Natural history study highlights functional capacity in Huntington’s
Most adults with disease-linked genetic defect maintain maximum over time
Most adults with the genetic defect associated with Huntington’s disease were completely able to perform daily activities and tasks at a first assessment, and maintained such skills over time, according to data from a natural history study of the neurodegenerative condition.
That study assessed participants using the total functioning capacity (TFC) scale — a “multifaceted designation of functional capacity” that, the researchers noted, the U.S. Food and Drug Administration has cited as “an important outcome measure in Huntington’s disease.”
Among those with functional capacity changes in the first study’s year, nearly two-thirds experienced a decline in the subsequent four years, the researchers noted. Meanwhile, about 1 in 6 participants showed a TFC score improvement the year after.
Additionally, age-related declines in TFC scores followed a specific sequence: occupation, household chores/finances, daily living, and care. More excess CAG repeats — the type of mutation that causes Huntington’s — also were associated with an earlier functional decline, the study found.
“The TFC effectively reflects changes in functional domains as intended,” the researchers wrote.
Their study, “Total functioning capacity scale in Huntington’s disease: natural course over time,” was published in the Journal of Neurology.
Natural history study focuses on number of CAG repeats
Huntington’s is caused by excessive repeats of three DNA building blocks — C, A, and G — in the HTT gene. While a healthy HTT gene contains 10 to 35 repeats, people carrying 40 CAG repeats or more almost always develop Huntington’s.
Individuals with fewer than 39 repeats may or may not develop Huntington’s; among those who do, symptoms may be milder, studies have shown. A higher number of CAG repeats is associated with the development of symptoms at a younger age.
Natural history studies are designed to track the course the disease typically follows. But they also are important to evaluate the effectiveness of therapies, either in clinical trials or real-world practice.
The TFC scale, part of the Unified Huntington’s Disease Rating Scale, is a standard tool used to assess a patient’s disease stage and progression. It works by measuring an individual’s ability to function independently in day-to-day life. As such, it assesses five domains: occupation, finances, domestic chores, activities of daily living, and care level. Scores range from zero to 13, with higher scores indicating better function.
While this and other disease rating scales have been reviewed and, according to the researchers “reaffirmed,” a natural history study can not, by its nature, be changed.
Thus, the team noted, “there has been a notable gap in research on the natural course of the TFC over the years in HD [Huntington’s disease].”
To address this gap, the researchers now investigated the natural progression of function in Huntington’s patients, focusing on TFC score changes related to age and CAG repeat length.
The scientists, from the Netherlands, analyzed data from Registry3 and Enroll-HD (NCT01574053). Registry3 was a European study that ran from 2004 to 2015, and which continued as part of Enroll-HD, the world’s largest observational study on Huntington’s.
In total, 15,527 people, ages 18-94 and carrying 36 to 51 CAG repeats, were included in the study. Slightly more than half (54.2%) were women.
Occupational declines were first seen for most patients
Overall, most participants had the maximum TFC score of 13 at the first visit and remained stable over time.
Of the 2,021 with a maximum TFC score and who experienced a score change in the first year, 55.3% had a one-point drop, 20.6% showed a two-point reduction, and 13.2% experienced a three-point drop. The year after the score decline, 11.2% returned to a maximum score of 13.
Four years after the initial change, 64.1% showed a further TFC score decline, while 17.7% showed a stable TFC score during subsequent visits. Also, 18.6% experienced a score increase, with 7.6% of them showing an increase of more than one point.
“When we focus on those who experienced a change in TFC score, the number of HD patients with regained functional capacity is substantial,” the researchers wrote.
The team noted that this finding “may influence outcome assessments in clinical trials.”
The occupational domain was the first to show a decline in most participants (61.1%). Domain changes appeared to shift across disease stages, starting with occupation in early-stage Huntington’s, activities of daily living in middle stage, and care level in late stages of the disease.
While this pattern was generally consistent between premanifest (asymptomatic) and manifest (symptomatic) participants, the manifest group showed a greater percentage of change across all disease stages, particularly in the care level domain, according to the researchers.
When we focus on those who experienced a change in TFC score, the number of [Huntington’s] patients with regained functional capacity is substantial. … [This finding] may influence outcome assessments in clinical trials.
Age-related declines also affected TFC domains in a specific sequence: occupation, household chores, finances, daily living, and care.
Among participants with 40 or more CAG repeats, those with fewer repeats began to decline across all domains at an older age, while those with more CAG repeats showed an earlier TFC decline, the data showed.
Also, those in Northern America began to lose the ability to manage finances at a younger age than those in Europe. Such differences were not found when analyzing the data based on sex or education.
Of the 113 people with 36-39 CAG repeats, domain changes showed different trajectories than those with at least 40 repeats. In people with 36 CAG repeats, a score shift in all TFC domains occurred earlier and with a greater variation than in those with 40 CAG repeats.
The findings further validate the TFC scale as an “overall robust functionality measure that describes the progression of ordinal functional decline,” the researchers wrote, adding however, that they “discourage using the TFC for making far-reaching decisions for participants with [fewer than 40 CAG repeats].”
The team also noted that “it is essential that researchers and clinicians bear in mind that an observed increase on the TFC scale may be due to natural variation rather than an actual improvement of functional capacity.”
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