Neurologica dellUniversita di Bari\): Claudia Cormio; Olimpia Difruscolo; Vittorio Sciruicchio; Claudia Serpino; )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(Marina de Tommaso Milan \(Fondazione IRCCS Istituto Neurologico Carlo Besta\): Alberto Albanese, Stefano Di Donato; )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(Caterina Mariotti, Paola Soliveri, Silvia Genitrini, Lorenzo Nanetti, Naples \(Dipartimento di Scienze Neurologiche Azienda )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Ospedaliera Universitaria Federico II\): Luigi Di Maio; Giuseppe De Michele; Carlo Rinaldi; Elena Salvatore; Tecla Tucci Pozzilli )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(\(IS\) \(Neurogenetics and Rare Diseases Centre IRCCS Neuromed\): Silvia Alberti, Francesca Elifani, Tiziana Martino; Sara )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(Orobello, Ferdinando Squitieri,)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(NORWAY )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(Oslo University Hospital \(Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology\): Arvid Heiberg; Marleen R van )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(Walsem Trondheim \(St. Olavs Hospital\): Inga Bjrnevoll; Sigrid Botne Sando)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(POLAND )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(Warsaw-IPiN \(Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology\): Jakub Antczak; Wioletta Krysa, )] TJ ET BT 26.250 471.167 Td /F1 9.8 Tf [(Maryla Rakowicz, Przemyslaw Richter; Danuta Ryglewicz; Anna Sulek, Grzegorz Witkowski, Jacek Zaremba; Elzbieta )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(Zdzienicka )] TJ ET BT 26.250 447.357 Td /F1 9.8 Tf [(SPAIN )] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Madrid RYC \(Hospital Ramn y Cajal, Neurologa\): Mnica Bascuana; Patricia Trigo )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(Cubillo; Marta Fatas Ventura; Jos Luis Lpez-Sendon Moreno; Guillermo Garca Ribas; Christine Schwarz, Justo Garca de )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(Ybenes )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(Sevilla \(Hospital Virgen del Roco\): Ftima Carrillo; Pablo Mir, Mara Jos Lama Suarez)] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(SWEDEN )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(Ume \(Ume University Hospital\): Ghada Loutfi, Eva-Lena Stattin, Laila Westman; Birgitta Wikstrm)] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(THE NETHERLANDS )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(Leiden \(Leiden University Medical Centre \(LUMC\)\): Reineke Bos; Eve M. )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(Dumas; Caroline K. Jurgens; Raymund A.C. Roos, Marie-Nolle Witjes-An; Simon J.A. van den Bogaard )] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(U.K. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(Aberdeen \(NHS Grampian, Clinical Genetics Centre\): Kirsty Matheson; Daniela Rae; Sheila Simpson; Fiona Summers; )] TJ ET BT 26.250 289.500 Td /F1 9.8 Tf [(Alexandra Ure )] TJ ET BT 26.250 277.596 Td /F1 9.8 Tf [(Cambridge \(Cambridge Centre for Brain Repair, Forvie Site\): Roger A Barker; Kate Fisher; Anna Olivia Goyder Goodman; )] TJ ET BT 26.250 265.691 Td /F1 9.8 Tf [(Susan Hill; Ann Kershaw; Sarah Mason; Lucy Raymond )] TJ ET BT 26.250 253.786 Td /F1 9.8 Tf [(Cardiff \(Cardiff University Schools of Medicine and Biosciences\): Monica Busse, Stephen Dunnett, Catherine Clenaghan, Olivia )] TJ ET BT 26.250 241.881 Td /F1 9.8 Tf [(Handley, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Sara Minster, Kathleen Price, Jenny Townhill, Anne Rosser )] TJ ET BT 26.250 229.977 Td /F1 9.8 Tf [(London-Guys Hospital: Thomasin Andrews; Nicola Coates, Andrew Dougherty; Fred Kavalier; Alison Lashwood; Dene )] TJ ET BT 26.250 218.072 Td /F1 9.8 Tf [(Robertson; Deborah Ruddy; Anna Whaite )] TJ ET BT 26.250 206.167 Td /F1 9.8 Tf [(London \(The National Hospital for Neurology and Neurosurgery\): Thomasin Andrews; Stefania Bruno; Charlotte Golding; Olivia )] TJ ET BT 26.250 194.262 Td /F1 9.8 Tf [(Handley; Susie Henley; Christine ODriscoll; Aakta Patel; Elisabeth Rosser; Sarah Tabrizi; Rachel Taylor; Thomas Warner; )] TJ ET BT 26.250 182.358 Td /F1 9.8 Tf [(Edward Wild )] TJ ET BT 26.250 170.453 Td /F1 9.8 Tf [(Manchester \(Manchester \(Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and )] TJ ET BT 26.250 158.548 Td /F1 9.8 Tf [(Central Manchester University Hospitals )] TJ ET BT 26.250 146.643 Td /F1 9.8 Tf [(NHS Foundation Trust\): Natalie Arran; Jenny Callaghan, David Craufurd; Ruth Fullam; Liz Howard; Susan Huson; Lucy )] TJ ET BT 26.250 134.739 Td /F1 9.8 Tf [(Partington-Jones; Nichola Ritchie; Julie Snowden; Annie Solom; Cheryl Stopford; Jennifer Thompson; Leann Westmoreland )] TJ ET BT 26.250 122.834 Td /F1 9.8 Tf [(Oxford \(Churchill Hospital\): Andrea H Nemeth; Gill Siuda)] TJ ET BT 26.250 86.231 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 58.777 