Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

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Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

Journal of Probability and Statistics ◽

10.1155/2012/375935 ◽

2012 ◽

Vol 2012 ◽

pp. 1-19 ◽

Cited By ~ 3

Author(s):

Tianle Chen ◽

Yuanjia Wang ◽

Yanyuan Ma ◽

Karen Marder ◽

Douglas R. Langbehn

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Family Member ◽

Disease Onset ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Observational Research ◽

Accurate Estimation ◽

Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

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Volumetric MRI-Based Biomarkers in Huntington's Disease: An Evidentiary Review

Frontiers in Neurology ◽

10.3389/fneur.2021.712555 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kirsi M. Kinnunen ◽

Adam J. Schwarz ◽

Emily C. Turner ◽

Dorian Pustina ◽

Emily C. Gantman ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Progression ◽

Neurodegenerative Disorder ◽

Motor Impairment ◽

Cag Repeat ◽

Longitudinal Change ◽

Cross Sectional ◽

Brain Volumes ◽

Basal Ganglia Structures

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

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A Patient-Derived Cellular Model for Huntington’s Disease Reveals Phenotypes at Clinically Relevant CAG Lengths

10.1101/291575 ◽

2018 ◽

Author(s):

Claudia Lin-Kar Hung ◽

Tamara Maiuri ◽

Laura Erin Bowie ◽

Ryan Gotesman ◽

Susie Son ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Lines ◽

Disease Onset ◽

Cag Repeat ◽

Dna Repeats ◽

Cellular Model ◽

Human Telomerase Reverse Transcriptase ◽

Huntingtin Protein ◽

Transformed Cell Lines

ABSTRACTThe huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.

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Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington’s disease patients

Scientific Reports ◽

10.1038/s41598-020-77164-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

C. Y. Daniel Lee ◽

Nan Wang ◽

Koning Shen ◽

Matthew Stricos ◽

Peter Langfelder ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

High Sensitivity ◽

Mutant Huntingtin ◽

Disease Manifestation ◽

Specific Domain ◽

Disease States ◽

Exon 1 ◽

A Cell

AbstractIn Huntington’s disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.

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CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset

Cell ◽

10.1016/j.cell.2019.06.036 ◽

2019 ◽

Vol 178 (4) ◽

pp. 887-900.e14 ◽

Cited By ~ 67

Author(s):

Jong-Min Lee ◽

Kevin Correia ◽

Jacob Loupe ◽

Kyung-Hee Kim ◽

Douglas Barker ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Cag Repeat

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Genomic architecture differences at the HTT locus associated with symptomatic and pre-symptomatic cases of Huntington’s disease in a pilot study

Edelweiss Psychiatry Open Access ◽

10.33805/2638-8073.131 ◽

2021 ◽

pp. 1-6

Author(s):

Matthew Salter ◽

Ryan Powell ◽

Jennifer Back ◽

Francis Grand ◽

Christina Koutsothanasi ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Symptoms ◽

Disease Onset ◽

Cag Repeat ◽

Cag Repeats ◽

Healthy Controls ◽

Chromosome Conformation ◽

Chromatin Architecture ◽

Patient Groups

Huntington’s Disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide Cytosine-Adenine-Guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this presymptomatic phase. Using peripheral blood samples from HD patients and healthy controls we used EpiSwitch®, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of the HTT gene. We evaluated chromatin conformations at 20 sites across 225 kb of the HTT locus in a small cohort of healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD. Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. 85% (6 out of 7) of the patients in the symptomatic HD cohort demonstrated at least one of the specific chromosome conformations associated with symptomatic HD. Our results provide the first evidence that chromatin architecture at the HTT locus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of Chromosome Conformation Signatures (CCS) warrant further study as a prognostic tool in HD.

