Journal of Personalized Medicine

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11 pages, 502 KiB

Open AccessArticle

The Vasopressin 1a Receptor Antagonist SRX246 Reduces Aggressive Behavior in Huntington’s Disease

by Hilda T. Maibach, Michael J. Brownstein, Steven M. Hersch, Karen E. Anderson, Debra E. Itzkowitz, Eve M. Damiano and Neal G. Simon

J. Pers. Med. 2022, 12(10), 1561; https://doi.org/10.3390/jpm12101561 - 22 Sep 2022

Cited by 4 | Viewed by 2059

Abstract

SRX246, an orally available CNS penetrant vasopressin (VP) V1a receptor antagonist, was studied in Huntington’s disease (HD) patients with irritability and aggressive behavior in the exploratory phase 2 trial, Safety, Tolerability, and Activity of SRX246 in Irritable HD patients (STAIR). This was a [...] Read more.

SRX246, an orally available CNS penetrant vasopressin (VP) V1a receptor antagonist, was studied in Huntington’s disease (HD) patients with irritability and aggressive behavior in the exploratory phase 2 trial, Safety, Tolerability, and Activity of SRX246 in Irritable HD patients (STAIR). This was a dose-escalation study; subjects received final doses of 120 mg BID, 160 mg BID, or placebo. The compound was safe and well tolerated. In this paper, we summarize the results of exploratory analyses of measures of problematic behaviors, including the Cohen–Mansfield Agitation Inventory (CMAI), Aberrant Behavior Checklist (ABC), Problem Behaviors Assessment-short form (PBA-s), Irritability Scale (IS), Clinical Global Impression (CGI), HD Quality of Life (QoL), and Caregiver Burden questionnaires. In addition to these, we asked subjects and caregivers to record answers to short questions about mood, irritability, and aggressive conduct in an eDiary. STAIR was the first rigorously designed study of behavioral endpoints like these in HD. The exploratory analyses showed that SRX246 reduced aggressive acts. Readily observed behaviors should be used as trial endpoints. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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19 pages, 1851 KiB

Open AccessCommunication

Using a Clinical Formulation to Understand Psychological Distress in People Affected by Huntington’s Disease: A Descriptive, Evidence-Based Model

by Maria Dale, Ashleigh Wood, Nicolò Zarotti, Fiona Eccles, Sarah Gunn, Reza Kiani, Amanda Mobley, Noelle Robertson and Jane Simpson

J. Pers. Med. 2022, 12(8), 1222; https://doi.org/10.3390/jpm12081222 - 27 Jul 2022

Cited by 7 | Viewed by 5137

Abstract

Huntington’s disease (HD) is an inherited, life-limiting neurodegenerative condition. People with HD experience changes in cognitive, motor and emotional functioning, and can also, mainly at later stages, exhibit behaviours that professionals and carers might find distressing such as hitting others, throwing objects, swearing [...] Read more.

Huntington’s disease (HD) is an inherited, life-limiting neurodegenerative condition. People with HD experience changes in cognitive, motor and emotional functioning, and can also, mainly at later stages, exhibit behaviours that professionals and carers might find distressing such as hitting others, throwing objects, swearing or making inappropriate comments. While clinical formulation (an individualised approach used by mental health professionals to describe an individual’s difficulties) is a helpful tool to conceptualise patients’ wellbeing, a specific formulation framework has not yet been developed for HD. However, evidence has shown that formulation can help guide clinical interventions and increase consistency of approach across multi-disciplinary teams, refine risk management, and improve staff or carers’ empathic skills and understanding of complex presentations. As a consequence, this paper proposes a new clinical formulation model for understanding distress among people with HD, based on a biopsychosocial framework. More specifically, this includes key elements centring on an individual’s past experience and personal narratives, as well as anticipatory cognitions and emotions about the future. In-depth discussions regarding the components of the model and their importance in HD formulations are included, and a fictional yet representative case example is presented to illustrate their application within the context of personalised care. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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10 pages, 749 KiB

Open AccessArticle

Sleep Quality and Related Clinical Manifestations in Huntington Disease

by Sabrina Maffi, Eugenia Scaricamazza, Simone Migliore, Melissa Casella, Consuelo Ceccarelli and Ferdinando Squitieri

J. Pers. Med. 2022, 12(6), 864; https://doi.org/10.3390/jpm12060864 - 25 May 2022

Cited by 6 | Viewed by 2911

Abstract

(1) Background: Sleep patterns are frequently disrupted in neurodegenerative disorders such as Huntington disease (HD); however, they are still poorly understood, especially their association with clinic features. Our study aimed to explore potential correlations between sleep features and motor, cognitive, behavioural and functional [...] Read more.