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 58.777 Td /F1 9.8 Tf [(\(1993\) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. )] TJ ET BT 26.250 46.872 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group. Cell 72: 971-983.)] TJ ET Q q 15.000 36.991 577.500 740.009 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Aachen \(Universittsklinikum Aachen, Neurologische Klinik\): Christoph Michael Kosinski; Daniela Probst; Christian Sass; )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Johannes Schiefer; Christiane Schlangen; Cornelius J. Werner )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Bochum \(Huntington-Zentrum \(NRW\) Bochum im St. Josef-Hospital\): Jrgen Andrich; Rainer Hoffmann; Christian Prehn, )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(Carsten Saft; Stephan Salmen; Katrin Straburger )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(Hamburg \(Universittsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fr Neurologie\): Alexander Mnchau; Michael Orth; )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(Lars Stubbe; Simone Zittel )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(Heiligenhafen \(Psychatrium Heiligenhafen\): Walburgis Heinicke )] TJ ET BT 26.250 684.143 Td /F1 9.8 Tf [(Marburg Uni \(Universitt Marburg, Neurologie\): Jens Carsten Mller; Ida Rissling )] TJ ET BT 26.250 672.238 Td /F1 9.8 Tf [(Mnster \(Universittsklinikum Mnster, Klinik und Poliklinik fr Neurologie\): Stefan Bohlen; Herwig Lange; Ralf Reilmann )] TJ ET BT 26.250 660.333 Td /F1 9.8 Tf [(Ulm \(Universittsklinikum Ulm, Neurologie\): Daniel Ecker; Carolin Eschenbach, Bernhard Landwehrmeyer; Franziska Lezius; )] TJ ET BT 26.250 648.429 Td /F1 9.8 Tf [(Michael Orth; Sonja Trautmann, Patrick Weydt)] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(ITALY)] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Bari \(Clinica Neurologica dellUniversita di Bari\): Claudia Cormio; Olimpia Difruscolo; Vittorio Sciruicchio; Claudia Serpino; )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(Marina de Tommaso Milan \(Fondazione IRCCS Istituto Neurologico Carlo Besta\): Alberto Albanese, Stefano Di Donato; )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(Caterina Mariotti, Paola Soliveri, Silvia Genitrini, Lorenzo Nanetti, Naples \(Dipartimento di Scienze Neurologiche Azienda )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Ospedaliera Universitaria Federico II\): Luigi Di Maio; Giuseppe De Michele; Carlo Rinaldi; Elena Salvatore; Tecla Tucci Pozzilli )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(\(IS\) \(Neurogenetics and Rare Diseases Centre IRCCS Neuromed\): Silvia Alberti, Francesca Elifani, Tiziana Martino; Sara )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(Orobello, Ferdinando Squitieri,)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(NORWAY )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(Oslo University Hospital \(Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology\): Arvid Heiberg; Marleen R van )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(Walsem Trondheim \(St. Olavs Hospital\): Inga Bjrnevoll; Sigrid Botne Sando)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(POLAND )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(Warsaw-IPiN \(Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology\): Jakub Antczak; Wioletta Krysa, )] TJ ET BT 26.250 471.167 Td /F1 9.8 Tf [(Maryla Rakowicz, Przemyslaw Richter; Danuta Ryglewicz; Anna Sulek, Grzegorz Witkowski, Jacek Zaremba; Elzbieta )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(Zdzienicka )] TJ ET BT 26.250 447.357 Td /F1 9.8 Tf [(SPAIN )] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Madrid RYC \(Hospital Ramn y Cajal, Neurologa\): Mnica Bascuana; Patricia Trigo )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(Cubillo; Marta Fatas Ventura; Jos Luis Lpez-Sendon Moreno; Guillermo Garca Ribas; Christine Schwarz, Justo Garca de )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(Ybenes )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(Sevilla \(Hospital Virgen del Roco\): Ftima Carrillo; Pablo Mir, Mara Jos Lama Suarez)] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(SWEDEN )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(Ume \(Ume University Hospital\): Ghada Loutfi, Eva-Lena Stattin, Laila Westman; Birgitta Wikstrm)] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(THE NETHERLANDS )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(Leiden \(Leiden University Medical Centre \(LUMC\)\): Reineke Bos; Eve M. )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(Dumas; Caroline K. Jurgens; Raymund A.C. Roos, Marie-Nolle Witjes-An; Simon J.A. van den Bogaard )] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(U.K. