LIMITED CORTICOSPINAL TRACT INVOLVEMENT IN AMYOTROPHIC-LATERAL-SCLEROSIS SUBJECTS WITH THE A4V MUTATION IN THE COPPER ZINC SUPEROXIDE-DISMUTASE GENE/

We examined 11 subjects with inherited amyotrophic lateral sclerosis ( familial amyotrophic lateral sclerosis, FALS) associated with the most common copper/zinc superoxide dismutase 1 (SOD1) mutation, an alanine for valine substitution in codon 4 (A4V). Autopsies were performed on 5 subjects. The clinical and pathological findings are described and compared with those of 9 sporadic ALS (SALS) subjects. There was no cl inical evidence of upper motor neuron (UMN) involvement in 10 FALS A4V subjects. All subjects had lower motor neuron (LMN) signs and electro physiological evidence of denervation in at least three limbs. All SAL S subjects had signs of both UMN and LMN involvement. Pathological stu dies found severe abnormalities of LMNs in all FALS and SALS subjects. UMN involvement was either absent or mild in the A4V SOD1 FALS subjec ts and severe in the SALS subjects. Pathological abnormalities in syst ems other than the motor neurons were more frequent in the FALS A4V su bjects. This information suggests that current diagnostic criteria for ALS, requiring clinical evidence for both upper and lower motor neuro n involvement, should be modified; ie, the diagnosis should be deemed established when there is evidence of denervation in three or more lim bs and a mutation in the gene for SOD1, even without clinical signs of UMN involvement.