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Brain Sciences
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Juvenile Onset Huntington's Disease
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Juvenile Onset Huntington's Disease

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 37201

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Peggy C. Nopoulos

E-Mail Website
Guest Editor
University of Iowa, Iowa City, IA, United States
Interests: brain development; gender differences; social cognition; schizophrenia, Huntington's Disease

Special Issue Information

Dear Colleagues,

The single-gene disorder, Huntington’s disease (HD), is experiencing tremendous advances with current phase III clinical trials for gene knock-down therapy (antisense oligonucleotide) and several more in the pipeline. Yet, in the HD community, there is a cohort of patients who are suffering but excluded from the excitement of these clinical trials—children who have early onset disease. Juvenile Huntington’s disease (JHD) is defined as onset of the disease prior to the age of 21 years. Many patients with JHD are eventually adults who can qualify for gene trials; however, they are often excluded due to severity of illness. Pediatric HD (PHD) is the term used to describe young people affected by HD who are currently <18 years of age. These subjects, due to their age alone, are also excluded from clinical trials. Even if PHD and JHD were eligible for trials, though, there are serious gaps in our understanding of early onset HD. In particular, the motor phenotype is strikingly different from typical adult onset HD. Yet basic questions of pathophysiology remain unanswered—how is early onset HD similar to typical adult onset HD, and how is it different? Are there symptoms unique to early onset HD? What are the appropriate biomarkers for disease progression in early onset HD? This Special Issue aims at providing an overview of topics—both clinical and research—on this rare and unique patient sample.

Prof. Peggy C. Nopoulos
Guest Editor

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Keywords

  • Huntington’s Disease
  • biomarkers
  • HD
  • JHD
  • typical adult onset HD
  • early onset HD

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Published Papers (8 papers)

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Editorial

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2 pages, 147 KiB  
Editorial
Special Issue: Juvenile Onset Huntington’s Disease
by Peg C. Nopoulos
Brain Sci. 2020, 10(9), 652; https://doi.org/10.3390/brainsci10090652 - 20 Sep 2020
Viewed by 2167
Abstract
[...] Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)