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(Aberdeen \(NHS Grampian, Clinical Genetics Centre\): Kirsty Matheson; Daniela Rae; Sheila Simpson; Fiona Summers; )] TJ ET BT 26.250 289.500 Td /F1 9.8 Tf [(Alexandra Ure )] TJ ET BT 26.250 277.596 Td /F1 9.8 Tf [(Cambridge \(Cambridge Centre for Brain Repair, Forvie Site\): Roger A Barker; Kate Fisher; Anna Olivia Goyder Goodman; )] TJ ET BT 26.250 265.691 Td /F1 9.8 Tf [(Susan Hill; Ann Kershaw; Sarah Mason; Lucy Raymond )] TJ ET BT 26.250 253.786 Td /F1 9.8 Tf [(Cardiff \(Cardiff University Schools of Medicine and Biosciences\): Monica Busse, Stephen Dunnett, Catherine Clenaghan, Olivia )] TJ ET BT 26.250 241.881 Td /F1 9.8 Tf [(Handley, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Sara Minster, Kathleen Price, Jenny Townhill, Anne Rosser )] TJ ET BT 26.250 229.977 Td /F1 9.8 Tf [(London-Guys Hospital: Thomasin Andrews; Nicola Coates, Andrew Dougherty; Fred Kavalier; Alison Lashwood; Dene )] TJ ET BT 26.250 218.072 Td /F1 9.8 Tf [(Robertson; Deborah Ruddy; Anna Whaite )] TJ ET BT 26.250 206.167 Td /F1 9.8 Tf [(London \(The National Hospital for Neurology and Neurosurgery\): Thomasin Andrews; Stefania Bruno; Charlotte Golding; Olivia )] TJ ET BT 26.250 194.262 Td /F1 9.8 Tf [(Handley; Susie Henley; Christine ODriscoll; Aakta Patel; Elisabeth Rosser; Sarah Tabrizi; Rachel Taylor; Thomas Warner; )] TJ ET BT 26.250 182.358 Td /F1 9.8 Tf [(Edward Wild )] TJ ET BT 26.250 170.453 Td /F1 9.8 Tf [(Manchester \(Manchester \(Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and )] TJ ET BT 26.250 158.548 Td /F1 9.8 Tf [(Central Manchester University Hospitals )] TJ ET BT 26.250 146.643 Td /F1 9.8 Tf [(NHS Foundation Trust\): Natalie Arran; Jenny Callaghan, David Craufurd; Ruth Fullam; Liz Howard; Susan Huson; Lucy )] TJ ET BT 26.250 134.739 Td /F1 9.8 Tf [(Partington-Jones; Nichola Ritchie; Julie Snowden; Annie Solom; Cheryl Stopford; Jennifer Thompson; Leann Westmoreland )] TJ ET BT 26.250 122.834 Td /F1 9.8 Tf [(Oxford \(Churchill Hospital\): Andrea H Nemeth; Gill Siuda)] TJ ET BT 26.250 86.231 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 58.777 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 58.777 Td /F1 9.8 Tf [(\(1993\) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. )] TJ ET BT 26.250 46.872 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group. Cell 72: 971-983.)] TJ ET Q q 15.000 36.991 577.500 740.009 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Aachen \(Universittsklinikum Aachen, Neurologische Klinik\): Christoph Michael Kosinski; Daniela Probst; Christian Sass; )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Johannes Schiefer; Christiane Schlangen; Cornelius J. Werner )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Bochum \(Huntington-Zentrum \(NRW\) Bochum im St. Josef-Hospital\): Jrgen Andrich; Rainer Hoffmann; Christian Prehn, )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(Carsten Saft; Stephan Salmen; Katrin Straburger )] TJ ET BT 26.250 719.857 Td /F1 9.8 Tf [(Hamburg \(Universittsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fr Neurologie\): Alexander Mnchau; Michael Orth; )] TJ ET BT 26.250 707.952 Td /F1 9.8 Tf [(Lars Stubbe; Simone Zittel )] TJ ET BT 26.250 696.048 Td /F1 9.8 Tf [(Heiligenhafen \(Psychatrium Heiligenhafen\): Walburgis Heinicke )] TJ ET BT 26.250 684.143 Td /F1 9.8 Tf [(Marburg Uni \(Universitt Marburg, Neurologie\): Jens Carsten Mller; Ida Rissling )] TJ ET BT 26.250 672.238 Td /F1 9.8 Tf [(Mnster \(Universittsklinikum Mnster, Klinik und Poliklinik fr Neurologie\): Stefan Bohlen; Herwig Lange; Ralf Reilmann )] TJ ET BT 26.250 660.333 Td /F1 9.8 Tf [(Ulm \(Universittsklinikum Ulm, Neurologie\): Daniel Ecker; Carolin Eschenbach, Bernhard Landwehrmeyer; Franziska Lezius; )] TJ ET BT 26.250 648.429 Td /F1 9.8 Tf [(Michael Orth; Sonja Trautmann, Patrick Weydt)] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(ITALY)] TJ ET BT 26.250 617.119 Td /F1 9.8 Tf [(Bari \(Clinica Neurologica dellUniversita di Bari\): Claudia Cormio; Olimpia Difruscolo; Vittorio Sciruicchio; Claudia Serpino; )] TJ ET BT 26.250 605.214 Td /F1 9.8 Tf [(Marina de Tommaso Milan \(Fondazione IRCCS Istituto Neurologico Carlo Besta\): Alberto Albanese, Stefano Di Donato; )] TJ ET BT 26.250 593.310 Td /F1 9.8 Tf [(Caterina Mariotti, Paola Soliveri, Silvia Genitrini, Lorenzo Nanetti, Naples \(Dipartimento di Scienze Neurologiche Azienda )] TJ ET BT 26.250 581.405 Td /F1 9.8 Tf [(Ospedaliera Universitaria Federico II\): Luigi Di Maio; Giuseppe De Michele; Carlo Rinaldi; Elena Salvatore; Tecla Tucci Pozzilli )] TJ ET BT 26.250 569.500 Td /F1 9.8 Tf [(\(IS\) \(Neurogenetics and Rare Diseases Centre IRCCS Neuromed\): Silvia Alberti, Francesca Elifani, Tiziana Martino; Sara )] TJ ET BT 26.250 557.595 Td /F1 9.8 Tf [(Orobello, Ferdinando Squitieri,)] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(NORWAY )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(Oslo University Hospital \(Rikshospitalet, Dept. of Medical Genetics and Dep. of Neurology\): Arvid Heiberg; Marleen R van )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(Walsem Trondheim \(St. Olavs Hospital\): Inga Bjrnevoll; Sigrid Botne Sando)] TJ ET BT 26.250 494.976 Td /F1 9.8 Tf [(POLAND )] TJ ET BT 26.250 483.072 Td /F1 9.8 Tf [(Warsaw-IPiN \(Institute