The physiological basis of conduction slowing in ALS patients homozygous for the D90A CuZn-SOD mutation

Familial amyotrophic lateral sclerosis (ALS) with the autosomal-recessively inherited D90A CuZn-superoxide dismutase (CuZn-SOD) mutation is characteri zed by a stereotypic slowly progressive, distinctive phenotype and very slo w central motor conduction. To determine the basis of this slowing, we asse ssed corticomotoneuronal function using peristimulus time histograms (PSTHs ) in 8 ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with findings in 10 patients with multiple sclerosis (MS), in which slowing of central motor conduction is common, and 11 healthy subjec ts. PSTHs were constructed from 3-7 different, voluntarily recruited motor units recorded in each patient from the extensor digitorum communis muscle (EDC). In D90A and MS patients, the stimulus threshold, onset latency, numb er of excess bins, duration, amplitude, and synchrony of the primary peak d iffered significantly from controls (P < 0.0004). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared to 23.6 ms for MS patients and 19.3 ms for normal subjects (P < 0.0001). In the D90A patients , the onset latencies of the primary peak had a bimodal distribution, where as in MS the distribution showed a continuum. Loss of synchrony was similar in D90A and MS patients, but the threshold, number of excess bins, and dur ation differed significantly (P < 0.0057), which suggests that either axona l loss or demyelination can result in delayed and desynchronized primary pe aks. We propose that conduction slowing in the D90A homozygotes results fro m selective toss of fast-conducting large pyramidal cells with preservation of slow-conducting mono- or polysynaptic corticomotoneuronal connections. (C) 2001 John Wiley 8 Sons, Inc.