Protection of Motor Neurons in Pre-Symptomatic Individuals Carrying SOD 1 Mutations: Results of Motor Unit Number Estimation (MUNE) Electrophysiology

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurones. There is a family history in approximately 10% percent of cases. Only 20% of such families have point mutations in the Cu, Zn superoxide dimutase 1 (SOD1) gene. Pre-symptomatic loss of motor neurons has been identified prior to the onset of symptoms in SOD1 mice. This loss was biphasic with initial loss in the pre-symptomatic phase followed by a period of stabilisation and then gradual loss at time of weakness to death. (Kong & Xu, 1998). In order to determine the time course of motor neurone loss prior to symptomatic onset of disease, a longitudinal study of at-risk asymptomatic individuals (i.e. SOD1 mutation carriers with no neurological symptoms or signs as determined by a neurologist) was performed. There was no detectable difference in the number of motor units in SOD1 mutation carriers compared to their SOD1 negative family controls. (Aggarwal & Nicholson, 2001). This may indicate that mutation carriers have undetectable loss of motor neurones until rapid and widespread cell death of motor neurones occurs, coinciding with the onset of symptomatic features. This implies that the disease is not the end result of the slow attrition of motor neurones. (Aggarwal, 2009). The longitudinal study was extended on 20 asymptomatic carriers of the Cu, Zn superoxide dimutase 1 (SOD1) point mutation. In 2 of the 20 mutation carriers, there was a sudden reduction in MUNE, several months prior to the onset of weakness. (Aggarwal & Nicholson 2002), which also occurred in another 3 mutation carriers over the course of the study. (Aggarwal, 2009). This suggests that gradual pre-clinical loss of motor neurones does not occur in asymptomatic SOD1 mutation carriers and supports the observation that sudden, catastrophic loss of motor neurones occurs immediately prior to the onset of symptoms and the development of the disease, rather than a gradual attrition of motor neurones over time. These results suggest that there may be a biological trigger initiating rapid cell loss, just prior to the onset of symptoms. This observation is an important contribution to the current understanding of the pathogenesis of MND.