of Psychiatry and Neurology Dep. of Genetics, Dep. of Neurology\): Jakub Antczak; Wioletta Krysa, )] TJ ET BT 26.250 471.167 Td /F1 9.8 Tf [(Maryla Rakowicz, Przemyslaw Richter; Danuta Ryglewicz; Anna Sulek, Grzegorz Witkowski, Jacek Zaremba; Elzbieta )] TJ ET BT 26.250 459.262 Td /F1 9.8 Tf [(Zdzienicka )] TJ ET BT 26.250 447.357 Td /F1 9.8 Tf [(SPAIN )] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Madrid RYC \(Hospital Ramn y Cajal, Neurologa\): Mnica Bascuana; Patricia Trigo )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(Cubillo; Marta Fatas Ventura; Jos Luis Lpez-Sendon Moreno; Guillermo Garca Ribas; Christine Schwarz, Justo Garca de )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(Ybenes )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(Sevilla \(Hospital Virgen del Roco\): Ftima Carrillo; Pablo Mir, Mara Jos Lama Suarez)] TJ ET BT 26.250 380.334 Td /F1 9.8 Tf [(SWEDEN )] TJ ET BT 26.250 368.429 Td /F1 9.8 Tf [(Ume \(Ume University Hospital\): Ghada Loutfi, Eva-Lena Stattin, Laila Westman; Birgitta Wikstrm)] TJ ET BT 26.250 349.024 Td /F1 9.8 Tf [(THE NETHERLANDS )] TJ ET BT 26.250 337.119 Td /F1 9.8 Tf [(Leiden \(Leiden University Medical Centre \(LUMC\)\): Reineke Bos; Eve M. )] TJ ET BT 26.250 325.215 Td /F1 9.8 Tf [(Dumas; Caroline K. Jurgens; Raymund A.C. Roos, Marie-Nolle Witjes-An; Simon J.A. van den Bogaard )] TJ ET BT 26.250 313.310 Td /F1 9.8 Tf [(U.K. )] TJ ET BT 26.250 301.405 Td /F1 9.8 Tf [(Aberdeen \(NHS Grampian, Clinical Genetics Centre\): Kirsty Matheson; Daniela Rae; Sheila Simpson; Fiona Summers; )] TJ ET BT 26.250 289.500 Td /F1 9.8 Tf [(Alexandra Ure )] TJ ET BT 26.250 277.596 Td /F1 9.8 Tf [(Cambridge \(Cambridge Centre for Brain Repair, Forvie Site\): Roger A Barker; Kate Fisher; Anna Olivia Goyder Goodman; )] TJ ET BT 26.250 265.691 Td /F1 9.8 Tf [(Susan Hill; Ann Kershaw; Sarah Mason; Lucy Raymond )] TJ ET BT 26.250 253.786 Td /F1 9.8 Tf [(Cardiff \(Cardiff University Schools of Medicine and Biosciences\): Monica Busse, Stephen Dunnett, Catherine Clenaghan, Olivia )] TJ ET BT 26.250 241.881 Td /F1 9.8 Tf [(Handley, Sarah Hunt, Lesley Jones, Una Jones, Hanan Khalil, Sara Minster, Kathleen Price, Jenny Townhill, Anne Rosser )] TJ ET BT 26.250 229.977 Td /F1 9.8 Tf [(London-Guys Hospital: Thomasin Andrews; Nicola Coates, Andrew Dougherty; Fred Kavalier; Alison Lashwood; Dene )] TJ ET BT 26.250 218.072 Td /F1 9.8 Tf [(Robertson; Deborah Ruddy; Anna Whaite )] TJ ET BT 26.250 206.167 Td /F1 9.8 Tf [(London \(The National Hospital for Neurology and Neurosurgery\): Thomasin Andrews; Stefania Bruno; Charlotte Golding; Olivia )] TJ ET BT 26.250 194.262 Td /F1 9.8 Tf [(Handley; Susie Henley; Christine ODriscoll; Aakta Patel; Elisabeth Rosser; Sarah Tabrizi; Rachel Taylor; Thomas Warner; )] TJ ET BT 26.250 182.358 Td /F1 9.8 Tf [(Edward Wild )] TJ ET BT 26.250 170.453 Td /F1 9.8 Tf [(Manchester \(Manchester \(Genetic Medicine, University of Manchester, Manchester Academic Health Sciences Centre and )] TJ ET BT 26.250 158.548 Td /F1 9.8 Tf [(Central Manchester University Hospitals )] TJ ET BT 26.250 146.643 Td /F1 9.8 Tf [(NHS Foundation Trust\): Natalie Arran; Jenny Callaghan, David Craufurd; Ruth Fullam; Liz Howard; Susan Huson; Lucy )] TJ ET BT 26.250 134.739 Td /F1 9.8 Tf [(Partington-Jones; Nichola Ritchie; Julie Snowden; Annie Solom; Cheryl Stopford; Jennifer Thompson; Leann Westmoreland )] TJ ET BT 26.250 122.834 Td /F1 9.8 Tf [(Oxford \(Churchill Hospital\): Andrea H Nemeth; Gill Siuda)] TJ ET BT 26.250 86.231 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 58.777 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 58.777 Td /F1 9.8 Tf [(\(1993\) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. )] TJ ET BT 26.250 46.872 Td /F1 9.8 Tf [(The Huntington's Disease Collaborative Research Group. Cell 72: 971-983.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 254 0 obj << /Type /Page /Parent 3 0 R /Contents 255 0 R >> endobj 255 0 obj << /Length 21382 >> stream 0.271 0.267 0.267 rg q 15.000 46.286 577.500 730.714 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Bruyn GW \(1969\) The Westphal variant and juvenile type of Huntington's chorea. . Progress in neurogenetics International )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(congress series no 175 Amsterdam: Excerpta Medica Foundation 1: 666-673.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Harper PS, Morris MR, Quarrell OWJ, Shaw DJ, Tyler AT, et al. \(1991\) Huntingtons Disease. London: Saunders.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(Went LN, Vegter-van der Vlis M, Bruyn GW \(1984\) Parental transmission in Huntington's disease. Lancet 1: 1100-1102.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(Groppi C, Barontini F, Bracco L, Sita D, Inzitari D, et al. \(1986\) Huntington's chorea: a prevalence study in the Florence area. )] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(Acta Neurol Scand 74: 266-268.