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 characterized by a stereotypic slowly progressive, distinctive phenotype and very slow central motor conduction. To determine the basis of this slowing, we assessed 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 subjects. 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, number of excess bins, duration, amplitude, and synchrony of the primary peak differed 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, whereas 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 duration differed significantly (P < 0.0057), which suggests that either axonal loss or demyelination can result in delayed and desynchronized primary peaks. We propose that conduction slowing in the D90A homozygotes results from selective loss of fast-conducting large pyramidal cells with preservation of slow-conducting mono- or polysynaptic corticomotoneuronal connections.
Weber
M
M
The Neuromuscular Diseases Unit, Vancouver Hospital and the University of British Columbia, Willow Pavilion, First Floor, 855 West 12th Avenue, Vancouver, British Columbia V5Z 1M9, Canada. maus@interchange.ubc.ca
Eisen
A
A
Stewart
H G
HG
Andersen
P M
PM
Hirota
N
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D019054:Evoked Potentials, Motor; D019706:Excitatory Postsynaptic Potentials; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000503:physiopathology*; D020125:Mutation, Missense / Q000235:genetics; D009431:Neural Conduction / Q000502:physiology; D011930:Reaction Time; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
D013482:Superoxide Dismutase