We analyzed data from 79 SMA participants (41 SMA 2 and 38 SMA 3). The mean (SD) follow-up time was 25 (13) months. Eleven subjects withdrew from follow-up prior to October 1, 2009. The reasons included the time and travel burden associated with visits (n = 5), entry into a treatment trial elsewhere (n = 3), family illness (n = 1), and waning interest in an observational study (n = 2).
The mean participant age in years was 11.3 (9.4), 47% were male, and 75% were white. Motor and pulmonary function, quality of life, muscle strength, CMAP amplitude and AUC, DXA fat-free mass, and SMN2 copy number were better in SMA 3 compared to SMA 2 participants at baseline ().
Motor function, determined by HFMSE, was significantly (p < 0.0001) associated with CMAP amplitude (r = 0.84; figure e-1), CMAP AUC (r = 0.79; ), FFMI (r = 0.64; figure e-2), FFMI Z score (r = 0.64; figure e-3), elbow flexion strength (r = 0.84; figure e-4), knee extension strength (r = 0.70; figure e-5), and knee flexion strength (r = 0.69; figure e-6). The distribution of HFMSE scores was significantly different for those with an SMN2 copy number of 3 (median = 16, interquartile range 6 to 30) compared to those with an SMN2 copy number of 4 or 5 (median = 55, interquartile range 47 to 58, p < 0.0001). Nearly identical associations were observed when the GMFM was used as the measure of motor function (data not shown).
Association between motor function (Expanded Hammersmith Functional Motor Scale [HFMSE] score) and maximal compound motor action potential (CMAP) area under the curve (AUC) (mV × msec) at baseline
Motor function appeared to decline in a nonlinear fashion when evaluated beyond 12 months, a finding confirmed by each of the 3 motor function measures (; ; figure e-7). The mean change at 36 months was −1.71 for the HFMSE (p = 0.01), −4.39 for the GMFM (p = 0.03), and −1.26 for the HFMS (p = 0.07). In terms of major motor milestones, 2 SMA 2 subjects and 1 SMA 3 subject lost the ability to sit during the study, and 5 SMA 3 subjects lost the ability to walk.
Estimated mean changes in motor and pulmonary function outcomes at 2 and 3 years obtained from mixed-effects models with linear and quadratic terms for timea
Mean change in Expanded Hammersmith Functional Motor Scale (HFMSE) score over time estimated using a repeated measures analysis of covariance model with time treated as a categorical variable
Pulmonary function was measurable in 60 of the 79 participants (76%) at baseline (). As with motor function, the average FVC (% predicted) decreased in a nonlinear fashion over time () with mean declines of approximately 3% at both 24 and 36 months ().
Mean change in forced expiratory vital capacity (FVC) (percentage of predicted normal) over time estimated using a repeated measures analysis of covariance model with time treated as a categorical variable
Knee extension appeared to be the weakest of the 3 muscles tested and was the least variable measure (). No significant mean changes in knee extension or knee flexion strength were detected over time. There was, however, a significant mean increase in elbow flexion strength over time (0.53 kg/year, p = 0.02, table e-2).
No significant change was observed in either CMAP amplitude or CMAP AUC, overall or by SMA type (table e-2).
Absolute fat-free mass estimated using DXA showed no significant change over time, but the mean annual rate of change in the fat-free mass Z score was significant (−0.18 units/year, p = 0.01, table e-2).
Quality of life.
Children consistently rated their physical quality of life higher than their parents, particularly those with SMA 2 (). There were no significant changes in quality of life over time (table e-2).
We found a low mean serum creatinine and CO2 in patients with SMA. Summary statistics on the baseline laboratory results are shown in table e-5. When looking at all participants who ever had an abnormal value on a given laboratory test, we found that for CO2 37 participants had results below the range at least once, compared to 35 who did not. For creatinine, 47 participants had results below the normal range, compared to 13 who did not. For AST, 12 participants had a result above the normal range at least once, compared to 61 who did not. For ALT, 19 participants had a result above normal, compared to 54 who did not.
Subgroup analyses of change.
Subjects with FVC ≥70% of predicted normal at baseline had a greater mean decline in pulmonary function at both 24 months (p = 0.02) and 36 months (p = 0.007) than subjects with FVC <70% (table e-3). We did not identify any other significant correlates of changes in motor and pulmonary function among subgroups defined by age, gender, SMA type, ambulatory status, baseline motor function, and baseline pulmonary function (table e-3).
All participants were homozygous for a deletion of SMN1. All SMA 2 subjects had 3 SMN2 copies. SMA 3 participants had 3 to 5 SMN2 copies (). There were no significant associations between SMN2 copy number and changes over time in either motor or pulmonary function (table e-3).
There were no significant differences between those who completed ≤18 months of follow-up (17 SMA 2 and 13 SMA 3 subjects) and those who completed >18 months (24 SMA 2 and 25 SMA 3 subjects) (table e-4). Eleven subjects prematurely withdrew from the study and 11 other subjects had scoliosis surgery during follow-up; the duration of follow-up varied among the other 57 subjects only because of staggered enrollment. There were no important subgroup differences in pulmonary or motor function changes over time when comparing shorter (≤18 months) with longer (>18 months) follow-up.
Nineteen of the 79 participants (24%) used at least 1 medication during the follow-up period. These medications included albuterol (n = 6), carnitine (n = 9), creatine (n = 5), hydroxyurea (n = 2), oral steroids (n = 1), and valproic acid (n = 7). There were no significant differences when comparing medication-exposed to unexposed participants with respect to mean changes over time in motor function and pulmonary functions (table e-3).