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Oliver JE \(1970\) Huntington's chorea in Northamptonshire. Br J Psychiatry 116: 241-253.)] TJ ET BT 26.250 639.143 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 639.143 Td /F1 9.8 Tf [(Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, et al. \(2004\) The gender effect in juvenile Huntington disease )] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(patients of Italian origin. Am J Med Genet B Neuropsychiatr Genet 125B: 92-98.)] TJ ET BT 26.250 607.833 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 607.833 Td /F1 9.8 Tf [(Claes S, Van Zand K, Legius E, Dom R, Malfroid M, et al. \(1995\) Correlations between triplet repeat expansion and clinical )] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(features in Huntington's disease. Arch Neurol 52: 749-753.)] TJ ET BT 26.250 576.524 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 576.524 Td /F1 9.8 Tf [(Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, et al. \(1993\) Trinucleotide repeat length instability and age of )] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(onset in Huntington's disease. Nat Genet 4: 387-392.)] TJ ET BT 26.250 545.214 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 545.214 Td /F1 9.8 Tf [(Persichetti F, Srinidhi J, Kanaley L, Ge P, Myers RH, et al. \(1994\) Huntington's disease CAG trinucleotide repeats in )] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(pathologically confirmed post-mortem brains. Neurobiol Dis 1: 159-166.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Nance MA, Myers RH \(2001\) Juvenile onset Huntington's disease -clinical and research perspectives. Ment Retard Dev )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Disabil Res Rev 7: 153-157.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Nance MA \(1997\) Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(Group. Neurology 49: 1048-1053.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Ruocco HH, Lopes-Cendes I, Laurito TL, Li LM, Cendes F \(2006\) Clinical presentation of juvenile Huntington disease. Arq )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(Neuropsiquiatr 64: 5-9. Epub 2006 Apr 2005.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Ribai P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, et al. \(2007\) Psychiatric and cognitive difficulties as )] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(indicators of juvenile huntington disease onset in 29 patients. Arch Neurol 64: 813-819.)] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 388.667 Td /F1 9.8 Tf [(Mahant N, McCusker EA, Byth K, Graham S \(2003\) Huntington's disease: clinical correlates of disability and progression. )] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(Neurology 61: 1085-1092.)] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 357.357 Td /F1 9.8 Tf [(Siesling S, Vegter-van der Vlis M, Roos RA \(1997\) Juvenile Huntington disease in the Netherlands. Pediatr Neurol 17: 37-)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(43.)] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 326.048 Td /F1 9.8 Tf [(van Dijk JG, van der Velde EA, Roos RA, Bruyn GW \(1986\) Juvenile Huntington disease. Hum Genet 73: 235-239.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Brackenridge CJ \(1980\) Factors influencing dementia and epilepsy in Huntington's disease of early onset. Acta Neurol )] TJ ET BT 26.250 294.738 Td /F1 9.8 Tf [(Scand 62: 305-311.)] TJ ET BT 26.250 275.334 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 275.334 Td /F1 9.8 Tf [(Squitieri F, Pustorino G, Cannella M, Toscano A, Maglione V, et al. \(2003\) Highly disabling cerebellar presentation in )] TJ ET BT 26.250 263.429 Td /F1 9.8 Tf [(Huntington disease. Eur J Neurol 10: 443-444.)] TJ ET BT 26.250 244.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 244.024 Td /F1 9.8 Tf [(Quarrell OW, Brewer HM, Squitieri F, Barker RA, Nance MA, Landwehrmeyer GB \(2009\) Juvenile Huntington's Disease. )] TJ ET BT 26.250 232.119 Td /F1 9.8 Tf [(Oxford: Oxford University Press.)] TJ ET BT 26.250 212.715 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 212.715 Td /F1 9.8 Tf [(Orth M, Handley OJ, Schwenke C, Dunnett SB, Craufurd D, et al. \(2010\) Observing Huntington's Disease: the European )] TJ ET BT 26.250 200.810 Td /F1 9.8 Tf [(Huntington's Disease Network's REGISTRY. PLoS Curr 2.: RRN1184.)] TJ ET BT 26.250 181.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 181.405 Td /F1 9.8 Tf [(\(2011\) British National Formulary.)] TJ ET BT 26.250 162.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 162.000 Td /F1 9.8 Tf [(Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. )] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(Epileptic Disord. 2007 Dec;9\(4\):353-412. Review. PubMed PMID: 18077226.)] TJ ET BT 26.250 130.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 130.691 Td /F1 9.8 Tf [(Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011 May;10\(5\):446-56. )] TJ ET BT 26.250 118.786 Td /F1 9.8 Tf [(Review. PubMed PMID: 21511198.)] TJ ET BT 26.250 99.