Clinical Presentation and Features of Juvenile-Onset Huntington’s Disease: A Systematic Review

Cronin, Thomas D.; Rosser, Anne Elizabeth; Massey, Thomas

doi:10.3233/jhd-180339

Cited by 40 publications

(60 citation statements)

References 15 publications

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“…In the present study, mutant HTT CAG repeat expansion length was negatively correlated with all measures, but reached statistical significance with Inhibit, Plan/Organize, Initiate, and Aggression/Opposition indicating that patients with longer repeat lengths (typically resulting in childhood-onset JOHD [ 18 ]) exhibit fewer problems in these domains, while patients with short repeats (typically resulting in adolescent-onset JOHD [ 18 ]) exhibit more problem behaviors. These findings align with current reports that older-onset JOHD patients exhibit more behavioral issues than younger-onset JOHD patients [ 7 ]. In addition, opposition and aggression behavior normally peak in adolescence; therefore, an active brain disease during a time in which these behaviors normally peak may be one potential rationale for the adolescent onset having greater behavioral disturbance.…”

Section: Discussionsupporting

confidence: 92%

“…Evidence of behavioral disturbances in JOHD is primarily predicated on retrospective medical record analyses [ 2 , 3 ] and caregiver reports [ 4 , 5 , 6 ] with few attempts to systematically evaluate these changes prospectively. Behavioral problems and cognitive decline are often among the first symptoms to present in individuals with JOHD [ 6 , 7 , 8 , 9 ] and can emerge years before the onset of motor symptoms [ 5 ], a pattern that is parallel with that of AOHD. Behavioral issues reported in JOHD include violence, aggression, oppositional behavior, obsession, depression, anxiety, impulsivity, attention issues, psychosis, and substance abuse [ 1 , 2 , 3 , 4 , 8 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Behavioral Deficits in Juvenile Onset Huntington’s Disease

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Behavioral Deficits in Juvenile Onset Huntington’s Disease

et al. 2020

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“…Mutation of the huntingtin (HTT) gene results in an expanded polyglutamine (Q n ) repeat within the HTT (mHTT) protein. Individuals with R40Q develop HD, with juvenile-onset cases before age 20 years typically occurring above 60 repeats (Cronin et al, 2019). HD symptoms include uncontrollable movement, psychiatric disturbances, and cognitive impairment (Tabrizi et al, 2019) with progressive neurodegeneration and brain atrophy.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

et al. 2020

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Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1 + neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation.

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“…Patients with JOHD often experience unique motor symptoms. Specifically, patients with JOHD may have less chorea, but more hypokinetic symptoms, including bradykinesia and dystonia [ 25 ]. These symptoms can be very difficult to treat and the underlying pathology of this difference between JOHD and AOHD is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington’s Disease

et al. 2020

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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.

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Clinical Presentation and Features of Juvenile-Onset Huntington’s Disease: A Systematic Review

Cited by 40 publications

References 15 publications

Behavioral Deficits in Juvenile Onset Huntington’s Disease

Behavioral Deficits in Juvenile Onset Huntington’s Disease

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington’s Disease

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