(1) Background: Sleep patterns are frequently disrupted in neurodegenerative disorders such as Huntington disease (HD); however, they are still poorly understood, especially their association with clinic features. Our study aimed to explore potential correlations between sleep features and motor, cognitive, behavioural and functional changes in manifest HD subjects. (2) Methods: We enrolled 42 patients who were assessed by the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) questionnaires; clinical features were evaluated by the validated ENROLL-HD platform assay, including the Unified Huntington’s Disease Rating Scale (UHDRS) and the Problem Behaviours Assessment Short Form (PBA-s). (3) Results: We found a significant association between the patients’ perception of sleep abnormalities and scores of impaired independence, cognitive and motor performances. Specifically, sleep efficiency (PSQI—C4 subscores) and the use of sleep medications (PSQI—C6 subscores) seem to be more frequently associated with the severity of the disease progression. (4) Conclusion: sleep abnormalities represent an important part of the HD clinical profile and can impair patients’ quality of life by affecting their level of independence, cognition performance and mental well-being. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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16 pages, 8586 KiB

Open AccessArticle

Self-Reported Social Relationship Capacities Predict Motor, Functional and Cognitive Decline in Huntington’s Disease

by Pablo Lemercier, Laurent Cleret de Langavant, Jennifer Hamet Bagnou, Katia Youssov, Laurie Lemoine, Etienne Audureau, Renaud Massart and Anne-Catherine Bachoud-Lévi

J. Pers. Med. 2022, 12(2), 174; https://doi.org/10.3390/jpm12020174 - 27 Jan 2022

Cited by 4 | Viewed by 2870

Abstract

Huntington’s Disease (HD) is an inherited neurodegenerative disease characterized by a combination of motor, cognitive, and behavioral disorders. The social and behavioral symptoms observed in HD patients impact their quality of life and probably explain their relational difficulties, conflicts, and social withdrawal. In [...] Read more.

Huntington’s Disease (HD) is an inherited neurodegenerative disease characterized by a combination of motor, cognitive, and behavioral disorders. The social and behavioral symptoms observed in HD patients impact their quality of life and probably explain their relational difficulties, conflicts, and social withdrawal. In this study, we described the development of the Social Relationship Self-Questionnaire (SRSQ), a self-reporting questionnaire that assesses how HD patients perceived their social relationships. The scale was proposed for 66 HD patients at an early stage of the disease, 32 PreHD patients (individuals carrying the mutant gene without motor symptoms), and 66 controls. The HD patients were included in a prospective longitudinal follow-up for an average of 1.07 years with motor, functional, cognitive, and behavioral assessments. Based on the HD patients’ answers at baseline, we identified two domains in the SRSQ. The first domain was related to social motivation and correlated with cognitive performance. The second domain was related to emotional insight and correlated with behavioral symptoms such as apathy, anxiety, and irritability. We discovered that both SRSQ domain scores at baseline predicted future motor, functional, and cognitive decline in HD. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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13 pages, 1516 KiB

Open AccessArticle

“Spazio Huntington”: Tracing the Early Motor, Cognitive and Behavioral Profiles of Kids with Proven Pediatric Huntington Disease and Expanded Mutations > 80 CAG Repeats

by Federica Graziola, Sabrina Maffi, Melissa Grasso, Giacomo Garone, Simone Migliore, Eugenia Scaricamazza, Consuelo Ceccarelli, Melissa Casella, Ludovica Busi, Barbara D’Alessio, Alessandro De Luca, Giovanna Stefania Colafati, Umberto Sabatini, Alessandro Capuano and Ferdinando Squitieri

J. Pers. Med. 2022, 12(1), 120; https://doi.org/10.3390/jpm12010120 - 17 Jan 2022

Cited by 2 | Viewed by 2605

Abstract

The “Spazio Huntington—A Place for Children” program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD [...] Read more.

The “Spazio Huntington—A Place for Children” program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children’s Yale–Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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11 pages, 287 KiB

Open AccessCommunication

More than Just a Brain Disorder: A Five-Point Manifesto for Psychological Care for People with Huntington’s Disease

by Nicolò Zarotti, Maria Dale, Fiona J. R. Eccles and Jane Simpson

J. Pers. Med. 2022, 12(1), 64; https://doi.org/10.3390/jpm12010064 - 7 Jan 2022

Cited by 18 | Viewed by 3509

Abstract

Huntington’s disease (HD) is a rare and complex condition where affected individuals, family members, caregivers, and clinicians face a number of both long-term and fluctuating challenges. The predominant biomedical framework adopted in HD to date has traditionally viewed it as a brain disorder [...] Read more.