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 99.381 Td /F1 9.8 Tf [(Cherny NI, Baselga J, de Conno F, Radbruch L \(2010\) Formulary availability and regulatory barriers to accessibility of )] TJ ET BT 26.250 87.477 Td /F1 9.8 Tf [(opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative. Ann Oncol 21: 615-626.)] TJ ET BT 26.250 68.072 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 68.072 Td /F1 9.8 Tf [(King N. Palliative care management of a child with juvenile onset Huntington's disease. Int J Palliat Nurs. 2005 )] TJ ET BT 26.250 56.167 Td /F1 9.8 Tf [(Jun;11\(6\):278-83. Review. PubMed PMID: 16010224.)] TJ ET Q q 15.000 46.286 577.500 730.714 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Bruyn GW \(1969\) The Westphal variant and juvenile type of Huntington's chorea. . Progress in neurogenetics International )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(congress series no 175 Amsterdam: Excerpta Medica Foundation 1: 666-673.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Harper PS, Morris MR, Quarrell OWJ, Shaw DJ, Tyler AT, et al. \(1991\) Huntingtons Disease. London: Saunders.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(Went LN, Vegter-van der Vlis M, Bruyn GW \(1984\) Parental transmission in Huntington's disease. Lancet 1: 1100-1102.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(Groppi C, Barontini F, Bracco L, Sita D, Inzitari D, et al. \(1986\) Huntington's chorea: a prevalence study in the Florence area. )] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(Acta Neurol Scand 74: 266-268.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Oliver JE \(1970\) Huntington's chorea in Northamptonshire. Br J Psychiatry 116: 241-253.)] TJ ET BT 26.250 639.143 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 639.143 Td /F1 9.8 Tf [(Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, et al. \(2004\) The gender effect in juvenile Huntington disease )] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(patients of Italian origin. Am J Med Genet B Neuropsychiatr Genet 125B: 92-98.)] TJ ET BT 26.250 607.833 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 607.833 Td /F1 9.8 Tf [(Claes S, Van Zand K, Legius E, Dom R, Malfroid M, et al. \(1995\) Correlations between triplet repeat expansion and clinical )] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(features in Huntington's disease. Arch Neurol 52: 749-753.)] TJ ET BT 26.250 576.524 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 576.524 Td /F1 9.8 Tf [(Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, et al. \(1993\) Trinucleotide repeat length instability and age of )] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(onset in Huntington's disease. Nat Genet 4: 387-392.)] TJ ET BT 26.250 545.214 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 545.214 Td /F1 9.8 Tf [(Persichetti F, Srinidhi J, Kanaley L, Ge P, Myers RH, et al. \(1994\) Huntington's disease CAG trinucleotide repeats in )] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(pathologically confirmed post-mortem brains. Neurobiol Dis 1: 159-166.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Nance MA, Myers RH \(2001\) Juvenile onset Huntington's disease -clinical and research perspectives. Ment Retard Dev )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Disabil Res Rev 7: 153-157.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Nance MA \(1997\) Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(Group. Neurology 49: 1048-1053.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Ruocco HH, Lopes-Cendes I, Laurito TL, Li LM, Cendes F \(2006\) Clinical presentation of juvenile Huntington disease. Arq )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(Neuropsiquiatr 64: 5-9. Epub 2006 Apr 2005.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Ribai P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, et al. \(2007\) Psychiatric and cognitive difficulties as )] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(indicators of juvenile huntington disease onset in 29 patients. Arch Neurol 64: 813-819.)] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 388.667 Td /F1 9.8 Tf [(Mahant N, McCusker EA, Byth K, Graham S \(2003\) Huntington's disease: clinical correlates of disability and progression. )] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(Neurology 61: 1085-1092.)] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 357.357 Td /F1 9.8 Tf [(Siesling S, Vegter-van der Vlis M, Roos RA \(1997\) Juvenile Huntington disease in the Netherlands. Pediatr Neurol 17: 37-)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(43.)] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 326.048 Td /F1 9.8 Tf [(van Dijk JG, van der Velde EA, Roos RA, Bruyn GW \(1986\) Juvenile Huntington disease. Hum Genet 73: 235-239.