Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen

Abstract

Objective: Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA.

Methods: Participants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement.

Results: Data from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (-14.2%±11.5%, n=17) vs baseline (-11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (-13.9%±6.7%) vs baseline (-16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration.

Conclusion: Adults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

Keywords: EMG; neuromuscular; spinal muscular atrophy.

Figure 1

Study timeline and participant recruitment.

Figure 2

Nusinersen does not result in overt improvement of CMAP decrement during RNS but does improve CMAP amplitude. (A) Cross-sectional analysis of CMAP decrement demonstrated no significant difference in assessments after 14 months of nusinersen (14 months of nusinersen treatment: −11.9%±8.3%, n=15, nine ambulatory) vs assessments prior to treatment (−14.2%±11.5% decrement, n=17, seven ambulatory) (unpaired t-test, p=0.5202). (B) Similarly, longitudinal assessment of a subset of participants (n=8, three ambulatory) demonstrated that CMAP amplitude decrement following 14 months of treatment (−13.9%±6.7%) was similar to baseline (−16.9%±13.4%) (paired t-test, p=0.5863). (C) Cross-sectional analysis of CMAP amplitude demonstrated no significant difference after 14 months of treatment (4.3±2.4 mV, n=15, nine ambulatory) vs assessments prior to treatment (4.3±3.4 mV, n=17, seven ambulatory) (unpaired t-test, p=0.9871). (D) In contrast, CMAP amplitude was significantly improved with nusinersen when analysed in a subset of participants (n=8, three ambulatory) that underwent assessment prior to treatment (2.6±2.0 mV) and after 14 months of nusinersen (4.2±2.8 mV) (paired t-test, p=0.0383). CMAP, compound muscle action potential; RNS, repetitive nerve stimulation.

Figure 3

At 14 months of nusinersen treatment, CMAP decrement was not associated with age or disease duration and was similar when stratified by ambulatory ability. CMAP decrement was not associated with (A) age (r²=0.0256, p=0.9364, n=15) or (B) disease duration (r²=0.03323, p=0.5328, n=14). (C) When stratified by ambulatory ability, CMAP decrement was not significantly different in ambulatory (−11.8%±9.5%, n=9) versus non-ambulatory (11.9%±7.0%, n=6) participants following 14 months of nusinersen treatment (unpaired t-test, p=0.9943). CMAP decrement for analyses obtained in participants at 14 months of nusinersen. R² is the square of Pearson correlation coefficients. CMAP, compound muscle action potential.

Figure 4

At 14 months of nusinersen treatment, CMAP amplitude did not significantly correlate with age or disease duration, but was different between groups when stratified by ambulatory ability. CMAP amplitude was not associated with (A) age (r²=0.1681, p=0.1290, n=15) or (B) disease duration (r²=0.05957, p=0.4004, n=14). (C) When stratified by ambulatory ability, CMAP amplitude was significantly higher in ambulatory (5.3±2.1 mV, n=9) versus non-ambulatory (2.7±2.1 mV, n=6) participants following 14 months of nusinersen treatment (unpaired t-test, p=0.0326). CMAP amplitudes for analyses obtained in participants at 14 months of nusinersen. R² is the square of Pearson correlation coefficients. CMAP, compound muscle action potential.

Figure 5

CMAP decrement showed significant associations with upper limb and lower limb strengths. (A) Hand grip (r²=0.6599, p=0.0143), (B) key pinch (r²=0.7080, p=0.0088), (C) elbow flexion (r²=0.6893, p=0.0107), (D) elbow extension (r²=0.7201, p=0.0077), (E) shoulder abduction (r²=0.9064, p=0.0003) and hip flexion (r²=0.6863, p=0.0111) showed significant correlations, whereas knee extension (r²=0.2623, p=0.1944) and knee flexion (r²=0.2865, p=0.1716) were not significantly correlated (not shown). R² is the square of Pearson correlation coefficients. n=8 ambulatory participants at 14 months of treatment with nusinersen (four women and four men). CMAP, compound muscle action potential.

Figure 6

CMAP decrement showed significant associations with upper limb and lower limb functions. (A) Revised Upper Limb Module score (r²=0.7631, p=0.0021), (B) 6MWT distance (r²=0.5012, p=0.0328) and (C) fatigue on the 6MWT (ratio of the distance walked during min 6 divided by the distance walked during min 1) (r²=0.6410, p=0.0095). CMAP decrement did not show a significant correlation with Hammersmith Functional Rating Scale Expanded score (r²=0.1679, p=0.2735) (not shown). R² is the square of Pearson correlation coefficients. n=9 ambulatory participants at 14 months of treatment with nusinersen (four women and five men). 6MWT, 6 min walk test; CMAP, compound muscle action potential.