Research

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7 pages, 680 KiB  
Communication
Autonomic Changes in Juvenile-Onset Huntington’s Disease
by Jordan L. Schultz and Peg C. Nopoulos
Brain Sci. 2020, 10(9), 589; https://doi.org/10.3390/brainsci10090589 - 26 Aug 2020
Cited by 6 | Viewed by 2894
Abstract
Patients with adult-onset Huntington’s Disease (AOHD) have been found to have dysfunction of the autonomic nervous system that is thought to be secondary to neurodegeneration causing dysfunction of the brain–heart axis. However, this relationship has not been investigated in patients with juvenile-onset HD [...] Read more.
Patients with adult-onset Huntington’s Disease (AOHD) have been found to have dysfunction of the autonomic nervous system that is thought to be secondary to neurodegeneration causing dysfunction of the brain–heart axis. However, this relationship has not been investigated in patients with juvenile-onset HD (JOHD). The aim of this study was to compare simple physiologic measures between patients with JOHD (n = 27 participants with 64 visits) and participants without the gene expansion that causes HD (GNE group; n = 259 participants with 395 visits). Using data from the Kids-JOHD study, we compared mean resting heart rate (rHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the JOHD and GNE groups. We also divided the JOHD group into those with childhood-onset JOHD (motor diagnosis received before the age of 13, [n = 16]) and those with adolescent-onset JOHD (motor diagnosis received at or after the age of 13 [n = 11]). We used linear mixed-effects models to compare the group means while controlling for age, sex, and parental socioeconomic status and including a random effect per participant and family. For the primary analysis, we found that the JOHD group had significant increases in their rHR compared to the GNE group. Conversely, the JOHD group had significantly lower SBP compared to the GNE group. The JOHD group also had lower DBP compared to the GNE group, but the results did not reach significance. SBP and DBP decreased as disease duration of JOHD increased, but rHR did not continue to increase. Resting heart rate is more sensitive to changes in autonomic function as compared to SBP. Therefore, these results seem to indicate that early neurodegenerative changes of the central autonomic network likely lead to an increase in rHR while later progression of JOHD leads to changes in blood pressure. We hypothesize that these later changes in blood pressure are secondary to neurodegeneration in brainstem regions such as the medulla. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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7 pages, 824 KiB  
Communication
The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington’s Disease
by Jordan L. Schultz, Amelia D. Moser and Peg C. Nopoulos
Brain Sci. 2020, 10(9), 575; https://doi.org/10.3390/brainsci10090575 - 20 Aug 2020
Cited by 5 | Viewed by 4477
Abstract
There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. [...] Read more.
There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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11 pages, 1000 KiB  
Article
Behavioral Deficits in Juvenile Onset Huntington’s Disease
by Kathleen E. Langbehn, Ashley M. Cochran, Ellen van der Plas, Amy L. Conrad, Eric Epping, Erin Martin, Patricia Espe-Pfeifer and Peg Nopoulos
Brain Sci. 2020, 10(8), 543; https://doi.org/10.3390/brainsci10080543 - 11 Aug 2020
Cited by 9 | Viewed by 3263
Abstract
Reports of behavioral disturbance in Juvenile-Onset Huntington’s Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young [...] Read more.
Reports of behavioral disturbance in Juvenile-Onset Huntington’s Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington’s Disease, but who did not inherit the disease themselves (Gene-Non-Expanded; GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p < 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p < 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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9 pages, 656 KiB  
Communication
Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington’s Disease
by Alexander V. Tereshchenko, Jordan L. Schultz, Ansley J. Kunnath, Joel E. Bruss, Eric A. Epping, Vincent A. Magnotta and Peg C. Nopoulos
Brain Sci. 2020, 10(8), 533; https://doi.org/10.3390/brainsci10080533 - 8 Aug 2020
Cited by 5 | Viewed by 2921
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 [...] Read more.
Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington’s disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington’s Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants’ motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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17 pages, 248 KiB  
Article
Clinical Manifestation of Juvenile and Pediatric HD Patients: A Retrospective Case Series
by Jannis Achenbach, Charlotte Thiels, Thomas Lücke and Carsten Saft
Brain Sci. 2020, 10(6), 340; https://doi.org/10.3390/brainsci10060340 - 3 Jun 2020
Cited by 20 | Viewed by 3795
Abstract
Background: Studies on the clinical manifestation and course of disease in children suffering from Huntington’s disease (HD) are rare. Case reports of juvenile HD (onset ≤ 20 years) describe heterogeneous motoric and non-motoric symptoms, often accompanied with a delay in diagnosis. We aimed [...] Read more.
Background: Studies on the clinical manifestation and course of disease in children suffering from Huntington’s disease (HD) are rare. Case reports of juvenile HD (onset ≤ 20 years) describe heterogeneous motoric and non-motoric symptoms, often accompanied with a delay in diagnosis. We aimed to describe this rare group of patients, especially with regard to socio-medical aspects and individual or common treatment strategies. In addition, we differentiated between juvenile and the recently defined pediatric HD population (onset < 18 years). Methods: Out of 2593 individual HD patients treated within the last 25 years in the Huntington Centre, North Rhine-Westphalia (NRW), 32 subjects were analyzed with an early onset younger than 21 years (1.23%, juvenile) and 18 of them younger than 18 years of age (0.69%, pediatric). Results: Beside a high degree of school problems, irritability or aggressive behavior (62.5% of pediatric and 31.2% of juvenile cases), serious problems concerning the social and family background were reported in 25% of the pediatric cohort. This includes an attempted rape and robbery at the age of 12, as problems caused by the affected children, but also alcohol-dependency in a two-year-old induced by a non-HD affected stepfather. A high degree of suicidal attempts and ideations (31.2% in pediatric and 33.3% in juvenile group) was reported, including drinking of solvents, swallowing razor blades or jumping from the fifth floor with following incomplete paraparesis. Beside dopaminergic drugs for treatment of bradykinesia, benzodiazepines and tetrabenazine for treatment of dystonia, cannabinoids, botulinum toxin injection and deep brain stimulation were used for the improvement of movement disorders, clozapine for the treatment of tremor, and dopa-induced hallucinations and zuclopenthixole for the treatment of severe aggressive behavior. Conclusions: Beside abnormalities in behavior from an early age due to HD pathology, children seem to have higher socio-medical problems related to additional burden caused by early affected parents, instable family backgrounds including drug abuse of a parent or multiple changes of partners. Treatment required individualized strategies in many cases. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
12 pages, 387 KiB  
Article
Diagnosing Juvenile Huntington’s Disease: An Explorative Study among Caregivers of Affected Children
by Mayke Oosterloo, Emilia K. Bijlsma, Christine de Die-Smulders and Raymund A. C. Roos
Brain Sci. 2020, 10(3), 155; https://doi.org/10.3390/brainsci10030155 - 7 Mar 2020
Cited by 10 | Viewed by 3566
Abstract
Objective: To investigate the reasons for the diagnostic delay of juvenile Huntington’s disease patients in the Netherlands. Methods: This study uses interpretative phenomenological analysis. Eligible participants were parents and caregivers of juvenile Huntington’s disease patients. Results: Eight parents were interviewed, who [...] Read more.
Objective: To investigate the reasons for the diagnostic delay of juvenile Huntington’s disease patients in the Netherlands. Methods: This study uses interpretative phenomenological analysis. Eligible participants were parents and caregivers of juvenile Huntington’s disease patients. Results: Eight parents were interviewed, who consulted up to four health care professionals. The diagnostic process lasted three to ten years. Parents believe that careful listening and follow-up would have improved the diagnostic process. Although they believe an earlier diagnosis would have benefited their child’s wellbeing, they felt they would not have been able to cope with more grief at that time. Conclusion: The delay in diagnosis is caused by the lack of knowledge among health care professionals on the one hand, and the resistance of the parent on the other. For professionals, the advice is to personalize their advice in which a conscious doctor’s delay is acceptable or even useful. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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Review