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Brackenridge CJ \(1980\) Factors influencing dementia and epilepsy in Huntington's disease of early onset. Acta Neurol )] TJ ET BT 26.250 294.738 Td /F1 9.8 Tf [(Scand 62: 305-311.)] TJ ET BT 26.250 275.334 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 275.334 Td /F1 9.8 Tf [(Squitieri F, Pustorino G, Cannella M, Toscano A, Maglione V, et al. \(2003\) Highly disabling cerebellar presentation in )] TJ ET BT 26.250 263.429 Td /F1 9.8 Tf [(Huntington disease. Eur J Neurol 10: 443-444.)] TJ ET BT 26.250 244.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 244.024 Td /F1 9.8 Tf [(Quarrell OW, Brewer HM, Squitieri F, Barker RA, Nance MA, Landwehrmeyer GB \(2009\) Juvenile Huntington's Disease. )] TJ ET BT 26.250 232.119 Td /F1 9.8 Tf [(Oxford: Oxford University Press.)] TJ ET BT 26.250 212.715 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 212.715 Td /F1 9.8 Tf [(Orth M, Handley OJ, Schwenke C, Dunnett SB, Craufurd D, et al. \(2010\) Observing Huntington's Disease: the European )] TJ ET BT 26.250 200.810 Td /F1 9.8 Tf [(Huntington's Disease Network's REGISTRY. PLoS Curr 2.: RRN1184.)] TJ ET BT 26.250 181.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 181.405 Td /F1 9.8 Tf [(\(2011\) British National Formulary.)] TJ ET BT 26.250 162.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 162.000 Td /F1 9.8 Tf [(Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. )] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(Epileptic Disord. 2007 Dec;9\(4\):353-412. Review. PubMed PMID: 18077226.)] TJ ET BT 26.250 130.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 130.691 Td /F1 9.8 Tf [(Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011 May;10\(5\):446-56. )] TJ ET BT 26.250 118.786 Td /F1 9.8 Tf [(Review. PubMed PMID: 21511198.)] TJ ET BT 26.250 99.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 99.381 Td /F1 9.8 Tf [(Cherny NI, Baselga J, de Conno F, Radbruch L \(2010\) Formulary availability and regulatory barriers to accessibility of )] TJ ET BT 26.250 87.477 Td /F1 9.8 Tf [(opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative. Ann Oncol 21: 615-626.)] TJ ET BT 26.250 68.072 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 68.072 Td /F1 9.8 Tf [(King N. Palliative care management of a child with juvenile onset Huntington's disease. Int J Palliat Nurs. 2005 )] TJ ET BT 26.250 56.167 Td /F1 9.8 Tf [(Jun;11\(6\):278-83. Review. PubMed PMID: 16010224.)] TJ ET Q q 15.000 46.286 577.500 730.714 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Bruyn GW \(1969\) The Westphal variant and juvenile type of Huntington's chorea. . Progress in neurogenetics International )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(congress series no 175 Amsterdam: Excerpta Medica Foundation 1: 666-673.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(Harper PS, Morris MR, Quarrell OWJ, Shaw DJ, Tyler AT, et al. \(1991\) Huntingtons Disease. London: Saunders.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(Went LN, Vegter-van der Vlis M, Bruyn GW \(1984\) Parental transmission in Huntington's disease. Lancet 1: 1100-1102.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(Groppi C, Barontini F, Bracco L, Sita D, Inzitari D, et al. \(1986\) Huntington's chorea: a prevalence study in the Florence area. )] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(Acta Neurol Scand 74: 266-268.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Oliver JE \(1970\) Huntington's chorea in Northamptonshire. Br J Psychiatry 116: 241-253.)] TJ ET BT 26.250 639.143 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 639.143 Td /F1 9.8 Tf [(Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, et al. \(2004\) The gender effect in juvenile Huntington disease )] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(patients of Italian origin. Am J Med Genet B Neuropsychiatr Genet 125B: 92-98.)] TJ ET BT 26.250 607.833 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 607.833 Td /F1 9.8 Tf [(Claes S, Van Zand K, Legius E, Dom R, Malfroid M, et al. \(1995\) Correlations between triplet repeat expansion and clinical )] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(features in Huntington's disease. Arch Neurol 52: 749-753.)] TJ ET BT 26.250 576.524 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 576.524 Td /F1 9.8 Tf [(Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, et al. \(1993\) Trinucleotide repeat length instability and age of )] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(onset in Huntington's disease. Nat Genet 4: 387-392.)] TJ ET BT 26.250 545.214 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 545.214 Td /F1 9.8 Tf [(Persichetti F, Srinidhi J, Kanaley L, Ge P, Myers RH, et al. \(1994\) Huntington's disease CAG trinucleotide repeats in )] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(pathologically confirmed post-mortem brains. Neurobiol Dis 1: 159-166.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Nance MA, Myers RH \(2001\) Juvenile onset Huntington's disease -clinical and research perspectives. Ment Retard Dev )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Disabil Res Rev 7: 153-157.