Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase.

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant neurodegenerative disorder affecting motor neurons and is associated with mutations in the Cu,Zn superoxide dismutase gene (SOD1) in a subset (approximately 15%) of FALS families. We analyzed 158 FALS patients from 27 families with mutations in SOD1. The mean age of onset was 45.5 +/- 8.9 years, and the mean duration of disease was 3.4 years. Forty-seven different mutations in SOD1 of FALS patients have been described worldwide. In North America, the ala4val mutation is the most common. In our patients, the ala4val mutation was associated with the most rapid progression of disease. The mean duration of disease was 1.0 +/- 0.4 years, which is significantly less than the mean duration of disease for FALS patients with mutations in SOD1 other than ala4val (p < 0.001). The duration of disease for the glu100gly mutation, 5.1 +/- 3.3 years, was significantly longer than the ala4val mutation (p < 0.001). We constructed Kaplan-Meier survival curves for the age of onset and duration of the disease for three groups of patients having mutations in SOD1: (1) ala4val; (2) glu100gly; and (3) ala4val, gly37arg, his43arg, gly85arg, gly93ala, glu100gly, leu106val, ile113thr, leu144phe, and val148gly, i.e., the entire patient population. There was no correlation between the genotype and the age of onset; 50% of affected individuals developed symptoms of ALS by the age of 47 years. As more data are collected, a more accurate prognostication of a patient's survival may be possible for specific SOD1 mutations.