Jump to: Editorial, Research

20 pages, 2513 KiB  
Review
Therapeutic Advances for Huntington’s Disease
by Ashok Kumar, Vijay Kumar, Kritanjali Singh, Sukesh Kumar, You-Sam Kim, Yun-Mi Lee and Jong-Joo Kim
Brain Sci. 2020, 10(1), 43; https://doi.org/10.3390/brainsci10010043 - 12 Jan 2020
Cited by 74 | Viewed by 13143
Abstract
Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein [...] Read more.
Huntington’s disease (HD) is a progressive neurological disease that is inherited in an autosomal fashion. The cause of disease pathology is an expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin gene (HTT) on chromosome 4 (4p16.3), which codes the huntingtin protein (mHTT). The common symptoms of HD include motor and cognitive impairment of psychiatric functions. Patients exhibit a representative phenotype of involuntary movement (chorea) of limbs, impaired cognition, and severe psychiatric disturbances (mood swings, depression, and personality changes). A variety of symptomatic treatments (which target glutamate and dopamine pathways, caspases, inhibition of aggregation, mitochondrial dysfunction, transcriptional dysregulation, and fetal neural transplants, etc.) are available and some are in the pipeline. Advancement in novel therapeutic approaches include targeting the mutant huntingtin (mHTT) protein and the HTT gene. New gene editing techniques will reduce the CAG repeats. More appropriate and readily tractable treatment goals, coupled with advances in analytical tools will help to assess the clinical outcomes of HD treatments. This will not only improve the quality of life and life span of HD patients, but it will also provide a beneficial role in other inherited and neurological disorders. In this review, we aim to discuss current therapeutic research approaches and their possible uses for HD. Full article
(This article belongs to the Special Issue Juvenile Onset Huntington's Disease)
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