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Background: Juvenile‐onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult‐onset HD. Methods: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids‐HD and Kids‐JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age‐matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. Results: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation‐carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. Conclusions: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The known genetic cause of Huntington's disease (HD) has fueled considerable progress in understanding its pathobiology and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain-derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole-brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole-brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole-brain atrophy in HD using a 2-year follow-up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2-year scan pair, age- and gender-standardized mean brain atrophy rate was greater ( P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62-1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00-0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence ( P= 0.048) of acceleration year-on-year (mean acceleration = 0.69% yr−2; 95% confidence interval: 0.01% yr−2 to 1.37% yr−2), although this was not formally significantly different from that in controls ( n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole-brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Tracking progression in neurodegenerative diseases is hampered by the limitations of the clinical rating scales, which are seldom linear, suffer from floor and ceiling effects, lack the ability to distinguish symptomatic change from disease modification, and are limited by imperfect intra- and inter-rater reliability. The promise of an era of neuroprotective therapies renders urgent the search for reliable measures of progression. Biomarkers have the potential to enhance several aspects of both therapeutic trials and clinical practice. MRI-based measures of cerebral volume can provide a surrogate for neuronal loss and several techniques have been applied to elucidate disease processes, aid diagnosis, and enable monitoring of progression in a variety of Parkinsonian disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and Huntington's disease. We review the approaches to, and findings revealed by, serial volumetric MRI in these disorders. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) classically presents with movement disorder, cognitive dysfunction and behavioral problems but is phenotypically variable. One percent of patients with HD-like symptoms lack the causative mutation and are considered HD phenocopies. Genetic diseases known to cause HD phenocopies include HD-like syndromes HDL1, HDL2, and HDL4 (SCA17). HD has phenotypic overlap with dentatorubral-pallidoluysian atrophy, the spinocerebellar ataxias and neuroferritinopathy. Identifying the genetic basis of HD phenocopies is important for diagnosis and may inform the search for HD genetic modifiers. We sought to identify neurogenetic diagnoses in the largest reported cohort of HD phenocopy patients. Two hundred eighty-five patients with syndromes consistent with HD, who were HD expansion-negative, were screened for mutations in PRNP, JPH3, TBP, DRPLA, SCA1, SCA2, SCA3, FTL and FRDA. Genetic diagnoses were made in 8 subjects: we identified 5 cases of HDL4, 1 of HDL1 and 1 of HDL2. One patient had Friedreich's ataxia. There were no cases of DRPLA, SCA1, SCA2, SCA3, or neuroferritinopathy. HD phenocopies are clinically and genetically diverse and a definitive genetic diagnosis is currently possible in only a minority of cases. When undertaken, it should be clinically directed and patients and clinicians should be prepared for the low probability of reaching a genetic diagnosis in this group of patients. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

ON THE COVER: A picture of George Huntington (1850–1916) for whom the disease is named, a representation of the huntingtin protein and quantitative motor deficits in tapping. Photo of Dr. Huntington courtesy of Wellcome Trust Library under Creative Commons Attribution only license. [ABSTRACT FROM AUTHOR]