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A patient-derived cellular model for Huntington’s disease reveals phenotypes at clinically relevant CAG lengths

Molecular Biology of the Cell ◽

10.1091/mbc.e18-09-0590 ◽

2018 ◽

Vol 29 (23) ◽

pp. 2809-2820 ◽

Cited By ~ 7

Author(s):

Claudia Lin-Kar Hung ◽

Tamara Maiuri ◽

Laura Erin Bowie ◽

Ryan Gotesman ◽

Susie Son ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Lines ◽

Disease Onset ◽

Cag Repeat ◽

Dna Repeats ◽

Cellular Model ◽

Human Telomerase Reverse Transcriptase ◽

Huntingtin Protein ◽

Transformed Cell Lines

The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset, and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios, and hypophosphorylated huntingtin protein. We additionally observed dysregulated reactive oxygen species (ROS)-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single-cell level, which, unlike transformed cell lines, maintains functions critical for huntingtin transcriptional regulation and genomic integrity.

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Genomic architecture differences at the HTT locus underlie symptomatic and pre-symptomatic cases of Huntington’s disease.

F1000Research ◽

10.12688/f1000research.15828.2 ◽

2019 ◽

Vol 7 ◽

pp. 1757

Author(s):

Matthew Salter ◽

Ryan Powell ◽

Jennifer Back ◽

Francis Grand ◽

Christina Koutsothanasi ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Symptoms ◽

Disease Onset ◽

Cag Repeat ◽

Cag Repeats ◽

Healthy Controls ◽

Chromosome Conformation ◽

Chromatin Architecture ◽

Patient Groups

Background:Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.Methods:Using peripheral blood samples from HD patients and healthy controls we usedEpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of theHTTgene. We evaluated chromatin conformations at 20 sites across 225 kb of theHTTlocus in healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD.Results:Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. Of the patients in the symptomatic HD cohort, 86% (6 out of 7) demonstrated at least one of the specific chromosome conformations associated with symptomatic HD.Conclusion:Our results provide the first evidence that chromatin architecture at theHTTlocus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of chromosome conformation signatures can be a valuable addition to prognostic assessment of HD patients.

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Juvenile Huntington’s Disease

10.1093/med/9780199929146.003.0004 ◽

2014 ◽

Cited By ~ 5

Author(s):

Oliver W. J. Quarrell

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Disease Process ◽

Evidence Base ◽

Cag Repeat ◽

Pathologic Features ◽

Pharmacologic Management ◽

Juvenile Huntington’S Disease ◽

The Brain

In approximately 5% of cases of Huntington’s disease, onset is before 20 years of age, and these cases are defined as juvenile Huntington’s disease (JHD). The clinical and pathologic features of JHD overlap with those of typical adult-onset disease, so it is not a distinct entity. As a generalization, however, dystonia and bradykinesia are more likely to occur earlier in the disease process, epilepsy is more frequent, the average CAG repeat length is longer, and the pathology within the brain is more widespread. There are conflicting reports in the literature regarding both disease duration and disease progression. Management of JHD patients, and their families, requires a multidisciplinary, symptomatic, and supportive approach. Despite the lack of an evidence base for pharmacologic management and other interventions, helpful reviews and suggestions are available.

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Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-200423 ◽

2021 ◽

Vol 10 (1) ◽

pp. 149-163

Author(s):

Xiaonan Zhao ◽

Daman Kumari ◽

Carson J. Miller ◽

Geum-Yi Kim ◽

Bruce Hayward ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Fragile X ◽

Friedreich Ataxia ◽

Disease Onset ◽

Neuronal Cell ◽

Repeat Expansion ◽

Cag Repeat ◽

Dna Repeats

Huntington’s disease (HD) is one of a large group of human disorders that are caused by expanded DNA repeats. These repeat expansion disorders can have repeat units of different size and sequence that can be located in any part of the gene and, while the pathological consequences of the expansion can differ widely, there is evidence to suggest that the underlying mutational mechanism may be similar. In the case of HD, the expanded repeat unit is a CAG trinucleotide located in exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine tract in the huntingtin protein. Expansion results in neuronal cell death, particularly in the striatum. Emerging evidence suggests that somatic CAG expansion, specifically expansion occurring in the brain during the lifetime of an individual, contributes to an earlier disease onset and increased severity. In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

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