Spinraza helps SMA type 3 motor function, maybe not fatigability
Treatment with Spinraza (nusinersen) extended the distance adults with spinal muscular atrophy (SMA) type 3 could walk during a six-minute walking test (6MWT), but they walked farther during the first minute than the sixth, a sign of fatigability despite treatment, a study suggests.
“The increase in 6WMT distance during the treatment period … suggested that the whole distance covered in 6MWT is not generally related to fatigability, but to global motor function,” the researchers wrote.
The study, “Six-minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen,” was published in Muscle & Nerve.
Fatigue, an overwhelming feeling of tiredness and exhaustion during daily activities, is a common symptom of SMA, an inherited disease marked by muscle weakness and atrophy, or shrinkage. It can be experienced as either subjectively perceived fatigue or physical fatigue, marked by a measurable decline in motor performance over time, which is referred to in this context as fatigability.
Still, “there is no consensus on which outcome measure should be used to test fatigability in SMA patients,” the researchers wrote.
The 6MWT is a common measure of motor performance in SMA patients and has been used to assess fatigability.
Spinraza’s effect on fatiguability in SMA
Here, researchers in Italy evaluated fatigability using the 6MWT, before and after treatment with Spinraza, in 48 adults (56% female) with SMA type 3 who could walk.
Spinraza significantly increased the mean total distance walked during the 6MWT, from 306.4 m before treatment (baseline) to 321.5 m after six months, 315.7 m at 10 months, and 333.9 m at 14 months.
Of the 27 patients who completed the entire 14-month follow-up, 37% improved, which was defined as an increase in 6MWT of at least 30 m, 48.2% remained stable, and 14.8% worsened, that is, had a 6MWT decline of at least 30 m.
Among those evaluated, the difference in meters walked in one minute and six minutes showed a statistically significant decline “suggestive of fatigability both at baseline and at all times thereafter,” the researchers wrote.
When fatigability was defined as a drop of at least 10% in the distance walked between the first and sixth minute of the 6MWT, 68% of patients showed fatigability at baseline. There was no relationship between baseline fatigability and the likelihood of reaching clinically meaningful 6MWT improvement during follow-up, however.
“We did not find a significant change in fatigability during the treatment period with [Spinraza],” the researchers wrote. “This may be explained by lack of effect of [Spinraza] on fatigability in SMA.”
Also, no correlations were found between fatigability and age at disease onset, age at baseline, or 6MWT distance at baseline.
Walking with Spinraza treatment
A subgroup analysis then focused on longer and shorter walkers, according to their ability to walk more or less than 300 m at baseline.
Among those who walked longer, starting Spinraza at a younger age was significantly correlated with a clinically meaningful gain in the 6MWT after 14 months of treatment. In the shorter walker group, none showed 6MWT worsening with no significant correlation with age at onset or beginning Spinraza.
The patients were assessed with two standard measures of motor function: the Hammersmith Functional Motor Scale-Expanded (HFMSE), which assesses overall motor function, and the Revised Upper Limb Module (RULM), which tests the function of the arms and hands.
When compared, HFMSE scores and 6MWT distance moderately correlated at baseline, at six and 10 months after starting treatment, and strongly correlated by 14 months. No correlation was found between 6MWT distance and RULM scores.
“Fatigability was detected at baseline in approximately [two-thirds] of SMA3 walker patients, without any correlation with clinical features, including motor performance,” the researchers wrote. “No effect on fatigability was observed during the 14-month treatment period with [Spinraza].”
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