Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene

Abstract

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.

Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis

“…For the population of French origin, the P413L variant conferred a 3.3-fold greater risk to develop ALS. The risk conferred by the P413L CHGB variant is quite robust when compared to other susceptibility genes reported so far (12)(13)(14)(15). In fact, a risk factor of 3.3 is comparable to the overrepresentation by threefold of APOE-4 isoform in Alzheimer's disease patients heterozygous carriers compared to aged healthy control individuals (16)(17)(18).…”

Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

“…Targeted inactivation of the Cntf gene in mice revealed its role in postnatal maintenance of motoneurons (17,18). Moreover, endogenous Cntf modulates onset and severity of disease in patients and mouse models for motoneuron disease and other neurological disorders (19)(20)(21). In progressive motor neuronopathy and wobbler mice, Cntf treatment protects motoneurons from cell death and improves motor performance (22,23), indicating that this factor is a major mediator of the protective effects of Schwann cells, both under physiological and pathological conditions.…”

A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13

“…Faster progression of disease has been reported in patients with a mutation in the ciliary neurotrophic factor (CNTF) gene associated with the SOD1 gene compared than in those who lack the CNTF mutation. 27 The authors concluded that CNTF is a modifier gene that could modulate the progression of the disease, but this finding was not confirmed by other investigators. 28 On the other hand, the vascular endothelial growth factor (VEGF) gene is considered a risk factor for sporadic amyotrophic lateral sclerosis.…”