Differential motor neuron impairment and axonal regeneration in sporadic and familiar amyotrophic lateral sclerosis with SOD-1 mutations: lessons from neurophysiology

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder of the motor system. About 10% of cases are familial and 20% of these families have point mutations in the Cu/Zn superoxide dismutase 1 (SOD-1) gene. SOD-1 catalyses the superoxide radical (O(-2)) into hydrogen peroxide and molecular oxygen. The clinical neurophysiology in ALS plays a fundamental role in differential diagnosis between the familial and sporadic forms and in the assessment of its severity and progression. Sixty ALS patients (34 males; 26 females) were enrolled in the study and examined basally (T0) and every 4 months (T1, T2, and T3). Fifteen of these patients are SOD-1 symptomatic mutation carriers (nine males, six females). We used Macro-EMG and Motor Unit Number Estimation (MUNE) in order to evaluate the neuronal loss and the re-innervation process at the onset of disease and during follow-up period.

Results and discussion: SOD-1 mutation carriers have a higher number of motor units at the moment of diagnosis when compared with the sporadic form, despite a more dramatic drop in later stages. Moreover, in familiar SOD-1 ALS there is not a specific time interval in which the axonal regeneration can balance the neuronal damage. Taken together, these results strengthen the idea of a different pathogenetic mechanism at the base of sALS and fALS.

Keywords: Amyotrophic Lateral Sclerosis; MUNE; SOD-1 carriers; macro-EMG.

Figure 1

MUNE values for biceps brachialis (BB, on the left) and abductor digiti minimi muscles (ADM, on the right). Note that, at the moment of diagnosis, motor units number is higher for familiar cases (black lines, fALS) compared with sporadic ones (gray lines, sALS); as the disease progresses, motor unit loss becomes more pronounced in the first group. Moreover, compared with sporadic form, patients carrying SOD-1 mutations did not show evidence of partial recovery within eight months from clinical onset (* p < 0.05; ** p < 0.01).

Figure 2

Histogram showing MUNE values in both BB (left) and ADM (right) muscles at every time of follow-up, in spinal (dark gray) and bulbar-onset (gray) cases of fALS. Note the lack of any significant difference between spinal ad bulbar forms for both proximal and distal muscles, throughout the entire follow-up period.

Figure 3

Histogram highlighting MUNE values in both BB (left) and ADM (right) muscles at every time of follow-up, in females (black columns) and males (gray columns); the top row shows the evolution of motor unit loss in the familiar form, whereas the bottom one the trend in sporadic cases. The lack of significant differences between males and females, in sporadic as well as in familiar forms, is consistent with results recently reported by Hegedus and colleagues (see the text for a more exhaustive discussion).

Figure 4

Time trend of Macro-EMG parameters (area, fiber density) with time. All the values increase more steeply in familiar than in sporadic forms (black and gray lines, respectively), strengthening the idea that in the first group there is a paradoxical more effective axonal sprouting (* p < 0.05; ** p < 0.01).