A New Genetic Cause of Amyotrophic Lateral Sclerosis
Abstract & Commentary
Source: Lambrechts D, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motor neurons against ischemic death. Nat Genet. 2003;34(4):383-394.
The cause of amyotrophic lateral sclerosis (ALS) is still an enigma. Nevertheless, genetic investigations have made considerable progress in identifying mutations associated with familial ALS (FALS). The identification of genetic alterations in patients with sporadic ALS, however, has lagged behind. The present study is a major advance in investigating the etiology of ALS. Besides a family history of ALS, age and male gender are the only established risk factors. Sporadic ALS is believed to be a multifactorial disease in which modifying genes may interact with environmental agents to affect their clinical manifestation. Lambrechts and associates previously used a genetic strategy to delete the hypoxy response element in the promotor region of the gene encoding vascular endothelial growth factor (VEGF) in mice. They demonstrated that impaired expression of VEGF predisposed mice to adult-onset progressive motor neuron degeneration with many of the neuropathological and clinical signs that occur in human ALS. It was unclear, however, whether this had any relevance to the human disease. Lambrechts et al have now extended their studies. They carried out a metaanalysis of more than 900 individuals from Sweden and 1000 individuals from Belgium and England. They now report that subjects homozygous with respect to 2 haplotypes in the VEGF promotor sequence had a 1.8 greater times risk of ALS. This was highly significant. The at-risk haplotypes had lower circulating VEGF levels in vivo and reduced VEGF gene transcription. Moreover, they carried out further studies, crossbreeding the mice with the G93A mutation and superoxide dismutase, which causes FALS with the mice deficient in VEGF. These mice died earlier due to severe motor neuron degeneration. They also demonstrated that the VEGF null mice were unusually susceptible to persistent paralysis after spinal cord ischemia and that treatment with VEGF protected the mice against ischemic motor neuron death.
Commentary
These studies are very important in identifying a risk factor, which may be important in patients with sporadic ALS. They are the first to find a genetic risk factor and have clearly demonstrated that having 2 different polymorphisms in the promotor of the VEGF gene increases the risk of ALS 1.8-fold. Calculation of the population attributable risk indicated that the influence of the VEGF at-risk genotypes resulted in net increases in the total number of individuals by 5.7%, 5.6%, and 10.4% in the Swedish, Belgian, and Birmingham populations, respectively. This is greater than the role of mutations in SOD1, which are responsible for approximately 2% of the entire ALS population. This study of almost 2000 individuals is the largest genetic association study with ALS that has thus far been performed. These studies in mice, which show that the VEGF-deficient mice are more sensitive to minor ischemic insults and that VEGF protects against ischemic motor neuron death, support a functional role of VEGF. Prior studies have shown a role of VEGF in neuronal survival, regeneration, growth, and axonal outgrowth. The findings raised the intriguing question as to whether long-term treatment with VEGF might have some efficacy in treating adult-onset motor neuron disease. — M. Flint Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY; Editor, Neurology Alert.
Genetic investigations have made considerable progress in identifying mutations associated with familial amyotrophic lateral sclerosis (ALS). The identification of genetic alterations in patients with sporadic ALS, however, has lagged behind. The present study is a major advance in investigating the etiology of ALS.
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