Neuromuscular transmission in amyotrophic lateral sclerosis

Abstract

The functional and structural characteristics of the neuromuscular junction were studied in anconeus muscle biopsies of 10 patients with amyotrophic lateral sclerosis (ALS). Intracellular recordings revealed decreased amplitudes of miniature endplate potentials (MEPPs). The MEPP frequencies were highly variable in ALS patients but the average MEPP frequency was not different from that of control patients. The mean quantal content of endplate potentials (m), the mean quanta available for immediate release (n), and the mean quantal stores (N) were all decreased. In contrast, the mean probability of quantal release (p) was normal and the mean probability of quantal store release (P) was surprisingly high at the majority of ALS endplates. Histologic evidence of denervation and small or absent nerve terminals were observed in all ALS patients. These functional and structural abnormalities of the neuromuscular junction may explain the fatigability and the electromyographic evidence of impaired neuromuscular transmission often encountered in ALS patients.

Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

“…Tetanic failure was observed in motor units of the medial gastrocnemius (MG) muscle (an ankle extensor) of older homozygote animals that had become extensively weakened by disease progress. A similar phenomenon occurs in human motor neuron disease, where it is observed as decrementing EMG potentials during repetitive activation of motor units (Mulder et al, 1959;Stålberg et al, 1975;Denys and Norris, 1979;Bernstein and Antel, 1981;Maselli et al, 1993). Understanding the underlying mechanisms and finding ways to inhibit tetanic failure or increase unit force are of particular interest, because tetanic failure unquestionably contributes to weakness and weakness is the major problem in motor neuron disease.…”

“…We have suggested that defective neuromuscular synaptic transmission or axonal conduction in motor axon terminal arbors underlies tetanic failure in older HCSMA homozygotes (Pinter et al, 1995), and it seems likely that similar defects underlie decrementing motor unit EMG responses in human motor neuron disease (Maselli et al, 1993). We thus reasoned that increasing neuromuscular transmission might improve motor unit performance in older homozygotes and provide a strategy for the treatment of symptoms.…”

“…A recent paper described a trial using 3,4 DAP in humans with amyotrophic lateral sclerosis and reported some benefits, but it used evaluation methods that are difficult to interpret in terms of motor unit performance (Aisen et al, 1995). Supporting the possibility that 4AP or 3,4 DAP might have some benefit are descriptions of EMG decrementing responses during repetitive motor unit activation in human motor neuron disease (Mulder et al, 1959;Stålberg et al, 1975;Denys and Norris, 1979;Bernstein and Antel, 1981;Maselli et al, 1993), a phenomenon very similar to that seen among failing motor units in HCSMA in which, as we showed above, 4AP can increase force production. We do not know at present whether the mechanisms of motor unit failure in human and HCSMA motor units are the same.…”

“…We do not know at present whether the mechanisms of motor unit failure in human and HCSMA motor units are the same. Limited available evidence indicates that decreased transmitter release (Maselli et al, 1993) and /or conduction failure in motor terminals (Stålberg and Thiele, 1972) might play a role in the human motor unit failure, in which case the aminopyridine drugs might be useful for enhancing motor unit performance. Any therapeutic benefit, however, will also depend on the number of motor units that are sensitive to 4AP as well as their location.…”

Assessment of Motor Units in Neuromuscular Disease

“…Collateral reinnervation can compensate for the loss of at least 50 % of the motor neuron pool [25], and probably occurs to some degree until only 5 % of the motor unit pool remains [27,28]. From collateral reinnervation, synaptic sprouts occur such that immature reinnervating end plates form unstable connections with muscle, creating motor unit instability [29]. The effective result of collateral reinnervation is the nonlinear preservation of muscle strength despite falling motor unit number.…”