VARIABLE CLINICAL SYMPTOMS IN FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS WITH A NOVEL POINT MUTATION IN THE CU ZN SUPEROXIDE-DISMUTASE GENE/

We report a novel missense point mutation in exon 4 of the Cu/Zn super oxide dismutase (SOD) gene of affected members of a Japanese kindred s egregating familial amyotrophic lateral sclerosis (FALS) through at le ast three successive generations. The mutation, which is predicted to cause the replacement of isoleucine at codon 104 by phenylalanine (I10 4F), is associated with a significant reduction in Cu/Zn SOD enzyme ac tivity but results in a highly variable clinical phenotype. Age at ons et varied from 6 to 55; the initial symptoms occurred in either the lo wer or upper extremities in different family members. The duration of the disease varied from 3 to 38 years. Two subjects, aged 59 and 34, r emained asymptomatic until their death from other causes, although the ir offspring carrying the same mutation have already developed clinica l evidence of the disease. These results suggest that FALS from this n ovel I104F mutation shows considerable clinical variation.