Faculty Opinions recommendation of Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease.

Pain was rarely studied in Huntington’s disease (HD). We presently aimed to extend our previous study on pain pathways functions by laser evoked potentials (LEPs) to a larger cohort of early unmedicated HD patients and a small group of presymptomatic HD (PHD) subjects. Forty-two early HD patients, 10 PHD patients, and 64 controls were submitted to LEPs by right-hand stimulation. Two series of 30 laser stimuli were delivered, and artifact-free responses were averaged. The N1, N2, and P2 latencies were significantly increased and the N2P2 amplitude significantly reduced in HD patients compared to controls. In the HD group, the LEPs abnormalities correlated with functional decline. PHD subjects showed a slight and insignificant increase in LEPs latencies, which was inversely correlated with the possible age of HD clinical onset. Data of the present study seem to suggest that the functional state of nociceptive pathways as assessed by LEPs may be a potential biomarker of disease onset and progression. The assessment of pain symptoms in premanifest and manifest HD may also open a new scenario in terms of subtle disturbances of pain processing, which may have a role in the global burden of the disease.

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Attention, inhibition, and proximity to clinical onset in preclinical mutation carriers for Huntington's disease

Journal of Clinical and Experimental Neuropsychology ◽

10.1080/13803390600657693 ◽

2007 ◽

Vol 29 (3) ◽

pp. 235-246 ◽

Cited By ~ 16

Author(s):

Maree Farrow ◽

Andrew Churchyard ◽

Phyllis Chua ◽

John L. Bradshaw ◽

Edmond Chiu ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Clinical Onset ◽

Mutation Carriers

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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

Journal of Experimental Medicine ◽

10.1084/jem.20080178 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1869-1877 ◽

Cited By ~ 337

Author(s):

Maria Björkqvist ◽

Edward J. Wild ◽

Jenny Thiele ◽

Aurelio Silvestroni ◽

Ralph Andre ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Immune Activation ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Innate Immune ◽

Brain Pathology ◽

Clinical Onset ◽

Gene Carriers ◽

A Cell

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.

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Dementia due to Huntington’s disease

New Oxford Textbook of Psychiatry ◽

10.1093/med/9780198713005.003.0045 ◽

2020 ◽

pp. 448-453

Author(s):

Russell L. Margolis

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Psychiatric Symptoms ◽

Cag Repeat ◽

Causative Mutation ◽

Clinical Onset ◽

Key Features ◽

Neurobiological Research ◽

Clinical Triad ◽

Near Future

Huntington’s disease (HD), first described in 1872, is perhaps the prototypical hereditary dementia and movement disorder. Key features include autosomal dominant inheritance, typically mid-life clinical onset, and a clinical triad of abnormal voluntary and involuntary movements, subcortical dementia, and psychiatric symptoms. The disease progresses inevitably, with death typically 15–20 years after onset. Neurodegeneration is most prominent in the striatum and cerebral cortex. The discovery of the causative mutation, an expanded CAG repeat in the gene huntingtin, has led to the development of reliable genetic testing for affected and at-risk individuals and an explosion of neurobiological research into HD pathogenesis. While present treatment of HD is limited to managing symptoms, there is considerable optimism that treatments to prevent, slow, or stop disease progression may be feasible in the near future.

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Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908113116 ◽

2019 ◽

Vol 116 (49) ◽

pp. 24840-24851 ◽

Cited By ~ 4

Author(s):

Ferah Yildirim ◽

Christopher W. Ng ◽

Vincent Kappes ◽

Tobias Ehrenberger ◽

Siobhan K. Rigby ◽

...

Keyword(s):

Transcription Factor ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Beneficial Effects ◽

Transcriptional Dysregulation ◽

Clinical Onset ◽

Transcriptional Changes ◽

Chromatin Profiling

Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.

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