The Clinical Features and Progression of Late-Onset Versus Younger-Onset in an Adult Cohort of Huntington’s Disease Patients

Abstract

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that typically manifests between the ages of 30 and 50 years. However, the disease can present at any age, and phenotypic differences between younger and later-onset patients have received limited attention. Objective: To compare clinical features of late- (>70 years of age) and younger-onset (<30 years of age) HD patients. Methods: Patients presenting to our regional NHS HD clinic with new-onset manifest HD diagnosed over the age of 70 years (LoHD) (n = 18) were compared with a younger cohort who developed disease under the age of 30 years (YoHD) (n = 12). Rate of progression over time on standard cognitive and motor measures was compared. Results: At first clinic presentation, both groups had the same total UHDRS scores. However, the LoHD group had higher chorea scores (F (1,28) = 6.52, p = 0.016), while the YoHD group had more dystonia (F (1,28) = 8.69, p = 0.006) and eye movement abnormalities (F (1,28) = 16.991, p < 0.001). The YoHD group also had a greater rate of motor progression, especially for bulbar measures (F (1, 28) = 6.96, p = 0.013) and bradykinesia (F (1, 28) = 7.99, p = 0.009). No differences were found in the rate of cognitive change (F (1,21) = 1.727, p = 0.203) nor functional capacity (F (1,28) = 1.388, p = 0.249) between the groups. Conclusion: Phenotypic differences between YoHD and LoHD patients were found in terms of initial presentation and rate of motor progression. This has implications for therapeutic trials involving HD patients of different ages, given their different clinical features and progression.

Late-onset Huntington’s disease associated with CAG repeat lengths of 30 and 31

“…Dear Sirs, Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by trinucleotide CAG repeat expansion in the huntingtin gene that presents with a movement disorder and cognitive deficits, along with neuropsychiatric problems. Typically, the movement disorder generally develops in the 4th or 5th decade of life, though it is now recognised that onset may occur in advanced age [1]. CAG lengths of more than 35 repeats are associated with disease (with complete penetrance occurring with alleles of greater than 39 repeats).…”

Huntington’s Disease Drug Development: A Phase 3 Pipeline Analysis

“…The phase 2/3 trial entitled "Impact of Deutetrabenazine on Functional Speech and Gait Dynamics in Huntington Disease" is currently evaluating the effect of this drug on the functional speech and gait dynamics in HD [57]. With 30 participants and an openlabel single-arm design, the primary outcome measures of this study are (1) the Sentence Intelligibility Test (SIT) and ( 2) Motor Speech Evaluation (MSE) [58]. The SIT measures speech intelligibility by requiring each participant to read aloud 11 sentences that increase in length from 5 to 10 words.…”

“…Huntington's Disease (HD) is a rare autosomal dominant neurodegenerative genetic disorder that has an average onset between 30 and 50 years of age [1]. The worldwide prevalence of HD is approximately 7 in 100,000 persons, with further evidence suggesting the worldwide prevalence may be increasing [2][3][4][5][6].…”

Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling

“…Mutant huntingtin protein (mHtt) is prone to proteolytic cleavage, misfolding, and aggregation. Clinically, HD is characterized by progressive motor, cognitive, and behavioral dysfunction largely due to the loss of γ-aminobutyric acid (GABAergic) medium spiny neurons in the striatum [ 152 ]. The energy impairment hypothesis of HD was first proposed in the early 1980s from clinical observations, which revealed deficits in brain glucose utilization and weight loss in HD patients [ 153 , 154 ].…”