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Nance MA \(1997\) Genetic testing of children at risk for Huntington's disease. US Huntington Disease Genetic Testing )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(Group. Neurology 49: 1048-1053.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Ruocco HH, Lopes-Cendes I, Laurito TL, Li LM, Cendes F \(2006\) Clinical presentation of juvenile Huntington disease. Arq )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(Neuropsiquiatr 64: 5-9. Epub 2006 Apr 2005.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Ribai P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, et al. \(2007\) Psychiatric and cognitive difficulties as )] TJ ET BT 26.250 408.072 Td /F1 9.8 Tf [(indicators of juvenile huntington disease onset in 29 patients. Arch Neurol 64: 813-819.)] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 388.667 Td /F1 9.8 Tf [(Mahant N, McCusker EA, Byth K, Graham S \(2003\) Huntington's disease: clinical correlates of disability and progression. )] TJ ET BT 26.250 376.762 Td /F1 9.8 Tf [(Neurology 61: 1085-1092.)] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 357.357 Td /F1 9.8 Tf [(Siesling S, Vegter-van der Vlis M, Roos RA \(1997\) Juvenile Huntington disease in the Netherlands. Pediatr Neurol 17: 37-)] TJ ET BT 26.250 345.453 Td /F1 9.8 Tf [(43.)] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 326.048 Td /F1 9.8 Tf [(van Dijk JG, van der Velde EA, Roos RA, Bruyn GW \(1986\) Juvenile Huntington disease. Hum Genet 73: 235-239.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Brackenridge CJ \(1980\) Factors influencing dementia and epilepsy in Huntington's disease of early onset. Acta Neurol )] TJ ET BT 26.250 294.738 Td /F1 9.8 Tf [(Scand 62: 305-311.)] TJ ET BT 26.250 275.334 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 275.334 Td /F1 9.8 Tf [(Squitieri F, Pustorino G, Cannella M, Toscano A, Maglione V, et al. \(2003\) Highly disabling cerebellar presentation in )] TJ ET BT 26.250 263.429 Td /F1 9.8 Tf [(Huntington disease. Eur J Neurol 10: 443-444.)] TJ ET BT 26.250 244.024 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 244.024 Td /F1 9.8 Tf [(Quarrell OW, Brewer HM, Squitieri F, Barker RA, Nance MA, Landwehrmeyer GB \(2009\) Juvenile Huntington's Disease. )] TJ ET BT 26.250 232.119 Td /F1 9.8 Tf [(Oxford: Oxford University Press.)] TJ ET BT 26.250 212.715 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 212.715 Td /F1 9.8 Tf [(Orth M, Handley OJ, Schwenke C, Dunnett SB, Craufurd D, et al. \(2010\) Observing Huntington's Disease: the European )] TJ ET BT 26.250 200.810 Td /F1 9.8 Tf [(Huntington's Disease Network's REGISTRY. PLoS Curr 2.: RRN1184.)] TJ ET BT 26.250 181.405 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 181.405 Td /F1 9.8 Tf [(\(2011\) British National Formulary.)] TJ ET BT 26.250 162.000 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 162.000 Td /F1 9.8 Tf [(Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. )] TJ ET BT 26.250 150.096 Td /F1 9.8 Tf [(Epileptic Disord. 2007 Dec;9\(4\):353-412. Review. PubMed PMID: 18077226.)] TJ ET BT 26.250 130.691 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 130.691 Td /F1 9.8 Tf [(Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011 May;10\(5\):446-56. )] TJ ET BT 26.250 118.786 Td /F1 9.8 Tf [(Review. PubMed PMID: 21511198.)] TJ ET BT 26.250 99.381 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 99.381 Td /F1 9.8 Tf [(Cherny NI, Baselga J, de Conno F, Radbruch L \(2010\) Formulary availability and regulatory barriers to accessibility of )] TJ ET BT 26.250 87.477 Td /F1 9.8 Tf [(opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative. Ann Oncol 21: 615-626.)] TJ ET BT 26.250 68.072 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 68.072 Td /F1 9.8 Tf [(King N. Palliative care management of a child with juvenile onset Huntington's disease. Int J Palliat Nurs. 2005 )] TJ ET BT 26.250 56.167 Td /F1 9.8 Tf [(Jun;11\(6\):278-83. Review. PubMed PMID: 16010224.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 256 0 obj << /Type /Page /Parent 3 0 R /Contents 257 0 R >> endobj 257 0 obj << /Length 1240 >> stream 0.271 0.267 0.267 rg q 15.000 730.691 577.500 46.309 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Rasmussen A, Macias R, Yescas P, Ochoa A, Davila G, et al. \(2000\) Huntington disease in children: genotype-phenotype )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(correlation. Neuropediatrics 31: 190-194.)] TJ ET Q q 15.000 730.691 577.500 46.309 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Rasmussen A, Macias R, Yescas P, Ochoa A, Davila G, et al. \(2000\) Huntington disease in children: genotype-phenotype )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(correlation. Neuropediatrics 31: 190-194.)] TJ ET Q q 15.000 730.691 577.500 46.309 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Rasmussen A, Macias R, Yescas P, Ochoa A, Davila G, et al. \(2000\) Huntington disease in children: genotype-phenotype )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(correlation. 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