Patients with early-onset Huntington’s disease (HD) experience more muscle and eye movement abnormalities, and more rapid progression of motor symptoms, than those with late-onset disease, according to a recent study.
According to researchers, the variation in clinical features and disease progression indicates a need to consider age of onset for therapeutic clinical trials that involve patients of different ages.
Huntington’s is a neurodegenerative disease caused by a genetic mutation in the huntingtin (HTT) gene that results from an expansion of CAG, a repeated triplet of nucleotides (the building blocks of DNA).
While healthy individuals have between 10 to 35 CAG repeats, in Huntington’s the repeats expand to as many as 120. Age of disease onset is associated with CAG repeat numbers, with longer repeats indicating earlier onset.
Symptoms typically emerge from age 30 to 50, but also can develop in children and older adults. Late-onset Huntington’s, characterized by some as emerging after age 5o and others after age 60, is thought to be less severe than earlier onset Huntington’s. However, much remains unknown about the clinical features of early onset disease.
Researchers sought to characterize and compare disease progression between late-onset and early-onset Huntington’s patients. Retrospective data from 30 patients from a Huntington’s clinic at the University of Cambridge were included in the study.
Of those, 18 were late-onset patients — defined as those who developed the disease after age 70 — and 12 were early-onset patients who were younger than 30 at disease onset.
Patient data were collected from the first clinical appointment through the end of the study, follow-up withdrawal, or death, for an average of six years for early-onset patients and 2.3 years for late-onset patients.
The Unified Huntington’s Disease Rating Scale (UHDRS) was used to evaluate independence, total functional capacity, and total motor score, as well as individual motor symptoms such as chorea (involuntary muscle movements), dystonia (muscle spasms), bradykinesia (slow movements), mouth, throat, and eye movements, and gait.
Cognitive function was assessed with the Mini-Mental State Examination (MMSE). Patients were excluded from individual analyses if they did not receive cognitive or independence assessments at their initial or follow-up clinic visits.
Late-onset patients had a mean age of 77.3 years at disease onset, while early-onset patients had a mean age of 23.5 at onset. As expected, early-onset patients had an average of 59.4 CAG repeats, significantly more than than the 38.7 repeats in late-onset patients.
At disease onset, no differences were observed in the initial total motor score, cognitive function, or independence. However, early-onset patients had more severe dystonia and eye movement abnormalities, while later-onset patients experienced more severe chorea.
When comparing disease progression between the two groups, investigators found that total motor defects, impairments of mouth and throat movements, and bradykinesia progressed faster in early-onset patients. Interestingly, no differences were observed in the progression of cognitive impairments or functional incapacity between groups.
“HD behaves differently depending on its age of onset … A better understanding of this graded change in phenotypic [observable disease features] expression and progression will be critical when we come to trial disease-modifying therapies for this disorder given their different dominant clinical features and the speed with which they progress with respect to these motor problems,” the researchers wrote.
Limitations of the study included: the small sample size; the use of the MMSE, which can be a poor indicator of cognitive decline in HD; the possibility of earlier or more accurate diagnosis in the more severe early-onset cases; and potential later diagnosis, misdiagnosis, and use of multiple treatments for other age-related illnesses in late-onset cases.
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