Sensory-Motor Circuit Dysfunction In Adult Ambulatory SMA Type 3 Patients (P4.087)

OBJECTIVE: Preclinical studies in SMA model systems have implicated afferent system (proprioceptive) to be affected early in the disease process. To determine whether sensory systems are affected in ambulatory SMA patients, we investigated the spinal stretch reflex electrophysiologically. BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease resulting in motor neuron death and muscle atrophy due to a homozygous deletion of the SMN1 gene. In SMA models, genetic restoration of SMN in proprioceptive neurons and interneurons, but not motor neurons, corrected the defects in SMA (Imlach et. al, 2012). However, little is known of the electrophysiology of SMA type-3 patients, especially as regards sensory involvement. DESIGN/METHODS: We analyzed baseline measures of adult ambulatory SMA patients recruited for a 4-aminopyridine clinical trial (N=8). Electrophysiological studies, including CMAP, H and F reflexes and repetitive nerve stimulation, were performed in our EMG laboratory according to standard procedures. Data were correlated with functional motor outcome measures (Hammersmith Motor Scale Expanded, (HMSE) and 6 minute walk tests, (6MWT) distance and percent fatigue). RESULTS: We found absent F waves in 2 patients and absent H reflex in 3 patients. Comparisons of functional outcomes in patients with and without H reflexes showed significant differences: HSME score (51.8 ± 3.1 versus 44.7 ± 1.5; p=.01) and 6MWT distance (feet) (379 ± 51 versus 189 ± 74, p=.005). In contrast, CMAP was not significantly correlated with functional outcomes (r=.62; p=.11). CONCLUSIONS: Our findings suggest that sensory-motor circuit dysfunction is a stronger predictor of motor impairment in ambulatory SMA patients than CMAP. Findings are congruent with preclinical findings by Mentis et. al (2011) and Imlach et. al (2012) implicating sensory impairment as the primary mechanism of SMA dysfunction, with motor impairment occurring as a secondary phenomenon. Unraveling the defects in sensory-motor circuits has therapeutic implications in SMA patients. Study Supported by: Department of Defense Grant W81XWH-11-10753 Disclosure: Dr. Chiriboga has received personal compensation for activities with Isis Pharmaceuticals Inc. as a consultant. Dr. Weimer has nothing to disclose. Dr. Marra has nothing to disclose. Dr. Holuba LaMarca has nothing to disclose. Dr. Montes has received personal compensation for activities with Isis Pharmeceuticals as a consultant. Dr. Dunaway has nothing to disclose. Dr. Mentis has nothing to disclose. Dr. McCabe has nothing to disclose. Dr. De Vivo has received personal compensation for activities with Isis Pharmaceuticals and Ultragenyx Pharmaceuticals.