The objectives of the current study were to: 1. Examine adult individuals (>18 years of age) with spinal muscular atrophy (SMA) for evidence of neuromuscular junction transmission (NMJ) defects on repetitive nerve stimulation (RNS). 2. Explore relationships between clinical biomarkers and outcomes with RNS decrement.

SMA is a motor neuron disorder caused by homozygous loss or mutation of the SMN1 gene resulting in low levels of SMN protein.  Preclinical and clinical studies have shown that SMA results in altered NMJ transmission.

As part of an ongoing study in adult SMA, 3 Hz RNS from the trapezius was recorded prior to and after initiation of nusinersen. CMAP amplitude decrement by >10% was considered abnormal. Other assessments included maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), forced vital capacity (FVC), and ulnar CMAP and Single Motor Unit Potential (SMUP).  

RNS has been performed at baseline (prior to nusinersen) in 12 participants. Abnormal RNS was demonstrated in 8 (67%) with a mean decrement of 19±5%.  No differences were noted between individuals with and without abnormal RNS, for mean age (43±13 years versus 38± years), age of onset (44±28 months versus 28±13 months), or disease duration (40±12 years versus 36±13 years).  RNS was associated with CMAP(r=0.842, p= 0.018) and SMUP(r=0.662, p=0.105); absolute FVC (r=0.833, p=0.020) and % predicted FVC(r=0.893, p=0.007); MVIC for key pinch(r=0.909, p=0.012), hand grip(r=0.780, p=0.067), knee extension(r=0.914, p=0.030), knee flexion(r=0.802, p=0.103); and RULM(r=0.789, p=0.035).

These results suggest that a high percentage of adult SMA patients have NMJ transmission defects. Correlation between RNS and other measures suggest that NMJ transmission is a promising SMA therapeutic target.  Progress in the SMA field has resulted in the availability of SMN restoring treatments. Our ongoing studies will also investigate whether NMJ transmission failure is modulated following SMN restoration with nusinersen.