Variable clinical symptoms in familial amyotrophic lateral sclerosis with a novel point mutation in the Cu/Zn superoxide dismutase gene

Abstract

We report a novel missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene of affected members of a Japanese kindred segregating familial amyotrophic lateral sclerosis (FALS) through at least three successive generations. The mutation, which is predicted to cause the replacement of isoleucine at codon 104 by phenylalanine (I104F), is associated with a significant reduction in Cu/Zn SOD enzyme activity but results in a highly variable clinical phenotype. Age at onset varied from 6 to 55; the initial symptoms occurred in either the lower or upper extremities in different family members. The duration of the disease varied from 3 to 38 years. Two subjects, aged 59 and 34, remained asymptomatic until their death from other causes, although their offspring carrying the same mutation have already developed clinical evidence of the disease. These results suggest that FALS from this novel I104F mutation shows considerable clinical variation.

Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions

“…Other mutations in patients with more than 10 year's survival were Gly37Arg in exon 1 [9], Gly41Asp in exon 1 [9], Asp90Ala in exon 4 [17], Gly93Cys in exon 4 [9], Gly93Asp in exon 4 [5], Ile104Phe in exon 4 [18], Leu144Ser in exon 5 [19], and Leu144Phe in exon5 [20]. There is no comprehensive effort to correlate the genotype of FALS patients having a SOD1 mutation and their phenotype characteristics.…”

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

“…13,54 Exceptionally, there are some ALS families with SOD1 mutations such as N86S, I104F and V148I, in which the clinical symptoms vary between the members. 29,39,52 Over 20 autopsy cases of SOD1 mutant familial ALS have been reported 44,53,[55][56][57][58][59][60][61][62][63][64][65][66][67] (Table 2). It is of interest that Bunina bodies, pathognomonic of sporadic ALS, have not been described in these reports.…”

Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

“…For example, the isoleucine-to-threonine substitution at position 113 of SOD1 (I113T) leads to a highly variable disease course that can differ by between 2 and 20 years in the same family [19]. The isoleucine-to-phenylalanine substitution mutation at position 104 of SOD1 (I104F) also results in a highly variable clinical phenotype: age at onset varies from 6 to 55 years, and the duration of the disease varies from 3 to 38 years [20]. These observations might suggest that, in addition to genetic background, some environmental and/or other genetic factors are contributing to the onset and progression of the disease; for example, ciliary neurotrophic factor has been cited as a candidate modifier gene [18].…”