Huntington’s disease (HD) is a rare and complex condition where affected individuals, family members, caregivers, and clinicians face a number of both long-term and fluctuating challenges. The predominant biomedical framework adopted in HD to date has traditionally viewed it as a brain disorder first and foremost. As a consequence, one of the most challenging aspects of the condition—psychological difficulties and their care—is often not given the emphasis it deserves in everyday clinical practice. Here, we propose a manifesto outlining five points to address the quality, effectiveness, availability, and accessibility of psychological care in HD. These include (1) Listening to People with HD, (2) Reformulating Difficulties Psychologically, (3) Exploring New Interventions, (4) Increasing Psychological Provision, and (5) Learning from Other Conditions. As the search for a cure continues, we hope that this manifesto will create a new impetus towards refining the current approach to psychological difficulties in HD and ultimately improve the quality of life of the tens of thousands of families affected by HD worldwide. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

13 pages, 244 KiB

Open AccessArticle

High Frequency of Concomitant Bladder, Bowel, and Sexual Symptoms in Huntington’s Disease: A Self-Reported Questionnaire Study

by Brenda G. Vicars, Alice B. Liu, Sarah Holt, Suman Jayadev, Thomas Bird and Claire C. Yang

J. Pers. Med. 2021, 11(8), 714; https://doi.org/10.3390/jpm11080714 - 25 Jul 2021

Cited by 4 | Viewed by 2374

Abstract

Huntington’s disease (HD) can be associated with pathologic involvement beyond the striatum including the autonomic nervous system. Bladder, bowel, and sexual dysfunction have been reported independently in HD, but little is known about their concomitant occurrence. To document this concomitant phenomena, forty-eight subjects [...] Read more.

Huntington’s disease (HD) can be associated with pathologic involvement beyond the striatum including the autonomic nervous system. Bladder, bowel, and sexual dysfunction have been reported independently in HD, but little is known about their concomitant occurrence. To document this concomitant phenomena, forty-eight subjects (54% male, ages 28–74 years, CAG repeat 38–61) with manifest/symptomatic HD completed detailed questionnaires regarding bladder, bowel, and sexual function. In total, 45 subjects (93.8%) reported symptoms in at least one organ system (bladder, bowel, or sexual), 13 (27.1%) reported symptoms in two systems, and 19 (39.6%) reported concomitant symptoms in all three systems. Urinary problems were most frequent in 42 subjects (87.5%) followed by lower bowel (60.4%) and sexual dysfunction (56.2%). Participants reporting concomitant symptoms were more likely to have longer duration of disease and lower Total Functional Capacity (TFC) scores. This study documents the high frequency of bladder, bowel, and sexual dysfunction in HD and the common occurrence of concomitance of these pelvic organ problems. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

Review

Jump to: Research

14 pages, 929 KiB

Open AccessReview

The Many Faces of Huntington’s Chorea Treatment: The Impact of Sudden Withdrawal of Tiapride after 40 Years of Use and a Systematic Review

by Stephanie Feleus, Malu van Schaijk, Raymund A. C. Roos and Susanne T. de Bot

J. Pers. Med. 2022, 12(4), 589; https://doi.org/10.3390/jpm12040589 - 6 Apr 2022

Cited by 2 | Viewed by 4100

Abstract

Huntington’s Disease (HD) is a rare, neurodegenerative disorder characterized by chorea, cognitive decline, and behavioral changes. Despite wide clinical use since the mid-1980s, tiapride was recently withdrawn from the Dutch market without rationale. Although alternatives are available, many patients experienced dysregulation after this [...] Read more.

Huntington’s Disease (HD) is a rare, neurodegenerative disorder characterized by chorea, cognitive decline, and behavioral changes. Despite wide clinical use since the mid-1980s, tiapride was recently withdrawn from the Dutch market without rationale. Although alternatives are available, many patients experienced dysregulation after this unwanted change. We provide insight into the impact of sudden tiapride withdrawal by reviewing medical records of HD patients who were using tiapride at the time of withdrawal. In addition, we performed a systematic search in five databases on tiapride efficacy and its safety profile in HD. Original research and expert opinions were included. In our patient group on tiapride, 50% required tiapride import from abroad. Regarding the review, 12 articles on original datasets and three expert opinions were included. The majority of studies showed an improvement in chorea while patients were on tiapride. Due to limited sample sizes, not all studies performed statistical tests on their results. Fifty percent of clinical experts prefer tiapride as initial chorea monotherapy, especially when comorbid behavioral symptoms are present. Side effects are often rare and mild. No safety concerns were reported. In conclusion, tiapride is almost irreplaceable for some patients and is an effective and safe chorea treatment in HD. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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23 pages, 3915 KiB

Open AccessReview

Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

by Annarita Fiorillo, Veronica Morea, Gianni Colotti and Andrea Ilari

J. Pers. Med. 2021, 11(12), 1309; https://doi.org/10.3390/jpm11121309 - 6 Dec 2021

Cited by 8 | Viewed by 4550

Abstract

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that [...] Read more.

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS), which has been shown to play a more important role than the autophagy–lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure–function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell. Full article

(This article belongs to the Special Issue The Many Faces of Huntington Disease)

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