Mutations in the
copper/
zinc superoxide dismutase 1 (SOD-1) gene are found in approximately 20% of patients with familial
amyotrophic lateral sclerosis (FALS), or
amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature
protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate modifier genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the
CNTF gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with
CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that
CNTF acts as a candidate modifier gene in FALS with mutations in the SOD-1 gene. Such hSOD-1G93A/
CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/
CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the
CNTF locus. In addition, patients with sporadic
amyotrophic lateral sclerosis who had a homozygous
CNTF gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that
CNTF acts as a modifier gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic
amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.