Lung function and upper limb abilities worsened over a two-year period in young people with spinal muscular atrophy (SMA) type 3 who were unable to walk (non-ambulatory), a U.K. study has found.
At the time of the study, the approved, disease-modifying therapy Spinraza (nusinersen) was unavailable to SMA type 3 patients in the U.K. who had lost their ability to walk for more than one year, which included the patients in this study, the researchers noted.
“This information is important as understanding the clinical course will be used to improve clinical trial design, inform future patient guidelines, and assist in interpretation of results of medical interventions,” they wrote.
The study, “Longitudinal changes in respiratory and upper limb function in a pediatric type III spinal muscular atrophy cohort after loss of ambulation,” was published in the journal Muscle & Nerve.
Nearly all cases of SMA are caused by a faulty SMN1 gene, which provides instructions to make a protein, SMN, critical for the function of nerve cells that control voluntary movements. Disease severity and age of onset are determined mainly by the number of copies of a second SMN2 gene, compensating for the lack of SMN1.
SMA type 3 is a relatively mild form of the condition in which patients often have three or four extra SMN2 copies. Symptoms typically appear in toddler-age children, but they can occur any time before early adulthood, and these patients generally have an average life expectancy.
Children with SMA type 3 can walk but lose motor function over time, and many become wheelchair-dependent. Moreover, about half of these patients develop scoliosis, an abnormal sideways curvature of the spine caused by weakness in back muscles.
Early studies suggested that those with type 3 SMA show no weakness in muscles that control breathing, but more recent reports show respiratory complications in these patients. Additionally, there is little information on upper limb function in people with SMA type 3 who can no longer walk.
In the new study, researchers based at the Great Ormond Street Hospital for Children in the U.K. assessed lung and upper limb function changes over two years in SMA type 3 patients who were unable to walk.
“The aim of this … multicenter natural history study is to assess whether SMA type  non-ambulant patients continue to significantly deteriorate in their pulmonary function and/or their upper limb strength following loss of ambulation,” the researchers wrote.
The study included 24 participants (nine males, 15 females) with a median age before the study (baseline) of 10.5 years (ranging from four to 15). Of these, 10 had scoliosis before the study, while four developed scoliosis during the study. One patient had spinal surgery prior to the study, and six had spinal surgery during the two-year study period. None needed night-time breathing support or had received Spinraza.
Overall, lung function, as assessed by the change in percentage of predicted forced vital capacity (FVC predicted) score — a measure of how much air a person can exhale after a forced breath — was 96% at baseline but dropped to 80.5% at two years, which reflected an average statistically significant decline of 17%. In all but one patient, lung function worsened over two years.
Lung function significantly worsened as the patients got older, but the decline was not statistically significant between patients older than 13 and those younger. Furthermore, worsening lung function correlated with a longer disease duration after the loss of walking abilities, with the median average disease duration being six months to a year.
Compared to patients who did not have scoliosis or surgery, those who had surgery within the study period deteriorated significantly faster in lung function scores. Lung function worsened by 27% in patients who had surgery, by 15% in those with scoliosis, and by 12% in patients with neither scoliosis nor surgery. Additionally, individuals who had or developed scoliosis over the two years — but who did not undergo surgery — did not deteriorate faster than those who did not have scoliosis.
“Scoliosis surgery has previously been shown to lead to a subsequent decline in gross motor function as well as pulmonary function,” the team wrote.
No correlations were seen between lung function and patients’ weight and a change in lung function and weight over two years. Also, there was no significant difference in the change of lung function between males and females, “likely due to the small sample size of each group,” the researchers added.
Upper limb function was assessed in 16 of the 24 participants (three males and 13 females) using the Revised Upper Limb Module (RULM), a measure of upper limb motor function, with higher scores indicating better function. Five of these patients already had scoliosis, and two developed the condition over two years, with one having previous spinal surgery and another five requiring surgery during the study.
At baseline, the overall median RULM score was 30, which dropped to 27 after two years, reflecting a significant average decline. RULM scores were lower in 12 patients and stable in three (all older than 13 years at baseline), while scores increased in one patient (younger than 9 at baseline).
Like with lung function, upper limb abilities significantly declined with increasing age, and the rate of change was the same regardless of age group. RULM scores also significantly decreased with longer disease duration after the loss of walking abilities.
Upper limb function declined as patients got taller, but “this is not unexpected as upper limb and trunk growth can affect the way in which patients perform activities with their arms making some of the RULM tasks more difficult to complete,” the scientists wrote.
In contrast with lung function, upper limb function change was no different in patients with or without scoliosis or between those who did or did not have surgery over the two years. Also, there was no correlation between weight and RULM scores, and no differences were seen between males and females.
Finally, lung function and upper limb function correlated at baseline and after two years, “demonstrating a significant global deterioration in this patient population in both respiratory function and upper limb strength following loss of ambulation,” the scientists added.
However, the change in both lung and upper limb function over two years was not related, which was “likely due to the two scales measuring different constructs and domains that may deteriorate at different rates,” the researchers wrote.
“The data from this study demonstrates that non-ambulant SMA type  patients significantly decline in both FVC% predicted and RULM following loss of ambulation over a 24-month period,” they wrote. “Additional studies aimed at assessing the impact of disease modifying drugs on these outcomes are required.”
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