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Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is a consultant for ACADIA Pharmaceuticals and US WorldMeds.
SYNOPSIS: In a study of more than 3,000 subjects, CAG-repeat-dependent factors affecting age at onset also influenced rates of progression of cognitive, motor, and functional impairments, providing optimism that developing interventions, such as gene silencing therapies, could provide benefit.
SOURCE: Aziz NA, van der Burg JMM, Tabrizi SJ, Landwehrmeyer GB. Overlap between age-at-onset and disease-progression determinants in Huntington disease. Neurology 2018;90:e2099-e2106.
Huntington’s disease (HD) is a devastating progressive neuropsychiatric disorder with autosomal dominant inheritance. Average age of onset is 44 years, with average disease duration until death of 16 years. However, there is variability, and age at onset is inversely correlated with the length of CAG trinucleotide repeats in the huntingtin (HTT) gene, in which greater expansions bring about earlier and more severe disease. However, there has been some controversy over the extent to which this genetic determinant of age of onset also affects the rate of disease progression.
Aziz and colleagues leveraged a large data set of 5,821 individuals, collected through the Enroll-HD international study (enrollhd.org), and developed a sophisticated statistical model to examine contributions of various factors to disease progression in multiple clinical domains of HD. Data used for their analysis were derived from 3,411 individuals, who all had a known age of onset of HD, data from at least two follow-up evaluations, and CAG repeat length of 40-57 (chosen to conform to assumptions for linear regression, and to eliminate outliers). As expected, based on previous data, HTT CAG repeat size is strongly associated with age at onset of HD and could account for approximately 69% of the total variance. Factors associated with age at onset accounted for about two-thirds of the association with progression, with CAG repeat length playing the largest role. From the Unified Huntington’s Disease Rating Scale, a total functional capacity, total motor score, and a cognitive summary score were derived to assess progression. Greater HTT CAG repeat length associated with motor and cognitive progression and functional decline accounted for about half of the variation observed. Interestingly, those with later age at onset than predicted from the CAG repeat length also had slower decline in all three domains. Of note, factors affecting age at onset did not associate as strongly with weight loss, although repeat size was associated with body weight. The investigators also adjusted for medication use (for example neuroleptics and antidepressants), finding no substantial differences in the results. Repeat analyses also included outliers, again demonstrating a lack of substantial difference in their results.
HD is a neurodegenerative disease resulting in chorea, sometimes other movement deficits (including parkinsonism, cognitive decline, and mood disorders), as well as other features, including weight loss. With improved understanding of many of the cellular processes that go awry in HD, there have been numerous attempts to identify disease-modifying and neuroprotective interventions (for example using creatine or coenzyme Q10), but without success. As noted above, HD arises because of CAG triplet repeat expansion in the HTT gene, and the degree of repeat expansion has a very strong effect on age at onset, accounting for about two-thirds of effects. Other factors that may influence age at onset are genetic modifiers and environmental factors.
In a very sophisticated analysis, Aziz et al examined how factors that affect age at onset and, in particular, CAG repeat length, affect various aspects of HD progression. The finding that CAG expansion remains an active driving force of progression in functional, motor, and cognitive domains provides optimism that targeting this specific genetic change might slow progression. An exciting possibility is the potential use of gene therapies that might use gene silencing or other approaches. Just recently, delivery of a microRNA targeting the HTT transcript within an adeno-associated virus 5 vector, was demonstrated to inhibit mutant huntingtin protein aggregation and ameliorate neuronal function in an animal model of HD.1 Importantly, however, these authors found that a certain degree of variance in progression cannot be accounted for by CAG repeat length, and it will be fascinating to see what factors will account for the remaining one-third of variability. Additionally, weight loss appears less dependent on CAG repeat length than the other domains examined. Ultimately, this sophisticated study leveraging a large database adds strength to the rationale for targeting the HTT gene CAG repeat expansion in HD therapeutics, but also raises more questions about what other factors must be addressed.
Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.